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Sample records for active zone molecule

  1. Presynaptic active zone density during development and synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Gwenaëlle L Clarke

    2012-02-01

    Full Text Available Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs, the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS, active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  2. Serpentine in active subduction zones

    Science.gov (United States)

    Reynard, Bruno

    2013-09-01

    Serpentinization is a key phenomenon for understanding the geodynamics of subduction zones in the 10-200 km depth range. Serpentines are a major water carrier, and their rheological properties have a strong influence on deformation partitioning and seismicity at depths. I review experimental investigations that have been conducted on serpentines, with emphasis on the large body of data acquired over the past decade. Determinations of physical properties at the pressure and temperature conditions of subductions allow interpreting geophysical data in active subduction in terms of mineralogy and petrology, and to link the presence of serpentinites with deformation and fluid circulation. The fluid budget can be partially constrained from geophysical data. Elasticity data provide a quantitative basis for mapping serpentinization in the mantle wedge and slab from seismic tomography. Anisotropy suggests the existence of thin serpentinite channels above the plate interface, that account for mechanical decoupling inferred from down-dip limit of the seismogenic zone and heat flow. Strain-rate dependent rheology of antigorite serpentine is consistent with stable deformation of this thin layer or channel over timescales ranging from those of the seismic cycle to those of thermal equilibration and exhumation of high-pressure rocks, and with the geological record of subduction-related deformation. Circulation of serpentinizing fluids depends on the permeability structure, and is imaged by electrical conductivity tomography. It could be controlled by fracturing in the undeformed cold nose of the mantle wedge, and by plastic deformation along the plate interface. Fluid migration mechanisms are similar to those inferred from petrological and geochemical data on exhumed serpentinites. Estimation of the fluid budget associated with serpentine formation will rely on numerical simulations for which coupling of kinetics of hydration and dehydration at scales ranging from grain size up

  3. Synaptic vesicle proteins and active zone plasticity

    Directory of Open Access Journals (Sweden)

    Robert J Kittel

    2016-04-01

    Full Text Available Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone. The complex molecular architecture of active zones mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of active zones vary significantly, even for a given connection. Thus, there appear to be distinct active zone states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the active zone.The protein-rich cytomatrix at the active zone (CAZ provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1 and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and active zone states, which has heretofore received little attention.

  4. Synaptic Vesicle Proteins and Active Zone Plasticity.

    Science.gov (United States)

    Kittel, Robert J; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

  5. Novel approaches for single molecule activation and detection

    CERN Document Server

    Benfenati, Fabio; Torre, Vincent

    2014-01-01

    How can we obtain tools able to process and exchange information at the molecular scale In order to do this, it is necessary to activate and detect single molecules under controlled conditions. This book focuses on the generation of biologically-inspired molecular devices. These devices are based on the developments of new photonic tools able to activate and stimulate single molecule machines. Additionally, new light sensitive molecules can be selectively activated by photonic tools. These technological innovations will provide a way to control activation of single light-sensitive molecules, a

  6. A Potent Activator of Melanogenesis Identified from Small Molecule Screening

    OpenAIRE

    McNaughton, Brian R.; Gareiss, Peter C.; Jacobs, Stacey E.; Fricke, Alex F.; Scott, Glynis A.; Miller, Benjamin L.

    2009-01-01

    Small molecules that increase the cellular level of melanin can be used to study melanogenesis, and have therapeutic potential for melanin-related diseases such as albinism. We describe the identification of a potent activator of melanogenesis from a targeted combinatorial library. Treating melanocytes with our most active molecule results in a 1.8-fold increase in melanin, and an increase in tyrosinase-catalyzed oxidation of L-tyrosine, a key step in melanin biosynthesis.

  7. Active zone stability:insights from fly neuromuscular junction

    Institute of Scientific and Technical Information of China (English)

    Xiaolin Tian; Chunlai Wu

    2015-01-01

    The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans-mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efifcacy. However, very little is known about the mechanism that controls the structural stability of active zone. By study-ing a model synapse, theDrosophila neuromuscular junction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephos-phorylation event at the nerve terminal. Here we discuss the major insights from our ifndings and their implications for future research.

  8. Exploration of the spontaneous fluctuating activity of single enzyme molecules

    NARCIS (Netherlands)

    Schwabe, A.; Maarleveld, T.R.; Bruggeman, F.J.

    2013-01-01

    Single enzyme molecules display inevitable, stochastic fluctuations in their catalytic activity. In metabolism, for instance, the stochastic activity of individual enzymes is averaged out due to their high copy numbers per single cell. However, many processes inside cells rely on single enzyme activ

  9. Exploration of the spontaneous fluctuating activity of single enzyme molecules

    OpenAIRE

    Schwabe, Anne; Maarleveld, Timo; Bruggeman, Frank

    2013-01-01

    Single enzyme molecules display inevitable, stochastic fluctuations in their catalytic activity. In metabolism, for instance, the stochastic activity of individual enzymes is averaged out due to their high copy numbers per single cell. However, many processes inside cells rely on single enzyme activity, such as transcription, replication, translation, and histone modifications. Here we introduce the main theoretical concepts of stochastic single-enzyme activity starting from the Michaelis–Men...

  10. Identification of small molecule activators of BMP signaling.

    Directory of Open Access Journals (Sweden)

    Karen Vrijens

    Full Text Available Bone Morphogenetic Proteins (BMPs are morphogens that play a major role in regulating development and homeostasis. Although BMPs are used for the treatment of bone and kidney disorders, their clinical use is limited due to the supra-physiological doses required for therapeutic efficacy causing severe side effects. Because recombinant BMPs are expensive to produce, small molecule activators of BMP signaling would be a cost-effective alternative with the added benefit of being potentially more easily deliverable. Here, we report our efforts to identify small molecule activators of BMP signaling. We have developed a cell-based assay to monitor BMP signaling by stably transfecting a BMP-responsive human cervical carcinoma cell line (C33A with a reporter construct in which the expression of luciferase is driven by a multimerized BMP-responsive element from the Id1 promoter. A BMP-responsive clone C33A-2D2 was used to screen a bioactive library containing ∼5,600 small molecules. We identified four small molecules of the family of flavonoids all of which induced luciferase activity in a dose-dependent manner and ventralized zebrafish embryos. Two of the identified compounds induced Smad1, 5 phosphorylation (P-Smad, Id1 and Id2 expression in a dose-dependent manner demonstrating that our assays identified small molecule activators of BMP signaling.

  11. Functionalization of hydroxyl terminated polybutadiene with biologically active fluorescent molecule

    Indian Academy of Sciences (India)

    R Murali Sankar; Subhadeep Saha; K Seeni Meera; Tushar Jana

    2009-10-01

    A biologically active molecule, 2-chloro-4,6-bis(dimethylamino)-1,3,5-triazine (CBDT), has been covalently attached at the terminal carbon atoms of the hydroxyl terminated polybutadiene (HTPB) backbone. The modification of HTPB backbone by CBDT molecule does not affect the unique physico-chemical properties such as fluidity, hydroxyl value and microstructure of the parent HTPB. The formation of hydrogen bonding between the terminal hydroxyl groups and the nitrogen atoms of triazine moiety is the driving force for the terminal attachment chemistry. The functionalized HTPB (HTPB–CBDT) shows a strong fluorescence emission at 385 nm.

  12. Small molecules reveal an alternative mechanism of Bax activation.

    Science.gov (United States)

    Brahmbhatt, Hetal; Uehling, David; Al-Awar, Rima; Leber, Brian; Andrews, David

    2016-04-15

    The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules that promoted both Bax targeting to and oligomerization at membranes. All five compounds initiated Bax oligomerization in the absence of membranes by a mechanism unlike Bax activation by Bcl-2 homology 3 domain (BH3) proteins. Some of the compounds induced Bax/Bak-dependent apoptosis in cells. Activation of Bax by the most active compound was poorly inhibited by the anti-apoptotic protein Bcl-XL and requires a cysteine residue at position 126 of Bax that is not required for activation by BH3 proteins. Our results reveal a novel pathway for Bax activation independent of pro-apoptotic BH3 proteins that may have important implications for the regulation of Bax activity in cells. PMID:26916338

  13. Structure and Structure-activity Relationship of Functional Organic Molecules

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    @@ Research theme The group is made up of junior scientists from the State Key Laboratory of Elemento-organic Chemistry, Nankai University.The scientists focus their studis on the structure and structure-activity relationship of functional organic molecules not only because it has been the basis of their research, but also because the functional study of organic compounds is now a major scientific issue for organic chemists around the world.

  14. Quantitative analysis on tectonic deformation of active rupture zones

    Institute of Scientific and Technical Information of China (English)

    JIANG Zai-sen; NIU An-fu; WANG Min; LI Kai-wu; FANG Ying; ZHANG Xi; ZHANG Xiao-liang

    2005-01-01

    Based on the regional GPS data of high spatial resolution, we present a method of quantitative analysis on the tectonic deformation of active rupture zones in order to predict the location of forthcoming major earthquakes. Firstly we divide the main fault area into certain deformation units, then derive the geometric deformation and relative dislocation parameters of each unit and finally estimate quantitatively the slip and strain rates in each segment of the rupture zone. Furthermore, by comparing the consistency of deformation in all segments of the whole rupture zone, we can determine the possible anomalous segments as well as their properties and amplitudes. In analyzing the eastern boundaries of Sichuan-Yunnan block with the GPS velocity data for the period of 1991~2001, we have discovered that the Mianning-Ningnan-Dongchuan segment on the Zemuhe-Xiaojiang fault zone is relatively locked and the left-lateral shear strain rate here is higher.

  15. Activity Tendency and Dynamic Characteristics of Shanxi Fault Zone

    Institute of Scientific and Technical Information of China (English)

    Yang Guohua; Wang Min; Han Yueping; Zhou Xiaoyan; Zhang Zhongfu; Wang Xiuwen; Guo Yuehong

    2003-01-01

    The tendency and dynamic characteristics of horizontal movement along the Shanxi fault zone have been analyzed using the data obtained from 6 repeated measurements (1996~2001) in the GPS monitoring network arranged along the Shanxi fault zone. The results indicate: (1) the tendentious activity of the present stage is characterized by a W-trending movement along the northern segment of the zone, an E-trending movement along the southern segment and counter clockwise differential activity on the whole, but the intensity of the tendentious activity is not high. The tendentious differential movement is only about 3 mm/a in the direction perpendicular to the fault zone from the south to the north, and its stretch in the SN direction is only 1 mm/a and mainly occurs along the north segment of the fault; (2) The azimuth of the principal compressive stress field reflected by the tendentious movement is 72°; (3) The property of annual activity is not the same, even contrary to one another or deviates from the tendentious activity. Therefore, the parameters of the strain field derived from them don't reflect the physical characteristics of the basic stress field. (4) The high-frequency movement (yearly) does not only exist but is also complicated by an intensity several times higher than that of the tendentious movement; (5) Obvious differential movements, including strike slip, can not be seen in either in secular activity or annual activity on both sides of any fault. The tendentious movement not only verifies the conjecture of "strong in the south and weak in north", which is the basic feature forcing the western boundary of the North China area, but it also extends to the hinterland of North China. The fact that there is no obvious differential activity on both sides of the fault might indicate that the differential activity among the intraplate blocks is completed by gradual variation in a certain space, rather than the abrupt change bordered by a fault or narrow

  16. Where Does Metonymy Stop? Senses, Facets, and Active Zones

    OpenAIRE

    Paradis, Carita

    2004-01-01

    The purpose of this article is to propose a constrained lexical semantic definition of referential metonymy within a model of meaning as ontology and construal. Due to their various types of lexical-referential pairings, 3 types of construals that are frequently referred to as metonymy in the cognitive literature are distinguished as metonymization, facetization, and zone activation. Metonymization involves the use of a lexical item to evoke the sense of something that is not conventionally l...

  17. Inhibition of Nek2 by Small Molecules Affects Proteasome Activity

    Directory of Open Access Journals (Sweden)

    Lingyao Meng

    2014-01-01

    Full Text Available Background. Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients. Materials and Methods. To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on proteasome and cell cycle activity in several cell lines. Results. Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited proteasome activity in these cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome-mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib-resistant multiple myeloma. Conclusion. Nek2 plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma.

  18. Bilirubin: an endogenous molecule with antiviral activity in vitro.

    Directory of Open Access Journals (Sweden)

    Rosaria eSantangelo

    2012-03-01

    Full Text Available Bilirubin-IX-alpha (BR is the final product of heme metabolism through the heme oxygenase/biliverdin reductase (HO/BVR system. Previous papers reported on the microbicidal effects of the HO by-products biliverdin-IX-alpha, carbon monoxide and iron, through either direct or indirect mechanisms. In this paper the evidence of a virucidal effect of BR against human herpes simplex virus type 1 (HSV-1 and the enterovirus EV71 was provided. Bilirubin-IX-alpha, at concentrations 1-10 µM, close to those found in blood and tissues, significantly reduced HSV-1 and EV71 replication in Hep-2 and Vero cell lines, respectively. Bilirubin-IX-alpha inhibited viral infection of Hep-2 and Vero cells when given 2 hours before, concomitantly and 2 hours after viral infection. Furthermore, BR retained its antiviral activity even complexed with a saturating concentration of human serum-albumin. Moreover, 10 µM BR increased the formation of nitric oxide and the phosphorylation of JNK in Vero and Hep-2 cell lines, respectively, thus implying a role of these two pathways in the mechanism of antiviral activity of the bile pigment. In conclusion, these results support the antiviral effect of BR against HSV-1 and enterovirus in vitro, and put the basis for further basic and clinical studies to understand the real role of BR as an endogenous antiviral molecule.

  19. Manipulating lipid bilayer material properties using biologically active amphipathic molecules

    Energy Technology Data Exchange (ETDEWEB)

    Ashrafuzzaman, Md [Department of Physiology and Biophysics, Weill Medical College of University of Cornell, New York, NY 10021 (United States); Lampson, M A [Department of Physiology and Biophysics, Weill Medical College of University of Cornell, New York, NY 10021 (United States); Greathouse, D V [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States); II, R E Koeppe [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States); Andersen, O S [Department of Physiology and Biophysics, Weill Medical College of University of Cornell, New York, NY 10021 (United States)

    2006-07-19

    Lipid bilayers are elastic bodies with properties that can be manipulated/controlled by the adsorption of amphipathic molecules. The resulting changes in bilayer elasticity have been shown to regulate integral membrane protein function. To further understand the amphiphile-induced modulation of bilayer material properties (thickness, intrinsic monolayer curvature and elastic moduli), we examined how an enantiomeric pair of viral anti-fusion peptides (AFPs)-Z-Gly-D-Phe and Z-Gly-Phe, where Z denotes a benzyloxycarbonyl group, as well as Z-Phe-Tyr and Z-D-Phe-Phe-Gly-alters the function of enantiomeric pairs of gramicidin channels of different lengths in planar bilayers. For both short and long channels, the channel lifetimes and appearance frequencies increase as linear functions of the aqueous AFP concentration, with no apparent effect on the single-channel conductance. These changes in channel function do not depend on the chirality of the channels or the AFPs. At pH 7.0, the relative changes in channel lifetimes do not vary when the channel length is varied, indicating that these compounds exert their effects primarily by causing a positive-going change in the intrinsic monolayer curvature. At pH 4.0, the AFPs are more potent than at pH 7.0 and have greater effects on the shorter channels, indicating that these compounds now change the bilayer elastic moduli. When AFPs of different anti-fusion potencies are compared, the rank order of the anti-fusion activity and the channel-modifying activity is similar, but the relative changes in anti-fusion potency are larger than the changes in channel-modifying activity. We conclude that gramicidin channels are useful as molecular force transducers to probe the influence of small amphiphiles upon lipid bilayer material properties.

  20. Activating Molecules, Ions, and Solid Particles with Acoustic Cavitation

    Science.gov (United States)

    Pflieger, Rachel; Chave, Tony; Virot, Matthieu; Nikitenko, Sergey I.

    2014-01-01

    The chemical and physical effects of ultrasound arise not from a direct interaction of molecules with sound waves, but rather from the acoustic cavitation: the nucleation, growth, and implosive collapse of microbubbles in liquids submitted to power ultrasound. The violent implosion of bubbles leads to the formation of chemically reactive species and to the emission of light, named sonoluminescence. In this manuscript, we describe the techniques allowing study of extreme intrabubble conditions and chemical reactivity of acoustic cavitation in solutions. The analysis of sonoluminescence spectra of water sparged with noble gases provides evidence for nonequilibrium plasma formation. The photons and the "hot" particles generated by cavitation bubbles enable to excite the non-volatile species in solutions increasing their chemical reactivity. For example the mechanism of ultrabright sonoluminescence of uranyl ions in acidic solutions varies with uranium concentration: sonophotoluminescence dominates in diluted solutions, and collisional excitation contributes at higher uranium concentration. Secondary sonochemical products may arise from chemically active species that are formed inside the bubble, but then diffuse into the liquid phase and react with solution precursors to form a variety of products. For instance, the sonochemical reduction of Pt(IV) in pure water provides an innovative synthetic route for monodispersed nanoparticles of metallic platinum without any templates or capping agents. Many studies reveal the advantages of ultrasound to activate the divided solids. In general, the mechanical effects of ultrasound strongly contribute in heterogeneous systems in addition to chemical effects. In particular, the sonolysis of PuO2 powder in pure water yields stable colloids of plutonium due to both effects. PMID:24747272

  1. Understanding Enzyme Activity Using Single Molecule Tracking (Poster)

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Y.-S.; Zeng, Y.; Luo, Y.; Xu, Q.; Himmel, M.; Smith S.; Wei, H.; Ding, S.-Y.

    2009-06-01

    This poster describes single-molecule tracking and total internal reflection fluorescence microscopy. It discusses whether the carbohydrate-binding module (CBM) moves on cellulose, how the CBM binds to cellulose, and the mechanism of cellulosome assembly.

  2. Small molecules with antiviral activity against the Ebola virus

    OpenAIRE

    Nadia Litterman; Christopher Lipinski; Sean Ekins

    2015-01-01

    The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important r...

  3. Nano-sensing of the orientation of fluorescing molecules with active coated nano-particles

    DEFF Research Database (Denmark)

    Arslanagic, Samel; Ziolkowski, Richard W.

    2015-01-01

    The potential of using active coated nano-particles to determine the orientation of fluorescing molecules is reported. By treating each fluorescing molecule as an electric Hertzian dipole, single and multiple fluorescing molecules emitting coherently and incoherently in various orientations are c...

  4. How to Make an Active Zone: Unexpected Universal Functional Redundancy between RIMs and RIM-BPs.

    Science.gov (United States)

    Acuna, Claudio; Liu, Xinran; Südhof, Thomas C

    2016-08-17

    RIMs and RIM-binding proteins (RBPs) are evolutionary conserved multidomain proteins of presynaptic active zones that are known to recruit Ca(2+) channels; in addition, RIMs perform well-recognized functions in tethering and priming synaptic vesicles for exocytosis. However, deletions of RIMs or RBPs in mice cause only partial impairments in various active zone functions and have no effect on active zone structure, as visualized by electron micrographs, suggesting that their contribution to active zone functions is limited. Here, we show in synapses of the calyx of Held in vivo and hippocampal neurons in culture that combined, but not individual, deletions of RIMs and RBPs eliminate tethering and priming of synaptic vesicles, deplete presynaptic Ca(2+) channels, and ablate active zone complexes, as analyzed by electron microscopy of chemically fixed synapses. Thus, RBPs perform unexpectedly broad roles at the active zone that together with those of RIMs are essential for all active zone functions. PMID:27537484

  5. 77 FR 26737 - Foreign-Trade Zone 235-Lakewood, NJ: Notification of Proposed Production Activity; Cosmetic...

    Science.gov (United States)

    2012-05-07

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Foreign-Trade Zones Board Foreign-Trade Zone 235--Lakewood, NJ: Notification of Proposed Production Activity; Cosmetic Essence Innovations, LLC (Fragrance Bottling); Holmdel, NJ Cosmetic Essence...

  6. Super-resolution microscopy of the synaptic active zone

    Directory of Open Access Journals (Sweden)

    Nadine eEhmann

    2015-01-01

    Full Text Available Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ a variety of specialised proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission.Calcium (Ca2+ channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modelling approaches has provided predictions of channel properties, numbers and even positions on the nanometre scale. However, elucidating the nanoscopic organisation of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how super-resolution microscopy can be used to obtain information on the organisation of AZ proteins.

  7. Super-resolution microscopy of the synaptic active zone.

    Science.gov (United States)

    Ehmann, Nadine; Sauer, Markus; Kittel, Robert J

    2015-01-01

    Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ) a variety of specialized proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modeling approaches has provided predictions of channel properties, numbers and even positions on the nanometer scale. However, elucidating the nanoscopic organization of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy (SRM) techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how SRM can be used to obtain information on the organization of AZ proteins.

  8. Small molecules with antiviral activity against the Ebola virus.

    Science.gov (United States)

    Litterman, Nadia; Lipinski, Christopher; Ekins, Sean

    2015-01-01

    The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine. The balance between using FDA approved drugs versus novel antivirals with minimal safety and no efficacy data in humans should be considered. We have evaluated 55 molecules from the perspective of an experienced medicinal chemist as well as using simple molecular properties and have highlighted 16 compounds that have desirable qualities as well as those that may be less desirable. In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus. PMID:25713700

  9. Quantitative super-resolution imaging of Bruchpilot distinguishes active zone states.

    Science.gov (United States)

    Ehmann, Nadine; van de Linde, Sebastian; Alon, Amit; Ljaschenko, Dmitrij; Keung, Xi Zhen; Holm, Thorge; Rings, Annika; DiAntonio, Aaron; Hallermann, Stefan; Ashery, Uri; Heckmann, Manfred; Sauer, Markus; Kittel, Robert J

    2014-08-18

    The precise molecular architecture of synaptic active zones (AZs) gives rise to different structural and functional AZ states that fundamentally shape chemical neurotransmission. However, elucidating the nanoscopic protein arrangement at AZs is impeded by the diffraction-limited resolution of conventional light microscopy. Here we introduce new approaches to quantify endogenous protein organization at single-molecule resolution in situ with super-resolution imaging by direct stochastic optical reconstruction microscopy (dSTORM). Focusing on the Drosophila neuromuscular junction (NMJ), we find that the AZ cytomatrix (CAZ) is composed of units containing ~137 Bruchpilot (Brp) proteins, three quarters of which are organized into about 15 heptameric clusters. We test for a quantitative relationship between CAZ ultrastructure and neurotransmitter release properties by engaging Drosophila mutants and electrophysiology. Our results indicate that the precise nanoscopic organization of Brp distinguishes different physiological AZ states and link functional diversification to a heretofore unrecognized neuronal gradient of the CAZ ultrastructure.

  10. Novel Molecular Non-Volatile Memory: Application of Redox-Active Molecules

    OpenAIRE

    Hao Zhu; Qiliang Li

    2015-01-01

    This review briefly describes the development of molecular electronics in the application of non-volatile memory. Molecules, especially redox-active molecules, have become interesting due to their intrinsic redox behavior, which provides an excellent basis for low-power, high-density and high-reliability non-volatile memory applications. Recently, solid-state non-volatile memory devices based on redox-active molecules have been reported, exhibiting fast speed, low operation voltage, excellent...

  11. Analysis of natural neutron flux in a seismically active zone

    Directory of Open Access Journals (Sweden)

    V. F. Ostapenko

    2003-01-01

    Full Text Available In a seismically active zone in the near Almaty area (Kazakhstan since 1996 observations of variations of a natural neutron flux have been conducted. Sometimes the neutron flux rises sharply within the one-hour interval in comparison with the background. It occurs on the eve of activation of seismic processes. Increase of the neutron flux level had taken place from 1 h to 10 days prior to earthquakes. It is also indicated a tendency of growth of the anomaly level in accordance with the growth of energetic class of the subsequent earthquake. A character of connection between the neutron flux and earthquakes is still not clear. It is proposed that the neutron flux anomalies caused by variations of cosmic radiation intensity under action of fluxes of solar material, which is burst into interplanetary space (solar wind during solar flares. Energy of the solar wind transferred to Earth puts into action a trigger mechanism of the process of initiation of earthquakes at those places where conditions have already been prepared for them. The neutron flux anomalies can be used as substantial additional information for classical geophysical methods of short-term earthquake prediction.

  12. Dynamics of water molecules in the active-site cavity of human cytochromes P450

    DEFF Research Database (Denmark)

    Rydberg, Patrik; Rod, Thomas Holm; Olsen, Lars;

    2007-01-01

    We have studied the dynamics of water molecules in six crystal structures of four human cytochromes P450, 2A6, 2C8, 2C9, and 3A4, with molecular dynamics simulations. In the crystal structures, only a few water molecules are seen and the reported sizes of the active-site cavity vary a lot. In the...... molecules close to the heme iron ion in these simulations of the high-spin ferric state (the average distance to the closest water molecule is 3.3-5 A), and there are few ordered water molecules in the active sites, none of which is conserved in all proteins.......We have studied the dynamics of water molecules in six crystal structures of four human cytochromes P450, 2A6, 2C8, 2C9, and 3A4, with molecular dynamics simulations. In the crystal structures, only a few water molecules are seen and the reported sizes of the active-site cavity vary a lot....... In the simulations, the cavities are completely filled with water molecules, although with approximately 20% lower density than in bulk water. The 2A6 protein differs from the other three in that it has a very small cavity with only two water molecules and no exchange with the surroundings. The other three proteins...

  13. High quality, small molecule-activity datasets for kinase research.

    Science.gov (United States)

    Sharma, Rajan; Schürer, Stephan C; Muskal, Steven M

    2016-01-01

    Kinases regulate cell growth, movement, and death. Deregulated kinase activity is a frequent cause of disease. The therapeutic potential of kinase inhibitors has led to large amounts of published structure activity relationship (SAR) data. Bioactivity databases such as the Kinase Knowledgebase (KKB), WOMBAT, GOSTAR, and ChEMBL provide researchers with quantitative data characterizing the activity of compounds across many biological assays. The KKB, for example, contains over 1.8M kinase structure-activity data points reported in peer-reviewed journals and patents. In the spirit of fostering methods development and validation worldwide, we have extracted and have made available from the KKB 258K structure activity data points and 76K associated unique chemical structures across eight kinase targets. These data are freely available for download within this data note. PMID:27429748

  14. Adhesion molecules levels in blood correlate with MRI activity and clinical activity in multiple sclerosis

    International Nuclear Information System (INIS)

    Research into pathogenesis of multiple sclerosis (MS) has prompted efforts to identify immunological markers associated with disease activity. Adhesion molecules ICAM-1 and VCAM-1 are associated with inflammatory mediated blood-brain barrier (BBB) dysfunction. In this study investigates the correlation between blood level of circulating ICAM-1 and VCAM-1 and magnetic resonance imaging (MRI) activity in different clinical phases of patients with MS. We show that RRMS and SPMS patients in clinically active phase with Gd-enhancing lesions in CNS had higher blood levels of cICAM-1 and cVCAM-1 compared these parameters levers of RRMS patients in remission stage. These results suggest that cICAM-1 and cVCAM-1 is a sensitive indicator of disease activity associated with BBB inflammatory dysfunction. Elevated blood level of cICAM-1 more strongly correlated with clinical activity and BBB damage, than cVCAM-1 and that could be used as biological marker of disease activity. Circulating VCAM-1 as an early indicator of BBB disturbance, may also serve as marker of beneficial activity in relapses phase of MS course. (authors)

  15. Active zone impact on deformation state of non-rigid pavement

    Science.gov (United States)

    Mandula, Ján

    2014-06-01

    The paper deals with the design of non-rigid pavement, with emphasis on the effect of active zone on its deformation state. The concepts of determination of active zone are described. The results of numerical modelling of pavement laying on elastic subgrade are presented in the paper

  16. Active zone impact on deformation state of non-rigid pavement

    Directory of Open Access Journals (Sweden)

    Mandula Ján

    2014-06-01

    Full Text Available The paper deals with the design of non-rigid pavement, with emphasis on the effect of active zone on its deformation state. The concepts of determination of active zone are described. The results of numerical modelling of pavement laying on elastic subgrade are presented in the paper

  17. Activated leukocyte cell adhesion molecule and prognosis in acute ischemic stroke

    DEFF Research Database (Denmark)

    Smedbakken, Linda; Jensen, Jesper K; Hallén, Jonas;

    2011-01-01

    Biomarkers predicting mortality and functional outcome in stroke may be clinically helpful in identification of patients likely to benefit from intervention. Activated leukocyte cell adhesion molecule (ALCAM) is upregulated during neuroinflammation; we investigated whether ALCAM concentrations ar...

  18. Atmospheric Aerosols: Cloud Condensation Nucleus Activity of Selected Organic Molecules

    Science.gov (United States)

    Rosenorn, T.; Henning, S.; Hartz, K. H.; Kiss, G.; Pandis, S.; Bilde, M.

    2005-12-01

    Gas/particle partitioning of vapors in the atmosphere plays a major role in both climate through micro meteorology and in the physical and chemical processes of a single particle. This work has focused on the cloud droplet activation of a number of pure and mixed compounds. The means used to investigate these processes have been the University of Copenhagen cloud condensation nucleus counter setup and the Carnegie Mellon University CCNC setup. The importance of correct water activity modeling has been addressed and it has been pointed out that the molecular mass is an important parameter to consider when choosing model compounds for cloud activation models. It was shown that both traditional Kohler theory and Kohler theory modified to account for limited solubility reproduce measurements of soluble compounds well. For less soluble compounds it is necessary to use Kohler theory modified to account for limited solubility. It was also shown that this works for mixtures of compounds containing both inorganic salts and dicarboxylic acids. It has also been shown that particle phase and humidity history is important for activation behavior of particles consisting of two slightly soluble organic substances (succinic and adipic acid) and a soluble salt (NaCl). Model parameters for terpene oxidation product cloud activation have been derived. These are based on two sets of average parameters covering monoterpene oxidation products and sesquiterpene oxidation products. All parameters except the solubility were estimated and an effective solubility was calculated as the fitting parameter. The average solubility of the model compound found for mono terpene oxidation products is similar to those of sodium chloride and ammonium sulfate; however the higher molecular weight leads to a slightly higher activation diameter at fixed supersaturation. On a molar basis the monoterpene oxidation products show a 1.5 times higher effective solubility than the sesquiterpene oxidation products.

  19. Interaction of metallic clusters with biologically active curcumin molecules

    Science.gov (United States)

    Gupta, Sanjeev K.; He, Haiying; Liu, Chunhui; Dutta, Ranu; Pandey, Ravindra

    2015-09-01

    We have investigated the interaction of subnano metallic Gd and Au clusters with curcumin, an important biomolecule having pharmacological activity. Gd clusters show different site preference to curcumin and much stronger interaction strength, in support of the successful synthesis of highly stable curcumin-coated Gd nanoparticles as reported recently. It can be attributed to significant charge transfer from the Gd cluster to curcumin together with a relatively strong hybridization of the Gd df-orbitals with curcumin p-orbitals. These results suggest that Gd nanoparticles can effectively be used as delivery carriers for curcumin at the cellular level for therapy and medical imaging applications.

  20. Release probability of hippocampal glutamatergic terminals scales with the size of the active zone.

    Science.gov (United States)

    Holderith, Noemi; Lorincz, Andrea; Katona, Gergely; Rózsa, Balázs; Kulik, Akos; Watanabe, Masahiko; Nusser, Zoltan

    2012-06-10

    Cortical synapses have structural, molecular and functional heterogeneity; our knowledge regarding the relationship between their ultrastructural and functional parameters is still fragmented. Here we asked how the neurotransmitter release probability and presynaptic [Ca(2+)] transients relate to the ultrastructure of rat hippocampal glutamatergic axon terminals. Two-photon Ca(2+) imaging-derived optical quantal analysis and correlated electron microscopic reconstructions revealed a tight correlation between the release probability and the active-zone area. Peak amplitude of [Ca(2+)] transients in single boutons also positively correlated with the active-zone area. Freeze-fracture immunogold labeling revealed that the voltage-gated calcium channel subunit Cav2.1 and the presynaptic protein Rim1/2 are confined to the active zone and their numbers scale linearly with the active-zone area. Gold particles labeling Cav2.1 were nonrandomly distributed in the active zones. Our results demonstrate that the numbers of several active-zone proteins, including presynaptic calcium channels, as well as the number of docked vesicles and the release probability, scale linearly with the active-zone area.

  1. Root Zone Microbial Populations, Urease Activities, and Purification Efficiency for a Constructed Wetland

    Institute of Scientific and Technical Information of China (English)

    LIANG Wei; WU Zhen-Bin; ZHAN Fa-Cui; DENG Jia-Qi

    2004-01-01

    In order to investigate the effects of microorganisms and their urease activities in macrophytic root zones on pollutant removal, four small-scale plots (SSPs) of vertical/reverse-vertical flow wetlands were set up to determine: a) the relationship between the abundance of microorganisms in the root zones and water purification efficiency; and b) the relationship between urease activities in the root zones and pollutant removal in a constructed wetland system. Total numbers of the microbial population (bacteria, fungi, and actinomyces) along with urease activities in the macrophytic root zones were determined. In addition, the relationships between microbial populations and urease activities as well as the wastewater purification efficiencies of total phosphorus (TP), total Kjeldahl nitrogen (TKN), biochemical oxygen demand in 5 days (BOD5), and chemical oxygen demand (COD) were also analyzed. The results showed that there was a highly significant positive correlation (r = 0.9772, P < 0.01) between the number of bacteria in the root zones and BOD5 removal efficiency and a significant negative correlation (r = -0.9092, P < 0.05) between the number of fungi and the removal efficiency of TKN. Meanwhile, there was a significant positive correlation (r -- 0.8830, P < 0.05) between urease activities in the root zones and the removal efficiency of TKN. Thus, during wastewater treatment in a constructed wetland system,microorganism and urease activities in the root zones were very important factors.

  2. [Differences of activations in visual and associative zones during figurative and verbal activity].

    Science.gov (United States)

    Nagornova, Zh V; Shemiakina, N V

    2014-04-01

    The study considers correlates of figurative and verbal tasks performance during attention paid to visual stimuli. There are 34 subjects (20 female, mean age 21, 2.5 [SD]) took parts in the study. During subjects performance of the task, there was carried out EEG registration from 19 sites according to 10-20%. Performance of the figurative creative task in comparison with control non-creative task of the same modality was accompanied by activation of occipital and parietal zones of the cerebral cortex (decrease of EEG spectral power in alpha 1 (7.5-9.5 Hz) and alpha2 (10-12.5 Hz) frequency bands was observed) whereas performance of a verbal creative task in the similar test-control comparison was accompanied by decrease of activation in occipital zones (revealed through increase of EEG spectral in alphal and alpha2 frequency bands). As visual stimuli were shown during the whole time of the creative and control tasks fulfilment was made an assumption observed distinction can be connected with redistribution of attention focus at various types of creative activity (figurative or verbal).

  3. Activation of complement by an IgG molecule without a genetic hinge.

    Science.gov (United States)

    Brekke, O H; Michaelsen, T E; Sandin, R; Sandlie, I

    1993-06-17

    The hinge region links the two Fab arms to the Fc portion of the IgG molecule. It mediates flexibility to the molecule and serves as a connecting structure between the two heavy chains. In addition it provides space between the Fab and Fc parts. All three properties have been proposed to be important for the ability of IgG to initiate complement activation leading to complement-mediated cell lysis (CML). Here we report the construction of a hinge-deleted mouse-human chimaeric IgG3 molecule with specificity for the hapten NIP (3-iodo-4-hydroxy-5-nitrophenacetyl), HM-1. HM-1 lacks the genetic hinge, but has an introduced cysteine between Ala 231 (EU numbering) and Pro 232 in the lower hinge encoded by the CH2 exon. The introduced cysteine forms a disulphide bond between the two heavy chains of the molecule. In CML, HM-1 shows a greater activity than IgG3 wild type. This is the first time an IgG molecule without a genetic hinge has been found to be active in CML. We conclude that the hinge functioning as a spacer is not a prerequisite for complement activation. Rather, its major role seems to be to connect the heavy chains to each other in the amino-terminal part of CH2. Because HM-1 is expected to have low Fab-Fc flexibility, this molecular feature is probably of no importance for complement activation.

  4. Auroral Electrojet Index Designed to Provide a Global Measure, Hourly Intervals, of Auroral Zone Magnetic Activity

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Auroral Electrojet (AE) index is designed to provide a global quantitative measure of auroral zone magnetic activity produced by enhanced ionospheric currents...

  5. Group Problem Solving as a Zone of Proximal Development activity

    Science.gov (United States)

    Brewe, Eric

    2006-12-01

    Vygotsky described learning as a process, intertwined with development, which is strongly influenced by social interactions with others that are at differing developmental stages.i These interactions create a Zone of Proximal Development for each member of the interaction. Vygotsky’s notion of social constructivism is not only a theory of learning, but also of development. While teaching introductory physics in an interactive format, I have found manifestations of Vygotsky’s theory in my classroom. The source of evidence is a paired problem solution. A standard mechanics problem was solved by students in two classes as a homework assignment. Students handed in the homework and then solved the same problem in small groups. The solutions to both the group and individual problem were assessed by multiple reviewers. In many cases the group score was the same as the highest individual score in the group, but in some cases, the group score was higher than any individual score. For this poster, I will analyze the individual and group scores and focus on three groups solutions and video that provide evidence of learning through membership in a Zone of Proximal Development. Endnotes i L. Vygotsky -Mind and society: The development of higher mental processes. Cambridge, MA: Harvard University Press. (1978).

  6. Active fault survey on the Tanlu fault zone in Laizhou Bay

    Institute of Scientific and Technical Information of China (English)

    WANG Zhi-cai; YANG Xi-ha; LI Chang-chuan; DENG Qi-dong; DU Xian-song; CHAO Hong-tai; WU Zi-quan; XIAO Lan-xi; SUN Zhao-ming; MIN Wei; LING Hong

    2006-01-01

    Shallow-depth acoustic reflection profiling survey has been conducted on the Tanlu fault zone in Laizhou Bay. It is found that the Tanlu fault zone is obviously active during the late Quaternary and it is still the dominating structure in this region. The Tanlu fault zone consists of two branches. The KL3 fault of the western branch is composed of several high angle normal faults which had been active during the period from the latest Pleistocene to early Holocene, dissected by a series of northeast or approximate east-west trending fault which leaped sediment of the late Pleistocene. The Longkou fault of the eastern branch consists of two right-laterally stepped segments. Late Quaternary offsets and growth strata developed along the Tanlu fault zone verify that the fault zone retained active in the latest Pleistocene to the early Holocene. The Anqiu-Juxian fault that passes through the middle of Shandong and corresponds to the Longkou fault is composed of a series of right-laterally stepped segments. The active faults along the eastern branch of the Tanlu fault zone from the Laizhou bay to the north of Anqiu make up a dextral simple shear deformation zone which is characterized by right-lateral strike-slip movement with dip-slip component during the late Quaternary.

  7. Factors affecting carbon-14 activity of unsaturated zone CO2 and implications for groundwater dating

    Science.gov (United States)

    Wood, Cameron; Cook, Peter G.; Harrington, Glenn A.; Meredith, Karina; Kipfer, Rolf

    2014-11-01

    Unsaturated zone processes may influence the carbon-14 (14C) activity of infiltrating groundwater and thus introduce error in derived groundwater residence times. However unsaturated zone 14C activities are rarely measured and there is little understanding of how they may vary spatially in a groundwater basin. In this study we measured 14C activity in unsaturated zone gas at five sites with different watertable depths (8.2-31.5 m) in the arid Ti Tree Basin, central Australia. We observed a relatively uniform decrease in 14C activity of unsaturated zone gas with depth at most sites, with variation in unsaturated zone depths leading to variation in 14C activities directly above the watertable at each site (ranging from 54 to 106 percent Modern Carbon (pMC)). Through modelling we show that the profiles are influenced by CO2 production at different depths from sources with different isotopic ratios, including production of ‘modern' CO2 in the root zone and production of ‘old' CO2 above the watertable. Scenario modelling showed that these processes are independent of recharge when recharge is low (0-10 mm y-1) but that higher recharge rates (>100 mm y-1) result in more advective transport of atmospheric CO2 to the watertable. The variation in 14C above the watertable was more sensitive to watertable depth and shallow and deep CO2 production rates. These findings offer insight into how unsaturated zone 14C activities may vary spatially and provide guidance as to when 14C depletion in unsaturated zone CO2 may become important for groundwater dating, particularly in arid settings.

  8. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.

    Science.gov (United States)

    Burns, Michael C; Sun, Qi; Daniels, R Nathan; Camper, DeMarco; Kennedy, J Phillip; Phan, Jason; Olejniczak, Edward T; Lee, Taekyu; Waterson, Alex G; Rossanese, Olivia W; Fesik, Stephen W

    2014-03-01

    Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.

  9. Geomorphic Indices in the Assessment of Tectonic Activity in Forearc of the Active Mexican Subduction Zone

    Science.gov (United States)

    Gaidzik, K.; Ramirez-Herrera, M. T.

    2015-12-01

    Rapid development of GIS techniques and constant advancement of digital elevation models significantly improved the accuracy of extraction of information on active tectonics from landscape features. Numerous attempts were made to quantitatively evaluate recent tectonic activity using GIS and DEMs, and a set of geomorphic indices (GI), however these studies focused mainly on sub-basins or small-scale areal units. In forearc regions where crustal deformation is usually large-scale and do not concentrate only along one specific fault, an assessment of the complete basin is more accurate. We present here the first attempt to implement thirteen GI in the assessment of active tectonics of a forearc region of an active convergent margin using the entire river basins. The GIs were divided into groups: BTAI - basin geomorphic indices (reflecting areal erosion vs. tectonics) and STAI - stream geomorphic indices (reflecting vertical erosion vs. tectonics). We calculated selected indices for 9 large (> 450 km2) drainage basins. Then we categorized the obtained results of each index into three classes of relative tectonic activity: 1 - high, 2 - moderate, and 3 - low. Finally we averaged these classes for each basin to determine the tectonic activity level (TAI). The analysis for the case study area, the Guerrero sector at the Mexican subduction zone, revealed high tectonic activity in this area, particularly in its central and, to a lesser degree, eastern part. This pattern agrees with and is supported by interpretation of satellite images and DEM, and field observations. The results proved that the proposed approach indeed allows identification and recognition of areas witnessing recent tectonic deformation. Moreover, our results indicated that, even though no large earthquake has been recorded in this sector for more than 100 years, the area is highly active and may represent a seismic hazard for the region.

  10. Investigating organic molecules responsible of auxin-like activity of humic acid fraction extracted from vermicompost.

    Science.gov (United States)

    Scaglia, Barbara; Nunes, Ramom Rachide; Rezende, Maria Olímpia Oliveira; Tambone, Fulvia; Adani, Fabrizio

    2016-08-15

    This work studied the auxin-like activity of humic acids (HA) obtained from vermicomposts produced using leather wastes plus cattle dung at different maturation stages (fresh, stable and mature). Bioassays were performed by testing HA concentrations in the range of 100-6000mgcarbonL(-1). (13)C CPMAS-NMR and GC-MS instrumental methods were used to assess the effect of biological processes and starting organic mixtures on HA composition. Not all HAs showed IAA-like activity and in general, IAA-like activity increased with the length of the vermicomposting process. The presence of leather wastes was not necessary to produce the auxin-like activity of HA, since HA extracted from a mix of cattle manure and sawdust, where no leather waste was added, showed IAA-like activity as well. CPMAS (13)CNMR revealed that HAs were similar independently of the mix used and that the humification process involved the increasing concentration of pre-existing alkali soluble fractions in the biomass. GC/MS allowed the identification of the molecules involved in IAA-like effects: carboxylic acids and amino acids. The concentration of active molecules, rather than their simple presence in HA, determined the bio-stimulating effect, and a good linear regression between auxin-like activity and active stimulating molecules concentration was found (R(2)=-0.85; p<0.01, n=6). PMID:27100009

  11. Brazing zone structure at active brazing of alumina ceramics

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    @@ Nowadays one of the most effective methods of joining of oxide ceramics with other elements of construction is active brazing based on using of active metals (Ti, Zr), which increase reactivity of brazing alloy relative to ceramic element of a joining.

  12. Brazing zone structure at active brazing of alumina ceramics

    Institute of Scientific and Technical Information of China (English)

    Demchuk; V.; A.; Kalinichenko; B.; B.

    2005-01-01

    Nowadays one of the most effective methods of joining of oxide ceramics with other elements of construction is active brazing based on using of active metals (Ti, Zr), which increase reactivity of brazing alloy relative to ceramic element of a joining.……

  13. Activated leukocyte cell adhesion molecule expression predicts lymph node metastasis in oral squamous cell carcinoma.

    NARCIS (Netherlands)

    Brand, M. van den; Takes, R.P.; Blokpoel-deRuyter, M.; Slootweg, P.J.; Kempen, L.C.L.T. van

    2010-01-01

    Lymphatic metastasis of oral squamous cell carcinoma (SCC) is important for prognosis and clinical decision making concerning the treatment of the neck but may be difficult to detect. Activated leukocyte cell adhesion molecule (ALCAM), has been shown to correlate with prognosis or tumor grade in dif

  14. Harnessing microbial metabolic exchange for the discovery of biologically active molecules

    OpenAIRE

    Liu, Wei-Ting

    2012-01-01

    Microbial metabolic exchange mediates microbial interactions and plays key roles in regulating biology and has shaped modern healthcare, agriculture and other commercial processes. In this thesis, cutting edge mass spectrometry techniques, new genome mining approaches, and innovative bioinformatics tools were coupled and developed into investigating microbial metabolic exchange and led to the identification and characterization of biological active molecules that may have therapeutic values. ...

  15. Single-molecule imaging of DNA polymerase I (Klenow fragment) activity by atomic force microscopy

    Science.gov (United States)

    Chao, J.; Zhang, P.; Wang, Q.; Wu, N.; Zhang, F.; Hu, J.; Fan, C. H.; Li, B.

    2016-03-01

    We report a DNA origami-facilitated single-molecule platform that exploits atomic force microscopy to study DNA replication. We imaged several functional activities of the Klenow fragment of E. coli DNA polymerase I (KF) including binding, moving, and dissociation from the template DNA. Upon completion of these actions, a double-stranded DNA molecule was formed. Furthermore, the direction of KF activities was captured and then confirmed by shifting the KF binding sites on the template DNA.We report a DNA origami-facilitated single-molecule platform that exploits atomic force microscopy to study DNA replication. We imaged several functional activities of the Klenow fragment of E. coli DNA polymerase I (KF) including binding, moving, and dissociation from the template DNA. Upon completion of these actions, a double-stranded DNA molecule was formed. Furthermore, the direction of KF activities was captured and then confirmed by shifting the KF binding sites on the template DNA. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06544e

  16. Single-active-electron potentials for molecules in intense laser fields

    DEFF Research Database (Denmark)

    Abu-Samha, Mahmoud; Madsen, Lars Bojer

    2010-01-01

    Single-active-electron potentials are computed for selected molecules, and molecular wave functions with the correct asymptotic behavior are produced. Asymptotic expansion coefficients are extracted from the wave functions and used to compute alignment-dependent ionization yields from molecular...

  17. Machine learning models identify molecules active against the Ebola virus in vitro.

    Science.gov (United States)

    Ekins, Sean; Freundlich, Joel S; Clark, Alex M; Anantpadma, Manu; Davey, Robert A; Madrid, Peter

    2015-01-01

    The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro. PMID:26834994

  18. Lessons from isolable nickel(I) precursor complexes for small molecule activation.

    Science.gov (United States)

    Yao, Shenglai; Driess, Matthias

    2012-02-21

    Small-molecule activation by transition metals is essential to numerous organic transformations, both biological and industrial. Creating useful metal-mediated activation systems often depends on stabilizing the metal with uncommon low oxidation states and low coordination numbers. This provides a redox-active metal center with vacant coordination sites well suited for interacting with small molecules. Monovalent nickel species, with their d(9) electronic configuration, are moderately strong one-electron reducing agents that are synthetically attractive if they can be isolated. They represent suitable reagents for closing the knowledge gap in nickel-mediated activation of small molecules. Recently, the first strikingly stable dinuclear β-diketiminate nickel(I) precursor complexes were synthesized, proving to be suitable promoters for small-molecule binding and activation. They have led to many unprecedented nickel complexes bearing activated small molecules in different reduction stages. In this Account, we describe selected achievements in the activation of nitrous oxide (N(2)O), O(2), the heavier chalcogens (S, Se, and Te), and white phosphorus (P(4)) through this β-diketiminatonickel(I) precursor species. We emphasize the reductive activation of O(2), owing to its promise in oxidation processes. The one-electron-reduced O(2) activation product, that is, the corresponding β-diketiminato-supported Ni-O(2) complex, is a genuine superoxonickel(II) complex, representing an important intermediate in the early stages of O(2) activation. It selectively acts as an oxygen-atom transfer agent, hydrogen-atom scavenger, or both towards exogenous organic substrates to yield oxidation products. The one-electron reduction of the superoxonickel(II) moiety was examined by using elemental potassium, β-diketiminatozinc(II) chloride, and β-diketiminatoiron(I) complexes, affording the first heterobimetallic complexes featuring a [NiO(2)M] subunit (M is K, Zn, or Fe). Through

  19. Water molecule network and active site flexibility of apo protein tyrosine phosphatase 1B

    DEFF Research Database (Denmark)

    Pedersen, A.K.; Peters, Günther H.J.; Møller, K.B.;

    2004-01-01

    Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including...... the conformation and flexibility of active-site residues as well as the water-molecule network, is a key issue in understanding ligand binding and enzyme kinetics and in structure-based drug design. A 1.95 Angstrom apo PTP1B structure has been obtained, showing four highly coordinated water molecules...

  20. Facilitating the medical response into an active shooter hot zone

    OpenAIRE

    Tierney, Martin T.

    2016-01-01

    Approved for public release; distribution is unlimited The response to active shooter attacks is not as effective as it could be. People die before receiving care because most jurisdictions have a policy in place that stipulates emergency medical services (EMS) wait to enter a scene until law enforcement (LE) announces that the scene is clear or secure. Since this can take some time, life-saving care is not immediately available to the people who most need it, and consequently, there can b...

  1. Aqueous phase adsorption of different sized molecules on activated carbon fibers: Effect of textural properties.

    Science.gov (United States)

    Prajapati, Yogendra N; Bhaduri, Bhaskar; Joshi, Harish C; Srivastava, Anurag; Verma, Nishith

    2016-07-01

    The effect that the textural properties of rayon-based activated carbon fibers (ACFs), such as the BET surface area and pore size distribution (PSD), have on the adsorption of differently sized molecules, namely, brilliant yellow (BY), methyl orange (MO) and phenol (PH), was investigated in the aqueous phase. ACF samples with different BET areas and PSDs were produced by steam-activating carbonized fibers for different activation times (0.25, 0.5, and 1 h). The samples activated for 0.25 h were predominantly microporous, whereas those activated for relatively longer times contained hierarchical micro-mesopores. The adsorption capacities of the ACFs for the adsorbate increased with increasing BET surface area and pore volume, and ranged from 51 to 1306 mg/g depending on the textural properties of the ACFs and adsorbate size. The adsorption capacities of the hierarchical ACF samples followed the order BY > MO > PH. Interestingly, the number of molecules adsorbed by the ACFs followed the reverse order: PH > MO > BY. This anomaly was attributed to the increasing molecular weight of the PH, MO and BY molecules. The equilibrium adsorption data were described using the Langmuir isotherm. This study shows that suitable textural modifications to ACFs are required for the efficient aqueous phase removal of an adsorbate. PMID:27107386

  2. Single molecule investigation of the onset and minimum size of the calcium-mediated junction zone in alginate.

    Science.gov (United States)

    Bowman, Kate A; Aarstad, Olav Andreas; Nakamura, Marcela; Stokke, Bjørn Torger; Skjåk-Bræk, Gudmund; Round, Andrew N

    2016-09-01

    One of the principal roles of alginate, both natively and in commercial applications, is gelation via Ca(2+)-mediated crosslinks between blocks of guluronic acid. In this work, single molecule measurements were carried out between well-characterised series of nearly monodisperse guluronic acid blocks ('oligoGs') using dynamic force spectroscopy. The measurements provide evidence that for interaction times on the order of tens of milliseconds the maximum crosslink strength is achieved by pairs of oligoGs long enough to allow the coordination of 4Ca(2+) ions, with both shorter and longer oligomers forming weaker links. Extending the interaction time from tens to hundreds of milliseconds allows longer oligoGs to achieve much stronger crosslinks but does not change the strength of individual links between shorter oligoGs. These results are considered in light of extant models for the onset of cooperative crosslinking in polyelectrolytes and an anisotropic distribution of oligoGs on interacting surfaces and provide a timescale for the formation and relaxation of alginate gels at the single crosslink level. PMID:27185115

  3. Alternative interpretation for the active zones of Cuba

    Science.gov (United States)

    Rodríguez, Mario Octavio Cotilla

    2014-11-01

    An alternative explanation to the seismoactivity of Cuban faults is presented. The model is a consequence of the interaction between Caribbean and North American plates. It is made with 12 geodynamic cells form by a set of 13 active faults and their 14 areas of intersection. These cells are recognized morpho-structural blocks. The area between Eastern Matanzas and Western Cauto-Nipe is excluded because of the low level of seismic information. Cuba has two types of seismogenetic structures: faults and intersection of faults.

  4. Heavy metals contamination characteristics in soil of different mining activity zones

    Institute of Scientific and Technical Information of China (English)

    LIAO Guo-li; LIAO Da-xue; LI Quan-ming

    2008-01-01

    Depending upon the polluted features of various mining activities in a typical nonferrous metal mine, the contaminated soil area was divided into four zones which were polluted by tailings, mine drainage, dust deposition in wind and spreading minerals during vehicle transportation, respectively. In each zone, soil samples were collected. Total 28 soil samples were dug and analyzed by ICP-AES and other relevant methods. The results indicate that the average contents of Zn, Pb, Cd, Cu and As in soils are 508.6, 384.8, 7.53, 356 and 44.6 mg/kg, respectively. But the contents of heavy metals in different zone have distinct differences. The proportion of oxidizing association with organic substance is small. Difference of the association of heavy metals is small in different polluted zones.

  5. Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d.

    Science.gov (United States)

    Gorham, Ronald D; Nuñez, Vicente; Lin, Jung-Hsin; Rooijakkers, Suzan H M; Vullev, Valentine I; Morikis, Dimitrios

    2015-12-24

    Complement activation plays a major role in many acute and chronic inflammatory conditions. C3d, a terminal product of complement activation, remains covalently attached to cells and is an excellent biomarker of complement-mediated inflammation. We employed a virtual high-throughput screening protocol to identify molecules with predicted binding to complement C3d and with intrinsic fluorescence properties to enable detection. Pharmacophore models were developed based on known C3d-ligand interactions and information from computational analysis of structural and molecular dynamics data. Iterative pharmacophore-based virtual screening was performed to identify druglike molecules with physicochemical similarity to the natural C3d ligand CR2. Hits from the pharmacophore screens were docked to C3d and ranked based on predicted binding free energies. Top-ranked molecules were selected for experimental validation of binding affinity to C3d, using microscale thermophoresis, and for their suitability to become molecular imaging agents, using fluorescence spectroscopy. This work serves as a foundation for identifying additional fluorescent molecules with high-affinity for C3d that will subsequently be explored as noninvasive in vivo diagnostics of complement-mediated inflammation, for spatiotemporal monitoring of disease progression, and for targeting therapeutics to sites of inflammation. PMID:26613117

  6. Visualizing repetitive diffusion activity of double-strand RNA binding proteins by single molecule fluorescence assays.

    Science.gov (United States)

    Koh, Hye Ran; Wang, Xinlei; Myong, Sua

    2016-08-01

    TRBP, one of double strand RNA binding proteins (dsRBPs), is an essential cofactor of Dicer in the RNA interference pathway. Previously we reported that TRBP exhibits repetitive diffusion activity on double strand (ds)RNA in an ATP independent manner. In the TRBP-Dicer complex, the diffusion mobility of TRBP facilitates Dicer-mediated RNA cleavage. Such repetitive diffusion of dsRBPs on a nucleic acid at the nanometer scale can be appropriately captured by several single molecule detection techniques. Here, we provide a step-by-step guide to four different single molecule fluorescence assays by which the diffusion activity of dsRBPs on dsRNA can be detected. One color assay, termed protein induced fluorescence enhancement enables detection of unlabeled protein binding and diffusion on a singly labeled RNA. Two-color Fluorescence Resonance Energy Transfer (FRET) in which labeled dsRBPs is applied to labeled RNA, allows for probing the motion of protein along the RNA axis. Three color FRET reports on the diffusion movement of dsRBPs from one to the other end of RNA. The single molecule pull down assay provides an opportunity to collect dsRBPs from mammalian cells and examine the protein-RNA interaction at single molecule platform. PMID:27012177

  7. Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d.

    Science.gov (United States)

    Gorham, Ronald D; Nuñez, Vicente; Lin, Jung-Hsin; Rooijakkers, Suzan H M; Vullev, Valentine I; Morikis, Dimitrios

    2015-12-24

    Complement activation plays a major role in many acute and chronic inflammatory conditions. C3d, a terminal product of complement activation, remains covalently attached to cells and is an excellent biomarker of complement-mediated inflammation. We employed a virtual high-throughput screening protocol to identify molecules with predicted binding to complement C3d and with intrinsic fluorescence properties to enable detection. Pharmacophore models were developed based on known C3d-ligand interactions and information from computational analysis of structural and molecular dynamics data. Iterative pharmacophore-based virtual screening was performed to identify druglike molecules with physicochemical similarity to the natural C3d ligand CR2. Hits from the pharmacophore screens were docked to C3d and ranked based on predicted binding free energies. Top-ranked molecules were selected for experimental validation of binding affinity to C3d, using microscale thermophoresis, and for their suitability to become molecular imaging agents, using fluorescence spectroscopy. This work serves as a foundation for identifying additional fluorescent molecules with high-affinity for C3d that will subsequently be explored as noninvasive in vivo diagnostics of complement-mediated inflammation, for spatiotemporal monitoring of disease progression, and for targeting therapeutics to sites of inflammation.

  8. Postsynaptic actin regulates active zone spacing and glutamate receptor apposition at the Drosophila neuromuscular junction.

    Science.gov (United States)

    Blunk, Aline D; Akbergenova, Yulia; Cho, Richard W; Lee, Jihye; Walldorf, Uwe; Xu, Ke; Zhong, Guisheng; Zhuang, Xiaowei; Littleton, J Troy

    2014-07-01

    Synaptic communication requires precise alignment of presynaptic active zones with postsynaptic receptors to enable rapid and efficient neurotransmitter release. How transsynaptic signaling between connected partners organizes this synaptic apparatus is poorly understood. To further define the mechanisms that mediate synapse assembly, we carried out a chemical mutagenesis screen in Drosophila to identify mutants defective in the alignment of active zones with postsynaptic glutamate receptor fields at the larval neuromuscular junction. From this screen we identified a mutation in Actin 57B that disrupted synaptic morphology and presynaptic active zone organization. Actin 57B, one of six actin genes in Drosophila, is expressed within the postsynaptic bodywall musculature. The isolated allele, act(E84K), harbors a point mutation in a highly conserved glutamate residue in subdomain 1 that binds members of the Calponin Homology protein family, including spectrin. Homozygous act(E84K) mutants show impaired alignment and spacing of presynaptic active zones, as well as defects in apposition of active zones to postsynaptic glutamate receptor fields. act(E84K) mutants have disrupted postsynaptic actin networks surrounding presynaptic boutons, with the formation of aberrant actin swirls previously observed following disruption of postsynaptic spectrin. Consistent with a disruption of the postsynaptic actin cytoskeleton, spectrin, adducin and the PSD-95 homolog Discs-Large are all mislocalized in act(E84K) mutants. Genetic interactions between act(E84K) and neurexin mutants suggest that the postsynaptic actin cytoskeleton may function together with the Neurexin-Neuroligin transsynaptic signaling complex to mediate normal synapse development and presynaptic active zone organization.

  9. Matrine inhibits the expression of adhesion molecules in activated vascular smooth muscle cells.

    Science.gov (United States)

    Liu, Jun; Zhang, Lihua; Ren, Yingang; Gao, Yanli; Kang, Li; Lu, Shaoping

    2016-03-01

    Atherosclerosis is a chronic inflammatory disease associated with increased expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Matrine is a main active ingredient of Sophora flavescens roots, which are used to treat inflammatory diseases. However, the effects of matrine on the expression of adhesion molecules in VSMCs have largely remained elusive. Therefore, the present study investigated the effects of matrine on the expression of adhesion molecules in tumor necrosis factor (TNF)‑α‑stimulated human aortic smooth muscle cells (HASMCs). The results showed that matrine inhibited the expression of vascular cell adhesion molecule‑1 (VCAM‑1) and intercellular adhesion molecule‑1 (ICAM‑1) in TNF‑α‑stimulated HASMCs. Matrine markedly inhibited the TNF‑α‑induced expression of nuclear factor (NF)‑κB p65 and prevented the TNF‑α‑caused degradation of inhibitor of NF‑κB; it also inhibited TNF‑α‑induced activation of mitogen‑activated protein kinases (MAPKs). Furthermore, matrine inhibited the production of intracellular reactive oxygen species (ROS) in TNF‑α‑stimulated HASMCs. In conclusion, the results of the present study demonstrated that matrine inhibited the expression of VCAM‑1 and ICAM‑1 in TNF‑α‑stimulated HASMCs via the suppression of ROS production as well as NF‑κB and MAPK pathway activation. Therefore, matrine may have a potential therapeutic use for preventing the advancement of atherosclerotic lesions.

  10. Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme.

    Directory of Open Access Journals (Sweden)

    Bilal Çakir

    Full Text Available BACKGROUND: Insulin-degrading enzyme (IDE is an allosteric Zn(+2 metalloprotease involved in the degradation of many peptides including amyloid-β, and insulin that play key roles in Alzheimer's disease (AD and type 2 diabetes mellitus (T2DM, respectively. Therefore, the use of therapeutic agents that regulate the activity of IDE would be a viable approach towards generating pharmaceutical treatments for these diseases. Crystal structure of IDE revealed that N-terminal has an exosite which is ∼30 Å away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is possible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we applied structure based drug design method combined with experimental methods to discover four novel molecules that enhance the activity of human IDE. The novel compounds, designated as D3, D4, D6, and D10 enhanced IDE mediated proteolysis of substrate V, insulin and amyloid-β, while enhanced degradation profiles were obtained towards substrate V and insulin in the presence of D10 only. CONCLUSION/SIGNIFICANCE: This paper describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro and in vivo activation of this important enzyme with small molecules is possible.

  11. Structure Based Discovery of Small Molecules to Regulate the Activity of Human Insulin Degrading Enzyme

    Science.gov (United States)

    Çakir, Bilal; Dağliyan, Onur; Dağyildiz, Ezgi; Bariş, İbrahim; Kavakli, Ibrahim Halil; Kizilel, Seda; Türkay, Metin

    2012-01-01

    Background Insulin-degrading enzyme (IDE) is an allosteric Zn+2 metalloprotease involved in the degradation of many peptides including amyloid-β, and insulin that play key roles in Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), respectively. Therefore, the use of therapeutic agents that regulate the activity of IDE would be a viable approach towards generating pharmaceutical treatments for these diseases. Crystal structure of IDE revealed that N-terminal has an exosite which is ∼30 Å away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is possible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates. Methodology/Principal Findings In this study, we applied structure based drug design method combined with experimental methods to discover four novel molecules that enhance the activity of human IDE. The novel compounds, designated as D3, D4, D6, and D10 enhanced IDE mediated proteolysis of substrate V, insulin and amyloid-β, while enhanced degradation profiles were obtained towards substrate V and insulin in the presence of D10 only. Conclusion/Significance This paper describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro and in vivo activation of this important enzyme with small molecules is possible. PMID:22355395

  12. Nanoscale charge transport in cytochrome c3/DNA network: Comparative studies between redox-active molecules

    Science.gov (United States)

    Yamaguchi, Harumasa; Che, Dock-Chil; Hirano, Yoshiaki; Suzuki, Masayuki; Higuchi, Yoshiki; Matsumoto, Takuya

    2015-09-01

    The redox-active molecule of a cytochrome c3/DNA network exhibits nonlinear current-voltage (I-V) characteristics with a threshold bias voltage at low temperature and zero-bias conductance at room temperature. I-V curves for the cytochrome c3/DNA network are well matched with the Coulomb blockade network model. Comparative studies of the Mn12 cluster, cytochrome c, and cytochrome c3, which have a wide variety of redox potentials, indicate no difference in charge transport, which suggests that the conduction mechanism is not directly related to the redox states. The charge transport mechanism has been discussed in terms of the newly-formed electronic energy states near the Fermi level, induced by the ionic interaction between redox-active molecules with the DNA network.

  13. Topoisomerase I as a Biomarker: Detection of Activity at the Single Molecule Level

    DEFF Research Database (Denmark)

    Proszek, Joanna; Roy, Amit; Jakobsen, Ann-Katrine;

    2014-01-01

    hTopI have been reported to result in CPT resistance. Therefore, hTOPI gene copy number, mRNA level, protein amount, and enzyme activity have been studied to explain differences in cellular response to CPT. We show that Rolling Circle Enhanced Enzyme Activity Detection (REEAD), allowing measurement...... of hTopI cleavage-religation activity at the single molecule level, may be used to detect posttranslational enzymatic differences influencing CPT response. These differences cannot be detected by analysis of hTopI gene copy number, mRNA amount, or protein amount, and only become apparent upon...... measuring the activity of hTopI in the presence of CPT. Furthermore, we detected differences in the activity of the repair enzyme tyrosyl-DNA phosphodiesterase 1, which is involved in repair of hTopI-induced DNA damage. Since increased TDP1 activity can reduce cellular CPT sensitivity we suggest that a...

  14. Morbilliviruses Use Signaling Lymphocyte Activation Molecules (CD150) as Cellular Receptors

    OpenAIRE

    Tatsuo, Hironobu; Ono, Nobuyuki; Yanagi, Yusuke

    2001-01-01

    Morbilliviruses comprise measles virus, canine distemper virus, rinderpest virus, and several other viruses that cause devastating human and animal diseases accompanied by severe immunosuppression and lymphopenia. Recently, we have shown that human signaling lymphocyte activation molecule (SLAM) is a cellular receptor for measles virus. In this study, we examined whether canine distemper and rinderpest viruses also use canine and bovine SLAMs, respectively, as cellular receptors. The Onderste...

  15. Anticancer molecule AS1411 exhibits low nanomolar antiviral activity against HIV-1.

    Science.gov (United States)

    Métifiot, Mathieu; Amrane, Samir; Mergny, Jean-Louis; Andreola, Marie-Line

    2015-11-01

    During clinical trials, a number of fully characterized molecules are dropped along the way because they do not provide enough benefit for the patient. Some of them show limited side effects and might be of great use for other applications. AS1411 is a nucleolin-targeting aptamer that underwent phase II clinical trials as anticancer agent. Here, we show that AS1411 exhibits extremely potent antiviral activity and is therefore an attractive new lead as anti-HIV agent. PMID:26363100

  16. Structure-property relationship of quinuclidinium surfactants--Towards multifunctional biologically active molecules.

    Science.gov (United States)

    Skočibušić, Mirjana; Odžak, Renata; Štefanić, Zoran; Križić, Ivana; Krišto, Lucija; Jović, Ozren; Hrenar, Tomica; Primožič, Ines; Jurašin, Darija

    2016-04-01

    Motivated by diverse biological and pharmacological activity of quinuclidine and oxime compounds we have synthesized and characterized novel class of surfactants, 3-hydroxyimino quinuclidinium bromides with different alkyl chains lengths (CnQNOH; n=12, 14 and 16). The incorporation of non conventional hydroxyimino quinuclidinium headgroup and variation in alkyl chain length affects hydrophilic-hydrophobic balance of surfactant molecule and thereby physicochemical properties important for its application. Therefore, newly synthesized surfactants were characterized by the combination of different experimental techniques: X-ray analysis, potentiometry, electrical conductivity, surface tension and dynamic light scattering measurements, as well as antimicrobial susceptibility tests. Comprehensive investigation of CnQNOH surfactants enabled insight into structure-property relationship i.e., way in which the arrangement of surfactant molecules in the crystal phase correlates with their solution behavior and biologically activity. The synthesized CnQNOH surfactants exhibited high adsorption efficiency and relatively low critical micelle concentrations. In addition, all investigated compounds showed very potent and promising activity against Gram-positive and clinically relevant Gram-negative bacterial strains compared to conventional antimicrobial agents: tetracycline and gentamicin. The overall results indicate that bicyclic headgroup with oxime moiety, which affects both hydrophilicity and hydrophobicity of CnQNOH molecule in addition to enabling hydrogen bonding, has dominant effect on crystal packing and physicochemical properties. The unique structural features of cationic surfactants with hydroxyimino quinuclidine headgroup along with diverse biological activity have made them promising structures in novel drug discovery. Obtained fundamental understanding how combination of different functionalities in a single surfactant molecule affects its physicochemical

  17. Identification of intrinsic catalytic activity for electrochemical reduction of water molecules to generate hydrogen

    KAUST Repository

    Shinagawa, Tatsuya

    2015-01-01

    Insufficient hydronium ion activities at near-neutral pH and under unbuffered conditions induce diffusion-limited currents for hydrogen evolution, followed by a reaction with water molecules to generate hydrogen at elevated potentials. The observed constant current behaviors at near neutral pH reflect the intrinsic electrocatalytic reactivity of the metal electrodes for water reduction. This journal is © the Owner Societies.

  18. A Novel Accessory Molecule Trim59 Involved in Cytotoxicity of BCG-Activated Macrophages

    OpenAIRE

    Zhao, Xiangfeng; Liu, Qihui; Du, Baiqiu; Li, Peng; Cui, Qu; Han, Xiao; Du, Bairong; Yan, Dongmei; Zhu, Xun

    2012-01-01

    BCG-activated macrophages (BAM) could kill the tumor cells through cell-cell contact. In this process membrane proteins play an important role. However, up to date, few membrane proteins were revealed. In this study, we selected a surface molecule named Trim59, which was specifically expressed on BAM membrane (compared with the negative control). We cloned and prokaryoticly expressed the extracellular domain of Trim59, purified the recombinant protein and generated polyclonal antibodies. Immu...

  19. Tsunamigenic potential of Mediterranean fault systems and active subduction zones

    Science.gov (United States)

    Petricca, Patrizio; Babeyko, Andrey

    2016-04-01

    Since the North East Atlantic and Mediterranean Tsunami Warning System (NEAMTWS) is under development by the European scientific community, it becomes necessary to define guidelines for the characterization of the numerous parameters must be taken into account in a fair assessment of the risk. Definition of possible tectonic sources and evaluation of their potential is one of the principal issues. In this study we systematically evaluate tsunamigenic potential of up-to-now known real fault systems and active subduction interfaces in the NEAMTWS region. The task is accomplished by means of numerical modeling of tsunami generation and propagation. We have simulated all possible uniform-slip ruptures populating fault and subduction interfaces with magnitudes ranging from 6.5 up to expected Mmax. A total of 15810 individual ruptures were processed. For each rupture, a tsunami propagation scenario was computed in linear shallow-water approximation on 1-arc minute bathymetric grid (Gebco_08) implying normal reflection boundary conditions. Maximum wave heights at coastal positions (totally - 23236 points of interest) were recorded for four hours of simulation and then classified according to currently adopted warning level thresholds. The resulting dataset allowed us to classify the sources in terms of their tsunamigenic potential as well as to estimate their minimum tsunamigenic magnitude. Our analysis shows that almost every source in the Mediterranean Sea is capable to produce local tsunami at the advisory level (i.e., wave height > 20 cm) starting from magnitude values of Mw=6.6. In respect to the watch level (wave height > 50 cm), the picture is less homogeneous: crustal sources in south-west Mediterranean as well as East-Hellenic arc need larger magnitudes (around Mw=7.0) to trigger watch levels even at the nearby coasts. In the context of the regional warning (i.e., source-to-coast distance > 100 km) faults also behave more heterogeneously in respect to the minimum

  20. Chemical activation of molecules by metals: Experimental studies of electron distributions and bonding

    International Nuclear Information System (INIS)

    This quarter has witnessed further progress both in our experimental methods of photoelectron spectroscopy and in our understanding the fundamental relationships between ionization energies and the chemistry of transition metal species. Progress continues on the new gas phase photoelectron spectrometer that combine improved capabilities for HeI/HeII UPS, XPS, and Auger investigations of organometallic molecules. Several measurements have been accomplished this year that were not possible previously. We have published the formal relationship between measured molecular ionization energies and thermodynamic bond dissociation energies, and applied the relationships to homonuclear and heteronuclear diatomic molecules, multiple bonds, and metal-ligand bonds. Studies of C-H bond activation have continued with examination of different degrees of Si-H bond addition to metals. the electronic effects of intermolecular interactions have been observed by comparing the ionizations of metal complexes in the gas phase with the ionizations of monolayer solid organometallic films prepared in ultra-high vacuum. The orientations of the molecules have been determined by scanning tunneling microscopy. Especially interesting has been the recent application of these techniques to the characterization of the soccer-ball shaped C60 molecule, buckminsterfullerene. Studies of the following complexes are described : Fe, Os, Nb, Mo, Rh, Re, Al, and Mn. 19 refs

  1. Early-Late Heterobimetallic Complexes Linked by Phosphinoamide Ligands. Tuning Redox Potentials and Small Molecule Activation

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, Christine M. [Brandeis Univ., Waltham, MA (United States)

    2015-08-01

    Recent attention in the chemical community has been focused on the energy efficient and environmentally benign conversion of abundant small molecules (CO2, H2O, etc.) to useful liquid fuels. This project addresses these goals by examining fundamental aspects of catalyst design to ultimately access small molecule activation processes under mild conditions. Specifically, Thomas and coworkers have targetted heterobimetallic complexes that feature metal centers with vastly different electronic properties, dictated both by their respective positions on the periodic table and their coordination environment. Unlike homobimetallic complexes featuring identical or similar metals, the bonds between metals in early/late heterobimetallics are more polarized, with the more electron-rich late metal center donating electron density to the more electron-deficient early metal center. While metal-metal bonds pose an interesting strategy for storing redox equivalents and stabilizing reactive metal fragments, the polar character of metal-metal bonds in heterobimetallic complexes renders these molecules ideally poised to react with small molecule substrates via cleavage of energy-rich single and double bonds. In addition, metal-metal interactions have been shown to dramatically affect redox potentials and promote multielectron redox activity, suggesting that metal-metal interactions may provide a mechanism to tune redox potentials and access substrate reduction/activation at mild overpotentials. This research project has provided a better fundamental understanding of how interactions between transition metals can be used as a strategy to promote and/or control chemical transformations related to the clean production of fuels. While this project focused on the study of homogeneous systems, it is anticipated that the broad conclusions drawn from these investigations will be applicable to heterogeneous catalysis as well, particularly on heterogeneous processes that occur at interfaces in

  2. Green Oxygenation Degradation of Rhodamine B by Using Activated Molecule Oxygen

    Institute of Scientific and Technical Information of China (English)

    Ke Jian DENG; Fei HUANG; Duo Yuan WANG; Zheng He PENG; Yun Hong ZHOU

    2004-01-01

    Iron(Ⅱ) tetra-(1,4-dithin)-porphyrazine, (FePz(dtn)4) is able to activate molecule oxygen for oxygenation degradation of rhodamine B (RhB) in an extensive pH region without light excitation. Experiments indicate that the RhB can be degraded nearly 52% in alkaline aqueous solution, bubbling with dioxygen for seven hours in the presence of FePz(dtn)4 and the hydrogen peroxides as an actve intermediate were determined by DPD method. The catalyst is recyclable and the catalyst activity was maintained after l0 recycles.

  3. Microbial respiration and extracellular enzyme activity in sediments from the Gulf of Mexico hypoxic zone

    Science.gov (United States)

    This study explores the relationship between sediment chemistry (TC, TN, TP) and microbial respiration (DHA) and extracellular enzyme activity (EEA) across the Gulf of Mexico (GOM) hypoxic zone. TC, TN, and TP were all positively correlated with each other (r=0.19-0.68). DHA was ...

  4. Reduced endogenous Ca2+ buffering speeds active zone Ca2+ signaling.

    Science.gov (United States)

    Delvendahl, Igor; Jablonski, Lukasz; Baade, Carolin; Matveev, Victor; Neher, Erwin; Hallermann, Stefan

    2015-06-01

    Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (∼ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission. PMID:26015575

  5. The Legality of Foreign Military Activities in the Exclusive Economic Zone under UNCLOS

    NARCIS (Netherlands)

    Geng, Jing

    2012-01-01

    During negotiations for the United Nations Convention on the Law of the Sea (UNCLOS), military activities in another state's Exclusive Economic Zone (EEZ) were a point of contention. Currently, the issue remains controversial in state practice. UNCLOS attempts to balance the differing interests of c

  6. Intercellular Cell Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, and Regulated on Activation Normal T Cell Expressed and Secreted Are Expressed by Human Breast Carcinoma Cells and Support Eosinophil Adhesion and Activation

    OpenAIRE

    Ali, Shahina; Kaur, Jaswinder; Patel, Kamala D.

    2000-01-01

    Eosinophils are usually associated with parasitic and allergic diseases; however, eosinophilia is also observed in several types of human tumors, including breast carcinomas. In this study we examined several human breast carcinoma cell lines for adhesion molecule expression and the ability to bind and activate eosinophils. MDA-MB-435S and MDA-MB-468 cells constitutively expressed both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and this expressio...

  7. Single-molecule kinetics under force: probing protein folding and enzymatic activity with optical tweezers

    Science.gov (United States)

    Wong, Wesley

    2010-03-01

    Weak non-covalent bonds between and within single molecules govern many aspects of biological structure and function (e.g. DNA base-paring, receptor-ligand binding, protein folding, etc.) In living systems, these interactions are often subject to mechanical forces, which can greatly alter their kinetics and activity. My group develops and applies novel single-molecule manipulation techniques to explore and quantify these force-dependent kinetics. Using optical tweezers, we have quantified the force-dependent unfolding and refolding kinetics of different proteins, including the cytoskeletal protein spectrin in collaboration with E. Evans's group [1], and the A2 domain of the von Willebrand factor blood clotting protein in collaboration with T. Springer's group [2]. Furthermore, we have studied the kinetics of the ADAMTS13 enzyme acting on a single A2 domain, and have shown that physiolgical forces in the circulation can act as a cofactor for enzymatic cleavage, regulating hemostatic activity [2]. References: 1. E. Evans, K. Halvorsen, K. Kinoshita, and W.P. Wong, Handbook of Single Molecule Biophysics, P. Hinterdorfer, ed., Springer (2009). 2. X. Zhang, K. Halvorsen, C.-Z. Zhang, W.P. Wong, and T.A. Springer, Science 324 (5932), 1330-1334 (2009).

  8. Single-Molecule Imaging Reveals the Activation Dynamics of Intracellular Protein Smad3 on Cell Membrane

    Science.gov (United States)

    Li, Nan; Yang, Yong; He, Kangmin; Zhang, Fayun; Zhao, Libo; Zhou, Wei; Yuan, Jinghe; Liang, Wei; Fang, Xiaohong

    2016-09-01

    Smad3 is an intracellular protein that plays a key role in propagating transforming growth factor β (TGF-β) signals from cell membrane to nucleus. However whether the transient process of Smad3 activation occurs on cell membrane and how it is regulated remains elusive. Using advanced live-cell single-molecule fluorescence microscopy to image and track fluorescent protein-labeled Smad3, we observed and quantified, for the first time, the dynamics of individual Smad3 molecules docking to and activation on the cell membrane. It was found that Smad3 docked to cell membrane in both unstimulated and stimulated cells, but with different diffusion rates and dissociation kinetics. The change in its membrane docking dynamics can be used to study the activation of Smad3. Our results reveal that Smad3 binds with type I TGF-β receptor (TRI) even in unstimulated cells. Its activation is regulated by TRI phosphorylation but independent of receptor endocytosis. This study offers new information on TGF-β/Smad signaling, as well as a new approach to investigate the activation of intracellular signaling proteins for a better understanding of their functions in signal transduction.

  9. Ethosomes for the delivery of anti-HSV-1 molecules: preparation, characterization and in vitro activity.

    Science.gov (United States)

    Cortesi, R; Ravani, L; Zaid, A N; Menegatti, E; Romagnoli, R; Drechsler, M; Esposito, E

    2010-10-01

    This paper describes the production, characterization and in vitro activity of ethosomes containing two molecules with antiviral activity, such as acyclovir (ACY) and N1-beta-D-ribofuranosyl-pyrazole [3,4d]pyridazin-7(6p-chlorine-phenyl)-one nucleoside (N1CP). Ethosomes were prepared and morphologically characterized by Cryo-TEM. The encapsulation efficiency was 92.3 +/- 2.5% for ACY and 94.2 +/- 2.8% for N1CP. The release of the drug from vesicles, determined by a Franz cell method, indicated that both drugs were released in a controlled manner. In order to possibly guarantee the stability during long-term storage ethosome suspensions was freeze-dried. It was found that the freeze-dried ethosomes' cakes were compact, glassy characterized by low density and quick re-hydration. However, the storage time slightly influences the percentage of drug encapsulation within ethosomes showing a drug leakage after re-hydration around 10%. The antiviral activity against HSV-1 of both drugs was tested by plaque reduction assay in monolayer cultures of Vero cells. Data showed that ethosomes allowed a reduction of the ED50 of N1CP evidencing an increase of its antiviral activity. However, ACY remains more active than N1CP. No differences are appreciable between drug-containing ethosomes before and after freeze-drying. Taken together these results, ethosomal formulation could be possibly proposed as mean for topical administration of anti-herpetic molecules.

  10. Ethosomes for the delivery of anti-HSV-1 molecules: preparation, characterization and in vitro activity.

    Science.gov (United States)

    Cortesi, R; Ravani, L; Zaid, A N; Menegatti, E; Romagnoli, R; Drechsler, M; Esposito, E

    2010-10-01

    This paper describes the production, characterization and in vitro activity of ethosomes containing two molecules with antiviral activity, such as acyclovir (ACY) and N1-beta-D-ribofuranosyl-pyrazole [3,4d]pyridazin-7(6p-chlorine-phenyl)-one nucleoside (N1CP). Ethosomes were prepared and morphologically characterized by Cryo-TEM. The encapsulation efficiency was 92.3 +/- 2.5% for ACY and 94.2 +/- 2.8% for N1CP. The release of the drug from vesicles, determined by a Franz cell method, indicated that both drugs were released in a controlled manner. In order to possibly guarantee the stability during long-term storage ethosome suspensions was freeze-dried. It was found that the freeze-dried ethosomes' cakes were compact, glassy characterized by low density and quick re-hydration. However, the storage time slightly influences the percentage of drug encapsulation within ethosomes showing a drug leakage after re-hydration around 10%. The antiviral activity against HSV-1 of both drugs was tested by plaque reduction assay in monolayer cultures of Vero cells. Data showed that ethosomes allowed a reduction of the ED50 of N1CP evidencing an increase of its antiviral activity. However, ACY remains more active than N1CP. No differences are appreciable between drug-containing ethosomes before and after freeze-drying. Taken together these results, ethosomal formulation could be possibly proposed as mean for topical administration of anti-herpetic molecules. PMID:21105576

  11. Theoretical investigation of the degradation mechanisms in host and guest molecules used in OLED active layers

    KAUST Repository

    Winget, Paul

    2014-10-08

    A feature of OLEDs that has to date received little attention is the prediction of the stability of the molecules involved in the electrical and optical processes. Here, we present computational results intended to aid in the development of stable systems. We identify degradation pathways and define new strategies to guide the synthesis of stable materials for OLED applications for both phosphorescent emitters and organic host materials. The chemical reactivity of these molecules in the active layers of the devices is further complicated by the fact that, during operation, they can be either oxidized or reduced (as they localize a hole or an electron) in addition to forming both singlet and triplet excitons. © (2014) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

  12. Bruchpilot and Synaptotagmin collaborate to drive rapid glutamate release and active zone differentiation

    Directory of Open Access Journals (Sweden)

    Mila M Paul

    2015-02-01

    Full Text Available The active zone (AZ protein Bruchpilot (Brp is essential for rapid glutamate release at Drosophila melanogaster neuromuscular junctions (NMJs. Quantal time course and measurements of action potential-waveform suggest that presynaptic fusion mechanisms are altered in brp null mutants (brp69. This could account for their increased evoked excitatory postsynaptic current (EPSC delay and rise time (by about one millisecond. To test the mechanism of release protraction at brp69 AZs, we performed knock-down of Synaptotagmin-1 (Syt via RNAi (sytKD in wildtype (wt, brp69 and rab3 null mutants (rab3rup, where Brp is concentrated at a small number of AZs. At wt and rab3rup synapses, sytKD lowered EPSC amplitude while increasing rise time and delay, consistent with the role of Syt as a release sensor. In contrast, sytKD did not alter EPSC amplitude at brp69 synapses, but shortened delay and rise time. In fact, following sytKD, these kinetic properties were strikingly similar in wt and brp69, which supports the notion that Syt protracts release at brp69 synapses. To gain insight into this surprising role of Syt at brp69 AZs, we analyzed the structural and functional differentiation of synaptic boutons at the NMJ. At ’tonic’ type Ib motor neurons, distal boutons contain more AZs, more Brp proteins per AZ and show elevated and accelerated glutamate release compared to proximal boutons. The functional differentiation between proximal and distal boutons is Brp-dependent and reduced after sytKD. Notably, sytKD boutons are smaller, contain fewer Brp positive AZs and these are of similar number in proximal and distal boutons. In addition, super-resolution imaging via dSTORM revealed that sytKD increases the number and alters the spatial distribution of Brp molecules at AZs, while the gradient of Brp proteins per AZ is diminished. In summary, these data demonstrate that normal structural and functional differentiation of Drosophila AZs requires concerted action

  13. Stellar Activity Masquerading as Planets in the Habitable Zone of the M dwarf Gliese 581

    CERN Document Server

    Robertson, Paul; Endl, Michael; Roy, Arpita

    2014-01-01

    The M dwarf Gliese 581 is believed to host four planets, including one (GJ 581d) near the habitable zone that could possibly support liquid water on its surface if it is a rocky planet. The detection of another habitable-zone planet--GJ 581g--is disputed, as its significance depends on the eccentricity assumed for d. Analyzing stellar activity using the H-alpha line, we measure a stellar rotation period of 130+/-2 days and a correlation for H-alpha modulation with radial velocity. Correcting for activity greatly diminishes the signal of GJ 581d (to 1.5 sigma), while significantly boosting the signals of the other known super-Earth planets. GJ 581d does not exist, but is an artifact of stellar activity which, when incompletely corrected, causes the false detection of planet g.

  14. Influence of the water molecules near surface of viral protein on virus activation process

    Energy Technology Data Exchange (ETDEWEB)

    O, Shepelenko S; S, Salnikov A; V, Rak S; P, Goncharova E; B, Ryzhikov A, E-mail: shep@vector.nsc.r, E-mail: shep@ngs.r [Federal State Research Institution State Research Center of Virology and Biotechnology VECTOR of the Federal Service for Surveillance in Consumer Rights Protection and Human Well-being (FSRI SRC VB VECTOR) Koltsovo, Novosibirsk Region (Russian Federation)

    2009-06-01

    The infection of a cell with influenza virus comprises the stages of receptor binding to the cell membrane, endocytosis of virus particle, and fusion of the virus envelope and cell endosome membrane, which is determined by the conformational changes in hemagglutinin, a virus envelope protein, caused by pH decrease within the endosome. The pH value that induces conformation rearrangements of hemagglutinin molecule considerably varies for different influenza virus strains, first and foremost, due to the differences in amino acid structure of the corresponding proteins. The main goal of this study was to construct a model making it possible to assess the critical pH value characterizing the fusogenic activity of influenza virus hemagglutinin from the data on hemagglutinin structure and experimental verification of this model. Under this model, we assume that when the electrostatic force between interacting hemagglutinin molecules in the virus envelop exceeds a certain value, the hemagglutinin HA1 subunits are arranged so that they form a cavity sufficient for penetration of water molecules. This event leads to an irreversible hydration of the inner fragments of hemagglutinin molecule in a trimer and to the completion of conformational changes. The geometry of electrostatic field in hemagglutinin trimer was calculated taking into account the polarization effects near the interface of two dielectrics, aqueous medium and protein macromolecule. The critical pH values for the conformational changes in hemagglutinin were measured by the erythrocyte hemolysis induced by influenza virus particles when decreasing pH. The critical pH value conditionally separating the pH range into the regions with and without the conformational changes was calculated for several influenza virus H1N1 and H3N2 strains based on the data on the amino acid structure of the corresponding hemagglutinin molecules. Comparison of the theoretical and experimental values of critical pH values for

  15. High Throughput Extraction of Plant, Marine and Fungal Specimens for Preservation of Biologically Active Molecules

    Directory of Open Access Journals (Sweden)

    Thomas G. McCloud

    2010-06-01

    Full Text Available The Developmental Therapeutics Program (DTP of the U.S. National Cancer Institute (NCI, at its NCI-Frederick facility, has built perhaps the largest and most diverse natural products screening library in the world for drug discovery. Composed of plant, marine organism and microbial extracts, it currently contains in excess of 230,000 unique materials. From the inception of this program to identify new anticancer chemotherapeutics from natural products sources in 1987, two extracts have been sequentially prepared from each specimen: one produced by organic solvent extraction, which yields a complex material that contains non- to moderately polar small molecules, and a water-soluble extract, a milieu largely unexplored for useful drugs in earlier years, which contains polar small to medium-sized molecules. Plant specimens and microbial ferments are extracted by modified traditional methods, while the method developed to produce extracts from marine organisms is unique and very different from that used by marine natural products chemists previously, but again yields both an organic solvent soluble and a water soluble material for inclusion into the screening library. Details of high throughput extract production for preservation of biologically active molecules are presented.

  16. In vitro and in vivo activity of a novel antifungal small molecule against Candida infections.

    Directory of Open Access Journals (Sweden)

    Sarah Sze Wah Wong

    Full Text Available Candida is the most common fungal pathogen of humans worldwide and has become a major clinical problem because of the growing number of immunocompromised patients, who are susceptible to infection. Moreover, the number of available antifungals is limited, and antifungal-resistant Candida strains are emerging. New and effective antifungals are therefore urgently needed. Here, we discovered a small molecule with activity against Candida spp. both in vitro and in vivo. We screened a library of 50,240 small molecules for inhibitors of yeast-to-hypha transition, a major virulence attribute of Candida albicans. This screening identified 20 active compounds. Further examination of the in vitro antifungal and anti-biofilm properties of these compounds, using a range of Candida spp., led to the discovery of SM21, a highly potent antifungal molecule (minimum inhibitory concentration (MIC 0.2-1.6 µg/ml. In vitro, SM21 was toxic to fungi but not to various human cell lines or bacterial species and was active against Candida isolates that are resistant to existing antifungal agents. Moreover, SM21 was relatively more effective against biofilms of Candida spp. than the current antifungal agents. In vivo, SM21 prevented the death of mice in a systemic candidiasis model and was also more effective than the common antifungal nystatin at reducing the extent of tongue lesions in a mouse model of oral candidiasis. Propidium iodide uptake assay showed that SM21 affected the integrity of the cell membrane. Taken together, our results indicate that SM21 has the potential to be developed as a novel antifungal agent for clinical use.

  17. In vitro and in vivo activity of a novel antifungal small molecule against Candida infections.

    Science.gov (United States)

    Wong, Sarah Sze Wah; Kao, Richard Yi Tsun; Yuen, Kwok Yong; Wang, Yu; Yang, Dan; Samaranayake, Lakshman Perera; Seneviratne, Chaminda Jayampath

    2014-01-01

    Candida is the most common fungal pathogen of humans worldwide and has become a major clinical problem because of the growing number of immunocompromised patients, who are susceptible to infection. Moreover, the number of available antifungals is limited, and antifungal-resistant Candida strains are emerging. New and effective antifungals are therefore urgently needed. Here, we discovered a small molecule with activity against Candida spp. both in vitro and in vivo. We screened a library of 50,240 small molecules for inhibitors of yeast-to-hypha transition, a major virulence attribute of Candida albicans. This screening identified 20 active compounds. Further examination of the in vitro antifungal and anti-biofilm properties of these compounds, using a range of Candida spp., led to the discovery of SM21, a highly potent antifungal molecule (minimum inhibitory concentration (MIC) 0.2-1.6 µg/ml). In vitro, SM21 was toxic to fungi but not to various human cell lines or bacterial species and was active against Candida isolates that are resistant to existing antifungal agents. Moreover, SM21 was relatively more effective against biofilms of Candida spp. than the current antifungal agents. In vivo, SM21 prevented the death of mice in a systemic candidiasis model and was also more effective than the common antifungal nystatin at reducing the extent of tongue lesions in a mouse model of oral candidiasis. Propidium iodide uptake assay showed that SM21 affected the integrity of the cell membrane. Taken together, our results indicate that SM21 has the potential to be developed as a novel antifungal agent for clinical use. PMID:24465737

  18. Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening.

    Directory of Open Access Journals (Sweden)

    Christelle Cabrol

    Full Text Available BACKGROUND: Hypocatabolism of the amyloid beta-protein (Abeta by insulin-degrading enzyme (IDE is implicated in the pathogenesis of Alzheimer disease (AD, making pharmacological activation of IDE an attractive therapeutic strategy. However, it has not been established whether the proteolytic activity of IDE can be enhanced by drug-like compounds. METHODOLOGY/PRINCIPAL FINDINGS: Based on the finding that ATP and other nucleotide polyphosphates modulate IDE activity at physiological concentrations, we conducted parallel high-throughput screening campaigns in the absence or presence of ATP and identified two compounds--designated Ia1 and Ia2--that significantly stimulate IDE proteolytic activity. Both compounds were found to interfere with the crosslinking of a photoaffinity ATP analogue to IDE, suggesting that they interact with a bona fide ATP-binding domain within IDE. Unexpectedly, we observed highly synergistic activation effects when the activity of Ia1 or Ia2 was tested in the presence of ATP, a finding that has implications for the mechanisms underlying ATP-mediated activation of IDE. Notably, Ia1 and Ia2 activated the degradation of Abeta by approximately 700% and approximately 400%, respectively, albeit only when Abeta was presented in a mixture also containing shorter substrates. CONCLUSIONS/SIGNIFICANCE: This study describes the first examples of synthetic small-molecule activators of IDE, showing that pharmacological activation of this important protease with drug-like compounds is achievable. These novel activators help to establish the putative ATP-binding domain as a key modulator of IDE proteolytic activity and offer new insights into the modulatory action of ATP. Several larger lessons abstracted from this screen will help inform the design of future screening campaigns and facilitate the eventual development of IDE activators with therapeutic utility.

  19. 34 CFR 299.3 - What priority may the Secretary establish for activities in an Empowerment Zone or Enterprise...

    Science.gov (United States)

    2010-07-01

    ... activities in an Empowerment Zone or Enterprise Community? For any ESEA discretionary grant program, the Secretary may establish a priority, as authorized by 34 CFR 75.105(b), for projects that will— (a) Use a... activities in an Empowerment Zone or Enterprise Community? 299.3 Section 299.3 Education Regulations of...

  20. Affinity of Drugs and Small Biologically Active Molecules to Carbon Nanotubes: A Pharmacodynamics and Nanotoxicity Factor?

    OpenAIRE

    Liu, John; Yang, Liu; Hopfinger, Anton J.

    2009-01-01

    The MM-PBSA MD method was used to estimate the affinity, as represented by log kb, of each of a variety of biologically active molecules to a carbon nanotube in an aqueous environment. These ligand-receptor binding simulations were calibrated by first estimating the log kb values for eight ligands to human serum albumin, HSA, whose log kb values have been observed. A validation linear correlation equation was established [R2 = 0.888 Q2 = 0.603] between the observed and estimated log kb values...

  1. Benzimidazole-1,2,3-triazole Hybrid Molecules: Synthesis and Evaluation for Antibacterial/Antifungal Activity

    OpenAIRE

    Ouahrouch, Abdelaaziz; Ighachane, Hana; Taourirte, Moha; Joachim W. Engels; Sedra, My Hassan; Lazrek, Hassan B.

    2014-01-01

    A novel series of hybrid molecules 4a–i and 5a–i were prepared by condensation of 4-(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines. These in turn were reacted with 2-(azidomethoxy)ethyl acetate in a Cu alkyne–azide cycloaddition (CuAAC) to generate the 1,2,3-triazole pharmacophore under microwave assistance. The newly synthesized compounds were examined for their in vitro antimicrobial activities against Gram-positive and Gram-negative bacteria and the phytopathoge...

  2. Structure Based Discovery of Small Molecules to Regulate the Activity of Human Insulin Degrading Enzyme

    OpenAIRE

    Bilal Çakir; Onur Dağliyan; Ezgi Dağyildiz; İbrahim Bariş; Ibrahim Halil Kavakli; Seda Kizilel; Metin Türkay

    2012-01-01

    Structure Based Discovery of Small Molecules to Regulate the Activity of Human Insulin Degrading Enzyme Bilal C¸ akir1, Onur Dag˘ liyan1, Ezgi Dag˘ yildiz1, I˙brahim Baris¸1, Ibrahim Halil Kavakli1,2*, Seda Kizilel1*, Metin Tu¨ rkay3* 1 Department of Chemical and Biological Engineering, Koc¸ University, Sariyer, Istanbul, Turkey, 2 Department of Molecular Biology and Genetics, Koc¸ University, Sariyer, Istanbul, Turkey, 3 Department of Industrial Engineering, Koc¸ University...

  3. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo

    Directory of Open Access Journals (Sweden)

    Lavu Siva

    2009-03-01

    Full Text Available Abstract Background Calorie restriction (CR produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM on gene expression data to elucidate downstream effects of SIRT1 activation. Results Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet. Conclusion CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.

  4. Mechanically activated switching of Si-based single-molecule junction as imaged with three-dimensional dynamic probe

    Science.gov (United States)

    Nakamura, Miki; Yoshida, Shoji; Katayama, Tomoki; Taninaka, Atsushi; Mera, Yutaka; Okada, Susumu; Takeuchi, Osamu; Shigekawa, Hidemi

    2015-10-01

    Understanding and extracting the full functions of single-molecule characteristics are key factors in the development of future device technologies, as well as in basic research on molecular electronics. Here we report a new methodology for realizing a three-dimensional (3D) dynamic probe of single-molecule conductance, which enables the elaborate 3D analysis of the conformational effect on molecular electronics, by the formation of a Si/single molecule/Si structure using scanning tunnelling microscopy (STM). The formation of robust covalent bonds between a molecule and Si electrodes, together with STM-related techniques, enables the stable and repeated control of the conformational modulation of the molecule. By 3D imaging of the conformational effect on a 1,4-diethynylbenzene molecule, a binary change in conductance with hysteresis is observed for the first time, which is considered to originate from a mechanically activated conformational change.

  5. Influence of platelet activating factor on expression of adhesion molecules in experimental pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Hua Zhao; Ji-Wei Chen; Ya-Kui Zhou; Xue-Feng Zhou; Pei-Yun Li

    2003-01-01

    AIM: To determine whether Platelet activating factor (PAF)has a regulation role in the expression of adhesion moleculesand accumulation of neutrophils in a murine model of acutepancreatitis.METHODS: One hundred twenty-eight Kunming mice weredivided into four groups. Group 1 received 0.1 mi saline s.c.every hour for three hours (sham). Group 2 received cerulein(50 μg/kg dose s.c.) every hour for three hours. Group 3received AP and additional challenge of PAF (50 rg/kg inabsolute ethanol) (AP/PAF). Group 4 received AP, plustherapeutic treatment with GAB (25 mg dose i.p.) immediatelyafter the first challenge of cerulein (AP/GAB). Animals weresacrificed at 12 h after the first challenge of saline or cerulein.Adhesion molecules of pancreas were semi-quantified bySP methods. Standard assays were performed for serumamylase and myeloperoxidase activity (MPO) of pancreas.Histology of pancreas was scored in a blind manner. Watercontent of pancreas was also measured at the same time.RESULTS: Control pancreata showed negligible adhesionmolecule expression and neutrophil accumulation. Therewere evident adhesion molecules expression and neutrophilaccumulation in AP and AP/PAF compared with sham (P<0.05).AP/GAB had a lower level of adhesion molecules, neutrophils,and water content versus AP and AP/PAF (P<0.05). Histologyshowed a trend toward improvement in AP/GAB, but didnot reach statistical significance.CONCLUSION: PAF can induce the expression of adhesionmolecules that mediate neutrophil accumulation. The PAFantagonist reduces the expression of adhesion moleculesand the severity of inflammation when given immediatelyafter the induction of mild AP in mice. These results suggestthat PAF antagonism may be useful in the treatment of mildpancreatitis after its clinical onset.

  6. Traumatic Brain Injury Activation of the Adult Subventricular Zone Neurogenic Niche

    Science.gov (United States)

    Chang, Eun Hyuk; Adorjan, Istvan; Mundim, Mayara V.; Sun, Bin; Dizon, Maria L. V.; Szele, Francis G.

    2016-01-01

    Traumatic brain injury (TBI) is common in both civilian and military life, placing a large burden on survivors and society. However, with the recognition of neural stem cells in adult mammals, including humans, came the possibility to harness these cells for repair of damaged brain, whereas previously this was thought to be impossible. In this review, we focus on the rodent adult subventricular zone (SVZ), an important neurogenic niche within the mature brain in which neural stem cells continue to reside. We review how the SVZ is perturbed following various animal TBI models with regards to cell proliferation, emigration, survival, and differentiation, and we review specific molecules involved in these processes. Together, this information suggests next steps in attempting to translate knowledge from TBI animal models into human therapies for TBI. PMID:27531972

  7. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.

    Science.gov (United States)

    Flores, Alyssa M; Casey, Scott D; Felix, Christian M; Phuan, Puay W; Verkman, A S; Levin, Marc H

    2016-05-01

    Dry eye disorders, including Sjögren's syndrome, constitute a common problem in the aging population, with limited effective therapeutic options available. The cAMP-activated Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR) is a major prosecretory channel at the ocular surface. We investigated whether compounds that target CFTR can correct the abnormal tear film in dry eye. Small-molecule activators of human wild-type CFTR identified by high-throughput screening were evaluated in cell culture and in vivo assays, to select compounds that stimulate Cl(-)-driven fluid secretion across the ocular surface in mice. An aminophenyl-1,3,5-triazine, CFTRact-K089, fully activated CFTR in cell cultures with EC50 ∼250 nM and produced an ∼8.5 mV hyperpolarization in ocular surface potential difference. When delivered topically, CFTRact-K089 doubled basal tear volume for 4 h and had no effect in CF mice. CFTRact-K089 showed sustained tear film bioavailability without detectable systemic absorption. In a mouse model of aqueous-deficient dry eye produced by lacrimal ablation, topical administration of 0.1 nmol CFTRact-K089 3 times daily restored tear volume to basal levels, preventing corneal epithelial disruption when initiated at the time of surgery and reversing it when started after development of dry eye. Our results support the potential utility of CFTR-targeted activators as a novel prosecretory treatment for dry eye.-Flores, A. M., Casey, S. D., Felix, C. M., Phuan, P. W., Verkman, A. S., Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.

  8. Incorporation and characterization of biological molecules in droplet-interface bilayer networks for novel active systems

    Science.gov (United States)

    Sarles, Stephen A.; Ghanbari Bavarsad, Pegah; Leo, Donald J.

    2009-03-01

    Biological molecules including phospholipids and proteins offer scientists and engineers a diverse selection of materials to develop new types of active materials and smart systems based on ion conduction. The inherent energy-coupling abilities of these components create novel kinds of transduction elements. Networks formed from droplet-interface bilayers (DIB) are a promising construct for creating cell mimics that allow for the assembly and study of these active biological molecules. The current-voltage relationship of symmetric, "lipid-in" dropletinterface bilayers are characterized using electrical impedance spectroscopy (EIS) and cyclic voltammetry (CV). "Lipid-in" diphytanoyl phosphatidylcholine (DPhPC) droplet-interface bilayers have specific resistances of nearly 10MΩ•cm2 and rupture at applied potentials greater than 300mV, indicating the "lipid-in" approach produces higher quality interfacial membranes than created using the original "lipid-out" method. The incorporation of phospholipids into the droplet interior allows for faster monolayer formation but does not inhibit the selfinsertion of transmembrane proteins into bilayer interfaces that separate adjacent droplets. Alamethicin proteins inserted into single and multi-DIB networks produce a voltage-dependent membrane conductance and current measurements on bilayers containing this type of protein exhibit a reversible, 3-4 order-of-magnitude conductance increase upon application of voltage.

  9. Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery

    DEFF Research Database (Denmark)

    Toft, P; Christiansen, K; Tønnesen, Else Kirstine;

    1997-01-01

    Following cardiac surgery with cardiopulmonary bypass (CPB), activated granulocytes may be involved with ischaemia/ reperfusion injury. The purpose of this study was to investigate whether steroids could reduce the oxidative burst activity of granulocytes, the expression of adhesion molecules...... cytometrically using 123-dihydrorhodamine. A panel of adhesion molecules was measured using monoclonal antibodies. Following CPB the oxidative burst activity and the expression of the adhesion molecule L-selectin more than doubled compared to initial values. There was no difference between the steroid group...... and the control group regarding the expression of adhesion molecules or the oxidative burst activity. In the steroid group the fluid gain during extracorporeal circulation (ECC) was 683 ml (median) compared to 1488 ml in the control group. Steroids prevented hyperthermia in the postoperative period but did...

  10. ABOUT THE WAVE MECHANISM OF ACTIVATION OF FAULTS IN SEISMIC ZONES OF THE LITHOSPHERE IN MONGOLIA

    Directory of Open Access Journals (Sweden)

    M. G. Mel’nikov

    2015-09-01

    Full Text Available The study is focused on earthquake migrations along active faults in seismic zones of Mongolia. The earthquake migrations are interpreted as a result of the influence of deformational waves. Vector velocities and other parameters of the deformational waves are studied. Based on data from largescale maps, local faults are compared, and differences and similarities of parameters of waves related to faults of different ranks are described.

  11. Discovery of novel small molecule activators of β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Folkert Verkaar

    Full Text Available Wnt/β-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/β-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed bona fide activators of β-catenin signaling. The compounds stabilized cytoplasmic β-catenin and activated β-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate β-catenin signaling has yet to be determined, several key regulators of Wnt/β-catenin signaling, including glycogen synthase kinase 3 and Frizzled receptors, were excluded as the molecular target. The compounds displayed remarkable selectivity, as they only induced β-catenin signaling in a human osteosarcoma U2OS cell line and not in a variety of other cell lines examined. Our data indicate that differences in cellular Wnt/β-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/β-catenin signaling.

  12. Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya, E-mail: jyli@mail.shcnc.ac.cn; Nan, Fa-Jun, E-mail: fjnan@mail.shcnc.ac.cn; Li, Jia, E-mail: jli@mail.shcnc.ac.cn

    2013-12-01

    AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome.

  13. Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

    International Nuclear Information System (INIS)

    AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome

  14. VAMP4 Is an Essential Cargo Molecule for Activity-Dependent Bulk Endocytosis.

    Science.gov (United States)

    Nicholson-Fish, Jessica C; Kokotos, Alexandros C; Gillingwater, Thomas H; Smillie, Karen J; Cousin, Michael A

    2015-12-01

    The accurate formation of synaptic vesicles (SVs) and incorporation of their protein cargo during endocytosis is critical for the maintenance of neurotransmission. During intense neuronal activity, a transient and acute accumulation of SV cargo occurs at the plasma membrane. Activity-dependent bulk endocytosis (ADBE) is the dominant SV endocytosis mode under these conditions; however, it is currently unknown how ADBE mediates cargo retrieval. We examined the retrieval of different SV cargo molecules during intense stimulation using a series of genetically encoded pH-sensitive reporters in neuronal cultures. The retrieval of only one reporter, VAMP4-pHluorin, was perturbed by inhibiting ADBE. This selective recovery was confirmed by the enrichment of endogenous VAMP4 in purified bulk endosomes formed by ADBE. VAMP4 was also essential for ADBE, with a cytoplasmic di-leucine motif being critical for this role. Therefore, VAMP4 is the first identified ADBE cargo and is essential for this endocytosis mode to proceed.

  15. Small Molecule-Induced Allosteric Activation of the Vibrio Cholerae RTX Cysteine Protease Domain

    Energy Technology Data Exchange (ETDEWEB)

    Lupardus, P.J.; Shen, A.; Bogyo, M.; Garcia, K.C.

    2009-05-19

    Vibrio cholerae RTX (repeats in toxin) is an actin-disrupting toxin that is autoprocessed by an internal cysteine protease domain (CPD). The RTX CPD is efficiently activated by the eukaryote-specific small molecule inositol hexakisphosphate (InsP{sub 6}), and we present the 2.1 angstrom structure of the RTX CPD in complex with InsP{sub 6}. InsP{sub 6} binds to a conserved basic cleft that is distant from the protease active site. Biochemical and kinetic analyses of CPD mutants indicate that InsP{sub 6} binding induces an allosteric switch that leads to the autoprocessing and intracellular release of toxin-effector domains.

  16. Neutron-activation analysis for investigation of biochemical manganese in soils cotton soweol zone of Uzbekistan

    International Nuclear Information System (INIS)

    Full text: For many years we neutron activation analysis of soils sampled from different areas of landscape-geochemical regions of Uzbekistan including zone of extreme ecological catastrophe of Aral. Content of manganese and some other elements in the 'soil-cotton' system was investigated. Neutron-activation method of manganese determining with productivity up to 400 samples on shift with detection limit of 1,1 10-5 % and discrepancies not more than 10%. Was developed extremely uniform distribution of manganese in cotton sowed soils of the Republic (340-1800mg/kg) is determined. Practically all soils of cotton-sowed zone of Republic are with lack of manganese. Distribution of manganese on soil profile of separate organs of cotton (leaves seeds etc.) was studied. Correlation between gross concentration of manganese and its active part extracted by distilled water on the basis of quantity analysis was found. Successive comparison of gross content of manganese in the soil with crop capacity of cotton in different zones of Republic made it possible to find interconnection between these quantities, which proves necessity of using micro-additions of manganese in the soils where its low concentration is detected

  17. Novel small-molecule AMP-activated protein kinase allosteric activator with beneficial effects in db/db mice.

    Directory of Open Access Journals (Sweden)

    Li-Na Zhang

    Full Text Available AMP-activated protein kinase (AMPK is an energy sensor of metabolism that is an attractive therapeutic target for type 2 diabetes mellitus and metabolic syndrome. Using a homogeneous scintillation proximity assay (SPA, we identified a new small-molecule AMPK activator, ZLN024, which allosterically stimulated active AMPK heterotrimers and the inactive α1 subunit truncations α1 (1-394 and α1 (1-335 but not α1 (1-312. AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2Cα. ZLN024 activated AMPK in L6 myotubes and stimulated glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. ZLN024 also activated AMPK in primary hepatocytes, decreased fatty acid synthesis and glucose output. Treatment of db/db mice with 15 mg/kg/day ZLN024 improved glucose tolerance; liver tissue weight, triacylglycerol and the total cholesterol content were decreased. The hepatic transcriptional level of G6Pase, FAS and mtGPAT were reduced. The transcription of genes involved in fatty acid oxidation and the mitochondrial biogenesis of muscle tissue were elevated. The ACC phosphorylation was increased in muscle and liver. This study provides a novel allosteric AMPK activator for functional study in vitro and in vivo and demonstrates that AMPK allosteric activators could be a promising therapeutic approach for type 2 diabetes mellitus and metabolic syndrome.

  18. A Model of Ischemia-Induced Neuroblast Activation in the Adult Subventricular Zone

    Science.gov (United States)

    Vergni, Davide; Castiglione, Filippo; Briani, Maya; Middei, Silvia; Alberdi, Elena; Reymann, Klaus G.; Natalini, Roberto; Volonté, Cinzia; Matute, Carlos; Cavaliere, Fabio

    2009-01-01

    We have developed a rat brain organotypic culture model, in which tissue slices contain cortex-subventricular zone-striatum regions, to model neuroblast activity in response to in vitro ischemia. Neuroblast activation has been described in terms of two main parameters, proliferation and migration from the subventricular zone into the injured cortex. We observed distinct phases of neuroblast activation as is known to occur after in vivo ischemia. Thus, immediately after oxygen/glucose deprivation (6–24 hours), neuroblasts reduce their proliferative and migratory activity, whereas, at longer time points after the insult (2 to 5 days), they start to proliferate and migrate into the damaged cortex. Antagonism of ionotropic receptors for extracellular ATP during and after the insult unmasks an early activation of neuroblasts in the subventricular zone, which responded with a rapid and intense migration of neuroblasts into the damaged cortex (within 24 hours). The process is further enhanced by elevating the production of the chemoattractant SDf-1α and may also be boosted by blocking the activation of microglia. This organotypic model which we have developed is an excellent in vitro system to study neurogenesis after ischemia and other neurodegenerative diseases. Its application has revealed a SOS response to oxygen/glucose deprivation, which is inhibited by unfavorable conditions due to the ischemic environment. Finally, experimental quantifications have allowed us to elaborate a mathematical model to describe neuroblast activation and to develop a computer simulation which should have promising applications for the screening of drug candidates for novel therapies of ischemia-related pathologies. PMID:19390597

  19. A model of ischemia-induced neuroblast activation in the adult subventricular zone.

    Directory of Open Access Journals (Sweden)

    Davide Vergni

    Full Text Available We have developed a rat brain organotypic culture model, in which tissue slices contain cortex-subventricular zone-striatum regions, to model neuroblast activity in response to in vitro ischemia. Neuroblast activation has been described in terms of two main parameters, proliferation and migration from the subventricular zone into the injured cortex. We observed distinct phases of neuroblast activation as is known to occur after in vivo ischemia. Thus, immediately after oxygen/glucose deprivation (6-24 hours, neuroblasts reduce their proliferative and migratory activity, whereas, at longer time points after the insult (2 to 5 days, they start to proliferate and migrate into the damaged cortex. Antagonism of ionotropic receptors for extracellular ATP during and after the insult unmasks an early activation of neuroblasts in the subventricular zone, which responded with a rapid and intense migration of neuroblasts into the damaged cortex (within 24 hours. The process is further enhanced by elevating the production of the chemoattractant SDf-1alpha and may also be boosted by blocking the activation of microglia. This organotypic model which we have developed is an excellent in vitro system to study neurogenesis after ischemia and other neurodegenerative diseases. Its application has revealed a SOS response to oxygen/glucose deprivation, which is inhibited by unfavorable conditions due to the ischemic environment. Finally, experimental quantifications have allowed us to elaborate a mathematical model to describe neuroblast activation and to develop a computer simulation which should have promising applications for the screening of drug candidates for novel therapies of ischemia-related pathologies.

  20. Chemical derivatives of a small molecule deubiquitinase inhibitor have antiviral activity against several RNA viruses.

    Directory of Open Access Journals (Sweden)

    Marta J Gonzalez-Hernandez

    Full Text Available Most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. The small molecule WP1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of WP1130 to identify compounds that retained the broad-spectrum antiviral activity of the parent compound in vitro but exhibited improved drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than WP1130 (1.9 to 2.6 log scale. Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus RNA. No significant cytotoxicity was observed at the working concentration of 5 µM for all compounds tested. In addition, the WP1130 derivatives maintained their broad-spectrum antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of WP1130 can maintain effective broad-spectrum antiviral activity while increasing aqueous solubility.

  1. ACTIVITY AND Vp/Vs RATIO OF VOLCANO-TECTONIC SEISMIC SWARM ZONES AT NEVADO DEL RUIZ VOLCANO, COLOMBIA

    Directory of Open Access Journals (Sweden)

    Londoño B. John Makario

    2010-06-01

    Full Text Available An analysis of the seismic activity for volcano-tectonic earthquake (VT swarms zones at Nevado del Ruiz Volcano (NRV was carried out for the interval 1985- 2002, which is the most seismic active period at NRV until now (2010. The swarm-like seismicity of NRV was frequently concentrated in very well defined clusters around the volcano. The seismic swarm zone located at the active crater was the most active during the entire time. The seismic swarm zone located to the west of the volcano suggested some relationship with the volcanic crises. It was active before and after the two eruptions occurred in November 1985 and September 1989. It is believed that this seismic activity may be used as a monitoring tool of volcanic activity. For each seismic swarm zone the Vp/Vs ratio was also calculated by grouping of earthquakes and stations. It was found that each seismic swarm zone had a distinct Vp/Vs ratio with respect to the others, except for the crater and west swarm zones, which had the same value. The average Vp/Vs ratios for the seismic swarm zones located at the active crater and to the west of the volcano are about 6-7% lower than that for the north swarm zone, and about 3% lower than that for the south swarm zone. We suggest that the reduction of the Vp/Vs ratio is due to degassing phenomena inside the central and western earthquake swarm zones, or due to the presence of microcracks inside the volcano. This supposition is in agreement with other studies of geophysics, geochemistry and drilling surveys carried out at NRV.

  2. Micro 3D ERT tomography for data assimilation modelling of active root zone

    Science.gov (United States)

    Vanella, Daniela; Busato, Laura; Boaga, Jacopo; Cassiani, Giorgio; Binley, Andrew; Putti, Mario; Consoli, Simona

    2016-04-01

    Within the soil-plant-atmosphere system, root activity plays a fundamental role, as it connects different domains and allows a large part of the water and nutrient exchanges necessary for plant sustenance. The understanding of these processes is not only useful from an environmental point of view, making a fundamental contribution to the understanding of the critical zone dynamics, but also plays a pivotal role in precision agriculture, where the optimisation of water resources exploitation is mandatory and often carried out through deficit irrigation techniques. In this work, we present the results of non-invasive monitoring of the active root zone of two orange trees (Citrus sinensis, cv Tarocco Ippolito) located in an orange orchard in eastern Sicily (Italy) and drip irrigated with two different techniques: partial root drying and 100% crop evapotranspiration. The main goal of the monitoring activity is to assess possible differences between the developed root systems and the root water uptake between the two irrigation strategies. The monitoring is conducted using 3D micro-electrical resistivity tomography (ERT) based on an apparatus composed of a number of micro-boreholes (about 1.2 m deep) housing 12 electrodes each, plus a number of surface electrodes. Time-lapse measurements conducted both with long-term periodicity and short-term repetition before and after irrigation clearly highlight the presence and distribution of root water uptake zone both at shallow and larger depth, likely to correspond to zones utilized during the irrigation period (shallow) and during the time when the crop is not irrigated (deep). Subsidiary information is available in terms of precipitation, sap flow measurements and micrometeorological evapotranspiration estimates. This data ensemble lends itself to the assimilation into a variably saturated flow model, where both soil hydraulic parameters and root distribution shall be identified. Preliminary results in this directions show

  3. Polyphosphate, an active molecule derived from probiotic Lactobacillus brevis, improves the fibrosis in murine colitis.

    Science.gov (United States)

    Kashima, Shin; Fujiya, Mikihiro; Konishi, Hiroaki; Ueno, Nobuhiro; Inaba, Yuhei; Moriichi, Kentaro; Tanabe, Hiroki; Ikuta, Katsuya; Ohtake, Takaaki; Kohgo, Yutaka

    2015-08-01

    Inflammatory bowel disease frequently causes intestinal obstruction because of extensive fibrosis. This study investigated whether polyphosphate (poly P), an active molecule derived from Lactobacillus brevis, could improve the fibrosis in a model of chronic colitis. In this study, dextran sodium sulfate (DSS)-induced chronic colitis models and trinitrobenzene sulfonic acid (TNBS)-induced colitis models were used as models of fibrosis. To clarify the mechanism responsible for the observed effects, Caco-2/brush border epithelial (BBE) and naive T helper lymphocyte (THP)-1 cells were treated with lipopolysaccharide (LPS) to induce inflammation. Non-cancer human colon fibroblast (CCD-18) cells were treated with transforming growth factor beta 1 (TGF-β1) to induce fibrosis. The expression levels of fibrosis- and inflammation-associated molecules were evaluated by both a Western blotting analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). The histologic inflammation and fibrosis were significantly improved in the group administered poly P in both the DSS and TNBS colitis models. The levels of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were significantly decreased by poly P treatment. The expression levels of TGF-β1 and collagens in the colitis mice were decreased by poly P. The LPS-induced expressions of IL-1β and TGF-β1 in Caco-2/BBE cells and of TNF-α in THP-1 cells were reduced by poly P treatment. Poly P did not affect the expression of collagens and connective tissue growth factor in the CCD-18 cells. In conclusion, poly P suppresses intestinal inflammation and fibrosis by downregulating the expression of inflammation- and fibrosis-associated molecules in the intestinal epithelium. The administration of poly P is therefore a novel option to treat fibrosis because of chronic intestinal inflammation. PMID:25766132

  4. Dendrimers and Polyamino-Phenolic Ligands: Activity of New Molecules Against Legionella pneumophila Biofilms

    Science.gov (United States)

    Andreozzi, Elisa; Barbieri, Federica; Ottaviani, Maria F.; Giorgi, Luca; Bruscolini, Francesca; Manti, Anita; Battistelli, Michela; Sabatini, Luigia; Pianetti, Anna

    2016-01-01

    Legionnaires’ disease is a potentially fatal pneumonia caused by Legionella pneumophila, an aquatic bacterium often found within the biofilm niche. In man-made water systems microbial biofilms increase the resistance of legionella to disinfection, posing a significant threat to public health. Disinfection methods currently used in water systems have been shown to be ineffective against legionella over the long-term, allowing recolonization by the biofilm-protected microorganisms. In this study, the anti-biofilm activity of previously fabricated polyamino-phenolic ligands and polyamidoamine dendrimers was investigated against legionella mono-species and multi-species biofilms formed by L. pneumophila in association with other bacteria that can be found in tap water (Aeromonas hydrophila, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae). Bacterial ability to form biofilms was verified using a crystal violet colorimetric assay and testing cell viability by real-time quantitative PCR and Plate Count assay. The concentration of the chemicals tested as anti-biofilm agents was chosen based on cytotoxicity assays: the highest non-cytotoxic chemical concentration was used for biofilm inhibition assays, with dendrimer concentration 10-fold higher than polyamino-phenolic ligands. While Macrophen and Double Macrophen were the most active substances among polyamino-phenolic ligands, dendrimers were overall twofold more effective than all other compounds with a reduction up to 85 and 73% of legionella and multi-species biofilms, respectively. Chemical interaction with matrix molecules is hypothesized, based on SEM images and considering the low or absent anti-microbial activity on planktonic bacteria showed by flow cytometry. These data suggest that the studied compounds, especially dendrimers, could be considered as novel molecules in the design of research projects aimed at the development of efficacious anti-biofilm disinfection treatments of water systems

  5. Dendrimers and polyamino-phenolic ligands: activity of new molecules against Legionella pneumophila biofilms.

    Directory of Open Access Journals (Sweden)

    Elisa eAndreozzi

    2016-03-01

    Full Text Available Legionnaires’ disease is a potentially fatal pneumonia caused by Legionella pneumophila, an aquatic bacterium often found within the biofilm niche. In man-made water systems microbial biofilms increase the resistance of legionella to disinfection, posing a significant threat to public health. Disinfection methods currently used in water systems have been shown to be ineffective against legionella over the long-term, allowing recolonization by the biofilm-protected microorganisms. In this study, the anti-biofilm activity of previously fabricated polyamino-phenolic ligands and polyamidoamine dendrimers was investigated against legionella mono-species and multi-species biofilms formed by L. pneumophila in association with other bacteria that can be found in tap water (Aeromonas hydrophila, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae. Bacterial ability to form biofilms was verified using a crystal violet colorimetric assay and testing cell viability by real-time quantitative PCR and Plate Count assay. The concentration of the chemicals tested as anti-biofilm agents was chosen based on cytotoxicity assays: the highest non-cytotoxic chemical concentration was used for biofilm inhibition assays, with dendrimer concentration ten-fold higher than polyamino-phenolic ligands. While Macrophen and Double Macrophen were the most active substances among polyamino-phenolic ligands, dendrimers were overall two-fold more effective than all other compounds with a reduction up to 85% and 73% of legionella and multi-species biofilms, respectively. Chemical interaction with matrix molecules is hypothesized, based on SEM images and considering the low or absent anti-microbial activity on planktonic bacteria showed by flow cytometry. These data suggest that the studied compounds, especially dendrimers, could be considered as novel molecules in the design of research projects aimed at the development of efficacious anti-biofilm disinfection

  6. Dendrimers and Polyamino-Phenolic Ligands: Activity of New Molecules Against Legionella pneumophila Biofilms.

    Science.gov (United States)

    Andreozzi, Elisa; Barbieri, Federica; Ottaviani, Maria F; Giorgi, Luca; Bruscolini, Francesca; Manti, Anita; Battistelli, Michela; Sabatini, Luigia; Pianetti, Anna

    2016-01-01

    Legionnaires' disease is a potentially fatal pneumonia caused by Legionella pneumophila, an aquatic bacterium often found within the biofilm niche. In man-made water systems microbial biofilms increase the resistance of legionella to disinfection, posing a significant threat to public health. Disinfection methods currently used in water systems have been shown to be ineffective against legionella over the long-term, allowing recolonization by the biofilm-protected microorganisms. In this study, the anti-biofilm activity of previously fabricated polyamino-phenolic ligands and polyamidoamine dendrimers was investigated against legionella mono-species and multi-species biofilms formed by L. pneumophila in association with other bacteria that can be found in tap water (Aeromonas hydrophila, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae). Bacterial ability to form biofilms was verified using a crystal violet colorimetric assay and testing cell viability by real-time quantitative PCR and Plate Count assay. The concentration of the chemicals tested as anti-biofilm agents was chosen based on cytotoxicity assays: the highest non-cytotoxic chemical concentration was used for biofilm inhibition assays, with dendrimer concentration 10-fold higher than polyamino-phenolic ligands. While Macrophen and Double Macrophen were the most active substances among polyamino-phenolic ligands, dendrimers were overall twofold more effective than all other compounds with a reduction up to 85 and 73% of legionella and multi-species biofilms, respectively. Chemical interaction with matrix molecules is hypothesized, based on SEM images and considering the low or absent anti-microbial activity on planktonic bacteria showed by flow cytometry. These data suggest that the studied compounds, especially dendrimers, could be considered as novel molecules in the design of research projects aimed at the development of efficacious anti-biofilm disinfection treatments of water systems in

  7. Regulation of invertase activity in different root zones of wheat (Triticum aestivum L.) seedlings in the course of osmotic adjustment under water deficit conditions.

    Science.gov (United States)

    Königshofer, Helga; Löppert, Hans-Georg

    2015-07-01

    Osmotic adjustment of roots is an essential adaptive mechanism to sustain water uptake and root growth under water deficit. In this paper, the role of invertases (β-fructofuranosidase, EC 3.2.1.26) in osmotic adjustment was investigated in the root tips (cell division and elongation zone) and the root maturation zone of wheat (Triticum aestivum L. cv. Josef) in the course of osmotic stress imposed by 20% polyethylene glycol (PEG) 6000. The two root zones investigated differed distinctly in the response of invertases to water deprivation. In the root tips, the activity of the vacuolar and cell wall-bound invertases increased markedly under water stress resulting in the accumulation of hexoses (glucose and fructose) that contributed significantly to osmotic adjustment. A transient rise in hydrogen peroxide (H2O2) preceded the enhancement of invertases upon exposure to osmotic stress. Treatment with the NADPH oxidase inhibitor diphenylene iodonium (DPI) abolished the stress induced H2O2 production and suppressed the stimulation of the vacuolar invertase activity, whereas the activity of the cell wall-bound invertase was not influenced by DPI. As a consequence of the inhibitory effect of DPI on the vacuolar invertase, hexose levels and osmotic adjustment were also markedly decreased in the root tips under water deficit in the presence of DPI. These data suggest that H2O2 probably generated by a NADPH oxidase is required as a signalling molecule for the up-regulation of the vacuolar invertase activity in the root tips under osmotic stress, thereby enhancing the capacity for osmotic adjustment. In the root maturation zone, an early H2O2 signal could not be detected in response to PEG application. Only an increase in the glucose level that was not paralleled by fructose and a slight stimulation of the activity of the vacuolar invertase occurred in the maturation zone after water deprivation. The stress induced accumulation of glucose in the maturation zone was not

  8. Nucleic Acid Chaperone Activity of HIV-1 NC Proteins Investigated by Single Molecule DNA Stretching

    Science.gov (United States)

    Williams, Mark C.; Gorelick, Robert J.; Musier-Forsyth, Karin; Bloomfield, Victor A.

    2002-03-01

    HIV-1 Nucleocapsid Protein (NC) is a nucleic acid chaperone protein that is responsible for facilitating numerous nucleic acid rearrangements throughout the reverse transcription cycle of HIV-1. To understand the mechanism of NC’s chaperone function, we carried out single molecule DNA stretching studies in the presence of NC and mutant forms of NC. Using an optical tweezers instrument, we stretch single DNA molecules from the double-stranded helical state to the single-stranded (coil) state. Based on the observed cooperativity of DNA force-induced melting, we find that the fraction of melted base pairs at room temperature is increased dramatically in the presence of NC. Thus, upon NC binding, increased thermal fluctuations cause continuous melting and reannealing of base pairs so that DNA strands are able to rapidly sample configurations in order to find the lowest energy state. While NC destabilizes the double-stranded form of DNA, a mutant form of NC that lacks the zinc finger structures does not. DNA stretching experiments carried out in the presence of NC variants containing more subtle changes in the zinc finger structures were conducted to elucidate the contribution of each individual finger to NC’s chaperone activity, and these results will be reported.

  9. Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution

    Science.gov (United States)

    Senavirathne, Gayan; Bertram, Jeffrey G.; Jaszczur, Malgorzata; Chaurasiya, Kathy R.; Pham, Phuong; Mak, Chi H.; Goodman, Myron F.; Rueda, David

    2015-12-01

    Activation-induced deoxycytidine deaminase (AID) generates antibody diversity in B cells by initiating somatic hypermutation (SHM) and class-switch recombination (CSR) during transcription of immunoglobulin variable (IgV) and switch region (IgS) DNA. Using single-molecule FRET, we show that AID binds to transcribed dsDNA and translocates unidirectionally in concert with RNA polymerase (RNAP) on moving transcription bubbles, while increasing the fraction of stalled bubbles. AID scans randomly when constrained in an 8 nt model bubble. When unconstrained on single-stranded (ss) DNA, AID moves in random bidirectional short slides/hops over the entire molecule while remaining bound for ~5 min. Our analysis distinguishes dynamic scanning from static ssDNA creasing. That AID alone can track along with RNAP during transcription and scan within stalled transcription bubbles suggests a mechanism by which AID can initiate SHM and CSR when properly regulated, yet when unregulated can access non-Ig genes and cause cancer.

  10. A Method of Permeabilization of Drosophila Embryos for Assays of Small Molecule Activity

    Science.gov (United States)

    Rand, Matthew D.

    2014-01-01

    The Drosophila embryo has long been a powerful laboratory model for elucidating molecular and genetic mechanisms that control development. The ease of genetic manipulations with this model has supplanted pharmacological approaches that are commonplace in other animal models and cell-based assays. Here we describe recent advances in a protocol that enables application of small molecules to the developing fruit fly embryo. The method details steps to overcome the impermeability of the eggshell while maintaining embryo viability. Eggshell permeabilization across a broad range of developmental stages is achieved by application of a previously described d-limonene embryo permeabilization solvent (EPS1) and by aging embryos at reduced temperature (18 °C) prior to treatments. In addition, use of a far-red dye (CY5) as a permeabilization indicator is described, which is compatible with downstream applications involving standard red and green fluorescent dyes in live and fixed preparations. This protocol is applicable to studies using bioactive compounds to probe developmental mechanisms as well as for studies aimed at evaluating teratogenic or pharmacologic activity of uncharacterized small molecules. PMID:25046169

  11. Stellar activity mimics a habitable-zone planet around Kapteyn's star

    CERN Document Server

    Robertson, Paul; Mahadevan, Suvrath

    2015-01-01

    Kapteyn's star is an old M subdwarf believed to be a member of the Galactic halo population of stars. A recent study has claimed the existence of two super-Earth planets around the star based on radial velocity (RV) observations. The innermost of these candidate planets--Kapteyn b (P = 48 days)--resides within the circumstellar habitable zone. Given recent progress in understanding the impact of stellar activity in detecting planetary signals, we have analyzed the observed HARPS data for signatures of stellar activity. We find that while Kapteyn's star is photometrically very stable, a suite of spectral activity indices reveals a large-amplitude rotation signal, and we determine the stellar rotation period to be 143 days. The spectral activity tracers are strongly correlated with the purported RV signal of "planet b," and the 48-day period is an integer fraction (1/3) of the stellar rotation period. We conclude that Kapteyn b is not a planet in the Habitable Zone, but an artifact of stellar activity.

  12. Dissecting allosteric effects of activator-coactivator complexes using a covalent small molecule ligand.

    Science.gov (United States)

    Wang, Ningkun; Lodge, Jean M; Fierke, Carol A; Mapp, Anna K

    2014-08-19

    Allosteric binding events play a critical role in the formation and stability of transcriptional activator-coactivator complexes, perhaps in part due to the often intrinsically disordered nature of one or more of the constituent partners. The kinase-inducible domain interacting (KIX) domain of the master coactivator CREB binding protein/p300 is a conformationally dynamic domain that complexes with transcriptional activators at two discrete binding sites in allosteric communication. The complexation of KIX with the transcriptional activation domain of mixed-lineage leukemia protein leads to an enhancement of binding by the activation domain of CREB (phosphorylated kinase-inducible domain of CREB) to the second site. A transient kinetic analysis of the ternary complex formation aided by small molecule ligands that induce positive or negative cooperative binding reveals that positive cooperativity is largely governed by stabilization of the bound complex as indicated by a decrease in koff. Thus, this suggests the increased binding affinity for the second ligand is not due to an allosteric creation of a more favorable binding interface by the first ligand. This is consistent with data from us and from others indicating that the on rates of conformationally dynamic proteins approach the limits of diffusion. In contrast, negative cooperativity is manifested by alterations in both kon and koff, suggesting stabilization of the binary complex.

  13. Topical Anti-inflammatory Activity of New Hybrid Molecules of Terpenes and Synthetic Drugs

    Directory of Open Access Journals (Sweden)

    Cristina Theoduloz

    2015-06-01

    Full Text Available The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1, imbricatolic acid (2 and oleanolic acid (3 with ibuprofen (4 or naproxen (5. The topical anti-inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA and 12-O-tetradecanoyl phorbol 13-acetate (TPA induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 µmol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9% and oleanoyl ibuprofenate methyl ester 15 (80.0%. In the AA assay, the best activity was observed for 12 at 3.2 µmol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%. All the terpenyl-synthetic anti-inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes.

  14. A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia.

    Directory of Open Access Journals (Sweden)

    Carrie Selin

    Full Text Available Infections with the bacteria Burkholderia cepacia complex (Bcc are very difficult to eradicate in cystic fibrosis patients due the intrinsic resistance of Bcc to most available antibiotics and the emergence of multiple antibiotic resistant strains during antibiotic treatment. In this work, we used a whole-cell based assay to screen a diverse collection of small molecules for growth inhibitors of a relevant strain of Bcc, B. cenocepacia K56-2. The primary screen used bacterial growth in 96-well plate format and identified 206 primary actives among 30,259 compounds. From 100 compounds with no previous record of antibacterial activity secondary screening and data mining selected a total of Bce bioactives that were further analyzed. An experimental pipeline, evaluating in vitro antibacterial and antibiofilm activity, toxicity and in vivo antibacterial activity using C. elegans was used for prioritizing compounds with better chances to be further investigated as potential Bcc antibacterial drugs. This high throughput screen, along with the in vitro and in vivo analysis highlights the utility of this experimental method to quickly identify bioactives as a starting point of antibacterial drug discovery.

  15. A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia.

    Science.gov (United States)

    Selin, Carrie; Stietz, Maria S; Blanchard, Jan E; Gehrke, Sebastian S; Bernard, Sylvain; Hall, Dennis G; Brown, Eric D; Cardona, Silvia T

    2015-01-01

    Infections with the bacteria Burkholderia cepacia complex (Bcc) are very difficult to eradicate in cystic fibrosis patients due the intrinsic resistance of Bcc to most available antibiotics and the emergence of multiple antibiotic resistant strains during antibiotic treatment. In this work, we used a whole-cell based assay to screen a diverse collection of small molecules for growth inhibitors of a relevant strain of Bcc, B. cenocepacia K56-2. The primary screen used bacterial growth in 96-well plate format and identified 206 primary actives among 30,259 compounds. From 100 compounds with no previous record of antibacterial activity secondary screening and data mining selected a total of Bce bioactives that were further analyzed. An experimental pipeline, evaluating in vitro antibacterial and antibiofilm activity, toxicity and in vivo antibacterial activity using C. elegans was used for prioritizing compounds with better chances to be further investigated as potential Bcc antibacterial drugs. This high throughput screen, along with the in vitro and in vivo analysis highlights the utility of this experimental method to quickly identify bioactives as a starting point of antibacterial drug discovery. PMID:26053039

  16. Screening and characterization of molecules that modulate the biological activity of IFNs-I.

    Science.gov (United States)

    Bürgi, Milagros; Zapol'skii, Viktor A; Hinkelmann, Bettina; Köster, Mario; Kaufmann, Dieter E; Sasse, Florenz; Hauser, Hansjörg; Etcheverrigaray, Marina; Kratje, Ricardo; Bollati-Fogolín, Mariela; Oggero, Marcos

    2016-09-10

    Type I Interferons (IFNs-I) are species-specific glycoproteins which play an important role as primary defence against viral infections and that can also modulate the adaptive immune system. In some autoimmune diseases, interferons (IFNs) are over-produced. IFNs are widely used as biopharmaceuticals for a variety of cancer indications, chronic viral diseases, and for their immuno-modulatory action in patients with multiple sclerosis; therefore, increasing their therapeutic efficiency and decreasing their side effects is of high clinical value. In this sense, it is interesting to find molecules that can modulate the activity of IFNs. In order to achieve that, it was necessary to establish a simple, fast and robust assay to analyze numerous compounds simultaneously. We developed four reporter gene assays (RGAs) to identify IFN activity modulator compounds by using WISH-Mx2/EGFP, HeLa-Mx2/EGFP, A549-Mx2/EGFP, and HEp2-Mx2/EGFP reporter cell lines (RCLs). All of them present a Z' factor higher than 0.7. By using these RGAs, natural and synthetic compounds were analyzed simultaneously. A total of 442 compounds were studied by the Low Throughput Screening (LTS) assay using the four RCLs to discriminate between their inhibitory or enhancing effects on IFN activity. Some of them were characterized and 15 leads were identified. Finally, one promising candidate with enhancing effect on IFN-α/-β activity and five compounds with inhibitory effect were described. PMID:27346232

  17. 78 FR 66330 - Foreign-Trade Zone (FTZ) 235-Lakewood, New Jersey, Notification of Proposed Production Activity...

    Science.gov (United States)

    2013-11-05

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Foreign-Trade Zones Board Foreign-Trade Zone (FTZ) 235--Lakewood, New Jersey, Notification of Proposed Production Activity, Cosmetic Essence Innovations, LLC, (Fragrance Bottling), Holmdel, New Jersey...

  18. 78 FR 7394 - Foreign-Trade Zone 41-Milwaukee, WI; Notification of Proposed Production Activity; CNH America...

    Science.gov (United States)

    2013-02-01

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Foreign-Trade Zones Board Foreign-Trade Zone 41--Milwaukee, WI; Notification of Proposed Production Activity; CNH America, LLC, Subzone 41I (Tractors and Tractor/Combine Components), Racine, WI The Port...

  19. 78 FR 56655 - Foreign-Trade Zone (FTZ) 203-Moses Lake, Washington; Notification of Proposed Production Activity...

    Science.gov (United States)

    2013-09-13

    ... Foreign-Trade Zones Board Foreign-Trade Zone (FTZ) 203--Moses Lake, Washington; Notification of Proposed Production Activity; AREVA Inc. (Fuel Rod Assemblies); Richland, Washington The Moses Lake Public Corporation... AREVA Inc. (AREVA), located in Richland, Washington. The notification conforming to the requirements...

  20. Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation.

    Science.gov (United States)

    Yang, Zijiang; Concannon, John; Ng, Kelvin S; Seyb, Kathleen; Mortensen, Luke J; Ranganath, Sudhir; Gu, Fangqi; Levy, Oren; Tong, Zhixiang; Martyn, Keir; Zhao, Weian; Lin, Charles P; Glicksman, Marcie A; Karp, Jeffrey M

    2016-07-26

    Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-κB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-α secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-α in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy.

  1. Osteogenic Activity of Locally Applied Small Molecule Drugs in a Rat Femur Defect Model

    Directory of Open Access Journals (Sweden)

    Jessica A. Cottrell

    2010-01-01

    Full Text Available The long-term success of arthroplastic joints is dependent on the stabilization of the implant within the skeletal site. Movement of the arthroplastic implant within the bone can stimulate osteolysis, and therefore methods which promote rigid fixation or bone growth are expected to enhance implant stability and the long-term success of joint arthroplasty. In the present study, we used a simple bilateral bone defect model to analyze the osteogenic activity of three small-molecule drug implants via microcomputerized tomography (micro-CT and histomorphometry. In this study, we show that local delivery of alendronate, but not lovastatin or omeprazole, led to significant new bone formation at the defect site. Since alendronate impedes osteoclast-development, it is theorized that alendronate treatment results in a net increase in bone formation by preventing osteoclast mediated remodeling of the newly formed bone and upregulating osteoblasts.

  2. Activation energy of fractional vortices and spectroscopy of a vortex molecule in long Josephson junction

    International Nuclear Information System (INIS)

    This thesis is divided into two parts, the measurement of the activation energy of a fractional vortex and the spectroscopy of a vortex-molecule. Fractional vortices can be studied in long 0-κ Josephson junctions, where a jump of the Josephson phase is created artificially with a pair of tiny current injectors. To compensate for this phase discontinuity, a ρ vortex is formed. Here, ρ describes the vortex's so called topological charge. The ρ vortices are pinned at the discontinuity and they carry the fraction (ρ/2).Φ0 of magnetic flux, with the magnetic flux quantum Φ0 2.07.10-15. Two stable vortex configurations are possible, a direct Vortex and a complementary one. ρ depends on the injector current. When the bias current of the junction exceeds a characteristic threshold, which dependents on ρ, the Lorentz force is bigger than the pinning force of the vortex and a fluxon is pulled away. In this case a complementary (ρ-2π) vortex is left behind. This switching of the ρ vortex and the resulting emission of a fluxon can be described as a Kramers like escape of a particle out of a tilted washboard potential. The washboard potential is tilted to the point where the barrier is small enough, so that the particle can escape via thermal or quantum fluctuations. In the case of thermal fluctuations the barrier height is called activation energy. The activation energy can be determined by measuring the junction's switching current statistics. In this thesis, the activation energy, necessary for the vortex escape, was measured as a function of ρ and a homogenous external magnetic field perpendicular to the junction. The main focus was the investigation of 0-π junctions. The temperature dependence of the activation energy was investigated, too. It turns out, that the transition-state-theory is convenient to describe the switching probability of the standard Nb-AlOx-Nb junctions at 4.2 K. For the measurements at 0.5 K a model of low to intermediate damping results

  3. Regulation of synaptic vesicle docking by different classes of macromolecules in active zone material.

    Directory of Open Access Journals (Sweden)

    Joseph A Szule

    Full Text Available The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission. Dense networks of macromolecules, called active zone material, (AZM are attached to the presynaptic membrane next to docked vesicles. Electron tomography has shown that some AZM macromolecules are connected to docked vesicles, leading to the suggestion that AZM is somehow involved in the docking process. We used electron tomography on the simply arranged active zones at frog neuromuscular junctions to characterize the connections of AZM to docked synaptic vesicles and to search for the establishment of such connections during vesicle docking. We show that each docked vesicle is connected to 10-15 AZM macromolecules, which fall into four classes based on several criteria including their position relative to the presynaptic membrane. In activated axon terminals fixed during replacement of docked vesicles by previously undocked vesicles, undocked vesicles near vacated docking sites on the presynaptic membrane have connections to the same classes of AZM macromolecules that are connected to docked vesicles in resting terminals. The number of classes and the total number of macromolecules to which the undocked vesicles are connected are inversely proportional to the vesicles' distance from the presynaptic membrane. We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane. Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.

  4. The Legality of Foreign Military Activities in the Exclusive Economic Zone under UNCLOS

    Directory of Open Access Journals (Sweden)

    Jing Geng

    2012-02-01

    Full Text Available During negotiations for the United Nations Convention on the Law of the Sea (UNCLOS, military activities in another state's Exclusive Economic Zone (EEZ were a point of contention. Currently, the issue remains controversial in state practice. UNCLOS attempts to balance the differing interests of coastal and maritime states, but is silent or ambiguous on the legality of military operations in foreign EEZs. Coastal states seek to assert increasing control over their maritime zones while maritime states prioritize the freedom of navigation. This article examines the competing views on these issues in the context of the 2009 Impeccable incident between China and the United States that occurred in the South China Sea. The issue of military activities in the EEZ will continue to be a complex subject, without clear definitions in the nature and scope of permissible activity. As state practice evolves, the potential for hostilities is high, particularly in semi-enclosed sea areas such as the South China Sea. This article concludes that states should create dialogues and form agreements to help clarify the contours of military activity in the EEZ, focusing on mutual interests, interdependence, and coexistence rather than perceiving the ocean as a zero-sum resource. 

  5. Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation

    Directory of Open Access Journals (Sweden)

    Telang Sucheta

    2012-05-01

    Full Text Available Abstract Background T cell activation is associated with a rapid increase in intracellular fructose-2,6-bisphosphate (F2,6BP, an allosteric activator of the glycolytic enzyme, 6-phosphofructo-1-kinase. The steady state concentration of F2,6BP in T cells is dependent on the expression of the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4 and the fructose-2,6-bisphosphatase, TIGAR. Of the PFKFB family of enzymes, PFKFB3 has the highest kinase:bisphosphatase ratio and has been demonstrated to be required for T cell proliferation. A small molecule antagonist of PFKFB3, 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO, recently has been shown to reduce F2,6BP synthesis, glucose uptake and proliferation in transformed cells. We hypothesized that the induction of PFKFB3 expression may be required for the stimulation of glycolysis in T cells and that exposure to the PFKFB3 antagonist, 3PO, would suppress T cell activation. Methods We examined PFKFB1-4 and TIGAR expression and F2,6BP concentration in purified CD3+ T cells stimulated with microbead-conjugated agonist antibodies specific for CD3 and the co-stimulatory receptor, CD28. We then determined the effect of 3PO on anti-CD3/anti-CD28-induced T cell activation, F2,6BP synthesis, 2-[1-14C]-deoxy-d-glucose uptake, lactate secretion, TNF-α secretion and proliferation. Finally, we examined the effect of 3PO administration on the development of delayed type hypersensitivity to methylated BSA and on imiquimod-induced psoriasis in mice. Results We found that purified human CD3+ T cells express PFKFB2, PFKFB3, PFKFB4 and TIGAR, and that anti-CD3/anti-CD28 conjugated microbeads stimulated a >20-fold increase in F2,6BP with a coincident increase in protein expression of the PFKFB3 family member and a decrease in TIGAR protein expression. We then found that exposure to the PFKFB3 small molecule antagonist, 3PO (1–10 μM, markedly attenuated the stimulation of F2,6BP

  6. Single molecule analysis of B cell receptor motion during signaling activation

    Science.gov (United States)

    Rey Suarez, Ivan; Koo, Peter; Mochrie, Simon; Song, Wenxia; Upadhyaya, Arpita

    B cells are an essential part of the adaptive immune system. They patrol the body looking for signs of infection in the form of antigen on the surface of antigen presenting cells. The binding of the B cell receptor (BCR) to antigen induces signaling cascades that lead to B cell activation and eventual production of high affinity antibodies. During activation, BCR organize into signaling microclusters, which are platforms for signal amplification. The physical processes underlying receptor movement and aggregation are not well understood. Here we study the dynamics of single BCRs on activated murine primary B cells using TIRF imaging and single particle tracking. The tracks obtained are analyzed using perturbation expectation-maximization (pEM) a systems-level analysis that allows the identification of different short-time diffusive states from a set of single particle tracks. We identified five different diffusive states on wild type cells, which correspond to different molecular states of the BCR. By using actin polymerization inhibitors and mutant cells lacking important actin regulators we were able to identify the BCR molecule configuration associated with each diffusive state.

  7. Along strike variation of tremor activities and thermal structures in various subduction zones

    Science.gov (United States)

    Yabe, S.; Ide, S.; Yoshioka, S.

    2012-12-01

    A family of slow earthquakes, e.g., deep low frequency tremors, low frequency earthquakes (LFEs), very low frequency earthquakes (VLFs) and slow slip events (SSEs), are observed in various subduction zones. These phenomena represent shear slip on the plate interface, and they are thought to be related to brittle-ductile transition behavior on the plate interface because they are often located near the transition zones of interplate coupling estimated from GPS data. Such slip behavior along the plate interface would be controlled by temperature. Furthermore, tremors are considered to be related to fluid dehydrated from the subducting slab, through temperature dependent chemical reactions. Therefore, tremors occurrences are expected to be influenced by temperature, though some studies have questioned about the relationship between tremor activity and temperature. Here we investigate the source locations of deep tremor using an envelope correlation method and compare them with the temperature and shear strength profiles along the plate interface calculated using a numerical model (Yoshioka and Sanshadokoro, 2002). The study areas include New Zealand, southern Chile, and Mexico, where tremor behavior changes significantly along the strike of the plate interface. Investigating such along-strike variation in individual subduction zone may clarify the temperature dependence of tremor because environmental conditions affecting tremor occurrence are similar, unlike the comparison between different subduction zones. In the Hikurangi subduction zone beneath the North Island, New Zealand, the depth of SSE are quite different along the strike, e.g., deeper in the central region and shallower in the northern region (e.g. Wallace and Beavan, 2010). We reanalyze tremors detected by previous studies (Kim et al., 2011; Ide, 2012) to estimate their absolute depth and confirm that tremors in North Island are on the plate interface in both the central and the northern regions. Thermal

  8. DEFORMATION WAVES AS A TRIGGER MECHANISM OF SEISMIC ACTIVITY IN SEISMIC ZONES OF THE CONTINENTAL LITHOSPHERE

    Directory of Open Access Journals (Sweden)

    S. I. Sherman

    2015-09-01

    Full Text Available Deformation waves as a trigger mechanism of seismic activity and migration of earthquake foci have been under discussion by researchers in seismology and geodynamics for over 50 years. Four sections of this article present available principal data on impacts of wave processes on seismicity and new data. The first section reviews analytical and experimental studies aimed at identification of relationships between wave processes in the lithosphere and seismic activity manifested as space-and-time migration of individual earthquake foci or clusters of earthquakes. It is concluded that with a systematic approach, instead of using a variety of terms to denote waves that trigger seismic process in the lithosphere, it is reasonable to apply the concise definition of ‘deformation waves’, which is most often used in fact.The second section contains a description of deformation waves considered as the trigger mechanism of seismic activity. It is concluded that a variety of methods are applied to identify deformation waves, and such methods are based on various research methods and concepts that naturally differ in sensitivity concerning detection of waves and/or impact of the waves on seismic process. Epicenters of strong earthquakes are grouped into specific linear or arc-shaped systems, which common criterion is the same time interval of the occurrence of events under analysis. On site the systems compose zones with similar time sequences, which correspond to the physical notion of moving waves (Fig. 9. Periods of manifestation of such waves are estimated as millions of years, and a direct consideration of the presence of waves and wave parameters is highly challenging. In the current state-of-the-art, geodynamics and seismology cannot provide any other solution yet.The third section presents a solution considering record of deformation waves in the lithosphere. With account of the fact that all the earthquakes with М≥3.0 are associated with

  9. Crust-mantle structure feature and the seismic activity of the main tectonic units in the North Tanlu fault zone

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Using recent data of geoscience transaction in Northeast China, the author analyses and studies the crust-upper mantle structure feature of the North Tanlu fault zone. The result shows the crust-mantle structure are obvious difference at both sides of the North Tanlu fault zone. The fault activity and segmentation are closely related with abruptly change zone of the crust-upper mantle structure. There is a clear mirror image relationship between the big geomorphic shape and asthenosphere undulate, the former restricts tectonic stability and tectonic style of different crustal units. The significantly strengthening seismicity of north set and south set in the North Tanlu fault zone just correspond to the low-velocity and high conductivity layer of crust-upper mantle. In the North Tanlu fault zone, the main controlling structure of the mid-strong seismic generally consists of the active fault sectors, whose crust-mantle structure is more complicated in rigidity massif.

  10. Auroral Electrojet Indices Designed to Provide a Global Measure, 2.5-Minute Intervals, of Auroral Zone Magnetic Activity

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Auroral Electrojet index (AE) is designed to provide a global quantitative measure of auroral zone magnetic activity produced by enhanced ionospheric currents...

  11. Auroral Electrojet Index Designed to Provide a Global Measure, l-minute Intervals, of Auroral Zone Magnetic Activity

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Auroral Electrojet index (AE) is designed to provide a global quantitative measure of auroral zone magnetic activity produced by enhanced ionospheric currents...

  12. Nitrogen transformations as inferred from the activities of key enzymes in the Arabian Sea oxygen minimum zone

    Digital Repository Service at National Institute of Oceanography (India)

    Shailaja, M.S.; Narvekar, P.V.; Alagarsamy, R.; Naqvi, S.W.A.

    Vertical distributions of the potential activities of some key enzymes mediating nitrification and denitrification were investigated within the oxygen (O2) minimum zone of the Arabian Sea at a number of locations between latitudes 17 and 21°N...

  13. Neotectonic Model of Formation of Oil and Gas Fields and Mineragenic Role of Geodynamic Active Zones

    Directory of Open Access Journals (Sweden)

    I. S. Kopylov

    2014-03-01

    Full Text Available The article considers the importance of role of geodynamic active zones in formation of mineral deposits, their distribution, and mineragenic characteristics. Geodynamic model of formation of the oil and gas fields is developed. It reflects the evolution of formation of oil and gas fields and, after the stage of learning, allows predicting the petroleum potential of local areas. The model building procedure uses the integrated analysis of all the available information and determining the most informative indicators for forecasting the oil and gas reserves. The article presents an example of model worked out for oil and gas fields of the Perm Kray.

  14. Studies of Active Ingredients in Cough Syrup by Capillary Zone Electrophoresis with Amperometric Detection

    Institute of Scientific and Technical Information of China (English)

    ZHOU Tian-shu; WANG Ai-fang; WU Fang; SHI Guo-yue; FANG Yu-zhi

    2003-01-01

    The present paper covers a simple, reliable and reproducible method, based on capillary zone electrophoresis(CZE) with amperometric detection(AD), for the separation and the determination of ephedrine hydrochloride, promethazine hydrochloride and codeine phosphate. Under the optimal conditions, the three analytes were base-line separated completely within 16 min. Good linear relationships between the peak heights and the concentrations of the three analytes were obtained with the correlation coefficients better than 0.9993. The method was directly applied to the determination of the active ingredients in pharmaceutical preparations and the assay results were satisfactory.

  15. Analysis of protein phosphorylation in nerve terminal reveals extensive changes in active zone proteins upon exocytosis.

    Science.gov (United States)

    Kohansal-Nodehi, Mahdokht; Chua, John Je; Urlaub, Henning; Jahn, Reinhard; Czernik, Dominika

    2016-01-01

    Neurotransmitter release is mediated by the fast, calcium-triggered fusion of synaptic vesicles with the presynaptic plasma membrane, followed by endocytosis and recycling of the membrane of synaptic vesicles. While many of the proteins governing these processes are known, their regulation is only beginning to be understood. Here we have applied quantitative phosphoproteomics to identify changes in phosphorylation status of presynaptic proteins in resting and stimulated nerve terminals isolated from the brains of Wistar rats. Using rigorous quantification, we identified 252 phosphosites that are either up- or downregulated upon triggering calcium-dependent exocytosis. Particularly pronounced were regulated changes of phosphosites within protein constituents of the presynaptic active zone, including bassoon, piccolo, and RIM1. Additionally, we have mapped kinases and phosphatases that are activated upon stimulation. Overall, our study provides a snapshot of phosphorylation changes associated with presynaptic activity and provides a foundation for further functional analysis of key phosphosites involved in presynaptic plasticity. PMID:27115346

  16. Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma.

    Science.gov (United States)

    Liu, Rui-Ming; Eldridge, Stephanie; Watanabe, Nobuo; Deshane, Jessy; Kuo, Hui-Chien; Jiang, Chunsun; Wang, Yong; Liu, Gang; Schwiebert, Lisa; Miyata, Toshio; Thannickal, Victor J

    2016-02-15

    Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms, there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators, has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small-molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyperresponsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor TM5275 may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling. PMID:26702150

  17. Small molecule regulation of self-association and catalytic activity in a supramolecular coordination complex.

    Science.gov (United States)

    McGuirk, C Michael; Stern, Charlotte L; Mirkin, Chad A

    2014-03-26

    Herein, we report the synthesis and characterization of the first weak-link approach (WLA) supramolecular construct that employs the small molecule regulation of intermolecular hydrogen bonding interactions for the in situ control of catalytic activity. A biaryl urea group, prone to self-aggregation, was functionalized with a phosphinoalkyl thioether (P,S) hemilabile moiety and incorporated into a homoligated Pt(II) tweezer WLA complex. This urea-containing construct, which has been characterized by a single crystal X-ray diffraction study, can be switched in situ from a rigid fully closed state to a flexible semiopen state via Cl(-) induced changes in the coordination mode at the Pt(II) structural node. FT-IR and (1)H NMR spectroscopy studies were used to demonstrate that while extensive urea self-association persists in the flexible semiopen complex, these interactions are deterred in the rigid, fully closed complex because of geometric and steric restraints. Consequently, the urea moieties in the fully closed complex are able to catalyze a Diels-Alder reaction between cyclopentadiene and methyl vinyl ketone to generate 2-acetyl-5-norbornene. The free urea ligand and the semiopen complex show no such activity. The successful incorporation and regulation of a hydrogen bond donating catalyst in a WLA construct open the doors to a vast and rapidly growing catalogue of allosteric catalysts for applications in the detection and amplification of organic analytes.

  18. Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae

    Directory of Open Access Journals (Sweden)

    Teufert Karen

    2004-05-01

    Full Text Available Abstract Background Despite its direct connection to the nasopharynx which harbors otitis media pathogens as part of its normal flora, the middle ear cavity is kept free of these bacteria by as yet unknown mechanisms. Respiratory mucosal epithelia, including those of the middle ear and eustachian tube, secrete antimicrobial effectors including lysozyme, lactoferrin and β defensins-1 and -2. To elucidate the role of these innate immune molecules in the normal defense and maintenance of sterility of respiratory mucosa such as that of the middle ear, we assessed their effect on the respiratory pathogens nontypeable Haemophilus influenzae (NTHi 12, Moraxella catarrhalis 035E, and Streptococcus pneumoniae 3, and 6B. Methods Two assay methods, the radial assay and the liquid broth assay, were employed for testing the antimicrobial activity of the molecules. This was done in order to minimize the possibility that the observed effects were artifacts of any single assay system employed. Also, transmission electron microscopy (TEM was employed to evaluate the effect of antimicrobial innate immune molecules on OM pathogens. For the statistical analysis of the data, Student's t-test was performed. Results Results of the radial diffusion assay showed that β defensin-2 was active against all four OM pathogens tested, while treatment with β defensin-1 appeared to only affect M. catarrhalis. The radial assay results also showed that lysozyme was quite effective against S. pneumoniae 3 and 6B and was partially bacteriostatic/bactericidal against M. catarrhalis. Lysozyme however, appeared not to affect the growth of NTHi. Thus, lysozyme seems to have a more pronounced impact on the growth of the Gram-positive S. pneumoniae as compared to that of Gram-negative pathogens. Lactoferrin on the other hand, enhanced the growth of the bacteria tested. The results of the radial assays were confirmed using liquid broth assays for antimicrobial activity, and showed that

  19. Simultaneous measurement of DNA motor protein conformation and activity with combined optical trap and single-molecule fluorescence

    Science.gov (United States)

    Chemla, Yann

    2013-03-01

    We present single-molecule measurements of Superfamily 1 UvrD helicase DNA unwinding that reveal directly how helicase stoichiometry and conformation regulate motor activity. Using a new instrument that combines high resolution optical tweezers with single-molecule fluorescence microscopy, we record DNA unwinding activity with base pair-scale resolution (via optical tweezers) simultaneously with helicase stoichiometry and conformation (via fluorescence). Quantifying the fluorescence signal from labeled UvrD, we observe that pairs of UvrD molecules are required for long distance unwinding but that individual molecules exhibit limited, non-processive unwinding activity. UvrD is also known to exhibit two different conformations, `closed' and `open', based on the orientation of its 2B regulatory domain. The function of these conformations has remained elusive. Measuring the fluorescence of FRET labeled proteins, we detect directly the conformation of the 2B domain of individual UvrD molecules during unwinding activity. We observe that UvrD is in the `closed' conformation during DNA unwinding but surprisingly switches to the `open' conformation upon reversal of helicase direction, i.e. when UvrD switches strands and translocates on the opposing strand with the DNA junction rezipping behind it. We hypothesize that the 2B domain acts as a conformational switch that controls DNA unwinding vs. re-annealing. Work supported by NSF (PHY-082261, Center for the Physics of Living Cells) and NIH (R21 RR025341A)

  20. Impacts of stellar evolution and dynamics on the habitable zone: The role of rotation and magnetic activity

    CERN Document Server

    Florian, Gallet; Louis, Amard; Sacha, Brun; Ana, Palacios; Stephane, Mathis

    2016-01-01

    In this article, we aim to provide the community with the dependence of the habitable zone upon the stellar mass, metallicity, rotation, and for various prescriptions of the limits of the habitable zone. We use the STAREVOL code to study the evolution of the habitable zone and of the continuously habitable zone limits. Mass and metallicity are the stellar parameters that have the most dramatic effects on the habitable zone limits. Conversely, for a given stellar mass and metallicity, stellar rotation has only a marginal effect on these limits and does not modify the width of the habitable zone. The evolution of the habitable zone limits is also correlated to the evolution of the stellar activity (through the Rossby number) that depends on the stellar mass considered. While the magnetic activity has negligible consequence in the case of more massive stars, these effects may have a strong impact on the habitability of a planet around M dwarf stars. Thus, stellar activity cannot be neglected and may have strong ...

  1. Characteristics of Relocated Quiet Zones Using Virtual Microphone Algorithm in an Active Headrest System

    Directory of Open Access Journals (Sweden)

    Seokhoon Ryu

    2016-01-01

    Full Text Available This study displays theoretical and experimental investigation on the characteristics of the relocated zone of quiet by a virtual microphone (VM based filtered-x LMS (FxLMS algorithm which can be embedded in a real-time digital controller for an active headrest system. The attenuation changes at the relocated zones of quiet by the variation of the distance between the ear and the error microphone are mainly examined. An active headrest system was implemented for the control experiment at a chair and consists of two (left and right secondary loudspeakers, two error microphones, two observer microphones at ear positions in a HATS, and other electronics including a dSPACE 1401 controller. The VM based FxLMS algorithm achieved an attenuation of about 22 dB in the control experiment against a narrowband primary noise by the variation of the distance between the ear and the error microphone. The important factors for the algorithm are discussed as well.

  2. Discovery of small molecule inhibitors of xyloglucan endotransglucosylase (XET) activity by high-throughput screening

    Science.gov (United States)

    Chormova, Dimitra; Franková, Lenka; Defries, Andrew; Cutler, Sean R.; Fry, Stephen C.

    2015-01-01

    Small molecules (xenobiotics) that inhibit cell-wall-localised enzymes are valuable for elucidating the enzymes’ biological roles. We applied a high-throughput fluorescent dot-blot screen to search for inhibitors of Petroselinum xyloglucan endotransglucosylase (XET) activity in vitro. Of 4216 xenobiotics tested, with cellulose-bound xyloglucan as donor-substrate, 18 inhibited XET activity and 18 promoted it (especially anthraquinones and flavonoids). No compounds promoted XET in quantitative assays with (cellulose-free) soluble xyloglucan as substrate, suggesting that promotion was dependent on enzyme–cellulose interactions. With cellulose-free xyloglucan as substrate, we found 22 XET-inhibitors – especially compounds that generate singlet oxygen (1O2) e.g., riboflavin (IC50 29 μM), retinoic acid, eosin (IC50 27 μM) and erythrosin (IC50 36 μM). The riboflavin effect was light-dependent, supporting 1O2 involvement. Other inhibitors included tannins, sulphydryl reagents and triphenylmethanes. Some inhibitors (vulpinic acid and brilliant blue G) were relatively specific to XET, affecting only two or three, respectively, of nine other wall-enzyme activities tested; others [e.g. (−)-epigallocatechin gallate and riboflavin] were non-specific. In vivo, out of eight XET-inhibitors bioassayed, erythrosin (1 μM) inhibited cell expansion in Rosa and Zea cell-suspension cultures, and 40 μM mycophenolic acid and (−)-epigallocatechin gallate inhibited Zea culture growth. Our work showcases a general high-throughput strategy for discovering wall-enzyme inhibitors, some being plant growth inhibitors potentially valuable as physiological tools or herbicide leads. PMID:26093490

  3. Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

    Directory of Open Access Journals (Sweden)

    Cardama GA

    2014-10-01

    Full Text Available Georgina A Cardama,1 Nazareno Gonzalez,1 Matias Ciarlantini,2 Lucia Gandolfi Donadío,2 María Julieta Comin,2 Daniel F Alonso,1 Pablo Lorenzano Menna,1,* Daniel E Gomez1,*1Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina; 2Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology, San Martín, Argentina, *These authors contributed equally to this workAbstract: Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.Keywords: GTPases. invasion, Dock180, small molecule

  4. Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Perry

    Full Text Available Ubiquitin (Ub is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs. However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA-mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1, a critical mediator of the unfolded protein response (UPR. WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1 through an IRE1-dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.

  5. Synthesis of Novel Hybrid Molecules from Precursors With Known Antiparasitic Activity

    Directory of Open Access Journals (Sweden)

    Ibrahim M. Mosleh

    2009-04-01

    Full Text Available Three novel new compounds derived from antiparasitic precursors have been synthesized and tested for their antiamoebic and antigiardial activities. The condensation of 2-(2-methyl-5-1H-nitroimidazolylethylamine (6 with 5-nitro-2-furylacrylic acid (7 gave 3-(5-nitrofuran-2-yl-N-[2-(5-nitroimidazol-1-ylethyl]acrylamide (8. Condensation of 7 with 7-chloro-4-(piperazin-1-ylquinoline (9 afforded 1-[4-(7-chloroquinolin-4-ylpiperazin-1-yl-3-(5-nitrofuran-2-ylpropenone as a mixture of two isomers; 10-a (the E-isomer and 10-b (the Z-isomer. In addition, the reaction of 9 with 1-(2-bromoethyl-2-methyl-5-nitroimidazole (11 in the presence of K2CO3 and NaI yielded 7-chloro-4-(4-[2-(5-nitroimidazol-1-ylethyl]-piprazin-1-ylquinoline (12. On the basis of preliminary screening data for these new compounds, compound 12 exhibited potent lethal activities against Entamoeba histolytica and Giardia intestinalis; its IC50 ( about 1 µM was lower, at least by a factor of five, compared to the standard drug, metronidazole. In addition, the IC50 of compound 12 against the tested parasites is 600 times below that against Hep-2 and Vero cells. Compounds 8 and 10-a also exhibited potent or moderate antiamoebic and antigiardial activities with IC50 values of about 5.5 µM, and 140 µM, respectively, against the tested parasites. These two hybrid molecules, 8, 10-a, were also non-cytotoxic at the lethal concentrations against the parasites.

  6. Study on Integrated Recurrence Behaviors of Strong Earthquakes Along Entire Active Fault Zones in the Sichuan-Yunnan Region, China

    Institute of Scientific and Technical Information of China (English)

    Yi Guixi; Wen Xueze; Xu Xiwei

    2003-01-01

    Based on historical earthquake data, we use statistical methods to study integrated recurrencebehaviors of strong earthquakes along 7 selected active fault zones in the Sichuan-Yunnanregion. The results show that recurrences of strong earthquakes in the 7 fault zones displaynear-random, random and clustering behaviors. The recurrence processes are never quasi-periodic, and are neither strength-time nor time-strength dependent. The more independentsegments for strong earthquake rupturing a fault zone has, the more complicated thecorresponding recurrence process is. And relatively active periods and quiescent periods forearthquake activity occur alternatively. Within the active periods, the distribution ofrecurrence time intervals between earthquakes has relatively large discretion, and can bemodelled well by a Weibull distribution. The time distribution of the quiescent periods hasrelatively small discretion, and can be approximately described by some distributions as thenormal. Both the durations of the active periods and the numbers of strong earthquakes withinthe active periods vary obviously cycle by cycle, leading to the relatively active periods havingnever repeated quasi-periodically. Therefore, the prohabilistic assessment for middle- and long-term seismic hazard for entireties of active fault zones based on data of historical strongearthquakes on the fault zones still faces difficulty.

  7. Earthworm activities in cassava and egusi melon fields in the transitional zone of Benin: linking farmers' perceptions with field studies

    NARCIS (Netherlands)

    Saïdou, A.; Kossou, D.; Brussaard, L.; Richards, P.; Kuyper, T.W.

    2008-01-01

    Farmers' perceptions of earthworm activities were studied in the transitional zone of Benin and linked to scientific explanations of earthworm casting activities. Earthworm activity was assessed in farmers' fields with three different cassava cultivars and in a field experiment with three different

  8. Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

    Institute of Scientific and Technical Information of China (English)

    Ping-zheng ZHOU; Joseph BABCOCK; Lian-qing LIU; Min LI; Zhao-bing GAO

    2011-01-01

    Human ether-a-go-go related gene (hERG) potassium (K+) channels play a critical role in cardiac action potential repolarlzatlon. Mutations that reduce hERG conductance or surface expression may cause congenital long QT syndrome (LQTS). Moreover, the channels can be inhibited by structurally diverse small molecules, resulting in an acquired form of LQTS. Consequently, small molecules that increase the hERG current may be of value for treatment of LQTS. So far, nine hERG activators have been reported. The aim of this review is to discuss recent advances concerning the identification and action mechanism of hERG activators.

  9. How Large Scale Flows in the Solar Convection Zone may Influence Solar Activity

    Science.gov (United States)

    Hathaway, D. H.

    2004-01-01

    Large scale flows within the solar convection zone are the primary drivers of the Sun s magnetic activity cycle. Differential rotation can amplify the magnetic field and convert poloidal fields into toroidal fields. Poleward meridional flow near the surface can carry magnetic flux that reverses the magnetic poles and can convert toroidal fields into poloidal fields. The deeper, equatorward meridional flow can carry magnetic flux toward the equator where it can reconnect with oppositely directed fields in the other hemisphere. These axisymmetric flows are themselves driven by large scale convective motions. The effects of the Sun s rotation on convection produce velocity correlations that can maintain the differential rotation and meridional circulation. These convective motions can influence solar activity themselves by shaping the large-scale magnetic field pattern. While considerable theoretical advances have been made toward understanding these large scale flows, outstanding problems in matching theory to observations still remain.

  10. TLR-induced activation of Btk- Role for endosomal MHC class Ⅱ molecules revealed

    Institute of Scientific and Technical Information of China (English)

    Joan Ni Gabhann; Caroline A Jefferies

    2011-01-01

    @@ MHC molecules have been shown to play key roles in the immune system including regulating T-cell repertoire development through the process of positive and negative selection.MHC molecules also function to bridge the innate and adaptive immune system through the presentation of processed antigenic peptides to T-cells.

  11. Evaluation of Activated Leukocyte Cell Adhesion Molecule as a Biomarker for Breast Cancer in Egyptian Patients

    International Nuclear Information System (INIS)

    In this study, serum activated leukocyte cell adhesion molecule (ALCAM) levels were evaluated in 41 primary breast cancer patients and 20 healthy females, and its diagnostic value was quantified, and compared with those of carbohydrate antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA). Also, its prognostic value was examined. Serum ALCAM levels were also evaluated before and after surgical treatment. Serum levels of ALCAM and CA 15-3 were significantly higher in breast cancer patients than healthy controls (P=0.002, P=0.043 respectively), but the difference in serum CEA levels did not reach statistical significance. Serum ALCAM levels had significant area under the curve (AUC) (P=0.002), but serum levels of CA 15-3 and CEA had nonsignificant AUCs, and various combinations between them did not result in any improvement. A significant association was found between serum levels of ALCAM and CEA with age and menopausal status in breast cancer patients. Non-significant difference was shown in serum levels of ALCAM, CA 15-3 and CEA before and after surgical treatment. In conclusion, this study suggests that serum ALCAM may represent a novel diagnostic bio marker for breast cancer

  12. Kinetics of T cell-activation molecules in response to Mycobacterium tuberculosis antigens

    Directory of Open Access Journals (Sweden)

    Antas Paulo RZ

    2002-01-01

    Full Text Available The phenotypic features acquired subsequent to antigen-specific stimulation in vitro were evaluated by means of the kinetic expressions of CD69 and CD25 activation molecules on T lymphocytes and assayed by flow cytometry in response to PPD, Ag85B, and ferritin in PPD-positive healthy control individuals. In response to PHA, CD69 staining on both CD4+ and CD8+ T cells became initially marked after 4 h, peaked at 24 h, and quickly decreased after 120 h. For CD25, a latter expression was detected around 8 h, having increased after 96 h. As expected, the response rate to the mycobacterial antigens was much lower than that to the mitogen. Positive staining was high after 96 h for CD25 and after 24 h for CD69. CD69 expression was significantly enhanced (p < 0.05 on CD8+ as compared to CD4+ T cells. High levels were also found between 96-120 h. Regarding Ag85B, CD25+ cells were mostly CD4+ instead of CD8+ T cells. Moreover, in response to ferritin, a lower CD25 expression was noted. The present data will allow further characterization of the immune response to new mycobacterial-specific antigens and their evaluation for possible inclusion in developing new diagnostic techniques for tuberculosis as well in a new vaccine to prevent the disease.

  13. NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease

    Science.gov (United States)

    Azeredo, E L; De Oliveira-Pinto, L M; Zagne, S M; Cerqueira, D I S; Nogueira, R M R; Kubelka, C F

    2006-01-01

    During the innate immune response against infections, Natural Killer (NK) cells are as important effector cells as are Cytotoxic T lymphocytes (CTL) generated after antigenic stimulation in the adaptative response. NK cells increase in numbers, after viral infection or vaccination. We investigated the NK cell and CD8 T lymphocyte status in 55 dengue infected patients. The NK (CD56+CD3−) and CD56+ T cell (CD56+CD3+) rates rise during the acute phase of disease. The majority of NK cells from dengue patients display early markers for activation (CD69, HLA-DR, and CD38) and cell adhesion molecules (CD44, CD11a) during the acute phase of disease. The intracellular cytotoxic granule, TIA-1, is also up-regulated early in NK cells. Most of these markers appear also on CD8+ T lymphocytes but during the late acute phase. Circulating IL-15 is elevated in a significant number of patients during early acute infection and its values were statistically correlated with NK frequencies and cytotoxic markers on NKs. We have therefore shown that dengue virus infection is very likely stimulating a cytotoxic response that may be efficient in controlling the virus in synergism with CD8+ T lymphocytes. Interestingly, the heightened CD56+CD3−, CD56+CD3+, CD56+TIA-1+ and CD56+CD11a+ cell rates are associated with mild dengue clinical manifestations and might indicate a good prognosis of the disease. PMID:16412060

  14. Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5.

    Science.gov (United States)

    Senisterra, Guillermo; Wu, Hong; Allali-Hassani, Abdellah; Wasney, Gregory A; Barsyte-Lovejoy, Dalia; Dombrovski, Ludmila; Dong, Aiping; Nguyen, Kong T; Smil, David; Bolshan, Yuri; Hajian, Taraneh; He, Hao; Seitova, Alma; Chau, Irene; Li, Fengling; Poda, Gennadiy; Couture, Jean-François; Brown, Peter J; Al-Awar, Rima; Schapira, Matthieu; Arrowsmith, Cheryl H; Vedadi, Masoud

    2013-01-01

    WDR5 (WD40 repeat protein 5) is an essential component of the human trithorax-like family of SET1 [Su(var)3-9 enhancer-of-zeste trithorax 1] methyltransferase complexes that carry out trimethylation of histone 3 Lys4 (H3K4me3), play key roles in development and are abnormally expressed in many cancers. In the present study, we show that the interaction between WDR5 and peptides from the catalytic domain of MLL (mixed-lineage leukaemia protein) (KMT2) can be antagonized with a small molecule. Structural and biophysical analysis show that this antagonist binds in the WDR5 peptide-binding pocket with a Kd of 450 nM and inhibits the catalytic activity of the MLL core complex in vitro. The degree of inhibition was enhanced at lower protein concentrations consistent with a role for WDR5 in directly stabilizing the MLL multiprotein complex. Our data demonstrate inhibition of an important protein-protein interaction and form the basis for further development of inhibitors of WDR5-dependent enzymes implicated in MLL-rearranged leukaemias or other cancers.

  15. The new generation drug candidate molecules: Spectral, electrochemical, DNA-binding and anticancer activity properties

    Science.gov (United States)

    Gölcü, Ayşegül; Muslu, Harun; Kılıçaslan, Derya; Çeşme, Mustafa; Eren, Özge; Ataş, Fatma; Demirtaş, İbrahim

    2016-09-01

    The new generation drug candidate molecules [Cu(5-Fu)2Cl2H2O] (NGDCM1) and [Zn(5-Fu)2(CH3COO)2] (NGDCM2) were obtained from the reaction of copper(II) and zinc(II) salts with the anticancer drug 5-fluoracil (5-Fu). These compounds have been characterized by spectroscopic and analytical techniques. Thermal behavior of the compounds were also investigated. The electrochemical properties of the compounds have been investigated by cyclic voltammetry (CV) using glassy carbon electrode. The biological activity of the NGDCM1 and NGDCM2 has been evaluated by examining their ability to bind to fish sperm double strand DNA (FSdsDNA) with UV spectroscopy. UV studies of the interaction of the 5-Fu and metal derivatives with FSdsDNA have shown that these compounds can bind to FSdsDNA. The binding constants of the compounds with FSdsDNA have also been calculated. Thermal decomposition of the compounds lead to the formation of CuO and ZnO as final products. The effect of proliferation 5-Fu, NGDCM1 and NGDCM2 were examined on the HeLa cells using real-time cell analyzer with three different concentrations.

  16. Active faults in the deformation zone off Noto Peninsula, Japan, revealed by high- resolution seismic profiles

    Science.gov (United States)

    Inoue, T.; Okamura, Y.; Murakami, F.; Kimura, H.; Ikehara, K.

    2008-12-01

    Recently, a lot of earthquakes occur in Japan. The deformation zone which many faults and folds have concentrated exists on the Japan Sea side of Japan. The 2007 Noto Hanto Earthquake (MJMA 6.9) and 2007 Chuetsu-oki Earthquake (MJMA 6.8) were caused by activity of parts of faults in this deformation zone. The Noto Hanto Earthquake occurred on 25 March, 2007 under the northwestern coast of Noto Peninsula, Ishikawa Prefecture, Japan. This earthquake is located in Quaternary deformation zone that is continued from northern margin of Noto Peninsula to southeast direction (Okamura, 2007a). National Institute of Advanced Industrial Science and Technology (AIST) carried out high-resolution seismic survey using Boomer and 12 channels short streamer cable in the northern part off Noto Peninsula, in order to clarify distribution and activities of active faults in the deformation zone. A twelve channels short streamer cable with 2.5 meter channel spacing developed by AIST and private corporation is designed to get high resolution seismic profiles in shallow sea area. The multi-channel system is possible to equip on a small fishing boat, because the data acquisition system is based on PC and the length of the cable is short and easy to handle. Moreover, because the channel spacing is short, this cable is very effective for a high- resolution seismic profiling survey in the shallow sea, and seismic data obtained by multi-channel cable can be improved by velocity analysis and CDP stack. In the northern part off Noto Peninsula, seismic profiles depicting geologic structure up to 100 meters deep under sea floor were obtained. The most remarkable reflection surface recognized in the seismic profiles is erosion surface at the Last Glacial Maximum (LGM). In the western part, sediments about 30 meters (40 msec) thick cover the erosional surface that is distributed under the shelf shallower than 100m in depth and the sediments thin toward offshore and east. Flexures like deformation in

  17. Tailoring activated carbon by surface chemical modification with O, S, and N containing molecules

    Directory of Open Access Journals (Sweden)

    Rachel RibeiroVieira Azzi Rios

    2003-06-01

    Full Text Available In this work the surface of activated carbon was chemically modified in order to introduce O, S and N containing groups. The activated carbon surface was selectively oxidized with concentrated HNO3 under controlled conditions. Characterization by thermogravimetric analyses, infrared spectroscopy and NaOH titration suggested the formation of mainly -COOH and small amounts of -OH groups, with concentration of approximately 4.10(21 groups/g of carbon. These -COOH functionalized carbons showed high adsorption capacity for metal cations in aqueous solution in the following order: Pb+2>Cu+2>Ni+2 >Cd+2~Co+2>Ca+2 , suggesting a cation exchange mechanism via a surface complex [COO-M+2]. These -COOHsurf groups can be reacted with SOCl2 to produce a surface acylchloride group, -COCl. This surface -COCl group proved to be a very reactive and versatile intermediate for the grafting of different S and N containing molecules onto the carbon surface, such as 1,2-ethaneditiol (EDT-, HSCH2CH2SH 1,7-dimercapto-4-thioheptane (DMTH-HSCH2CH2CH2SCH2CH 2CH2SH or 1,2-ethylenediamine (EDA- NH2CH2CH2NH2 and triethyltetraamine, TEA (H2NCH2CH2NHCH2CH 2NHCH2CH2 NH2. The characterization of these materials was carried out by TG, IR and TPDMS (Temperature Programmed Decomposition Mass Spectrometry experiments suggesting the formation of thioesther and amide surface groups, i.e. -COSR and -CONHR, with yields of approximately 50 and 75% for the reaction with DME and EDA, respectively. Preliminary adsorption experiments showed that these materials can efficiently remove metals such as Pb+2, Cu+2 and Ni+2 from aqueous medium.

  18. NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation

    Directory of Open Access Journals (Sweden)

    Fabio eCavaliere

    2013-12-01

    Full Text Available Multipotent cells from the juvenile subventricular zone (SVZ possess the ability to differentiate into new neural cells. Depending on local signals, SVZ can generate new neurons, astrocytes or oligodendrocytes. We previously demonstrated that activation of NMDA receptors in SVZ progenitors increases the rate of oligodendrocyte differentiation. Here we investigated the mechanisms involved in NMDA receptor-dependent differentiation. Using functional studies performed with the reporter gene luciferase we found that activation of NMDA receptor stimulates PKC. In turn, stimulation of PKC precedes the activation of NADPH oxidase (NOX as demonstrated by translocation of the p67phox subunit to the cellular membrane. We propose that NOX2 is involved in the transduction of the signal from NMDA receptors through PKC activation as the inhibitor gp91 reduced their pro-differentiation effect. In addition, our data and that from other groups suggest that signaling through the NMDA receptor/PKC/NOX2 cascade generates ROS that activate the PI3/mTOR pathway and finally leads to the generation of new oligodendrocytes.

  19. Stellar Activity Mimics a Habitable-zone Planet around Kapteyn's Star

    Science.gov (United States)

    Robertson, Paul; Roy, Arpita; Mahadevan, Suvrath

    2015-06-01

    Kapteyn’s star is an old M subdwarf believed to be a member of the Galactic halo population of stars. A recent study has claimed the existence of two super-Earth planets around the star based on radial velocity (RV) observations. The innermost of these candidate planets—Kapteyn b (P = 48 days)—resides within the circumstellar habitable zone (HZ). Given recent progress in understanding the impact of stellar activity in detecting planetary signals, we have analyzed the observed HARPS data for signatures of stellar activity. We find that while Kapteyn’s star is photometrically very stable, a suite of spectral activity indices reveal a large-amplitude rotation signal, and we determine the stellar rotation period to be 143 days. The spectral activity tracers are strongly correlated with the purported RV signal of “planet b,” and the 48-day period is an integer fraction (1/3) of the stellar rotation period. We conclude that Kapteyn b is not a planet in the HZ, but an artifact of stellar activity.

  20. Alignment of synaptic vesicle macromolecules with the macromolecules in active zone material that direct vesicle docking.

    Directory of Open Access Journals (Sweden)

    Mark L Harlow

    Full Text Available Synaptic vesicles dock at active zones on the presynaptic plasma membrane of a neuron's axon terminals as a precondition for fusing with the membrane and releasing their neurotransmitter to mediate synaptic impulse transmission. Typically, docked vesicles are next to aggregates of plasma membrane-bound macromolecules called active zone material (AZM. Electron tomography on tissue sections from fixed and stained axon terminals of active and resting frog neuromuscular junctions has led to the conclusion that undocked vesicles are directed to and held at the docking sites by the successive formation of stable connections between vesicle membrane proteins and proteins in different classes of AZM macromolecules. Using the same nanometer scale 3D imaging technology on appropriately stained frog neuromuscular junctions, we found that ∼10% of a vesicle's luminal volume is occupied by a radial assembly of elongate macromolecules attached by narrow projections, nubs, to the vesicle membrane at ∼25 sites. The assembly's chiral, bilateral shape is nearly the same vesicle to vesicle, and nubs, at their sites of connection to the vesicle membrane, are linked to macromolecules that span the membrane. For docked vesicles, the orientation of the assembly's shape relative to the AZM and the presynaptic membrane is the same vesicle to vesicle, whereas for undocked vesicles it is not. The connection sites of most nubs on the membrane of docked vesicles are paired with the connection sites of the different classes of AZM macromolecules that regulate docking, and the membrane spanning macromolecules linked to these nubs are also attached to the AZM macromolecules. We conclude that the luminal assembly of macromolecules anchors in a particular arrangement vesicle membrane macromolecules, which contain the proteins that connect the vesicles to AZM macromolecules during docking. Undocked vesicles must move in a way that aligns this arrangement with the AZM

  1. An enzymatic deconjugation method for the analysis of small molecule active drugs on antibody-drug conjugates.

    Science.gov (United States)

    Li, Yi; Gu, Christine; Gruenhagen, Jason; Yehl, Peter; Chetwyn, Nik P; Medley, Colin D

    2016-01-01

    Antibody-drug conjugates (ADCs) are complex therapeutic agents that use the specific targeting properties of antibodies and the highly potent cytotoxicity of small molecule drugs to selectively eliminate tumor cells while limiting the toxicity to normal healthy tissues. Two critical quality attributes of ADCs are the purity and stability of the active small molecule drug linked to the ADC, but these are difficult to assess once the drug is conjugated to the antibody. In this study, we report a enzyme deconjugation approach to cleave small molecule drugs from ADCs, which allows the drugs to be subsequently characterized by reversed-phase high performance liquid chromatography. The model ADC we used in this study utilizes a valine-citrulline linker that is designed to be sensitive to endoproteases after internalization by tumor cells. We screened several proteases to determine the most effective enzyme. Among the 3 cysteine proteases evaluated, papain had the best efficiency in cleaving the small molecule drug from the model ADC. The deconjugation conditions were further optimized to achieve complete cleavage of the small molecule drug. This papain deconjugation approach demonstrated excellent specificity and precision. The purity and stability of the active drug on an ADC drug product was evaluated and the major degradation products of the active drug were identified. The papain deconjugation method was also applied to several other ADCs, with the results suggesting it could be applied generally to ADCs containing a valine-citrulline linker. Our results indicate that the papain deconjugation method is a powerful tool for characterizing the active small molecule drug conjugated to an ADC, and may be useful in ensuring the product quality, efficacy and the safety of ADCs. PMID:26891281

  2. Outcome of early active mobilization after flexor tendons repair in zones II-V in hand

    Directory of Open Access Journals (Sweden)

    Saini Narender

    2010-01-01

    Full Text Available Background: The functional outcome of a flexor tendon injury after repair depends on multiple factors. The postoperative management of tendon injuries has paved a sea through many mobilization protocols. The improved understanding of splinting techniques has promoted the understanding and implication of these mobilization protocols. We conducted a study to observe and record the results of early active mobilization of repaired flexor tendons in zones II-V. Materials and Methods: 25 cases with 75 digits involving 129 flexor tendons including 8 flexor pollicis longus (FPL tendons in zones II-V of thumb were subjected to the early active mobilization protocol. Eighteen (72% patients were below 30 years of age. Twenty-four cases (96% sustained injury by sharp instrument either accidentally or by assault. Ring and little finger were involved in 50% instances. In all digits, either a primary repair (n=26 or a delayed primary repair (n=49 was done. The repair was done with the modified Kessler core suture technique with locking epitendinous sutures with a knot inside the repair site, using polypropylene 3-0/4-0 sutures. An end-to-end repair of the cut nerves was done under loupe magnification using a 6-0/8-0 polyamide suture. The rehabilitation program adopted was a modification of Kleinert′s regimen, and Silfverskiold regimen. The final assessment was done at 14 weeks post repair using the Louisville system of Lister et al. Results: Eighteen of excellent results were attributed to ring and little fingers where there was a flexion lag of < 1 cm and an extension lag of < 15o. FPL showed 75% (n=6 excellent flexion. 63% (n=47 digits showed excellent results whereas good results were seen in 19% (n=14 digits. Nine percent (n=7 digits showed fair and the same number showed poor results. The cases where the median (n=4 or ulnar nerve (n=6 or both (n=3 were involved led to some deformity (clawing/ape thumb at 6 months postoperatively. The cases with digital

  3. Activated platelets form protected zones of adhesion on fibrinogen and fibronectin-coated surfaces

    OpenAIRE

    1993-01-01

    Leukocytes form zones of close apposition when they adhere to ligand- coated surfaces. Because plasma proteins are excluded from these contact zones, we have termed them protected zones of adhesion. To determine whether platelets form similar protected zones of adhesion, gel-filtered platelets stimulated with thrombin or ADP were allowed to adhere to fibrinogen- or fibronectin-coated surfaces. The protein- coated surfaces with platelets attached were stained with either fluorochrome-conjugate...

  4. Zeolite H-BEA catalysed multicomponent reaction: One-pot synthesis of amidoalkyl naphthols - Biologically active drug-like molecules

    Indian Academy of Sciences (India)

    Sunil R Mistry; Rikesh S Joshi; Kalpana C Maheria

    2011-07-01

    Zeolite has been used as an efficient and a novel heterogeneous catalyst for one-pot synthesis of biologically active drug-like molecules, amidoalkyl naphthols. This green route involves multicomponent reaction of 2-naphthol, aromatic aldehydes and amide in the presence of a catalytic amount of zeolite H-Beta (H-BEA) under solvent reflux as well as solvent-free conditions.

  5. HLA-DR molecules enhance signal transduction through the CD3/Ti complex in activated T cells

    DEFF Research Database (Denmark)

    Odum, Niels; Martin, P J; Schieven, G L;

    1991-01-01

    Crosslinking HLA-DR molecules by monoclonal antibodies (mAb) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic Ca2+ concentration ([Ca2+]i) in activated human T cells. Here we have studied the effect of DR on CD3-induced signal transduction...

  6. Single molecule activity measurements of cytochrome P450 oxidoreductase reveal the existence of two discrete functional states

    DEFF Research Database (Denmark)

    Laursen, Tomas; Singha, Aparajita; Rantzau, Nicolai;

    2014-01-01

    Electron transfer between membrane spanning oxi-doreductase enzymes crucially controls vital meta-bolic processes. Here we studied for the first time with single molecule resolution the function of P450 oxidoreductase (POR), the canonical membrane spanning activator of all microsomal cytochrome P...

  7. Complement activating soluble pattern recognition molecules with collagen-like regions, mannan-binding lectin, ficolins and associated proteins

    DEFF Research Database (Denmark)

    Thiel, Steffen

    2007-01-01

    Mannan-binding lectin (MBL), L-ficolin, M-ficolin and H-ficolin are all complement activating soluble pattern recognition molecules with recognition domains linked to collagen-like regions. All four may form complexes with four structurally related proteins, the three MBL-associated serine...

  8. Machine learning models identify molecules active against the Ebola virus in vitro [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sean Ekins

    2016-01-01

    Full Text Available The search for small molecule inhibitors of Ebola virus (EBOV has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in

  9. Machine learning models identify molecules active against the Ebola virus in vitro [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sean Ekins

    2015-10-01

    Full Text Available The search for small molecule inhibitors of Ebola virus (EBOV has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in

  10. Structure-activity relationship studies of strigolactone-related molecules for branching inhibition in garden pea: molecule design for shoot branching.

    Science.gov (United States)

    Boyer, François-Didier; de Saint Germain, Alexandre; Pillot, Jean-Paul; Pouvreau, Jean-Bernard; Chen, Victor Xiao; Ramos, Suzanne; Stévenin, Arnaud; Simier, Philippe; Delavault, Philippe; Beau, Jean-Marie; Rameau, Catherine

    2012-08-01

    Initially known for their role in the rhizosphere in stimulating the seed germination of parasitic weeds such as the Striga and Orobanche species, and later as host recognition signals for arbuscular mycorrhizal fungi, strigolactones (SLs) were recently rediscovered as a new class of plant hormones involved in the control of shoot branching in plants. Herein, we report the synthesis of new SL analogs and, to our knowledge, the first study of SL structure-activity relationships for their hormonal activity in garden pea (Pisum sativum). Comparisons with their action for the germination of broomrape (Phelipanche ramosa) are also presented. The pea rms1 SL-deficient mutant was used in a SL bioassay based on axillary bud length after direct SL application on the bud. This assay was compared with an assay where SLs were fed via the roots using hydroponics and with a molecular assay in which transcript levels of BRANCHED1, the pea homolog of the maize TEOSINTE BRANCHED1 gene were quantified in axillary buds only 6 h after application of SLs. We have demonstrated that the presence of a Michael acceptor and a methylbutenolide or dimethylbutenolide motif in the same molecule is essential. It was established that the more active analog 23 with a dimethylbutenolide as the D-ring could be used to control the plant architecture without strongly favoring the germination of P. ramosa seeds. Bold numerals refer to numbers of compounds. PMID:22723084

  11. SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression.

    Science.gov (United States)

    Mochida, Sumiko; Hida, Yamato; Tanifuji, Shota; Hagiwara, Akari; Hamada, Shun; Abe, Manabu; Ma, Huan; Yasumura, Misato; Kitajima, Isao; Sakimura, Kenji; Ohtsuka, Toshihisa

    2016-09-13

    Short-term synaptic depression (STD) is a common form of activity-dependent plasticity observed widely in the nervous system. Few molecular pathways that control STD have been described, but the active zone (AZ) release apparatus provides a possible link between neuronal activity and plasticity. Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. A phosphomimetic CAST (S45D) mimics CAST deletion, which enhances STD by delaying reloading of the readily releasable pool (RRP), resulting in a pool size decrease. A phosphonegative CAST (S45A) inhibits STD and accelerates RRP reloading. Our results suggest that the CAST/SAD-B reaction serves as a brake on synaptic transmission by temporal calibration of activity and synaptic depression via RRP size regulation. PMID:27626661

  12. Growth of the active zone in nitride based long wavelength laser structures

    Science.gov (United States)

    Rossow, U.; Jönen, H.; Brendel, M.; Dräger, A.; Langer, T.; Hoffmann, L.; Bremers, H.; Hangleiter, A.

    2011-01-01

    In xGa 1- xN/GaN quantum well (QW) structures grown on c-plane surfaces for long wavelength light emitters have been investigated intended. We reached indium concentrations of xIn≥0.35 with good optical and structural quality. For QW thicknesses dQW≤2 nm a fully strained layer structure is observed. QWs of such high indium concentrations, however, are very sensitive to the growth conditions of the subsequent layers and thermal stability/degradation becomes an important issue. We modified the growth of the QWs to avoid or minimize V-pit formation without temperature ramping in the barriers and showed that their properties were unchanged when used in the active zone of a laser structure.

  13. Determination of dissociation constants of pharmacologically active xanthones by capillary zone electrophoresis with diode array detection.

    Science.gov (United States)

    Wu, Xiaomu; Gong, Suxuan; Bo, Tao; Liao, Yiping; Liu, Huwei

    2004-12-24

    In this article, the dissociation constants (pKa) of 10 pharmacologically active xanthones isolated from herbal medicine Securidaca inappendiculata were determined by capillary zone electrophoresis with diode array detection. The pKa values determined by the method based on the electrophoretic mobilities (calculated from migration times) have been proved by the method based on UV absorbance calculated from the online spectra corresponding peaks. No conspicuous difference was observed between the two methods with acceptable reproducibility. Two pKa values (pKa1 and pKa2) were found for four xanthones while generally the 10 compounds possess the pKa values ranging from 6.4 to 9.2. PMID:15641365

  14. Radon variations in an active landslide zone from Himalaya: A preliminary study

    International Nuclear Information System (INIS)

    The radon concentration was measured in soil and water samples from an active landslide zone in the Garhwal Himalaya. The landslide is compound in nature i.e. slump in the crown portion and debris slide in the lower part. The measured radon concentration varies from 3.1 to 18.3 Bq/l in water whereas in soil/debris samples it varies from 2.3 to 12.2 kBq/m3. The crown portion (upper portion) show higher radon values in comparison to distal portion. The higher radon concentration in crown portion may be because of the failure plane of landslide associated with high fracturing and crushing whereas, increased porosity of debris of slide does not allow radon to accumulate in soil and water in the lower portion. (author)

  15. Coordination geometries of Zn(II) and Cd(II) in phosphotriesterase: Influence of water molecules in the active site

    DEFF Research Database (Denmark)

    Krauss, M; Olsen, Lars; Antony, J;

    2002-01-01

    Models of the metal ion binding sites of native ZnZn and of cadmium-substituted ZnCd and CdCd phosphotriesterase, including full amino acid side chains, were geometry optimized with quantum mechanical methods, with effective fragment potentials (EFP) representing the protein environment surrounding...... the active site. One to three water molecules were included in the active site in addition to the bridging hydroxide. Comparison with recent X-ray diffraction results Benning, M. M.; Shim, H.; Raushel, F. M.; Holden, H. M. Biochemistry 2001, 40, 2712-22 is hindered by the presence of ethylene glycol...... molecules in the active site. We suggest that the ethylene glycol required for crystallization distorts the structure of the water network in the active site and that the theoretical structures provide a better description of the system in aqueous solution. Cd-113 NMR isotropic shielding calculations were...

  16. APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.

    Science.gov (United States)

    Laßek, Melanie; Weingarten, Jens; Wegner, Martin; Mueller, Benjamin F; Rohmer, Marion; Baeumlisberger, Dominic; Arrey, Tabiwang N; Hick, Meike; Ackermann, Jörg; Acker-Palmer, Amparo; Koch, Ina; Müller, Ulrike; Karas, Michael; Volknandt, Walter

    2016-04-01

    The hallmarks of Alzheimer's disease (AD) are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP) has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ) highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs) was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI) networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network. PMID:27092780

  17. APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.

    Directory of Open Access Journals (Sweden)

    Melanie Laßek

    2016-04-01

    Full Text Available The hallmarks of Alzheimer's disease (AD are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.

  18. The property of fault zone and fault activity of Shionohira Fault, Fukushima, Japan

    Science.gov (United States)

    Seshimo, K.; Aoki, K.; Tanaka, Y.; Niwa, M.; Kametaka, M.; Sakai, T.; Tanaka, Y.

    2015-12-01

    The April 11, 2011 Fukushima-ken Hamadori Earthquake (hereafter the 4.11 earthquake) formed co-seismic surface ruptures trending in the NNW-SSE direction in Iwaki City, Fukushima Prefecture, which were newly named as the Shionohira Fault by Ishiyama et al. (2011). This earthquake was characterized by a westward dipping normal slip faulting, with a maximum displacement of about 2 m (e.g., Kurosawa et al., 2012). To the south of the area, the same trending lineaments were recognized to exist even though no surface ruptures occurred by the earthquake. In an attempt to elucidate the differences of active and non-active segments of the fault, this report discusses the results of observation of fault outcrops along the Shionohira Fault as well as the Coulomb stress calculations. Only a few outcrops have basement rocks of both the hanging-wall and foot-wall of the fault plane. Three of these outcrops (Kyodo-gawa, Shionohira and Betto) were selected for investigation. In addition, a fault outcrop (Nameishi-minami) located about 300 m south of the southern tip of the surface ruptures was investigated. The authors carried out observations of outcrops, polished slabs and thin sections, and performed X-ray diffraction (XRD) to fault materials. As a result, the fault zones originating from schists were investigated at Kyodo-gawa and Betto. A thick fault gouge was cut by a fault plane of the 4.11 earthquake in each outcrop. The fault materials originating from schists were fault bounded with (possibly Neogene) weakly deformed sandstone at Shionohira. A thin fault gouge was found along the fault plane of 4.11 earthquake. A small-scale fault zone with thin fault gouge was observed in Nameishi-minami. According to XRD analysis, smectite was detected in the gouges from Kyodo-gawa, Shionohira and Betto, while not in the gouge from Nameishi-minami.

  19. Troglitazone, a PPAR-γ activator prevents endothelial cell adhesion molecule expression and lymphocyte adhesion mediated by TNF-α

    OpenAIRE

    Itoh Makoto; Joh Takashi; Minagar Alireza; Welbourne Tomas; Jordan Paul; Sasaki Makoto; Elrod John W; Alexander J Steven

    2005-01-01

    Abstract Background Cytokine mediated induction of the mucosal addressin cell adhesion molecule-1(MAdCAM-1) expression is associated with the onset and progression of inflammatory bowel disease (IBD). Results Using western blotting and cell-based ELISA, we show in this study that troglitazone, an activator of the peroxisome proliferator-activated receptor-γ (PPAR-γ), widely used in the treatment of diabetes, has as well recently been highlighted as protective in models of inflammation and can...

  20. Interplay of solvent additive concentration and active layer thickness on the performance of small molecule solar cells.

    Science.gov (United States)

    Love, John A; Collins, Samuel D; Nagao, Ikuhiro; Mukherjee, Subhrangsu; Ade, Harald; Bazan, Guillermo C; Nguyen, Thuc-Quyen

    2014-11-19

    A relationship between solvent additive concentration and active layer thickness in small-molecule solar cells is investigated. Specifically, the additive concentration must scale with the amount of semiconductor material and not as absolute concentration in solution. Devices with a wide range of active layers with thickness up to 200 nm can readily achieve efficiencies close to 6% when the right concentration of additive is used.

  1. Significant foreshock activities of M>7.5 earthquakes in the Kuril subduction zone

    Science.gov (United States)

    Harada, T.; Yokoi, S.; Satake, K.

    2014-12-01

    In the Kuril subduction zone, some M>7.5 earthquakes are accompanied by significant foreshock activities, providing a good opportunity to understand the characteristics of foreshocks for large interplate events such as occur along the Japan Trench and Nankai Trough etc. Some preliminary results from our examination of the foreshock sequences are as follows. Relocated foreshocks tend to migrate with time toward the trench axis. Foreshock distributions of the interplate earthquakes do not overlap with the large coseismic slips (asperities) of the mainshocks. Foreshocks of the 2007 northern Kuril outer-rise event, however, were distributed on the entire rupture area. Foreshock sequences seem to be limited in the regions where the background seismicity rates are relatively high. The foreshock activities were found in the examination of the space-time pattern of M>7 events along the northern Japan to Kuril trench since 1913 (e.g. Harada, Satake, and Ishibashi, 2011:AGU, 2012:AOGS). The large earthquakes preceded by active foreshock sequences are: the 2006 (M8.3), 2007 (M8.1) offshore Simushir earthquakes, the 1963 (M8.5), 1991 (M7.6), 1995 (M7.9) offshore Urup events, the 1978 (M7.8) offshore Iturup events, the 1969 (M8.2) offshore Shikotan event. In contrast, M>7.5 interplate earthquakes offshore Hokkaido (1952 (M8.1), 1973 (M7.8), 2003 (M8.1)) and intraslab earthquakes (1958 (M8.3), 1978 (M7.8), 1993 (M7.6), 1994 (M8.3)) had few or no foreshocks. In the examination of the active foreshocks, we relocated foreshocks by the Modified JHD method (Hurukawa, 1995), compared relocated foreshock areas with mainshock coseismic slip distributions estimated by the teleseismic body-wave inversion (Kikuchi and Kanamori, 2003), and examined the relation between active foreshock sequences and regional background seismicity. This study was supported by the MEXT's "New disaster mitigation research project on Mega thrust earthquakes around Nankai/Ryukyu subduction zones".

  2. Phosphate Activation via Reduced Oxidation State Phosphorus (P. Mild Routes to Condensed-P Energy Currency Molecules

    Directory of Open Access Journals (Sweden)

    Claire R. Cousins

    2013-07-01

    Full Text Available The emergence of mechanisms for phosphorylating organic and inorganic molecules is a key step en route to the earliest living systems. At the heart of all contemporary biochemical systems reside reactive phosphorus (P molecules (such as adenosine triphosphate, ATP as energy currency molecules to drive endergonic metabolic processes and it has been proposed that a predecessor of such molecules could have been pyrophosphate [P2O74−; PPi(V]. Arguably the most geologically plausible route to PPi(V is dehydration of orthophosphate, Pi(V, normally a highly endergonic process in the absence of mechanisms for activating Pi(V. One possible solution to this problem recognizes the presence of reactive-P containing mineral phases, such as schreibersite [(Fe,Ni3P] within meteorites whose abundance on the early Earth would likely have been significant during a putative Hadean-Archean heavy bombardment. Here, we propose that the reduced oxidation state P-oxyacid, H-phosphite [HPO32−; Pi(III] could have activated Pi(V towards condensation via the intermediacy of the condensed oxyacid pyrophosphite [H2P2O52−; PPi(III]. We provide geologically plausible provenance for PPi(III along with evidence of its ability to activate Pi(V towards PPi(V formation under mild conditions (80 °C in water.

  3. Anti-biofilm activity of pseudoalteromonas haloplanktis tac125 against staphylococcus epidermidis biofilm: Evidence of a signal molecule involvement?

    Science.gov (United States)

    Parrilli, E; Papa, R; Carillo, S; Tilotta, M; Casillo, A; Sannino, F; Cellini, A; Artini, M; Selan, L; Corsaro, M M; Tutino, M L

    2015-03-01

    Staphylococcus epidermidis is recognized as cause of biofilm-associated infections and interest in the development of new approaches for S. epidermidis biofilm treatment has increased. In a previous paper we reported that the supernatant of Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 presents an anti-biofilm activity against S. epidermidis and preliminary physico-chemical characterization of the supernatant suggested that this activity is due to a polysaccharide. In this work we further investigated the chemical nature of the anti-biofilm P. haloplanktis TAC125 molecule. The production of the molecule was evaluated in different conditions, and reported data demonstrated that it is produced in all P. haloplanktis TAC125 biofilm growth stages, also in minimal medium and at different temperatures. By using a surface coating assay, the surfactant nature of the anti-biofilm compound was excluded. Moreover, a purification procedure was set up and the analysis of an enriched fraction demonstrated that the anti-biofilm activity is not due to a polysaccharide molecule but that it is due to small hydrophobic molecules that likely work as signal. The enriched fraction was also used to evaluate the effect on S. epidermidis biofilm formation in dynamic condition by BioFlux system. PMID:25816412

  4. Calculations of Induced Activity in the ATLAS Experiment for Nuclear Waste Zoning.

    CERN Document Server

    Morev, M N

    2007-01-01

    Extensive calculations were performed with the general activation formula using the fluxes of high-energy hadrons and low-energy neutrons previously obtained from simulations with the GCALOR code of the ATLAS detector. Three sets of proton cross-sections were used for hadrons energy above 20 MeV: (a) one set calculated with the YIELDX code (i.e., the Silberberg-Tsao formula of partial proton spallation cross-sections), (b) one set calculated with the Rudstam formula, and (c) the ‘best-estimate' dataset which was a compilation of the available experimental and calculated data. In the energy region below 20 MeV, neutron activation cross-sections were taken from evaluated nuclear data files. The activity of each nuclide for a predefined operation scenario (i.e., number and duration of irradiation and shutdown cycles) was normalized to reference values taken from the European or Swiss legislations, to obtain an aggregate estimate of the radiological hazard comparable with a nuclear waste zoning definition cr...

  5. Underground Corrosion of Activated Metals in an Arid Vadose Zone Environment

    Energy Technology Data Exchange (ETDEWEB)

    Adler Flitton, Mariana Kay; Mizia, Ronald Eugene; Bishop, Carolyn Wagoner

    2002-04-01

    The subsurface radioactive disposal site located at the Idaho National Engineering and Environmental Laboratory contains neutron-activated metals from nonfuel nuclear-reactor- core components. A long-term corrosion test is being conducted to obtain site-specific corrosion rates to support efforts to more accurately estimate the transfer of activated elements in an arid vadose zone environment. The tests use nonradioactive metal coupons representing the prominent neutron-activated material buried at the disposal location, namely, Type 304L stainless steel, Type 315L stainless steel, nickel-chromium alloy (UNS NO7718), beryllium, aluminum 6061-T6, and a zirconium alloy, (UNS R60804). In addition, carbon steel (the material presently used in the cask disposal liners and other disposal containers) and a duplex stainless steel (UNS S32550) (the proposed material for the high- integrity disposal containers) are also included in the test program. This paper briefly describes the test program and presents the early corrosion rate results after 1 year and 3 years of underground exposure.

  6. Underground Corrosion of Activated Metals in an Arid Vadose Zone Environment

    Energy Technology Data Exchange (ETDEWEB)

    Adler Flitton, M.K; Mizia, R.E.; Bishop, C.W.

    2001-10-24

    The subsurface radioactive disposal site located at the Idaho National Engineering and Environmental Laboratory contains neutron-activated metals from nonfuel nuclear-reactor- core components. A long-term corrosion test is being conducted to obtain site-specific corrosion rates to support efforts to more accurately estimate the transfer of activated elements in an arid vadose zone environment. The tests use nonradioactive metal coupons representing the prominent neutron-activated material buried at the disposal location, namely, Type 304L stainless steel, Type 315L stainless steel, nickel-chromium alloy (UNS NO7718), beryllium, aluminum 6061-T6, and a zirconium alloy, (UNS R60804). In addition, carbon steel (the material presently used in the cask disposal liners and other disposal containers) and a duplex stainless steel (UNS S32550) (the proposed material for the high- integrity disposal containers) are also included in the test program. This paper briefly describes the test program and presents the early corrosion rate results after 1 year and 3 years of underground exposure.

  7. Conformational, spectroscopic and nonlinear optical properties of biologically active N,N-dimethyltryptamine molecule: A theoretical study

    Science.gov (United States)

    Öner, Nazmiye; Tamer, Ömer; Avcı, Davut; Atalay, Yusuf

    2014-12-01

    The effective psychoactive properties of N,N-dimethyltryptamine (DMT) known as the near-death molecule have encouraged the imagination of many research disciplines for several decades. Although there is no theoretical study, a number of paper composed by experimental techniques have been reported for DMT molecule. In this study, the molecular modeling of DMT was carried out using B3LYP and HSEh1PBE levels of density functional theory (DFT). Our calculations showed that the energy gap between HOMO and LUMO is low, demonstrating that DMT is a biologically active molecule. Large hyperconjugation interaction energies imply that molecular charge transfer occurs in DMT. Moreover, NLO analysis indicates that DMT can be used an effective NLO material.

  8. Active tectonics west of New Zealand's Alpine Fault: South Westland Fault Zone activity shows Australian Plate instability

    Science.gov (United States)

    De Pascale, Gregory P.; Chandler-Yates, Nicholas; Dela Pena, Federico; Wilson, Pam; May, Elijah; Twiss, Amber; Cheng, Che

    2016-04-01

    The 300 km long South Westland Fault Zone (SWFZ) is within the footwall of the Central Alpine Fault (Plate is shown with cumulative dip-slip displacements up to 5.9 m (with 3 m throw) on Pleistocene and Holocene sediments and gentle hanging wall anticlinal folding. Cone penetration test (CPT) stratigraphy shows repeated sequences within the fault scarp (consistent with thrusting). Optically stimulated luminescence (OSL) dating constrains the most recent rupture post-12.1 ± 1.7 ka with evidence for three to four events during earthquakes of at least Mw 6.8. This study shows significant deformation is accommodated on poorly characterized Australian Plate structures northwest of the Alpine Fault and demonstrates that major active and seismogenic structures remain uncharacterized in densely forested regions on Earth.

  9. Combined single channel and single molecule detection identifies subunit composition of STIM1-activated transient receptor potential canonical (TRPC) channels.

    Science.gov (United States)

    Asanov, Alexander; Sampieri, Alicia; Moreno, Claudia; Pacheco, Jonathan; Salgado, Alfonso; Sherry, Ryan; Vaca, Luis

    2015-01-01

    Depletion of intracellular calcium ion stores initiates a rapid cascade of events culminating with the activation of the so-called Store-Operated Channels (SOC) at the plasma membrane. Calcium influx via SOC is essential in the initiation of calcium-dependent intracellular signaling and for the refilling of internal calcium stores, ensuring the regeneration of the signaling cascade. In spite of the significance of this evolutionary conserved mechanism, the molecular identity of SOC has been the center of a heated controversy spanning over the last 20 years. Initial studies positioned some members of the transient receptor potential canonical (TRPC) channel superfamily of channels (with the more robust evidence pointing to TRPC1) as a putative SOC. Recent evidence indicates that Stromal Interacting Molecule 1 (STIM1) activates some members from the TRPC family of channels. However, the exact subunit composition of TRPC channels remains undetermined to this date. To identify the subunit composition of STIM1-activated TRPC channels, we developed novel method, which combines single channel electrophysiological measurements based on the patch clamp technique with single molecule fluorescence imaging. We termed this method Single ion Channel Single Molecule Detection technique (SC-SMD). Using SC-SMD method, we have obtained direct evidence of the subunit composition of TRPC channels activated by STIM1. Furthermore, our electrophysiological-imaging SC-SMD method provides evidence at the molecular level of the mechanism by which STIM1 and calmodulin antagonize to modulate TRPC channel activity.

  10. Interaction of an immunodominant epitope with Ia molecules in T-cell activation

    DEFF Research Database (Denmark)

    Adorini, L; Sette, A; Buus, S;

    1988-01-01

    The amino acid sequence corresponding to residues 107-116 of hen egg-white lysozyme (HEL) has been identified as containing an immunodominant T-cell epitope recognized in association with the I-Ed molecule. The immunodominance of this epitope in HEL-primed H-2d mice was demonstrated by analysis o......-120)-peptide was found to be immunogenic in H-2d mice. Thus, a single semiconservative substitution drastically reduces binding capacity and abolishes immunogenicity, suggesting that a strict correlation exists between binding of a peptide to Ia molecules and its immunogenicity....

  11. Activation of Carbonyl-Containing Molecules with Solid Lewis Acids in Aqueous Media

    Energy Technology Data Exchange (ETDEWEB)

    Román-Leshkov, Yuriy [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Chemical Engineering; Davis, Mark E. [California Inst. of Technology (CalTech), Pasadena, CA (United States). Chemical Engineering

    2011-09-28

    Current interest in reacting carbonyl-containing molecules in aqueous media is primarily due to the growing emphasis on conversion of biomass to fuels and chemicals. Recently, solid Lewis acids have been shown to perform catalytic reactions with carbonyl-containing molecules such as sugars in aqueous media. Here, catalysis mediated by Lewis acids is briefly discussed, Lewis acid solids that perform catalysis in aqueous media are then described, and the review is concluded with a few comments on the outlook for the future.

  12. Activation of a water molecule coordinated to manganese: four study cases

    International Nuclear Information System (INIS)

    The daunting energy consumption of western societies calls for the development of renewable energies. Among them, hydrogen stands as a major candidate. The cleanest way of producing hydrogen is water electro- or photolysis. This reaction is carried out in natural photosynthesis by a manganese-oxo cluster, the functioning of which remains unknown. Insight into this mechanism would greatly help the search for low-cost water splitting catalysts. Our contribution to this field is the understanding of the fundamental processes that govern the activation of water by manganese complexes. This manuscript describes our attempts to generate electrochemically mononuclear manganese(IV) complexes bearing a fully deprotonated water molecule (oxo ligand). We have studied four different cases, which reflect different possible coordination spheres capable of stabilizing such species. In the first chapter, we will give a brief overview of the present energetic challenges faced by western societies. In the second chapter, we will present general considerations about manganese chemistry and a description of the structure and functioning of the water oxidizing enzyme. We will also describe the basic requirements for the splitting of water and present the goals of our work. In the third chapter, we will present the synthesis of a new family of tetradentate ligands, together with the synthesis and full characterization of the corresponding nickel(II) complexes. The first results obtained with the manganese analogue will also be shown. Chapter four presents the formation and the full characterization of a mononuclear manganese(IV)-oxo complex, by electrochemical oxidation of a manganese(II)-aqua complex. We will present different pathways to generate this species and show which intermediates are involved in this 2 e-, 2 H+ reaction. Chapter five describes the formation of a mononuclear manganese(IV) complex, by electrochemical oxidation of a manganese(III)-hydroxo complex. The manganese

  13. An Assessment of Variation in Active Ingredients of Ampucare from Different Zones of India

    Directory of Open Access Journals (Sweden)

    Naveen Pathak

    2010-04-01

    Full Text Available The present study was designed to assess the variation in curcumin content of Curcuma longa rhizome and total polyphenols in Azadirachta indica bark samples procured from different zones of India. Physico-chemical tests such as total ash, acid insoluble ash, alcohol soluble extractive, water soluble extractive, volatile oil content etc. were also determined. A slight variation was seen in the bark samples of Azadirachta indica. Total ash ranged from 4.25±0.15 (East zone to 5.57±0.20 (Central zone whereas acid insoluble ash ranged from 0.80±0.07 (East zone to 1.52±0.06 (Central zone. Alcohol soluble extractive value of East zone sample was found to be more than 4 times higher 16.95±0.80 than that of central zone 3.85±0.12, where lowest value was recorded. Water soluble extractive value was also found to be highest in East zone sample 17.80±1.10 which was 2 times more than that of Central zone sample 8.45±0.15. This variation may be due to variation in climatic conditions, soil type, pollution stress etc. All the results were within the limits as given in The Ayurvedic Pharmacopoeia of India. Total Polyphenols ranged from 190.0 mgGAE/g of dry weight (Central zone to 510.0 mgGAE/g of dry weight (East zone. All the samples were found to be rich in total polyphenols. In Curcuma longa samples, Total ash ranged from 3.10±0.20 (South zone to 4.80±0.25 (North zone whereas acid insoluble ash ranged from 0.55±0.04 (South zone to 1.24±0.06 (North zone. Alcohol soluble extractive value was found to be highest in South zone sample 14.80±0.30 which was found to be more than 3 times higher than that of central zone 4.28±0.19 where lowest value was recorded. Water soluble extractive value was also found to be highest in West zone sample 12.55±0.69 and lowest in Central zone sample 8.90±0.37. Volatile oil ranged from 3.50±0.21 North zone sample to 5.50±0.20 South zone sample, where highest volatile oil was recovered. All the results were within

  14. Persistent downregulation of the pancarcinoma-associated epithelial cell adhesion molecule via active intranuclear methylation

    NARCIS (Netherlands)

    van der Gun, Bernardina T. F.; Wasserkort, Reinhold; Monami, Amelie; Jeltsch, Albert; Rasko, Tamits; Slaska-Kiss, Krystyna; Cortese, Rene; Rots, Marianne G.; de Leij, Lou F. M. H.; Ruiters, Marcel H. J.; Kiss, Antal; Weinhold, Elmar; McLaughlin, Pamela M. J.

    2008-01-01

    The epithelial cell adhesion molecule (EpCAM) is expressed at high levels on the surface of most carcinoma cells. SiRNA silencing of EpCAM expression leads to reduced metastatic potential of tumor cells demonstrating its importance in oncogenesis and tumor progression. However, siRNA therapy require

  15. Unequal Activities of Enantiomers via Biological Receptors: Examples of Chiral Drug, Pesticide, and Fragrance Molecules

    Science.gov (United States)

    Mannschreck, Albrecht; Kiesswetter, Roland; von Angerer, Erwin

    2007-01-01

    A molecule coming from outside an organism can form a ligand-receptor complex. Upon its formation, a message is transmitted, for example, to certain cells. In this way, two enantiomers can emit messages that differ, either quantitatively or qualitatively. In the present article, these facts are taken as a common basis for the actions of chiral…

  16. Active tectonics west of New Zealand's Alpine Fault: South Westland Fault Zone activity shows Australian Plate instability

    Science.gov (United States)

    De Pascale, Gregory P.; Chandler-Yates, Nicholas; Dela Pena, Federico; Wilson, Pam; May, Elijah; Twiss, Amber; Cheng, Che

    2016-04-01

    The 300 km long South Westland Fault Zone (SWFZ) is within the footwall of the Central Alpine Fault (<20 km away) and has 3500 m of dip-slip displacement, but it has been unknown if the fault is active. Here the first evidence for SWFZ thrust faulting in the "stable" Australian Plate is shown with cumulative dip-slip displacements up to 5.9 m (with 3 m throw) on Pleistocene and Holocene sediments and gentle hanging wall anticlinal folding. Cone penetration test (CPT) stratigraphy shows repeated sequences within the fault scarp (consistent with thrusting). Optically stimulated luminescence (OSL) dating constrains the most recent rupture post-12.1 ± 1.7 ka with evidence for three to four events during earthquakes of at least Mw 6.8. This study shows significant deformation is accommodated on poorly characterized Australian Plate structures northwest of the Alpine Fault and demonstrates that major active and seismogenic structures remain uncharacterized in densely forested regions on Earth.

  17. An Active Area Model of Rapid Infiltration Response at Substantial Depth in the Unsaturated Zone

    Science.gov (United States)

    Mitchell, L.; Nimmo, J. R.

    2011-12-01

    In a porous medium subject to preferential flow, response to surface water infiltration can occur rapidly even at substantial depth in the unsaturated zone. In a ponding experiment at the Idaho National Laboratory (INL) the profile of undisturbed natural soil, seasonally dry at the start, was observed to approach field saturation throughout a 2 meter depth within 6 hours (Nimmo and Perkins, 2007). Traditional use of Richards' equation would require an unrealistically large unsaturated hydraulic conductivity of 40 m/day to capture the observed non-classic wetting behavior. Here we present a model for rapid flow using an active area concept similar to the active fracture model (Liu and others, 1998, WRR 34:2633-2646). The active area concept is incorporated within the preferential flow domain (which allows rapid downward movement) of a dual-domain model that also contains a diffuse-flow domain in which flow can be described by Richards' equation. Development of the active area model is motivated by observation of rapid wetting at substantial depth, as well as a phenomenon in which deep flow is observed before shallow flow. In this model water movement in the preferential domain can be physically conceptualized as laminar flow in free-surface films of constant average thickness. For a given medium, the preferential domain is characterized by an effective areal density (area per unit bulk volume) that describes the free-surface film capacity of the domain as a function of depth. The active area is defined as a portion of the effective areal density that dictates the depth and temporal distribution of domain-exchange and new infiltration within the preferential domain. With the addition of the active area concept, the model is capable of simulating non-diffusive vertical transport patterns. Advantages of the model include simulating rapid response for a variety of infiltration types, including ponding and rain events, as well as modeling relatively rapid aquifer

  18. Functional role of HLA class I cell-surface molecules in human T-lymphocyte activation and proliferation.

    OpenAIRE

    Taylor, D S; Nowell, P C; Kornbluth, J

    1986-01-01

    This investigation addressed the role of major histocompatibility complex-encoded class I molecules in the activation and proliferation of human lymphocytes. We studied the effect of antibodies specific for HLA-A and HLA-B locus gene products on mitogen-stimulated peripheral blood mononuclear cell (PBMC) subpopulations. Three individually derived, well-characterized anti-HLA class I monoclonal antibodies were demonstrated to inhibit the proliferation of human PBMC stimulated by either OKT3 or...

  19. Major histocompatibility complex class II (DR) antigen and costimulatory molecules on in vitro and in vivo activated human polymorphonuclear neutrophils

    Science.gov (United States)

    Sandilands, Gavin P; McCrae, Jame; Hill, Kathryn; Perry, Martin; Baxter, Derek

    2006-01-01

    We have previously shown that normal human peripheral blood polymorphonuclear neutrophils (PMNs) contain cytoplasmic ‘stores’ of three key molecules normally associated with antigen presentation and T-cell costimulation, i.e. major histocompatibility complex class II (DR) antigen, CD80 (B7-1) and CD86 (B7-2). These cytoplasmic molecules were found to translocate to the cell surface within a few minutes following cross-linking (X-L) of Mac-1: an early neutrophil activation signal. In this study we have compared X-L of Mac −1 in parallel with four other well documented in vitro neutrophil activators: phorbol myristate acetate, N-formyl methionyl leucyl phenylalanine, lipopolysaccharide, and phagocytosis of immunoglobulin G–Latex particles. In addition, we have used paired samples of neutrophils obtained from peripheral blood (as a control) and synovial fluid from patients with rheumatoid arthritis as a source of in vivo activated cells. With the exception of phagocytosis, all activators resulted in the rapid (within 30 min) generation of two populations of activated neutrophils (designated P1 and P2) based on flow-cytometry measurements of size, granularity and phenotype. Significant up-regulation of DR and costimulatory molecules was observed, predominantly on P2 cells, with all activators except phagocytosis. CD80 and CD86 were noted to respond to the various activation signals in a different pattern suggesting that their intracellular granule location may be different. Dual-staining confocal laser microscopy studies showed that CD80 is largely confined to secretory vesicles (SVs) while CD86 appears to have a much wider distribution being found in SVs and within secondary (specific) and primary (azurophilic) granules. Increased surface expression of these antigens was also observed on P2 synovial fluid neutrophils appearing as large heterogeneous clusters on the cell surface when visualized by confocal laser microscopy. PMID:17034427

  20. Single molecule measurements of DNA helicase activity with magnetic tweezers and t-test based step-finding analysis.

    Science.gov (United States)

    Seol, Yeonee; Strub, Marie-Paule; Neuman, Keir C

    2016-08-01

    Magnetic tweezers is a versatile and easy to implement single-molecule technique that has become increasingly prevalent in the study of nucleic acid based molecular motors. Here, we provide a description of the magnetic tweezers instrument and guidelines for measuring and analyzing DNA helicase activity. Along with experimental methods, we describe a robust method of single-molecule trajectory analysis based on the Student's t-test that accommodates continuous transitions in addition to the discrete transitions assumed in most widely employed analysis routines. To illustrate the single-molecule unwinding assay and the analysis routine, we provide DNA unwinding measurements of Escherichia coli RecQ helicase under a variety of conditions (Na+, ATP, temperature, and DNA substrate geometry). These examples reveal that DNA unwinding measurements under various conditions can aid in elucidating the unwinding mechanism of DNA helicase but also emphasize that environmental effects on DNA helicase activity must be considered in relation to in vivo activity and mechanism. PMID:27131595

  1. Guidance on a better integration of aquaculture, fisheries, and other activities in the coastal zone: from tools to practical examples

    NARCIS (Netherlands)

    Stelzenmüller, V.; Schulze, T.; Gimpel, A.; Bartelings, H.; Bello, E.; Bergh, O.; Bolman, B.; Caetano, M.; Davaasuren, N.; Fabi, G.; Ferreira, J.G.; Gault, J.; Gramolini, R.; Grati, F.; Hamon, K.G.; Jak, R.G.; Kopke, K.; Laurans, M.; Mäkinen, T.; O’Donnell, V.; O’Hagan, A.M.; O’Mahony, C.; Oostenbrugge, van H.; Ramos, J.; Saurel, C.; Sell, A.L.; Silvo, K.; Sinschek, K.; Soma, K.; Stenberg, C.; Taylor, N.; Vale, C.; Vasquez, F.; Verner-Jeffreys, D.W.

    2013-01-01

    This guidance document provides a comprehensive assessment of the conflicts and synergies between fisheries, aquaculture and other activities in the coastal zone in six COEXIST case study areas. It forms deliverable D5.2 of the COEXIST project and synthesises deliverable D5.1, which provides a more

  2. Photochemical activation and reactivity of polynuclear transition metal complex molecules. Final report

    International Nuclear Information System (INIS)

    Several bi- and trinuclear metal complexes containing ligands from β-polyketonates have been synthesized and characterized including homo- and hetero-polynuclear complexes. New synthetic approaches to the preparation of heterobi- and trinuclear complexes have been developed that allow the preparation of a large number of molecules containing heavy-metal ions such as Pd2+ or UO22+ and a first-row transition-metal ion. The electrochemical properties of these complexes have been investigated and many exhibit the ability to transfer two electrons at very nearly the same potential. Photochemical studies on binuclear Cu(II) and Ni(II) showed that these compounds yielded reduced metal species and decomposition upon irradiation. Luminescence of hetero-complexes of uranyl polyketonates is observed at 770K with the UO22+ moiety functioning as an isolated chromophore in which emission is observed only on direct excitation of UO22+ and energy transfer to lower states in the molecule is not observed

  3. Activation of Small Molecules by DyI_2 and Dy

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    1 Results The reactivities of dysprosium diiodide and metallic dysprosium toward small molecules are discussed.For instance,DyI2-induced silyl radical reactions are described.The combination of dysprosium diiodide and dichloromethane can serve as an effective methylene transfer reagent for cyclopropanation of unfunctionalized alkenes beyond that possible with other metal-dichloromethane systems.Furthermore,we report that the combination of chlorosilane and metallic Dy can also serve as an effective prom...

  4. Activation of CO2 and Related Small Molecules by Neopentyl-Derivatized Uranium Complexes

    OpenAIRE

    Schmidt, Anna-Corina

    2015-01-01

    The world´s concern about the environment has continued to intensify as the effects of greenhouse gases or complicated work-up and disposal of radioactive substances become more obvious and profound. Unsurprisingly, the number of publications related to the solution of these issues has greatly increased in the last 15 years. Thus, a basic understanding of the specific properties and behavior of small molecules is crucial for the reduction of greenhouse gases, which may be realized through act...

  5. Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets

    OpenAIRE

    Cicmil, Milenko; Stevens, Jo; Leduc, Mireille; Bon, Cassian; Gibbins, Jonathan M.

    2002-01-01

    Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is a 130-kd transmembrane glycoprotein and a member of the growing family of receptors with immunoreceptor tyrosine-based inhibitory motifs (ITIMs). PECAM-1 is expressed on platelets, certain T cells, monocytes, neutrophils, and vascular endothelial cells and is involved in a range of cellular processes, though the role of PECAM-1 in platelets is unclear. Cross-linking of PECAM-1 results in phosphorylation of the ITIM allowing the r...

  6. Distribution of 210Pb activity concentrations in marine surface sediments within East Coast Peninsula Malaysia Exclusive Economic Zone (EEZ)

    International Nuclear Information System (INIS)

    A sampling expedition into the East Coast Peninsula Malaysia Exclusive Economic Zone (EEZ) was carried in June 2008. Marine surface sediment samples were taken and the activity concentrations of 210Pb have been determined. Its distribution was plotted and the findings show that the activity concentrations decline from north to south. On the other hand, the activity concentrations are increasing from west to east right to the edge of the EEZ. The highest activity concentrations were found to be near offshore oil platforms. The 210Pb activity concentrations were found to be in the range of 18.3 - 123.1 Bq/ kg. (author)

  7. Chemical activation of molecules by metals: Experimental studies of electron distributions and bonding

    International Nuclear Information System (INIS)

    The formal relationship between measured molecular ionization energies and thermodynamic bond dissociation energies has been developed into a single equation which unifies the treatment of covalent bonds, ionic bonds, and partially ionic bonds. This relationship has been used to clarify the fundamental thermodynamic information relating to metal-hydrogen, metal-alkyl, and metal-metal bond energies. We have been able to obtain a direct observation and measurement of the stabilization energy provided by the agostic interaction of the C-H bond with the metal. The ionization energies have also been used to correlate the rates of carbonyl substitution reactions of (η5-C5H4X)Rh(CO)2 complexes, and to reveal the electronic factors that control the stability of the transition state. The extent that the electronic features of these bonding interactions transfer to other chemical systems is being investigated in terms of the principle of additivity of ligand electronic effects. Specific examples under study include metal- phosphines, metal-halides, and metallocenes. Especially interesting has been the recent application of these techniques to the characterization of the soccer-ball shaped C60 molecule, buckminsterfullerene, and its interaction with a metal surface. The high-resolution valence ionizations in the gas phase reveal the high symmetry of the molecule, and studies of thin films of C60 reveal weak intermolecular interactions. Scanning tunneling and atomic force microscopy reveal the arrangement of spherical molecules on gold substrates, with significant delocalization of charge from the metal surface. 21 refs

  8. Determination of Four Active Ingredients in Vc Yinqiao Tablets by Capillary Zone Electrophoresis with Amperometric Detection

    Institute of Scientific and Technical Information of China (English)

    L(U),Jin; WANG,Qing-Jiang; CHENG,Xi; LIU,Hai-Yan; HE,Pin-Gang; FANG,Yu-Zhi

    2006-01-01

    A simple, reliable and reproducible method, based on capillary zone electrophoresis with amperometric detection (CZE-AD), has been developed for simultaneous determination of four active ingredients in Vc Yinqiao tablets including paracetamol, vitamin C, caffeic acid and chlorogenic acid. A carbon-disk electrode was used as working electrode and 0.95 V (versus SCE) was selected as detection potential. The optimal conditions of CZE experiment were 30 mmol·L-1 borate solution (pH 9.5) as running buffer, 14 kV as separation voltage and 8 s (14 kV) as electro-kinetic sampling time. Under the selected optimum conditions, paracetamol, vitamin C, caffeic acid and chlorogenic acid could be perfectly separated within 22 min, and their detection limits (S/N=3) ranged from 5 × 10-7 to 1×10-6 mol·L-1. This proposed method demonstrated good reproducibility with relative standard deviations of less than 3% for both migration time and peak current (n=7). The utility of this method was demonstrated by monitoring a kind of compound medicine named Vc Yinqiao tablets and the assay results were satisfactory.

  9. Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling.

    Science.gov (United States)

    Böhme, Mathias A; Beis, Christina; Reddy-Alla, Suneel; Reynolds, Eric; Mampell, Malou M; Grasskamp, Andreas T; Lützkendorf, Janine; Bergeron, Dominique Dufour; Driller, Jan H; Babikir, Husam; Göttfert, Fabian; Robinson, Iain M; O'Kane, Cahir J; Hell, Stefan W; Wahl, Markus C; Stelzl, Ulrich; Loll, Bernhard; Walter, Alexander M; Sigrist, Stephan J

    2016-10-01

    Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca(2+) channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca(2+) channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A(null) mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca(2+)-channel topology whose developmental tightening optimizes synaptic transmission.

  10. Synaptophysin 1 Clears Synaptobrevin 2 from the Presynaptic Active Zone to Prevent Short-Term Depression

    Directory of Open Access Journals (Sweden)

    Rajit Rajappa

    2016-02-01

    Full Text Available Release site clearance is an important process during synaptic vesicle (SV recycling. However, little is known about its molecular mechanism. Here we identify self-assembly of exocytosed Synaptobrevin 2 (Syb2 and Synaptophysin 1 (Syp1 by homo- and hetero-oligomerization into clusters as key mechanisms mediating release site clearance for preventing cis-SNARE complex formation at the active zone (AZ. In hippocampal neurons from Syp1 knockout mice, neurons expressing a monomeric Syb2 mutant, or after acute block of the ATPase N-ethylmaleimide-sensitive factor (NSF, responsible for cis-SNARE complex disassembly, we found strong frequency-dependent short-term depression (STD, whereas retrieval of Syb2 by compensatory endocytosis was only affected weakly. Defects in Syb2 endocytosis were stimulus- and frequency-dependent, indicating that Syp1 is not essential for Syb2 retrieval, but for its efficient clearance upstream of endocytosis. Our findings identify an SV protein as a release site clearance factor.

  11. Liparid and macrourid fishes of the hadal zone: in situ observations of activity and feeding behaviour.

    Science.gov (United States)

    Jamieson, A J; Fujii, T; Solan, M; Matsumoto, A K; Bagley, P M; Priede, I G

    2009-03-22

    Using baited camera landers, the first images of living fishes were recorded in the hadal zone (6000-11000 m) in the Pacific Ocean. The widespread abyssal macrourid Coryphaenoides yaquinae was observed at a new depth record of approximately 7000 m in the Japan Trench. Two endemic species of liparid were observed at similar depths: Pseudoliparis amblystomopsis in the Japan Trench and Notoliparis kermadecensis in the Kermadec Trench. From these observations, we have documented swimming and feeding behaviour of these species and derived the first estimates of hadal fish abundance. The liparids intercepted bait within 100-200 min but were observed to preferentially feed on scavenging amphipods. Notoliparis kermadecensis act as top predators in the hadal food web, exhibiting up to nine suction-feeding events per minute. Both species showed distinctive swimming gaits: P. amblystomopsis (mean length 22.5 cm) displayed a mean tail-beat frequency of 0.47 Hz and mean caudal:pectoral frequency ratio of 0.76, whereas N. kermadecensis (mean length 31.5 cm) displayed respective values of 1.04 and 2.08 Hz. Despite living at extreme depths, these endemic liparids exhibit similar activity levels compared with shallow-water liparids. PMID:19129104

  12. Activated peripheral lymphocytes with increased expression of cell adhesion molecules and cytotoxic markers are associated with dengue fever disease.

    Science.gov (United States)

    Azeredo, Elzinandes L; Zagne, Sonia M O; Alvarenga, Allan R; Nogueira, Rita M R; Kubelka, Claire F; de Oliveira-Pinto, Luzia M

    2006-06-01

    The immune mechanisms involved in dengue fever and dengue hemorrhagic/dengue shock syndrome are not well understood. The ex vivo activation status of immune cells during the dengue disease in patients was examined. CD4 and CD8 T cells were reduced during the acute phase. Interestingly, CD8 T cells co-expressing activation marker HLA-DR, Q, P, and cytolytic granule protein-Tia-1 were significantly higher in dengue patients than in controls. Detection of adhesion molecules indicated that in dengue patients the majority of T cells (CD4 and CD8) express the activation/memory phenotype, characterized as CD44HIGH and lack the expression of the naïve cell marker, CD62L LOW. Also, the levels of T cells co-expressing ICAM-1 (CD54), VLA-4, and LFA-1 (CD11a) were significantly increased. CD8 T lymphocytes expressed predominantly low levels of anti-apoptotic molecule Bcl-2 in the acute phase, possibly leading to the exhibition of a phenotype of activated/effector cells. Circulating levels of IL-18, TGF-b1 and sICAM-1 were significantly elevated in dengue patients. Early activation events occur during acute dengue infection which might contribute to viral clearance. Differences in expression of adhesion molecules among CD4 and CD8 T cells might underlie the selective extravasation of these subsets from blood circulation into lymphoid organs and/or tissues. In addition, activated CD8 T cells would be more susceptible to apoptosis as shown by the alteration in Bcl-2 expression. Cytokines such as IL-18, TGF-b1, and sICAM-1 may be contributing by either stimulating or suppressing the adaptative immune response, during dengue infection, thereby perhaps establishing a relationship with disease severity.

  13. Activated peripheral lymphocytes with increased expression of cell adhesion molecules and cytotoxic markers are associated with dengue fever disease

    Directory of Open Access Journals (Sweden)

    Elzinandes L Azeredo

    2006-06-01

    Full Text Available The immune mechanisms involved in dengue fever and dengue hemorrhagic/dengue shock syndrome are not well understood. The ex vivo activation status of immune cells during the dengue disease in patients was examined. CD4and CD8 T cells were reduced during the acute phase. Interestingly, CD8 T cells co-expressing activation marker HLA-DR, Q, P, and cytolytic granule protein-Tia-1 were significantly higher in dengue patients than in controls. Detection of adhesion molecules indicated that in dengue patients the majority of T cells (CD4 and CD8 express the activation/memory phenotype, characterized as CD44HIGH and lack the expression of the naïve cell marker, CD62L LOW. Also, the levels of T cells co-expressing ICAM-1 (CD54, VLA-4, and LFA-1 (CD11a were significantly increased. CD8 T lymphocytes expressed predominantly low levels of anti-apoptotic molecule Bcl-2 in the acute phase, possibly leading to the exhibition of a phenotype of activated/effector cells. Circulating levels of IL-18, TGF-b1 and sICAM-1 were significantly elevated in dengue patients. Early activation events occur during acute dengue infection which might contribute to viral clearance. Differences in expression of adhesion molecules among CD4 and CD8 T cells might underlie the selective extravasation of these subsets from blood circulation into lymphoid organs and/or tissues. In addition, activated CD8 T cells would be more susceptible to apoptosis as shown by the alteration in Bcl-2 expression. Cytokines such as IL-18, TGF-b1, and sICAM-1 may be contributing by either stimulating or suppressing the adaptative immune response, during dengue infection, thereby perhaps establishing a relationship with disease severity.

  14. Structural Insights into the Activation of Human Relaxin Family Peptide Receptor 1 by Small-Molecule Agonists.

    Science.gov (United States)

    Hu, Xin; Myhr, Courtney; Huang, Zaohua; Xiao, Jingbo; Barnaeva, Elena; Ho, Brian A; Agoulnik, Irina U; Ferrer, Marc; Marugan, Juan J; Southall, Noel; Agoulnik, Alexander I

    2016-03-29

    The GPCR relaxin family peptide receptor 1 (RXFP1) mediates the action of relaxin peptide hormone, including its tissue remodeling and antifibrotic effects. The peptide has a short half-life in plasma, limiting its therapeutic utility. However, small-molecule agonists of human RXFP1 can overcome this limitation and may provide a useful therapeutic approach, especially for chronic diseases such as heart failure and fibrosis. The first small-molecule agonists of RXFP1 were recently identified from a high-throughput screening, using a homogeneous cell-based cAMP assay. Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, and excellent in vitro ADME and pharmacokinetic properties. Here, we undertook extensive site-directed mutagenesis studies in combination with computational modeling analysis to probe the molecular basis of the small-molecule binding to RXFP1. The results showed that the agonists bind to an allosteric site of RXFP1 in a manner that closely interacts with the seventh transmembrane domain (TM7) and the third extracellular loop (ECL3). Several residues were determined to play an important role in the agonist binding and receptor activation, including a hydrophobic region at TM7 consisting of W664, F668, and L670. The G659/T660 motif within ECL3 is crucial to the observed species selectivity of the agonists for RXFP1. The receptor binding and activation effects by the small molecule ML290 were compared with the cognate ligand, relaxin, providing valuable insights on the structural basis and molecular mechanism of receptor activation and selectivity for RXFP1. PMID:26866459

  15. Negative regulation of active zone assembly by a newly identified SR protein kinase.

    Directory of Open Access Journals (Sweden)

    Ervin L Johnson

    2009-09-01

    Full Text Available Presynaptic, electron-dense, cytoplasmic protrusions such as the T-bar (Drosophila or ribbon (vertebrates are believed to facilitate vesicle movement to the active zone (AZ of synapses throughout the nervous system. The molecular composition of these structures including the T-bar and ribbon are largely unknown, as are the mechanisms that specify their synapse-specific assembly and distribution. In a large-scale, forward genetic screen, we have identified a mutation termed air traffic controller (atc that causes T-bar-like protein aggregates to form abnormally in motoneuron axons. This mutation disrupts a gene that encodes for a serine-arginine protein kinase (SRPK79D. This mutant phenotype is specific to SRPK79D and is not secondary to impaired kinesin-dependent axonal transport. The srpk79D gene is neuronally expressed, and transgenic rescue experiments are consistent with SRPK79D kinase activity being necessary in neurons. The SRPK79D protein colocalizes with the T-bar-associated protein Bruchpilot (Brp in both the axon and synapse. We propose that SRPK79D is a novel T-bar-associated protein kinase that represses T-bar assembly in peripheral axons, and that SRPK79D-dependent repression must be relieved to facilitate site-specific AZ assembly. Consistent with this model, overexpression of SRPK79D disrupts AZ-specific Brp organization and significantly impairs presynaptic neurotransmitter release. These data identify a novel AZ-associated protein kinase and reveal a new mechanism of negative regulation involved in AZ assembly. This mechanism could contribute to the speed and specificity with which AZs are assembled throughout the nervous system.

  16. Shoreline changes and its impact on activities in the coastal zone in Greenland

    Science.gov (United States)

    Kroon, A.; Bendixen, M.; Elberling, B.

    2015-12-01

    Almost all coastal environments in Greenland are developed in high-relief areas, along fjords, or hard-rock cliffs. The sedimentary shores often fringe these areas and a large number of small deltas (areal delta surface temperatures, ice and snow. There is a seasonal variation with open waters and active rivers in summer and ice-covered coastal waters and frozen rivers in winter. The coastal processes by waves and tides are thus often limited to summer and early fall. Nowadays, global climate changes induce many changes along the arctic coasts. Global sea-levels are rising due to thermal expansion and an increased fresh water flux from the glaciers and land ice masses, while ice coverage of the coastal waters decreases and the open water periods in summer extend. However, it is still unknown if the extra input of fluvial sediments can cope with increased erosion rates at the shores. Besides, the rate of actual sea-level rise in West Greenland is probably less than the local rate of isostatic uplift, leading to local relative sea level fall.The focus in this presentation is on shoreline changes and its impact on two coastal environments in Greenland: the Young Sound area (fjord environment in North-East Greenland), and the southern shore of Disko Island (open sea embayment in West Greenland). These coastal environments exhibit a wide variety of coastal landforms like deltas, spits, barriers, etc. The coastal landforms were mapped and aerial images, orthogonal photos, and satellite images were used to digitize successive shorelines. The shoreline changes were estimated using the digital shoreline analysis system (DSAS) of the USGS. The spatial variability of accumulation and erosion patterns was detected and shows a surprising thread for ancient settlements and present-day activities in the coastal zone. The same patterns are finally discussed in terms of coastal risk assessment.

  17. Near infrared emission from molecule-like silver clusters confined in zeolite A assisted by thermal activation

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Hui, E-mail: linh8112@163.com; Imakita, Kenji; Rong Gui, Sa Chu; Fujii, Minoru, E-mail: fujii@eedept.kobe-u.ac.jp [Department of Electrical and Electronic Engineering, Graduate School of Engineering, Kobe University, Rokkodai, Nada, Kobe 657-8501 (Japan)

    2014-07-07

    Strong and broad near infrared (NIR) emission peaked at ~855 nm upon optimal excitation at 342 nm has been observed from molecule-like silver clusters (MLSCs) confined in zeolite A assisted by thermal activation. To the best of our knowledge, this is the first observation of NIR emission peaked at longer than 800 nm from MLSCs confined in solid matrices. The decay time of the NIR emission is over 10 μs, which indicates that it is a spin-forbidden transition. The ~855 nm NIR emission shows strong dependence on the silver loading concentration and the thermal activation temperature.

  18. Living microbial ecosystems within the active zone of catagenesis: Implications for feeding the deep biosphere

    Science.gov (United States)

    Horsfield, B.; Schenk, H. J.; Zink, K.; Ondrak, R.; Dieckmann, V.; Kallmeyer, J.; Mangelsdorf, K.; di Primio, R.; Wilkes, H.; Parkes, R. J.; Fry, J.; Cragg, B.

    2006-06-01

    Earth's largest reactive carbon pool, marine sedimentary organic matter, becomes increasingly recalcitrant during burial, making it almost inaccessible as a substrate for microorganisms, and thereby limiting metabolic activity in the deep biosphere. Because elevated temperature acting over geological time leads to the massive thermal breakdown of the organic matter into volatiles, including petroleum, the question arises whether microorganisms can directly utilize these maturation products as a substrate. While migrated thermogenic fluids are known to sustain microbial consortia in shallow sediments, an in situ coupling of abiotic generation and microbial utilization has not been demonstrated. Here we show, using a combination of basin modelling, kinetic modelling, geomicrobiology and biogeochemistry, that microorganisms inhabit the active generation zone in the Nankai Trough, offshore Japan. Three sites from ODP Leg 190 have been evaluated, namely 1173, 1174 and 1177, drilled in nearly undeformed Quaternary and Tertiary sedimentary sequences seaward of the Nankai Trough itself. Paleotemperatures were reconstructed based on subsidence profiles, compaction modelling, present-day heat flow, downhole temperature measurements and organic maturity parameters. Today's heat flow distribution can be considered mainly conductive, and is extremely high in places, reaching 180 mW/m 2. The kinetic parameters describing total hydrocarbon generation, determined by laboratory pyrolysis experiments, were utilized by the model in order to predict the timing of generation in time and space. The model predicts that the onset of present day generation lies between 300 and 500 m below sea floor (5100-5300 m below mean sea level), depending on well location. In the case of Site 1174, 5-10% conversion has taken place by a present day temperature of ca. 85 °C. Predictions were largely validated by on-site hydrocarbon gas measurements. Viable organisms in the same depth range have been

  19. Evolution of surface motor activation zones in hemiplegic patients during 20 sessions of FES therapy with multi-pad electrodes

    Directory of Open Access Journals (Sweden)

    Jovana Malešević

    2016-06-01

    Full Text Available The purpose of this study was to examine surface motor activation zones for wrist, fingers and thumb extension movements and their temporal change during 20 therapy sessions using advanced multi-pad functional electrical stimulation system. Results from four hemiplegic patients indicate that certain zones have higher probability of eliciting each of the target movements. However, mutual overlap and variations of the zones are present not just between the subjects, but also on the intrasubject level, reflected through these session to session transformations of the selected virtual electrodes. The obtained results could be used as a priori knowledge for semi-automated optimization algorithm and could shorten the time required for calibration of the multi-pad electrode.

  20. A structure activity-relationship study of the bacterial signal molecule HHQ reveals swarming motility inhibition in Bacillus atrophaeus.

    Science.gov (United States)

    Reen, F Jerry; Shanahan, Rachel; Cano, Rafael; O'Gara, Fergal; McGlacken, Gerard P

    2015-05-21

    The sharp rise in antimicrobial resistance has been matched by a decline in the identification and clinical introduction of new classes of drugs to target microbial infections. Thus new approaches are being sought to counter the pending threat of a post-antibiotic era. In that context, the use of non-growth limiting small molecules, that target virulence behaviour in pathogens, has emerged as a solution with real clinical potential. We have previously shown that two signal molecules (HHQ and PQS) from the nosocomial pathogen Pseudomonas aeruginosa have modulatory activity towards other microorganisms. This current study involves the synthesis and evaluation of analogues of HHQ towards swarming and biofilm virulence behaviour in Bacillus atrophaeus, a soil bacterium and co-inhibitor with P. aeruginosa. Compounds with altered C6-C8 positions on the anthranilate-derived ring of HHQ, display a surprising degree of biological specificity, with certain candidates displaying complete motility inhibition. In contrast, anti-biofilm activity of the parent molecule was completely lost upon alteration at any position indicating a remarkable degree of specificity and delineation of phenotype. PMID:25880413

  1. Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell

    Science.gov (United States)

    Chattopadhyay, Anasuya; O’Connor, Cornelius J.; Zhang, Fengzhi; Galvagnion, Celine; Galloway, Warren R. J. D.; Tan, Yaw Sing; Stokes, Jamie E.; Rahman, Taufiq; Verma, Chandra; Spring, David R.; Itzhaki, Laura S.

    2016-04-01

    Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer. Thus, molecules that bind the PPI interface of gankyrin and interrupt these interactions are of considerable interest. Herein, we report the discovery of a small molecule termed cjoc42 that is capable of binding to gankyrin. Cell-based experiments demonstrate that cjoc42 can inhibit gankyrin activity in a dose-dependent manner: cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin, and it restores p53-dependent transcription and sensitivity to DNA damage. The results represent the first evidence that gankyrin is a “druggable” target with small molecules.

  2. Lysine-Based Small Molecules That Disrupt Biofilms and Kill both Actively Growing Planktonic and Nondividing Stationary Phase Bacteria.

    Science.gov (United States)

    Konai, Mohini M; Haldar, Jayanta

    2015-10-01

    The emergence of bacterial resistance is a major threat to global health. Alongside this issue, formation of bacterial biofilms is another cause of concern because most antibiotics are ineffective against these recalcitrant microbial communities. Ideal future antibacterial therapeutics should possess both antibacterial and anti-biofilm activities. In this study we engineered lysine-based small molecules, which showed not only commendable broad-spectrum antibacterial activity but also potent biofilm-disrupting properties. Synthesis of these lipophilic lysine-norspermidine conjugates was achieved in three simple reaction steps, and the resultant molecules displayed potent antibacterial activity against various Gram-positive (Staphylococcus aureus, Enterococcus faecium) and Gram-negative bacteria (Escherichia coli) including drug-resistant superbugs MRSA (methicillin-resistant S. aureus), VRE (vancomycin-resistant E. faecium), and β-lactam-resistant Klebsiella pneumoniae. An optimized compound in the series showed activity against planktonic bacteria in the concentration range of 3-10 μg/mL, and bactericidal activity against stationary phase S. aureus was observed within an hour. The compound also displayed about 120-fold selectivity toward both classes of bacteria (S. aureus and E. coli) over human erythrocytes. This rapidly bactericidal compound primarily acts on bacteria by causing significant membrane depolarization and K(+) leakage. Most importantly, the compound disrupted preformed biofilms of S. aureus and did not trigger bacterial resistance. Therefore, this class of compounds has high potential to be developed as future antibacterial drugs for treating infections caused by planktonic bacteria as well as bacterial biofilms. PMID:27623313

  3. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement

    DEFF Research Database (Denmark)

    Frederiksen, Pernille Dorthea; Thiel, Steffen; Larsen, Claus Bindslev;

    2005-01-01

    Ficolins play a role in the innate immune defence as pathogen-associated molecular pattern recognition molecules. Three ficolins are found in humans: H-ficolin, L-ficolin and M-ficolin. L-ficolin and H-ficolin circulate in blood in complexes with mannan-binding lectin-associated serine proteases...... system. We developed a monoclonal rat anti-human-M/L-ficolin antibody and verified by flow cytometric analysis the presence of ficolin on the surface of peripheral blood monocytes....

  4. Immobilisation of redox active molecules as precursors for nanowire self-assembly

    OpenAIRE

    Campagnoli, Elena

    2007-01-01

    Spontaneously adsorbed monolayers of [Co(ttp-CH2-SH)2](PF6)2 have been formed on platinum microelectrodes by exposure to micromolar solutions of the complex in 0.1 M TBABF4 in acetonitrile, ttp-CH2-SH is 4'-(p-(thiolmethyl)-phenyl)-2,2':6',2''- terpyridine. Resonance Raman spectroscopy on roughened polycrystalline platinum macro electrodes show that the molecule undergoes adsorption by sulphur atom onto the platinum surface. The monolayers show reversible and well defined cyclic voltammetry w...

  5. Auroral Electrojet (AE, AL, AO, AU) - A Global Measure of Auroral Zone Magnetic Activity

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The AE index is derived from geomagnetic variations in the horizontal component observed at selected (10-13) observatories along the auroral zone in the northern...

  6. Activation of protein phosphatase 1 by a small molecule designed to bind to the enzyme's regulatory site.

    Science.gov (United States)

    Tappan, Erin; Chamberlin, A Richard

    2008-02-01

    The activity of protein phosphatase 1 (PP1), a serine-threonine phosphatase that participates ubiquitously in cellular signaling, is controlled by a wide variety of regulatory proteins that interact with PP1 at an allosteric regulatory site that recognizes a "loose" consensus sequence (usually designated as RVXF) found in all such regulatory proteins. Peptides containing the regulatory consensus sequence have been found to recapitulate the binding and PP1 activity modulation of the regulatory proteins, suggesting that it might be possible to design small-molecule surrogates that activate PP1 rather than inhibiting it. This prospect constitutes a largely unexplored way of controlling signaling pathways that could be functionally complementary to the much more extensively explored stratagem of kinase inhibition. Based on these principles, we have designed a microcystin analog that activates PP1. PMID:18291321

  7. Histone deacetylase inhibitor givinostat: the small-molecule with promising activity against therapeutically challenging haematological malignancies.

    Science.gov (United States)

    Ganai, Shabir Ahmad

    2016-08-01

    Histone acetyl transferases and histone deacetylases (HDACs) are counteracting epigenetic enzymes regulating the turnover of histone acetylation thereby regulating transcriptional events in a precise manner. Deregulation of histone acetylation caused by aberrant expression of HDACs plays a key role in tumour onset and progression making these enzymes as candidate targets for anticancer drugs and therapy. Small-molecules namely histone deacetylase inhibitors (HDACi) modulating the biological function of HDACs have shown multiple biological effects including differentiation, cell cycle arrest and apoptosis in tumour models. HDACi in general have been described in plethora of reviews with respect to various cancers. However, no review article is available describing thoroughly the role of inhibitor givinostat (ITF2357 or [6-(diethylaminomethyl) naphthalen-2-yl] methyl N-[4-(hydroxycarbamoyl) phenyl] carbamate) in haematological malignancies. Thus, the present review explores the intricate role of novel inhibitor givinostat in the defined malignancies including multiple myeloma, acute myelogenous leukaemia, Hodgkin's and non-Hodgkin's lymphoma apart from myeloproliferative neoplasms. The distinct molecular mechanisms triggered by this small-molecule inhibitor in these cancers to exert cytotoxic effect have also been dealt with. The article also highlights the combination strategy that can be used for enhancing the therapeutic efficiency of this inhibitor in the upcoming future. PMID:27121910

  8. Exoplanet detection. Stellar activity masquerading as planets in the habitable zone of the M dwarf Gliese 581.

    Science.gov (United States)

    Robertson, Paul; Mahadevan, Suvrath; Endl, Michael; Roy, Arpita

    2014-07-25

    The M dwarf star Gliese 581 is believed to host four planets, including one (GJ 581d) near the habitable zone that could possibly support liquid water on its surface if it is a rocky planet. The detection of another habitable-zone planet--GJ 581g--is disputed, as its significance depends on the eccentricity assumed for d. Analyzing stellar activity using the Hα line, we measure a stellar rotation period of 130 ± 2 days and a correlation for Hα modulation with radial velocity. Correcting for activity greatly diminishes the signal of GJ 581d (to 1.5 standard deviations) while significantly boosting the signals of the other known super-Earth planets. GJ 581d does not exist, but is an artifact of stellar activity which, when incompletely corrected, causes the false detection of planet g.

  9. Coordinated trafficking of synaptic vesicle and active zone proteins prior to synapse formation

    Directory of Open Access Journals (Sweden)

    Sabo Shasta L

    2011-05-01

    Full Text Available Abstract Background The proteins required for synaptic transmission are rapidly assembled at nascent synapses, but the mechanisms through which these proteins are delivered to developing presynaptic terminals are not understood. Prior to synapse formation, active zone proteins and synaptic vesicle proteins are transported along axons in distinct organelles referred to as piccolo-bassoon transport vesicles (PTVs and synaptic vesicle protein transport vesicles (STVs, respectively. Although both PTVs and STVs are recruited to the same site in the axon, often within minutes of axo-dendritic contact, it is not known whether or how PTV and STV trafficking is coordinated before synapse formation. Results Here, using time-lapse confocal imaging of the dynamics of PTVs and STVs in the same axon, we show that vesicle trafficking is coordinated through at least two mechanisms. First, a significant proportion of STVs and PTVs are transported together before forming a stable terminal. Second, individual PTVs and STVs share pause sites within the axon. Importantly, for both STVs and PTVs, encountering the other type of vesicle increases their propensity to pause. To determine if PTV-STV interactions are important for pausing, PTV density was reduced in axons by expression of a dominant negative construct corresponding to the syntaxin binding domain of syntabulin, which links PTVs with their KIF5B motor. This reduction in PTVs had a minimal effect on STV pausing and movement, suggesting that an interaction between STVs and PTVs is not responsible for enhancing STV pausing. Conclusions Our results indicate that trafficking of STVs and PTVs is coordinated even prior to synapse development. This novel coordination of transport and pausing might provide mechanisms through which all of the components of a presynaptic terminal can be rapidly accumulated at sites of synapse formation.

  10. Communities on the move: Pedestrian-oriented zoning as a facilitator of adult active travel to work in the United States

    Directory of Open Access Journals (Sweden)

    Jamie Friedman Chriqui

    2016-04-01

    Full Text Available Background: Communities across the United States have been reforming their zoning codes to create pedestrian-friendly neighborhoods with increased street connectivity, mixed-use and higher density, open space, transportation infrastructure, and a traditional neighborhood structure. Zoning code reforms include new urbanist zoning such as the SmartCode, form-based codes, transects, transportation and pedestrian-oriented developments, and traditional neighborhood developments.Purpose: To examine the relationship of zoning code reforms and more active living-oriented zoning provisions with adult active travel to work via walking, biking, or by using public transit.Methods: Zoning codes effective as of 2010 were compiled for 3,914 municipal-level jurisdictions located in 471 counties and 2 consolidated cities in 48 states and the District of Columbia, and that collectively covered 72.9% of the U.S. population. Zoning codes were evaluated for the presence of code reform zoning and nine pedestrian-oriented zoning provisions (1=yes: sidewalks, crosswalks, bike-pedestrian connectivity, street connectivity, bike lanes, bike parking, bike-pedestrian trails/paths, mixed use development, and other walkability/pedestrian-orientation. A zoning scale reflected the number of provisions addressed (out of 10. Five continuous outcome measures were constructed using 2010-2014 American Community Survey municipal-level 5-year estimates to assess the percentage of workers: walking, biking, walking or biking, or taking public transit to work OR engaged in any active travel to work. Regression models controlled for municipal-level socioeconomic characteristics and a GIS-constructed walkability scale and were clustered on county with robust standard errors. Results: Adjusted models indicated that several pedestrian-oriented zoning provisions were statistically associated (p<.05 or lower with increased rates of walking, biking, or engaging in any active travel (walking

  11. Aftershocks illuninate the 2011 Mineral, Virginia, earthquake causative fault zone and nearby active faults

    Science.gov (United States)

    Horton, Jr., J. Wright; Shah, Anjana K.; McNamara, Daniel E.; Snyder, Stephen L.; Carter, Aina M

    2015-01-01

    Deployment of temporary seismic stations after the 2011 Mineral, Virginia (USA), earthquake produced a well-recorded aftershock sequence. The majority of aftershocks are in a tabular cluster that delineates the previously unknown Quail fault zone. Quail fault zone aftershocks range from ~3 to 8 km in depth and are in a 1-km-thick zone striking ~036° and dipping ~50°SE, consistent with a 028°, 50°SE main-shock nodal plane having mostly reverse slip. This cluster extends ~10 km along strike. The Quail fault zone projects to the surface in gneiss of the Ordovician Chopawamsic Formation just southeast of the Ordovician–Silurian Ellisville Granodiorite pluton tail. The following three clusters of shallow (aftershocks illuminate other faults. (1) An elongate cluster of early aftershocks, ~10 km east of the Quail fault zone, extends 8 km from Fredericks Hall, strikes ~035°–039°, and appears to be roughly vertical. The Fredericks Hall fault may be a strand or splay of the older Lakeside fault zone, which to the south spans a width of several kilometers. (2) A cluster of later aftershocks ~3 km northeast of Cuckoo delineates a fault near the eastern contact of the Ordovician Quantico Formation. (3) An elongate cluster of late aftershocks ~1 km northwest of the Quail fault zone aftershock cluster delineates the northwest fault (described herein), which is temporally distinct, dips more steeply, and has a more northeastward strike. Some aftershock-illuminated faults coincide with preexisting units or structures evident from radiometric anomalies, suggesting tectonic inheritance or reactivation.

  12. The time-dependent generalized active space configuration interaction approach to correlated ionization dynamics of diatomic molecules

    Science.gov (United States)

    Bauch, S.; Larsson, H. R.; Hinz, C.; Bonitz, M.

    2016-03-01

    In this contribution, we review the time-dependent generalized-active-space configuration interaction (TD-GAS-CI) approach to the photoionization dynamics of atoms and molecules including electron correlation effects. It is based on the configuration interaction (CI) expansion of the many-body wave function and the restriction of the determinantal space to a reduced subspace. For its numerically efficient application to photoionization, a partially-rotated basis set is used which adopts features of a localized basis with a good reference description and a grid representation for escaping wave packets. After reviewing earlier applications of the theory, we address the strong-field ionization of a one-dimensional model of the four-electron LiH molecule using TD-GAS-CI and demonstrate the importance of electron-electron correlations in the ionization yield for different orientations of the molecule w.r.t the peak of the linearly polarized laser field. A pronounced orientation-dependent variation of the yield with the pulse duration and the level of considered electron-electron correlations is observed.

  13. Xalpha-DVM investigation of double water molecule interactions with active sites of alpha- and beta-subunits of hemoglobin

    Science.gov (United States)

    Yuryeva, Elmira I.

    In this work, the results of Xalpha-discrete variation method calculations of the electronic structure and interatomic parameters of chemical bonding between iron (II) and oxygen molecule with and without extra electrons and protons in active site (AS) of alpha- and beta-subunits of oxyhemoglobin are presented. The Skulachev model of O2 molecule existing in respiration medium in the 2H2O form was used. The introduction of extra electrons does not change considerably the interaction of the iron atom with the O2 oxygen molecule, but strengthens the repulsion in the Fe bond N bonds. In this case, the estimated effective charge of the iron atom is +1.8/1.5e for AS of alpha-/beta-subunits of oxyhemoglobin, and the magnetic moment of iron atoms becomes zero. The deoxygenation effect of the AS of the alpha- and beta-subunits of oxyhemoglobin is due to the ability of extra protons to break down covalent attraction between the iron atom and the nearest oxygen atom and also to weakening of the repulsive component of the covalent Fe bond N interactions.

  14. Raman and surface enhanced Raman spectroscopic studies of specific, small molecule activator of histone acetyltransferase p300

    Science.gov (United States)

    Kundu, Partha P.; Pavan Kumar, G. V.; Mantelingu, Kempegowda; Kundu, Tapas K.; Narayana, Chandrabhas

    2011-07-01

    We report for the first time, the Raman and surface enhanced Raman scattering (SERS) studies of N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB). This molecule is specific activator of human histone acetyltransferase (HAT), p300, and serves as lead molecule to design anti-neoplastic therapeutics. A detailed Raman and SERS band assignments have been performed for CTB, which are compared with the density functional theory calculations. The observed red shift of N sbnd H stretching frequency from the computed wavenumber indicates the weakening of N sbnd H bond resulting from proton transfer to the neighboring oxygen atom. We observe Ag sbnd N vibrational mode at 234 cm -1 in SERS of CTB. This indicates there is a metal-molecule bond leading to chemical enhancement in SERS. We also observe, enhancement in the modes pertaining to substituted benzene rings and methyl groups. Based on SERS analysis we propose the adsorption sites and the orientation of CTB on silver surface.

  15. Neural progenitor cells isolated from the subventricular zone present hemichannel activity and form functional gap junctions with glial cells

    Directory of Open Access Journals (Sweden)

    Rocío eTalaverón

    2015-10-01

    Full Text Available The postnatal subventricular zone lining the walls of the lateral ventricles contains neural progenitor cells (NPCs that generate new olfactory bulb interneurons. Communication via gap junctions between cells in the subventricular zone is involved in NPC proliferation and in neuroblast migration towards the olfactory bulb. Subventricular zone NPCs can be expanded in vitro in the form of neurospheres that can be used for transplantation purposes after brain injury. We have previously reported that neurosphere-derived NPCs form heterocellular gap junctions with host glial cells when they are implanted after mechanical injury. To analyze functionality of NPC-glial cell gap junctions we performed dye coupling experiments in co-cultures of subventricular zone NPCs with astrocytes or microglia. Neurosphere-derived cells expressed mRNA for at least the hemichannel/gap junction channel proteins connexin 26 (Cx26, Cx43, Cx45 and pannexin 1. Dye coupling experiments revealed that gap junctional communication occurred among neurosphere cells (incidence of coupling: 100%. Moreover, hemichannel activity was also detected in neurosphere cells as evaluated in time-lapse measurements of ethidium bromide uptake. Heterocellular coupling between NPCs and glial cells was evidenced in co-cultures of neurospheres with astrocytes (incidence of coupling: 91.0 ± 4.7% or with microglia (incidence of coupling: 71.9 ± 6.7%. Dye coupling in neurospheres and in co-cultures was inhibited by octanol, a gap junction blocker. Altogether, these results suggest the existence of functional hemichannels and gap junction channels in postnatal subventricular zone neurospheres. In addition, they demonstrate that subventricular zone-derived NPCs can establish functional gap junctions with astrocytes or microglia. Therefore, cell-cell communication via gap junctions and hemichannels with host glial cells might subserve a role in the functional integration of NPCs after implantation in

  16. Understanding the adsorption behavior of surface active molecules on ZnO nanostructures by experimental and first-principles calculations.

    Science.gov (United States)

    Singh, Baljinder; Singh, Satvinder; Singh, Janpreet; Saini, G S S; Mehta, D S; Singh, Gurinder; Tripathi, S K; Kaura, Aman

    2015-11-11

    Zinc oxide (ZnO) nanostructures with different morphologies are prepared in the presence of surface active molecules such as sodium dodecyl sulphate (SDS), Tween 80 and Triton X-100 by a chemical method. The experimental and first principles methods are employed to understand the microscopic origin of the asymmetric growth mechanism of ZnO in the presence of various surface active molecules. Effect of increase in the amount of surface active molecules and temperature is studied on the growth morphology of ZnO. An innovative method is developed to synthesize ZnO nanowires (NWs) in the presence of SDS. Spherical nanoparticles (NPs) to spherical clusters are obtained in the presence of Triton X-100 and Tween 80. These results are then supported by first principles calculations. The adsorption of the -OH functional group on both polar and nonpolar surfaces of ZnO is modelled by using density functional theory (DFT). The calculated binding energy (BE) is almost equivalent on both the surfaces with no preference on any particular surface. The calculated value of BE shows that the -OH group is physio-adsorbed on both the surfaces. This results in the spherical morphology of nanoparticles prepared in the presence of Tween 80. Bader charge analysis shows that the charge transfer mainly takes place on top two layers of the ZnO(101[combining macron]0) surface. The absence of high values of electron localization function (ELF) reflects the lack of covalent bonding between the -OH group and the ZnO(101[combining macron]0) surface. PMID:26510134

  17. Role of the primer activation signal in tRNA annealing onto the HIV-1 genome studied by single-molecule FRET microscopy

    NARCIS (Netherlands)

    N. Beerens (Nancy); M.D.E. Jepsen (Mette); V. Nechyporuk-Zloy (Volodymyr); A.C. Krüger (Asger); J.-L. Darlix (Jean-Luc); J. Kjems (Jørgen); V. Birkedal (Victoria)

    2013-01-01

    textabstractHIV-1 reverse transcription is primed by a cellular tRNAlys3 molecule that binds to the primer binding site (PBS) in the genomic RNA. An additional interaction between the tRNA molecule and the primer activation signal (PAS) is thought to regulate the initiation of reverse transcription.

  18. Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery

    DEFF Research Database (Denmark)

    Toft, P; Christiansen, K; Tønnesen, Else Kirstine;

    1997-01-01

    on granulocytes and improve clinical outcome. Sixteen patients undergoing open heart surgery participated in the study. Eight were randomized to receive methylprednisolone (30 mg/kg intravenously) at the start of anaesthesia while eight patients served as a control group. The oxidative burst was measured flow...... not improve the weaning from the ventilator or reduce the stay in the intensive-care unit. In conclusion, treatment with steroids prevented hyperthermia following open heart surgery with CPB and reduced capillary leak during ECC. Methylprednisolone, however, did not reduce the oxidative burst activity......Following cardiac surgery with cardiopulmonary bypass (CPB), activated granulocytes may be involved with ischaemia/ reperfusion injury. The purpose of this study was to investigate whether steroids could reduce the oxidative burst activity of granulocytes, the expression of adhesion molecules...

  19. A small molecule inhibitor for ATPase activity of Hsp70 and Hsc70 enhances the immune response to protein antigens

    Science.gov (United States)

    Baek, Kyung-Hwa; Zhang, Haiying; Lee, Bo Ryeong; Kwon, Young-Guen; Ha, Sang-Jun; Shin, Injae

    2015-12-01

    The ATPase activities of Hsp70 and Hsc70 are known to be responsible for regulation of various biological processes. However, little is known about the roles of Hsp70 and Hsc70 in modulation of immune responses to antigens. In the present study, we investigated the effect of apoptozole (Az), a small molecule inhibitor of Hsp70 and Hsc70, on immune responses to protein antigens. The results show that mice administered with both protein antigen and Az produce more antibodies than those treated with antigen alone, showing that Az enhances immune responses to administered antigens. Treatment of mice with Az elicits production of antibodies with a high IgG2c/IgG1 ratio and stimulates the release of Th1 and Th2-type cytokines, suggesting that Az activates the Th1 and Th2 immune responses. The observations made in the present study suggest that inhibition of Hsp70 and Hsc70 activities could be a novel strategy designing small molecule-based adjuvants in protein vaccines.

  20. Activation of Relaxin Family Receptor 1 from Different Mammalian Species by Relaxin Peptide and Small-Molecule Agonist ML290

    OpenAIRE

    Huang, Zaohua; Myhr, Courtney; Bathgate, Ross A. D.; Ho, Brian A.; Bueno, Amaya; Hu, Xin; Xiao, Jingbo; Southall, Noel; Barnaeva, Elena; Agoulnik, Irina U; Marugan, Juan J; Ferrer, Marc; Agoulnik, Alexander I.

    2015-01-01

    Relaxin peptide (RLN), which signals through the relaxin family peptide 1 (RXFP1) GPCR receptor, has shown therapeutic effects in an acute heart failure clinical trial. We have identified a small-molecule agonist of human RXFP1, ML290; however, it does not activate the mouse receptor. To find a suitable animal model for ML290 testing and to gain mechanistic insights into the interaction of various ligands with RXFP1, we have cloned rhesus macaque, pig, rabbit, and guinea pig RXFP1s and analyz...

  1. PdM (M = Pt, Au) bimetallic alloy nanowires with enhanced electrocatalytic activity for electro-oxidation of small molecules

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Chengzhou; Guo, Shaojun; Dong, Shaojun [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022 (China)

    2012-05-02

    A facile and general method has been developed to synthesize well-defined PdPt and PdAu alloy nanowires, which exhibit significantly enhanced activity towards small molecules, such as ethanol, methanol, and glucose electro-oxidation in an alkaline medium. Considering the important role of one-dimensional alloy nanowires in electrocatalytic systems, the present Pd-based alloy nanostructures could offer a promising new class of advanced electrocatalysts for direct alcohol fuel cells and electrochemical sensors. (Copyright copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  2. The range of excursion of flexor tendons in Zone V: a comparison of active vs passive flexion mobilisation regimes.

    LENUS (Irish Health Repository)

    Panchal, J

    1997-10-01

    A number of early postoperative mobilisation regimes have been developed in an attempt to increase tendon excursion and gliding and thereby reduce formation of adhesions following repair of flexor tendons. Early active flexion mobilisation regimes are becoming more popular, and have replaced early passive flexion regimes in many centres. The aim of the present study was: (a) to determine the range of excursion of flexor tendons in Zone V, and (b) to compare the excursion ranges between active (Belfast) and passive (modified Duran) flexion mobilisation regimes postoperatively. This was done (a) in two cadavers, and (b) in two patients intraoperatively, and postoperatively at 10 days, 3 weeks and 6 weeks. With passive flexion, the mean tendon excursion in Zone V in cadavers was 1 mm for flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP) and flexor pollicis longus (FPL) tendons respectively. With simulated active flexion, the mean tendon excursion was 14 mm, 10 mm and 11 mm respectively. The mean tendon excursion in clinical cases intraoperatively following passive flexion was 2 mm for FDS, FDP and FPL respectively; following simulated active flexion it was 10 mm, 11 mm and 11 mm for FDS, FDP and FPL respectively. On the tenth day following repair, the mean excursions of FDS, FDP and FPL were 1 mm, 4 mm and 4 mm on passive flexion as compared to 3 mm, 10 mm and 12 mm on active flexion respectively. Three weeks postoperatively, the mean excursions of FDS, FDP and FPL tendons were 1 mm, 2 mm and 1 mm on passive flexion as compared to 5 mm, 15 mm on active flexion respectively. Six weeks postoperatively, the mean excursions of FDS, FDP and FPL tendons were 9 mm, 7 mm and 4 mm on passive flexion as compared to 12 mm, 33 mm and 20 mm on active flexion respectively. These results demonstrate an increased excursion of repaired flexor tendons in Zone V following an active flexion mobilisation regime as compared to a passive flexion mobilisation regime.

  3. Activation of toll-like receptors and dendritic cells by a broad range of bacterial molecules

    NARCIS (Netherlands)

    Boele, L.C.L.; Bajramovic, J.J.; Vries, A.M.M.B.C. de; Voskamp-Visser, I.A.I.; Kaman, W.E.; Kleij, D. van der

    2009-01-01

    Activation of pattern recognition receptors such as Toll-like receptors (TLRs) by pathogens leads to activation and maturation of dendritic cells (DC), which orchestrate the development of the adaptive immune response. To create an overview of the effects of a broad range of pathogenic bacteria, the

  4. High quality, small molecule-activity datasets for kinase research [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Rajan Sharma

    2016-06-01

    Full Text Available Kinases regulate cell growth, movement, and death. Deregulated kinase activity is a frequent cause of disease. The therapeutic potential of kinase inhibitors has led to large amounts of published structure activity relationship (SAR data. Bioactivity databases such as the Kinase Knowledgebase (KKB, WOMBAT, GOSTAR, and ChEMBL provide researchers with quantitative data characterizing the activity of compounds across many biological assays. The KKB, for example, contains over 1.8M kinase structure-activity data points reported in peer-reviewed journals and patents. In the spirit of fostering methods development and validation worldwide, we have extracted and have made available from the KKB 258K structure activity data points and 76K associated unique chemical structures across eight kinase targets. These data are freely available for download within this data note.

  5. Identification of novel orosensory active molecules in cured vanilla Beans (Vanilla planifolia).

    Science.gov (United States)

    Schwarz, Bernd; Hofmann, Thomas

    2009-05-13

    Sequential application of solvent extraction, gel permeation chromatography, and HPLC in combination with taste dilution analyses, followed by LC-MS and 1D/2D NMR experiments, led to the discovery of seven velvety mouth-coating molecules in cured beans of Vanilla planifolia . Among these, 5-(4-hydroxybenzyl)vanillin, 4-(4-hydroxybenzyl)-2-methoxyphenol, 4-hydroxy-3-(4-hydroxy-3-methoxybenzyl)-5-methoxybenzaldehyde, (1-O-vanilloyl)-(6-O-feruloyl)-beta-d-glucopyranoside, americanin A, and 4',6'-dihydroxy-3',5-dimethoxy-[1,1'-biphenyl]-3-carboxaldehyde were previously not reported in vanilla beans. Sensory studies revealed human recognition thresholds for the velvety mouth-coating sensation between 1.0 and 5.0 mumol/kg (water). Interestingly, the biphenyl derivatives were found to enhance the perception of creaminess and fatty body of sweetened skim milk, among which 4',6'-dihydroxy-3',5-dimethoxy-[1,1'-biphenyl]-3-carboxaldehyde showed the lowest threshold level of 5 mumol/kg. Quantitative analysis of these compounds in cured vanilla beans from different origins as well as in noncured beans revealed that, with the exception of americanin A, all of the other taste compounds are not present in the green vanilla beans and are formed during the bean curing process.

  6. The Salton Seismic Imaging Project (SSIP): Active Rift Processes in the Brawley Seismic Zone

    Science.gov (United States)

    Han, L.; Hole, J. A.; Stock, J. M.; Fuis, G. S.; Rymer, M. J.; Driscoll, N. W.; Kent, G.; Harding, A. J.; Gonzalez-Fernandez, A.; Lazaro-Mancilla, O.

    2011-12-01

    The Salton Seismic Imaging Project (SSIP), funded by NSF and USGS, acquired seismic data in and across the Salton Trough in southern California and northern Mexico in March 2011. The project addresses both rifting processes at the northern end of the Gulf of California extensional province and earthquake hazards at the southern end of the San Andreas Fault system. Seven lines of onshore refraction and low-fold reflection data were acquired in the Coachella, Imperial, and Mexicali Valleys, two lines and a grid of airgun and OBS data were acquired in the Salton Sea, and onshore-offshore data were recorded. Almost 2800 land seismometers and 50 OBS's were used in almost 5000 deployments at almost 4300 sites, in spacing as dense as 100 m. These instruments received seismic signals from 126 explosive shots up to 1400 kg and over 2300 airgun shots. In the central Salton Trough, North American lithosphere appears to have been rifted completely apart. Based primarily on a 1979 seismic refraction project, the 20-22 km thick crust is apparently composed entirely of new crust added by magmatism from below and sedimentation from above. Active rifting of this new crust is manifested by shallow (geothermal energy production. This presentation is focused on an onshore-offshore line of densely sampled refraction and low-fold reflection data that crosses the Brawley Seismic Zone and Salton Buttes in the direction of plate motion. At the time of abstract submission, data analysis was very preliminary, consisting of first-arrival tomography of the onshore half of the line for upper crustal seismic velocity. Crystalline basement (>5 km/s), comprised of late-Pliocene to Quaternary sediment metamorphosed by the high heat flow, occurs at ~2 km depth beneath the Salton Buttes and geothermal field and ~4 km depth south of the BSZ. Preliminary result suggests that the velocity of basement is lower in the BSZ than to the south, which may result from fracturing. Basement velocity appears to be

  7. CD26 surface molecule involvement in T cell activation and lymphokine synthesis in rheumatoid and other inflammatory synovitis.

    Science.gov (United States)

    Gerli, R; Muscat, C; Bertotto, A; Bistoni, O; Agea, E; Tognellini, R; Fiorucci, G; Cesarotti, M; Bombardieri, S

    1996-07-01

    T cell surface expression and the functional role of CD26 antigen (Ag), a surface ectoenzyme involved in T cell activation and migration across the extracellular matrix, were analyzed in the peripheral blood (PB) and synovial fluid (SF) from patients with inflammatory arthritides. CD26 membrane expression on T cells was detected by cytofluorometry using two different monoclonal antibodies, anti-Ta1 and anti-1F7, while cell proliferation and both IL-2 and IFN-gamma production were evaluated in anti-CD3- or anti-CD2-stimulated cell cultures after Ag surface modulation with anti-1F7. The results showed that Ta1 and 1F7 Ag expression were increased on T cells from PB of patients with active, but not inactive, rheumatoid arthritis (RA). Most SF T cells from RA or other inflammatory arthritides displayed the memory marker CD45R0 and the Ta1 Ag, but lacked the 1F7 molecule. In addition, in vitro 1F7 modulation, which enhanced RA PB T cell proliferation and both IL-2 and IFN-gamma synthesis, did not synergize with anti-CD3 or anti-CD2 in inducing IL-2-dependent activation of SF T cells, but reduced IFN-gamma production. A spontaneous reappearance of 1F7 Ag on the SF T cell surface was seen after 2-5 days in culture. Phorbol myristate acetate, able to accelerate its reexpression, also restored a normal response of SF T cells to anti-1F7 comitogenic effects. These data confirm a role of the CD26 surface molecule in regulating T cell activation and lymphokine synthesis. This observation may have important implications in the regulation of T cell activity at the joint level during chronic inflammatory processes. PMID:8674237

  8. Single Molecule Instrument for Surface Enhanced Raman Optical Activity of Biomolecules Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Stereochemistry is an essential element of our organic life. Only certain enantiomers are useful as drugs for the human body. Raman Optical Activity (ROA) and...

  9. Single Molecule Instrument for Surface Enhanced Raman Optical Activity of Biomolecules Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Stereochemistry is an essential element of our organic life. Only certain enantiomers are useful as drugs for the human body. Raman optical activity (ROA) provides...

  10. Small molecule activators of pre-mRNA 3′ cleavage

    OpenAIRE

    Ryan, Kevin; Khleborodova, Asya; Pan, Jingyi; Ryan, Xiaozhou P.

    2009-01-01

    3′ Cleavage and polyadenylation are obligatory steps in the biogenesis of most mammalian pre-mRNAs. In vitro reconstitution of the 3′ cleavage reaction from human cleavage factors requires high concentrations of creatine phosphate (CP), though how CP activates cleavage is not known. Previously, we proposed that CP might work by competitively inhibiting a cleavage-suppressing serine/threonine (S/T) phosphatase. Here we show that fluoride/EDTA, a general S/T phosphatase inhibitor, activates in ...

  11. Isolation and molecular characterization of biofouling bacteria and profiling of quorum sensing signal molecules from membrane bioreactor activated sludge.

    Science.gov (United States)

    Lade, Harshad; Paul, Diby; Kweon, Ji Hyang

    2014-02-04

    The formation of biofilm in a membrane bioreactor depends on the production of various signaling molecules like N-acyl homoserine lactones (AHLs). In the present study, a total of 200 bacterial strains were isolated from membrane bioreactor activated sludge and screened for AHLs production using two biosensor systems, Chromobacterium violaceum CV026 and Agrobacterium tumefaciens A136. A correlation between AHLs production and biofilm formation has been made among screened AHLs producing strains. The 16S rRNA gene sequence analysis revealed the dominance of Aeromonas and Enterobacter sp. in AHLs production; however few a species of Serratia, Leclercia, Pseudomonas, Klebsiella, Raoultella and Citrobacter were also identified. The chromatographic characterization of sludge extract showed the presence of a broad range of quorum sensing signal molecules. Further identification of sludge AHLs by thin layer chromatography bioassay and high performance liquid chromatography confirms the presence of C4-HSL, C6-HSL, C8-HSL, 3-oxo-C8-HSL, C10-HSL, C12-HSL, 3-oxo-C12-HSL and C14-HSL. The occurrence of AHLs in sludge extract and dominance of Aeromonas and Enterobacter sp. in activated sludge suggests the key role of these bacterial strains in AHLs production and thereby membrane fouling.

  12. Isolation and Molecular Characterization of Biofouling Bacteria and Profiling of Quorum Sensing Signal Molecules from Membrane Bioreactor Activated Sludge

    Directory of Open Access Journals (Sweden)

    Harshad Lade

    2014-02-01

    Full Text Available The formation of biofilm in a membrane bioreactor depends on the production of various signaling molecules like N-acyl homoserine lactones (AHLs. In the present study, a total of 200 bacterial strains were isolated from membrane bioreactor activated sludge and screened for AHLs production using two biosensor systems, Chromobacterium violaceum CV026 and Agrobacterium tumefaciens A136. A correlation between AHLs production and biofilm formation has been made among screened AHLs producing strains. The 16S rRNA gene sequence analysis revealed the dominance of Aeromonas and Enterobacter sp. in AHLs production; however few a species of Serratia, Leclercia, Pseudomonas, Klebsiella, Raoultella and Citrobacter were also identified. The chromatographic characterization of sludge extract showed the presence of a broad range of quorum sensing signal molecules. Further identification of sludge AHLs by thin layer chromatography bioassay and high performance liquid chromatography confirms the presence of C4-HSL, C6-HSL, C8-HSL, 3-oxo-C8-HSL, C10-HSL, C12-HSL, 3-oxo-C12-HSL and C14-HSL. The occurrence of AHLs in sludge extract and dominance of Aeromonas and Enterobacter sp. in activated sludge suggests the key role of these bacterial strains in AHLs production and thereby membrane fouling.

  13. Modulation of Pantothenate Kinase 3 Activity by Small Molecules that Interact with the Substrate/Allosteric Regulatory Domain

    Energy Technology Data Exchange (ETDEWEB)

    Leonardi, Roberta; Zhang, Yong-Mei; Yun, Mi-Kyung; Zhou, Ruobing; Zeng, Fu-Yue; Lin, Wenwei; Cui, Jimmy; Chen, Taosheng; Rock, Charles O.; White, Stephen W.; Jackowski, Suzanne (SJCH)

    2010-09-27

    Pantothenate kinase (PanK) catalyzes the rate-controlling step in coenzyme A (CoA) biosynthesis. PanK3 is stringently regulated by acetyl-CoA and uses an ordered kinetic mechanism with ATP as the leading substrate. Biochemical analysis of site-directed mutants indicates that pantothenate binds in a tunnel adjacent to the active site that is occupied by the pantothenate moiety of the acetyl-CoA regulator in the PanK3 acetyl-CoA binary complex. A high-throughput screen for PanK3 inhibitors and activators was applied to a bioactive compound library. Thiazolidinediones, sulfonylureas and steroids were inhibitors, and fatty acyl-amides and tamoxifen were activators. The PanK3 activators and inhibitors either stimulated or repressed CoA biosynthesis in HepG2/C3A cells. The flexible allosteric acetyl-CoA regulatory domain of PanK3 also binds the substrates, pantothenate and pantetheine, and small molecule inhibitors and activators to modulate PanK3 activity.

  14. Phytohormones as Important Biologically Active Molecules – Their Simple Simultaneous Detection

    Directory of Open Access Journals (Sweden)

    Ladislav Havel

    2009-05-01

    Full Text Available Phytohormones, their functions, synthesis and effects, are of great interest. To study them in plant tissues accurate and sensitive methods are required. In the present study we aimed at optimizing experimental conditions to separate and determine not only plant hormones but also their metabolites, by liquid chromatography coupled with a UV-VIS detector. The mixture we analyzed was composed of benzyladenine, kinetin, trans-zeatin, cis-zeatin, dihydrozeatin, meta-topolin, ortho-topolin, α-naphthalene acetic acid, indole-3-acetic acid, trans-zeatin-7-glucoside, trans-zeatin-O-glucoside, trans-zeatin-9-riboside, meta-topolin-9-riboside and ortho-topolin-9-riboside. We measured the calibration dependences and estimated limits of detection and quantification under the optimal chromatographic conditions (column: Polaris C18; mobile phase: gradient starting at 2:98 (methanol:0.001% TFA and was increasing to 55:45 during twenty minutes, and then decreasing for 10 min to 35:65, flow rate: 200 µL·min-1, temperature: 50 °C, wavelength: 210 nm. The detection limits for the target molecules were estimated as tens of ng per mL. We also studied the effect of flax extracts on the phytohormones’ signals. Recovery of aliphatic and aromatic cytokinins, metabolites of cytokinins and auxinswere within the range from 87 to 105 %. The experimental conditions were tested on a mass selective detector. In addition we analysed a commercial product used for stimulation of roots formation in cuttings of poorly rooting plants. The determined content of α-naphthalene acetic acid was in good agreement with that declared by the manufacturer.

  15. Involvement of Signaling Molecules on Na+/H+ Exchanger-1 Activity in Human Monocytes

    OpenAIRE

    Sarigianni, Maria; Tsapas, Apostolos; Mikhailidis, Dimitri P; Kaloyianni, Martha; Koliakos, George; Paletas, Konstantinos

    2010-01-01

    Background: Sodium/hydrogen exchanger-1 (NHE-1) contributes to maintaining intracellular pH (pHi). We assessed the effect of glucose, insulin, leptin and adrenaline on NHE-1 activity in human monocytes in vitro. These cells play a role in atherogenesis and disturbances in the hormones evaluated are associated with obesity and diabetes. Methods and Results: Monocytes were isolated from 16 healthy obese and 10 lean healthy subjects. NHE-1 activity was estimated by measuring pHi with a fluoresce...

  16. MS-1020 is a novel small molecule that selectively inhibits JAK3 activity

    OpenAIRE

    Kim, Byung Hak; Oh, Sei-Ryang; Yin, Chang-Hong; Lee, Sangku; Kim, Eun-Ah; Kim, Min-Seok; Sandoval, Claudio; Jayabose, Somasundaram; Bach, Erika A.; Lee, Hyeong-Kyu; Baeg, Gyeong-Hun

    2009-01-01

    To identify JAK/STAT signaling inhibitors, we performed a cell-based high throughput screening using a plant extract library and identified Nb-(α-hydroxynaphthoyl)serotonin called MS-1020 as a novel JAK3 inhibitor. MS-1020 potently inhibited persistently-active STAT3 in a cell type-specific manner. Upon further examination, we found that MS-1020 selectively blocks constitutively-active JAK3. MS-1020 consistently suppressed IL-2-induced JAK3/STAT5 signaling but not prolactin-induced JAK2/STAT5...

  17. Long-Term Uplift in the Altiplano-Puna Neovolcanic Zone: Evidence of an Active Magmatic Diapir?

    Science.gov (United States)

    Fialko, Y.; Pearse, J.

    2012-12-01

    We present InSAR observations of a long-term uplift in the Altiplano-Puna neovolcanic zone (central Andes, South America). Previous observations revealed a a massive Ultra Low Velocity Zone (ULVZ) at depth of 17-19 km (Zandt et al., 2003), and surface deformation that was attributed to Uturuncu, a dormant volcano in the middle of the Altiplano-Puna neovolcanic zone (Pritchard and Simons, 2002). Our time series analysis of combined data from different sensors (ERS-1/2 and ENVISAT), satellite tracks, and observation modes (fine beam and ScanSAR) reveals that the central uplift has persisted at a nearly constant rate of ~1 cm/yr over the last two decades, and is surrounded by a broad zone of subsidence. We use the satellite line-of-sight velocities from different look directions to constrain the depth and geometry of the inferred sources of magmatic unrest. Inversions based on elastic half-space models indicate that the inflation source is located well below the brittle-ductile transition, and likely resides at the depth of the seismically imaged ULVZ. We investigated the effects of inelastic deformation in the ambient crust using finite element models. The models incorporated laboratory-derived rheologies of the ambient crust, and geotherms appropriate for an active neo-volcanic zone such as the one in the Altiplano-Puna province. Based on a large number of numerical simulations constrained by the observed surface velocities, we conclude that the ongoing uplift and peripheral subsidence result from a large mid-crustal diapir fed by a partially molten source region in the middle crust. The observed pattern of surface deformation due to the Altiplano-Puna ULVZ is remarkably similar to that due to the Socorro Magma Body (SMB) in central New Mexico, USA (Pearse and Fialko, 2010), suggesting a common process. mosaic of the mean LOS velocity showing uplift and peripheral subsidence due to the inferred mid-crustal diapir.

  18. Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms.

    Science.gov (United States)

    Torres, Nelson S; Abercrombie, Johnathan J; Srinivasan, Anand; Lopez-Ribot, Jose L; Ramasubramanian, Anand K; Leung, Kai P

    2016-10-01

    It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 μM, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies. PMID:27401577

  19. Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms.

    Science.gov (United States)

    Torres, Nelson S; Abercrombie, Johnathan J; Srinivasan, Anand; Lopez-Ribot, Jose L; Ramasubramanian, Anand K; Leung, Kai P

    2016-10-01

    It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 μM, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies.

  20. Preconditioning of Carbon Monoxide Releasing Molecule-derived CO Attenuates LPS-induced Activation of HUVEC

    Directory of Open Access Journals (Sweden)

    Bingwei Sun, Xiangqian Zou, Yueling Chen, Ping Zhang, Gengsheng Shi

    2008-01-01

    Full Text Available Objective: To investigate the effects and potential mechanisms of preconditioning of tricarbonyldichlororuthenium (III dimer (CORM-2-liberated CO on LPS-induced activation of endothelial cells (HUVEC. Methods: HUVEC were pretreated with CORM-2 at the concentration of 50 or 100μM for 2 hrs, washed and stimulated with LPS (10μg/ml for additional 4 hrs. Activation (oxidative stress of HUVEC was assessed by measuring intracellular oxidation of DHR 123 or nitration of DAF-FM, specific H2O2 and NO fluorochromes, respectively. The expression of HO-1, iNOS (Western blot and ICAM-1 (cell ELISA proteins and activation of inflammation-relevant transcription factor, NF-κB (EMSA were assessed. In addition, PMN adhesion to HUVEC was also assessed. Results: The obtained data indicate that pretreatment of HUVEC with CORM-2 results in: 1 decrease of LPS-induced production of ROS and NO; 2 up-regulation of HO-1 but decrease in iNOS at the protein levels; 3 inhibition of LPS-induced activation of NF-κB; and 4 downregulation of expression of ICAM-1, and this was accompanied by a decrease of PMN adhesion to LPS-stimulated HUVEC. Conclusions: Preconditioning of CO liberated by CORM-2 elicited its anti-inflammatory effects by interfering with the induction of intracellular oxidative stress. In addition, it also supports the notion that CO is a potent inhibitor of iNOS and NF-κB.

  1. Interleukin 3 stimulates proliferation and triggers endothelial-leukocyte adhesion molecule 1 gene activation of human endothelial cells.

    Science.gov (United States)

    Brizzi, M F; Garbarino, G; Rossi, P R; Pagliardi, G L; Arduino, C; Avanzi, G C; Pegoraro, L

    1993-06-01

    Proliferation and functional activation of endothelial cells within a tissue site of inflammation are regulated by humoral factors released by cells, such as T lymphocytes and monocytes, infiltrating the perivascular space. In the present study we investigated the effects of interleukin 3 (IL-3), an activated T lymphocyte-derived cytokine, on cultured human umbilical vein endothelial cells (HUVEC). Proliferative activity, evaluated both by estimation of the fraction of cells in the S phase and by direct cell count demonstrated that IL-3, at the dose of 25 ng/ml, enhances more than threefold both DNA synthesis and cell proliferation above baseline control conditions. Binding studies with radioiodinated ligand demonstrated that HUVEC constitutively express a smaller number of IL-3 binding sites (approximately 99 binding sites per cell, with an apparent Kd of 149 pM). Accordingly, molecular analysis showed the presence of transcripts for both alpha and beta subunits of the IL-3 receptor. Functional activation of endothelial cells was evaluated by the expression of the endothelial-leukocyte adhesion molecule 1 (ELAM-1) transcript and by leukocyte adhesion. The ELAM-1 gene transcript was clearly detectable 4 h after IL-3 addition and started to decrease after 12 h. Moreover, IL-3-induced ELAM-1 transcription was followed by enhanced adhesion of neutrophils and CD4+ T cells to HUVEC. The findings that IL-3 can stimulate both proliferation and functional activation of endothelial cells suggest that this cytokine can be involved in sustaining the process of chronic inflammation.

  2. Time-dependent generalized-active-space configuration-interaction approach to photoionization dynamics of atoms and molecules

    Science.gov (United States)

    Bauch, S.; Sørensen, L. K.; Madsen, L. B.

    2014-12-01

    We present a wave-function-based method to solve the time-dependent many-electron Schrödinger equation with special emphasis on strong-field ionization phenomena. The theory builds on the configuration-interaction (CI) approach supplemented by the generalized-active-space concept from quantum chemistry. The latter allows for a controllable reduction in the number of configurations in the CI expansion by imposing restrictions on the active orbital space. The method is similar to the recently formulated time-dependent restricted-active-space CI method [D. Hochstuhl and M. Bonitz, Phys. Rev. A 86, 053424 (2012), 10.1103/PhysRevA.86.053424]. We present details of our implementation and address convergence properties with respect to the active spaces and the associated account of electron correlation in both ground-state and excitation scenarios. We apply the time-dependent generalized-active-space CI theory to strong-field ionization of polar diatomic molecules and illustrate how the method allows us to uncover a strong correlation-induced shift of the preferred direction of emission of photoelectrons.

  3. Holocene activities of the Taigu fault zone,Shanxi Province, and their relations with the 1303 Hongdong M=8 earthquake

    Institute of Scientific and Technical Information of China (English)

    谢新生; 江娃利; 王焕贞; 冯西英

    2004-01-01

    The Taigu fault zone is one of the major 12 active boundary faults of the Shanxi fault-depression system, locatedon the eastern boundary of the Jinzhong basin. As the latest investigation indicated, the fault zone had dislocatedgully terrace of the f1rst order, forming fault-scarp in front of the loess mesa. It has been discovered in many placesin ground surface and trenches that Holocene deposits were dislocated. The latest activity was the 1303 Hongdongearthquake M=8, the fault appeared as right-lateral strike-slip with normal faulting. During that earthquake, theTaigu fault together with the Mianshan western-side fault on the Lingshi upheaval and the Huoshan pediment faulton the eastern boundary of the Linfen basin was being active, forming a surface rupture belt of 160 km in length.Moreover, the Taigu fault were active in the mid-stage of Holocene and near 7 700 aB.P. From these we learnt that,in Shanxi fault-depression system, the run-through activity of two boundary faults of depression-basins mightgenerate great earthquake with M=8.

  4. Active source monitoring at the Wenchuan fault zone: coseismic velocity change associated with aftershock event and its implication

    Science.gov (United States)

    Yang, Wei; Ge, Hongkui; Wang, Baoshan; Hu, Jiupeng; Yuan, Songyong; Qiao, Sen

    2014-12-01

    With the improvement of seismic observation system, more and more observations indicate that earthquakes may cause seismic velocity change. However, the amplitude and spatial distribution of the velocity variation remains a controversial issue. Recent active source monitoring carried out adjacent to Wenchuan Fault Scientific Drilling (WFSD) revealed unambiguous coseismic velocity change associated with a local M s5.5 earthquake. Here, we carry out forward modeling using two-dimensional spectral element method to further investigate the amplitude and spatial distribution of observed velocity change. The model is well constrained by results from seismic reflection and WFSD coring. Our model strongly suggests that the observed coseismic velocity change is localized within the fault zone with width of ~120 m rather than dynamic strong ground shaking. And a velocity decrease of ~2.0 % within the fault zone is required to fit the observed travel time delay distribution, which coincides with rock mechanical experiment and theoretical modeling.

  5. Dynamic fracturing by successive coseismic loadings leads to pulverization in active fault zones

    Science.gov (United States)

    Aben, F. M.; Doan, M.-L.; Mitchell, T. M.; Toussaint, R.; Reuschlé, T.; Fondriest, M.; Gratier, J.-P.; Renard, F.

    2016-04-01

    Previous studies show that pulverized rocks observed along large faults can be created by single high-strain rate loadings in the laboratory, provided that the strain rate is higher than a certain pulverization threshold. Such loadings are analogous to large seismic events. In reality, pulverized rocks have been subject to numerous seismic events rather than one single event. Therefore, the effect of successive "milder" high-strain rate loadings on the pulverization threshold is investigated by applying loading conditions below the initial pulverization threshold. Single and successive loading experiments were performed on quartz-monzonite using a Split Hopkinson Pressure Bar apparatus. Damage-dependent petrophysical properties and elastic moduli were monitored by applying incremental strains. Furthermore, it is shown that the pulverization threshold can be reduced by successive "milder" dynamic loadings from strain rates of ~180 s-1 to ~90 s-1. To do so, it is imperative that the rock experiences dynamic fracturing during the successive loadings prior to pulverization. Combined with loading conditions during an earthquake rupture event, the following generalized fault damage zone structure perpendicular to the fault will develop: furthest from the fault plane, there is a stationary outer boundary that bounds a zone of dynamically fractured rocks. Closer to the fault, a pulverization boundary delimits a band of pulverized rock. Consecutive seismic events will cause progressive broadening of the band of pulverized rocks, eventually creating a wider damage zone observed in mature faults.

  6. TOPONYMS AS REFLECTION OF THE PECULIARITIES OF CRAFT ACTIVITY (ON THE MATERIAL OF SMOLENSK-VITEBSK BORDER-ZONE

    Directory of Open Access Journals (Sweden)

    Evseeva Olga Sergeevna

    2014-09-01

    Full Text Available The geographical names are important units, representing the connection with the cultural and historical traditions and national-specific context of a specific time period; due to the inherent cumulative functions they fix and retain the essential features of a variety of information: linguistic, cultural, social, historical, psychological, ethnographic. The article deals with the toponyms, spread on the territory of the Smolensk-Vitebsk borderzone and recorded in modern lexicographical sources (toponymic and dialect dictionaries. The card index of geographical names collected by the author includes 1196 units, 604 of which are registered in the Smolensk border-zone and 592 in the Vitebsk border-zone. The conducted analysis allowed us to identify nine groups of the studied units, depending on the semantics of motivating word. Special attention is paid to the toponyms formed from appellatives associated with industrial activity, which was widely spread on the territory of Smolensk region in different historical periods. These units reflect the linguistic, historical, cultural and economic specifics of Smolensk-Vitebsk border-zone. The toponyms which present the development of mining, brick production, the manufacture of household utensils (glass and clay are the most frequent. The author reveals that the dialectal units and borrowed words confirming the close language contact among the frontier inhabitants, as well as Slavic vocabulary, were used as appellatives that served as the basis for toponyms. The results of the linguistic and culturological analysis allowed to conclude that the fragment of toponymic system, based on the craft activity of Smolensk-Vitebsk border-zone residents, testified to the community and the interaction between cultures and languages of closely related peoples – Russians and Belarusians.

  7. Modelling active sites for the Beckmann rearrangement reaction in boron-containing zeolites and their interaction with probe molecules.

    Science.gov (United States)

    Lezcano-González, Inés; Vidal-Moya, Alejandro; Boronat, Mercedes; Blasco, Teresa; Corma, Avelino

    2010-06-28

    Theoretical calculations and in situ solid state NMR spectroscopy have been combined to get insight on the nature of the active sites for the Beckmann rearrangement reaction in borosilicate zeolites. The interaction of a B site in zeolite Beta with a series of probe molecules (ammonia, pyridine, acetone and water) has been modelled and the (15)N and (11)B NMR isotropic chemical shift of the resulting complexes calculated and compared with experimental in situ NMR results. This approach has allowed validation of the methodology to model the adsorption on a zeolite boron site of molecules of varying basicity which are either protonated or non-protonated. The limitation is that theoretical calculations overestimate the effect of molecular adsorption through hydrogen bonds on the calculated isotropic (11)B NMR chemical shift.Theoretical and experimental results on the adsorption of acetophenone and cyclohexanone oximes on zeolite B-Beta indicate that Brønsted acid sites protonate the oximes, changing the boron coordination from trigonal to tetrahedral. Comparison of theoretical and experimental (15)N NMR chemical shifts of the adsorbed amides (acetanilide and epsilon-caprolactam) indicates that they are non-protonated, and the (11)B NMR spectra show that, as expected, boron remains in trigonal coordination with an isotropic delta(11)B(exp) which differs from the calculated value delta(11)B(calc).

  8. A novel molecule integrating therapeutic and diagnostic activities reveals multiple aspects of stem cell-based therapy.

    Science.gov (United States)

    Hingtgen, Shawn D; Kasmieh, Randa; van de Water, Jeroen; Weissleder, Ralph; Shah, Khalid

    2010-04-01

    Stem cells are promising therapeutic delivery vehicles; however pre-clinical and clinical applications of stem cell-based therapy would benefit significantly from the ability to simultaneously determine therapeutic efficacy and pharmacokinetics of therapies delivered by engineered stem cells. In this study, we engineered and screened numerous fusion variants that contained therapeutic (TRAIL) and diagnostic (luciferase) domains designed to allow simultaneous investigation of multiple events in stem cell-based therapy in vivo. When various stem cell lines were engineered with the optimized molecule, SRL(O)L(2)TR, diagnostic imaging showed marked differences in the levels and duration of secretion between stem cell lines, while the therapeutic activity of the molecule showed the different secretion levels translated to significant variability in tumor cell killing. In vivo, simultaneous diagnostic and therapeutic monitoring revealed that stem cell-based delivery significantly improved pharmacokinetics and anti-tumor effectiveness of the therapy compared to intravenous or intratumoral delivery. As treatment for highly malignant brain tumor xenografts, tracking SRL(O)L(2)TR showed stable stem cell-mediated delivery significantly regressed peripheral and intracranial tumors. Together, the integrated diagnostic and therapeutic properties of SRL(O)L(2)TR answer critical questions necessary for successful utilization of stem cells as novel therapeutic vehicles. PMID:20127797

  9. Human L-ficolin, a recognition molecule of the lectin activation pathway of complement, activates complement by binding to pneumolysin, the major toxin of Streptococcus pneumoniae.

    Science.gov (United States)

    Ali, Youssif M; Kenawy, Hany I; Muhammad, Adnan; Sim, Robert B; Andrew, Peter W; Schwaeble, Wilhelm J

    2013-01-01

    The complement system is an essential component of the immune response, providing a critical line of defense against different pathogens including S. pneumoniae. Complement is activated via three distinct pathways: the classical (CP), the alternative (AP) and the lectin pathway (LP). The role of Pneumolysin (PLY), a bacterial toxin released by S. pneumoniae, in triggering complement activation has been studied in vitro. Our results demonstrate that in both human and mouse sera complement was activated via the CP, initiated by direct binding of even non-specific IgM and IgG3 to PLY. Absence of CP activity in C1q(-/-) mouse serum completely abolished any C3 deposition. However, C1q depleted human serum strongly opsonized PLY through abundant deposition of C3 activation products, indicating that the LP may have a vital role in activating the human complement system on PLY. We identified that human L-ficolin is the critical LP recognition molecule that drives LP activation on PLY, while all of the murine LP recognition components fail to bind and activate complement on PLY. This work elucidates the detailed interactions between PLY and complement and shows for the first time a specific role of the LP in PLY-mediated complement activation in human serum.

  10. Activation of cell signaling via optical manipulation of gold-coated liposomes encapsulating signaling molecules

    Science.gov (United States)

    Orsinger, Gabriel V.; Leung, Sarah J.; Romanowski, Marek

    2013-02-01

    Many diseases involve changes in cell signaling cascades, as seen commonly in drug resistant cancers. To better understand these intricate signaling events in diseased cells and tissues, experimental methods of probing cellular communication at a single to multi-cell level are required. We recently introduced a general platform for activation of selected signaling pathways by optically controlled delivery and release of water soluble factors using gold-coated liposomes. In the example presented here, we encapsulated inositol trisphosphate (IP3), a ubiquitous intracellular secondary messenger involved in GPCR and Akt signaling cascades, within 100 nm gold-coated liposomes. The high polarizability of the liposome's unique gold pseudo-shell allows stable optical trapping for subcellular manipulation in the presence of cells. We take this optical manipulation further by optically injecting IP3-containing liposomes into the cytosol of a single cell to initiate localized cell signaling. Upon optical injection of liposomal IP3 into a single ovarian carcinoma cell, we observed localized activation as reported by changes in Indo-1 fluorescence intensity. With established gap junctions between the injected cell and neighboring cells, we monitored propagation of this signaling to and through nearby cells.

  11. Kidney Injury Molecule-1 Protects against Gα12 Activation and Tissue Damage in Renal Ischemia-Reperfusion Injury

    Science.gov (United States)

    Ismail, Ola Z.; Zhang, Xizhong; Wei, Junjun; Haig, Aaron; Denker, Bradley M.; Suri, Rita S.; Sener, Alp; Gunaratnam, Lakshman

    2016-01-01

    Ischemic acute kidney injury is a serious untreatable condition. Activation of the G protein α12 (Gα12) subunit by reactive oxygen species is a major cause of tissue damage during renal ischemia-reperfusion injury. Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein that is highly up-regulated during acute kidney injury, but the physiologic significance of this up-regulation is unclear. Here, we report for the first time that Kim-1 inhibits Gα12 activation and protects mice against renal ischemia-reperfusion injury. We reveal that Kim-1 physically interacts with and inhibits cellular Gα12 activation after inflammatory stimuli, including reactive oxygen species, by blocking GTP binding to Gα12. Compared with Kim-1+/+ mice, Kim-1−/− mice exhibited greater Gα12 and downstream Src activation both in primary tubular epithelial cells after in vitro stimulation with H2O2 and in whole kidneys after unilateral renal artery clamping. Finally, we show that Kim-1–deficient mice had more severe kidney dysfunction and tissue damage after bilateral renal artery clamping, compared with wild-type mice. Our results suggest that KIM-1 is an endogenous protective mechanism against renal ischemia-reperfusion injury through inhibition of Gα12. PMID:25759266

  12. Identification of Quorum-Sensing Signal Molecules and a Biosynthetic Gene in Alicycliphilus sp. Isolated from Activated Sludge.

    Science.gov (United States)

    Morohoshi, Tomohiro; Okutsu, Noriya; Xie, Xiaonan; Ikeda, Tsukasa

    2016-01-01

    Activated sludge is a complicated mixture of various microorganisms that is used to treat sewage and industrial wastewater. Many bacteria produce N-acylhomoserine lactone (AHL) as a quorum-sensing signal molecule to regulate the expression of the exoenzymes used for wastewater treatment. Here, we isolated an AHL-producing bacteria from an activated sludge sample collected from an electronic component factory, which we named Alicycliphilus sp. B1. Clone library analysis revealed that Alicycliphilus was a subdominant genus in this sample. When we screened the activated sludge sample for AHL-producing strains, 12 of 14 the AHL-producing isolates were assigned to the genus Alicycliphilus. A putative AHL-synthase gene, ALISP_0667, was cloned from the genome of B1 and transformed into Escherichia coli DH5α. The AHLs were extracted from the culture supernatants of the B1 strain and E. coli DH5α cells harboring the ALISP_0667 gene and were identified by liquid chromatography-mass spectrometry as N-(3-hydroxydecanoyl)-l-homoserine lactone and N-(3-hydroxydodecanoyl)-l-homoserine lactone. The results of comparative genomic analysis suggested that the quorum-sensing genes in the B1 strain might have been acquired by horizontal gene transfer within activated sludge. PMID:27490553

  13. Time-dependent generalized-active-space configuration-interaction approach to photoionization dynamics of atoms and molecules

    CERN Document Server

    Bauch, Sebastian; Madsen, Lars Bojer

    2014-01-01

    We present a wave-function based method to solve the time-dependent many-electron Schr\\"odinger equation (TDSE) with special emphasis on strong-field ionization phenomena. The theory builds on the configuration-interaction (CI) approach supplemented by the generalized-active-space (GAS) concept from quantum chemistry. The latter allows for a controllable reduction in the number of configurations in the CI expansion by imposing restrictions on the active orbital space. The method is similar to the recently formulated time-dependent restricted-active-space (TD-RAS) CI method [D. Hochstuhl, and M. Bonitz, Phys. Rev. A 86, 053424 (2012)]. We present details of our implementation and address convergence properties with respect to the active spaces and the associated account of electron correlation in both ground state and excitation scenarios. We apply the TD-GASCI theory to strong-field ionization of polar diatomic molecules and illustrate how the method allows us to uncover a strong correlation-induced shift of ...

  14. Activation of cord T lymphocytes. IV. Analysis of surface expression and functional role of 1F7 (CD26) molecule.

    Science.gov (United States)

    Gerli, R; Agea, E; Muscat, C; Ercolani, R; Bistoni, O; Tognellini, R; Mariggió, M A; Spinozzi, F; Bertotto, A

    1994-04-15

    A role for CD26 surface antigen (Ag) in both CD3- and CD2-mediated T cell activation has been previously demonstrated. To analyze the functional role of CD26 in the CD3- and CD2-induced activation pathways of cord T cells, which represent the most reliable source of Ag-unprimed T cells, we employed a newly developed anti-CD26 monoclonal antibody, termed anti-1F7, anti-CD3 and anti-CD2 in activating T lymphocytes. The results showed that CD26 Ag is expressed on the surface of almost all resting cord T cells and that its fluorescence intensity is enhanced by activation. The binding of anti-1F7 induced a decrease in CD26 membrane expression, with no detectable effect on the surface expression of other cord T cell-related molecules. Moreover, the modulation of CD26 resulted in an increase in anti-CD3-mediated cord T cell activation through an enhancement in intracellular calcium levels, IL-2 receptor expression, and IL-2 synthesis, whereas it had no effect on cord T cell activation induced by anti-CD2 or anti-CD2 plus exogenous IL-2. The fact that the selective involvement of CD26 in the activation pathway triggered by anti-CD3, but not anti-CD2, could be reversed by prior stimulation of cord T cells with anti-CD3 suggests that this functional feature, which resembles that of mature thymocytes, may be linked to the Ag-unprimed cell phenotype of cord T lymphocytes. PMID:7909498

  15. Diversity and dynamics of active microbial eukaryotes in the anoxic zone of a freshwater meromictic lake (Pavin, France

    Directory of Open Access Journals (Sweden)

    CECILE eLEPERE

    2016-02-01

    Full Text Available Microbial eukaryotes play a crucial role in ecosystem functioning and oxygen is considered to be one of the strongest barriers against their local dispersal. However, diversity of microbial eukaryotes in freshwater habitats with oxygen gradients has previously received very little attention. We applied high-throughput sequencing (V4 region of the 18S rRNA gene in conjunction with quantitative PCR (DNA and RNA and fluorescent in situ hybridization analyses, to provide an unique spatio-temporal analysis of microbial eukaryotes diversity and potential activity in a meromictic freshwater lake (lake Pavin. This study revealed a high genetic diversity of unicellular eukaryotes in the permanent anoxic zone of lake Pavin and allowed the discrimination of active vs. inactive components. 42 % of the OTUs (Operational taxonomic Units are exclusively present in the monimolimnion, where Alveolata (Ciliophora and Dinophyceae and Fungi (Dikarya and Chytrids are the most active phyla and are probably represented by species capable of anaerobic metabolism. Pigmented eukaryotes (Haptophyceae and Chlorophyceae are also present and active in this zone, which opens up questions regarding their metabolism.

  16. Diversity and Dynamics of Active Small Microbial Eukaryotes in the Anoxic Zone of a Freshwater Meromictic Lake (Pavin, France)

    Science.gov (United States)

    Lepère, Cécile; Domaizon, Isabelle; Hugoni, Mylène; Vellet, Agnès; Debroas, Didier

    2016-01-01

    Microbial eukaryotes play a crucial role in ecosystem functioning and oxygen is considered to be one of the strongest barriers against their local dispersal. However, diversity of microbial eukaryotes in freshwater habitats with oxygen gradients has previously received very little attention. We applied high-throughput sequencing (V4 region of the 18S rRNA gene) in conjunction with quantitative PCR (DNA and RNA) and fluorescent in situ hybridization (FISH) analyses, to provide an unique spatio-temporal analysis of microbial eukaryotes diversity and potential activity in a meromictic freshwater lake (lake Pavin). This study revealed a high genetic diversity of unicellular eukaryotes in the permanent anoxic zone of lake Pavin and allowed the discrimination of active vs. inactive components. Forty-two percent of the OTUs (Operational Taxonomic Units) are exclusively present in the monimolimnion, where Alveolata (Ciliophora and Dinophyceae) and Fungi (Dikarya and Chytrids) are the most active phyla and are probably represented by species capable of anaerobic metabolism. Pigmented eukaryotes (Haptophyceae and Chlorophyceae) are also present and active in this zone, which opens up questions regarding their metabolism. PMID:26904006

  17. High activity in catalytic cracking of large molecules over micro-mesoporous silicoaluminophosphate with controlled morphology

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A novel micro-mesoporous silicoaluminophosphate(MUS-5) with controlled morphology has been first synthesized in a two-step route.The physical properties of the silicoaluminophosphate were characterized using XRD,SEM,TEM,nitrogen adsorption-desorption and NH3-TPD techniques.When the pH value of the solution system was varied in the range from 2.0 to 5.0,three different morphologies of silicoaluminophosphate including chain-like,flower-like and barrel-like morphology were obtained.Catalytic tests showed that the silicoaluminophosphate exhibited higher catalytic activity compared with the conventional microporous SAPO-5 under the same conditions for catalytic cracking of 1,3,5-triisopropylbenzene heavy aromatics.The remarkable catalytic reactivity was mainly attributed to the presence of the hierarchical porosity in the silicoaluminophosphate catalyst.

  18. A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.

    Directory of Open Access Journals (Sweden)

    Elizabeth R Sharlow

    Full Text Available BACKGROUND: The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK, an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. METHODOLOGY/PRINCIPAL FINDINGS: Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics. CONCLUSIONS/SIGNIFICANCE: The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome.

  19. Update on the Pathophysiological Activities of the Cardiac Molecule Cardiotrophin-1 in Obesity

    Directory of Open Access Journals (Sweden)

    Mohamed Asrih

    2013-01-01

    Full Text Available Cardiotrophin-1 (CT-1 is a heart-targeting cytokine that has been reported to exert a variety of activities also in other organs such as the liver, adipose tissue, and atherosclerotic arteries. CT-1 has been shown to induce these effects via binding to a transmembrane receptor, comprising the leukaemia inhibitory factor receptor (LIFRβ subunit and the glycoprotein 130 (gp130, a common signal transducer. Both local and systemic concentrations of CT-1 have been shown to potentially play a critical role in obesity. For instance, CT-1 plasma concentrations have been shown to be increased in metabolic syndrome (a cluster disease including obesity probably due to adipose tissue overexpression. Interestingly, treatment with exogenous CT-1 has been shown to improve lipid and glucose metabolism in animal models of obesity. These benefits might suggest a potential therapeutic role for CT-1. However, beyond its beneficial properties, CT-1 has been also shown to induce some adverse effects, such as cardiac hypertrophy and adipose tissue inflammation. Although scientific evidence is still needed, CT-1 might be considered as a potential example of damage/danger-associated molecular pattern (DAMP in obesity-related cardiovascular diseases. In this narrative review, we aimed at discussing and updating evidence from basic research on the pathophysiological and potential therapeutic roles of CT-1 in obesity.

  20. The small molecule NS11021 is a potent and specific activator of Ca2+-activated big-conductance K+ channels

    DEFF Research Database (Denmark)

    Bentzen, Bo Hjorth; Nardi, Antonio; Calloe, Kirstine;

    2007-01-01

    Large-conductance Ca(2+)- and voltage-activated K(+) channels (Kca1.1/BK/MaxiK) are widely expressed ion channels. They provide a Ca(2+)-dependent feedback mechanism for the regulation of various body functions such as blood flow, neurotransmitter release, uresis, and immunity. In addition...... analysis revealed that NS11021 increased the open probability of the channel by altering gating kinetics without affecting the single-channel conductance. NS11021 (10 microM) influenced neither a number of cloned Kv channels nor endogenous Na(+) and Ca(2+) channels (L- and T-type) in guinea pig cardiac...... myocytes. In conclusion, NS11021 is a novel KCa1.1 channel activator with better specificity and a 10 times higher potency compared with the most broadly applied KCa1.1 opener, NS1619. Thus, NS11021 might be a valuable tool compound when addressing the physiological and pathophysiological roles of KCa1...

  1. The Receptor for Activated C Kinase in Plant Signaling: Tale of a Promiscuous Little Molecule

    Directory of Open Access Journals (Sweden)

    Tania Islas Flores

    2015-12-01

    Full Text Available Two decades after the first report of the plant homologue of the Receptor for Activated C Kinase 1 (RACK1 in cultured tobacco BY2 cells, a significant advancement has been made in the elucidation of its celular and molecular role. The protein is now implicated in many biological functions including protein translation, multiple hormonal responses, developmental processes, pathogen infection resistance, environmental stress responses, and miRNA production. Such multiple functional roles are consistent with the scaffolding nature of the plant RACK1 protein. A significant advance was achieved when the β-propeller structure of the Arabidopsis RACK1A isoform was elucidated, thus revealing that its conserved seven WD repeats also assembled into this typical topology. From its crystal structure, it became apparent that it shares the structural platform for the interaction with ligands identified in other systems such as mammals. Although RACK1 proteins maintain conserved Protein Kinase C binding sites, the lack of a bona fide PKC adds complexity and enigma to the nature of the ligand partners with which RACK1 interacts in plants. Nevertheless, ligands recently identified using the split-ubiquitin based and conventional yeast two-hybrid assays, have revealed that plant RACK1 is involved in several processes that include defense response, drought and salt stress, ribosomal function, cell wall biogenesis, and photosynthesis. The information acquired indicates that, in spite of the high degree of conservation of its structure, the functions of the plant RACK1 homologue appear to be distinct and diverse from those in yeast, mammals, insects, etc. In this review, we take a critical look at the novel information regarding the many functions in which plant RACK1 has been reported to participate, with a special emphasis on the information on its currently identified and missing ligand partners.

  2. Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model

    Directory of Open Access Journals (Sweden)

    Jakob Appel Østergaard

    2016-01-01

    Full Text Available Background. Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL, is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus. Methods. We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice. Results. After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6–2.5 immunofluorescence intensity from anti-MBL antibodies compared with controls (P<0.001. Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P=0.04. Conclusion. 20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes.

  3. Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model

    Science.gov (United States)

    Østergaard, Jakob Appel; Ruseva, Marieta Milkova; Malik, Talat Habib; Hoffmann-Petersen, Ingeborg Torp; Pickering, Matthew Caleb; Thiel, Steffen; Hansen, Troels Krarup

    2016-01-01

    Background. Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL), is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus. Methods. We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice. Results. After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6–2.5) immunofluorescence intensity from anti-MBL antibodies compared with controls (P < 0.001). Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P = 0.04). Conclusion. 20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes. PMID:26977416

  4. Late Quaternary Activity and Seismogenic Potential of the Gonave Microplate: Plantain Garden Strike-Slip Fault Zone of Eastern Jamaica

    Science.gov (United States)

    Mann, P.; Prentice, C.; King, W.; Demets, C.; Wiggins-Grandison, M.; Benford, B.

    2008-12-01

    At the longitude of Jamaica, Caribbean (Carib)-North America (Noam) plate motion of 19 ± 2 mm/a is carried by two parallel, left-lateral strike-slip faults, the Oriente fault zone, immediately south of Cuba, and the Enriquillo-Plantain Garden fault zone (EPGFZ), which lies 100-150 km further south. It has been postulated that the lithosphere between these faults constitutes an independent Gonave microplate that has formed in response to the ongoing collision between the leading edge of Carib in Hispaniola and the Bahama carbonate platform. GPS measurements in Jamaica and Hispanola is supportive of the microplate hypothesis and indicates that roughly half of Carib-Noam plate motion (8-14 mm/a) is carried by the EPGFZ of southern Hispaniola and eastern Jamaica. This study applies geomorphic and paleoseismic methods as a direct test of the activity and amount of microplate motion carried on the Plantain Garden fault segment of eastern Hispaniola and how this motion is distributed across a large restraining bend that has formed the island of Jamaica since the late Miocene. The EPFZ curves gently to the northeast and forming a steep mountain front to the Blue Mountains restraining bend with elevations up to 2200 m. Geomorphic fault-related features along the mountain front fault zone include left-laterally deflected rivers and streams, but no small scale features indicative of Holocene activity. River and stream deflections range from 0.1 to 0.5 km. We identified and trenched the most active trace of the mountain front fault at the Morant River where the fault is characterized by a 1.5-m-wide sub-vertical fault zone juxtaposing sheared alluvium and fault Cretaceous basement rocks This section is overlain by a 6-m-thick fluvial terrace. Trenching in the unfaulted terrace immediately overlying the fault trace revealed radiocarbon and OSL ages ranging from 20 to 21 ka that are consistent with a prominent unfaulted alluvial fan along the projection of this fault 1.5 km to

  5. High-resolution water column survey to identify active sublacustrine hydrothermal discharge zones within Lake Rotomahana, North Island, New Zealand

    Science.gov (United States)

    Walker, Sharon L.; de Ronde, Cornel E. J.; Fornari, Daniel; Tivey, Maurice A.; Stucker, Valerie K.

    2016-03-01

    Autonomous underwater vehicles were used to conduct a high-resolution water column survey of Lake Rotomahana using temperature, pH, turbidity, and oxidation-reduction potential (ORP) to identify active hydrothermal discharge zones within the lake. Five areas with active sublacustrine venting were identified: (1) the area of the historic Pink Terraces; (2) adjacent to the western shoreline subaerial "Steaming Cliffs," boiling springs and geyser; (3) along the northern shoreline to the east of the Pink Terrace site; (4) the newly discovered Patiti hydrothermal system along the south margin of the 1886 Tarawera eruption rift zone; and (5) a location in the east basin (northeast of Patiti Island). The Pink Terrace hydrothermal system was active prior to the 1886 eruption of Mount Tarawera, but venting along the western shoreline, in the east basin, and the Patiti hydrothermal system appear to have been initiated in the aftermath of the eruption, similar to Waimangu Valley to the southwest. Different combinations of turbidity, pH anomalies (both positive and negative), and ORP responses suggest vent fluid compositions vary over short distances within the lake. The seasonal period of stratification limits vertical transport of heat to the surface layer and the hypolimnion temperature of Lake Rotomahana consequently increases with an average warming rate of ~ 0.010 °C/day due to both convective hydrothermal discharge and conductive geothermal heating. A sudden temperature increase occurred during our 2011 survey and was likely the response to an earthquake swarm just 11 days prior.

  6. Molecule nanoweaver

    Science.gov (United States)

    Gerald, II; Rex E.; Klingler, Robert J.; Rathke, Jerome W.; Diaz, Rocio; Vukovic, Lela

    2009-03-10

    A method, apparatus, and system for constructing uniform macroscopic films with tailored geometric assemblies of molecules on the nanometer scale. The method, apparatus, and system include providing starting molecules of selected character, applying one or more force fields to the molecules to cause them to order and condense with NMR spectra and images being used to monitor progress in creating the desired geometrical assembly and functionality of molecules that comprise the films.

  7. Diverse redox-active molecules bearing O-, S-, or Se-terminated tethers for attachment to silicon in studies of molecular information storage.

    Science.gov (United States)

    Balakumar, Arumugham; Lysenko, Andrey B; Carcel, Carole; Malinovskii, Vladimir L; Gryko, Daniel T; Schweikart, Karl-Heinz; Loewe, Robert S; Yasseri, Amir A; Liu, Zhiming; Bocian, David F; Lindsey, Jonathan S

    2004-03-01

    A molecular approach to information storage employs redox-active molecules tethered to an electroactive surface. Attachment of the molecules to electroactive surfaces requires control over the nature of the tether (linker and surface attachment group). We have synthesized a collection of redox-active molecules bearing different linkers and surface anchor groups in free or protected form (hydroxy, mercapto, S-acetylthio, and Se-acetylseleno) for attachment to surfaces such as silicon, germanium, and gold. The molecules exhibit a number of cationic oxidation states, including one (ferrocene), two [zinc(II)porphyrin], three [cobalt(II)porphyrin], or four (lanthanide triple-decker sandwich compound). Electrochemical studies of monolayers of a variety of the redox-active molecules attached to Si(100) electrodes indicate that molecules exhibit a regular mode of attachment (via a Si-X bond, X = O, S, or Se), relatively homogeneous surface organization, and robust reversible electrochemical behavior. The acetyl protecting group undergoes cleavage during the surface deposition process, enabling attachment to silicon via thio or seleno groups without handling free thiols or selenols. PMID:14986994

  8. Isolation of a small molecule with anti-MRSA activity from a mangrove symbiont Streptomyces sp. PVRK-1 and its biomedical studies inZebrafish embryos

    Institute of Scientific and Technical Information of China (English)

    Rajaretinam Rajesh Kannan; Appadurai Muthamil Iniyan; Vincent Samuel Gnana Prakash

    2011-01-01

    Objective: The aim of the present study was to isolate the anti-MRSA (Methicillin ResistantStaphylococcus aureus ) molecule from the Mangrove symbiont Streptomyces and its biomedical studies in Zebrafish embryos. Methods: MRSA was isolated from the pus samples of Colachal hospitals and confirmed by amplification of mecA gene. Anti-MRSA molecule producing strain was identified by 16s rRNA gene sequencing. Anti-MRSA compound production was optimized by Solid State Fermentation (SSF) and the purification of the active molecule was carried out by TLC and RP-HPLC. The inhibitory concentration and LC50 were calculated using Statistical software SPSS. The Biomedical studies including the cardiac assay and organ toxicity assessment were carried out in Zebrafish. Results: The bioactive anti-MRSA small molecule A2 was purified by TLC with Rf value of 0.37 with 1.389 retention time at RP-HPLC. The Inhibitory Concentration of the purified molecule A2 was 30 μg/mL but, the inhibitory concentration of the MRSA in the infected embryo was 32-34 μg/mL for TLC purified molecule A2 with LC50 mean value was 61.504 μg/mL. Zebrafish toxicity was assessed in 48-60 μg/mL by observing the physiological deformities and the heart beat rates (HBR) of embryos for anti MRSA molecule showed the mean of 41.33-41.67 HBR/15 seconds for 40 μg/mL and control was 42.33-42.67 for 15 seconds which significantly showed that the anti-MRSA molecule A2 did not affected the HBR. Conclusions:Anti-MRSA molecule from Streptomyces sp PVRK-1 was isolated and biomedical studies in Zebrafish model assessed that the molecule was non toxic at the minimal inhibitory concentration of MRSA.

  9. Ground motion parameters of Shillong plateau: One of the most seismically active zones of northeastern India

    Institute of Scientific and Technical Information of China (English)

    Saurabh Baruah; Santanu Baruah; Naba Kumar Gogoi; Olga Erteleva; Felix Aptikaev; J.R.Kayal

    2009-01-01

    Strong ground motion parameters for Shillong plateau of northeastern India are examined. Empirical relations are obtained for main parameters of ground motions as a function of earthquake magnitude, fault type, source depth, velocity characterization of medium and distance. Correlation between ground motion parameters and characteristics of seismogenic zones are established. A new attenuation relation for peak ground acceleration is developed, which predicts higher expected PGA in the region. Parameters of strong motions, particularly the predominant periods and duration of vibrations, depend on the morphology of the studied area. The study measures low estimates of logarithmic width in Shillong plateau. The attenuation relation estimated for pulse width critically indicates increased pulse width dependence on the logarithmic distance which accounts for geometrical spreading and anelastic attenuation.

  10. Photogrammetry surveys and mosaic: a useful tool to monitor active zones. Applications to the Indonesian Lusi eruption site.

    Science.gov (United States)

    Romeo, Giovanni; Di Stefano, Giuseppe; Mazzini, Adriano; Iarocci, Alessandro; Caramelli, Antonio

    2016-04-01

    Unmanned and remotely operated aircraft showed to be an efficient and cost effective way to explore remote or extreme environments. Comparative photogrammetry studies are an efficient way to study and monitor he evolution of geologically active areas and ongoing events and are able to highlight details that are typically lost during traditional field campaigns. The Lusi mud eruption in eastern Java (Indonesia) represents one of the most spectacular geological phenomena that is ongoing since May 2006. In the framework of the Lusi Lab project (ERC grant n° 308126) we designed and constructed a multipurpose drone to survey the eruption site. Among the numerous other payloads, the Lusi drone is equipped with Olympus EPM-2 and Go-Pro Hero3 cameras that allow the operator to collect video stills, high quality pictures and to complete photogrammetry surveys. Targeted areas have been selected for detailed studies in the 7 km2 region inside the embankment that was prevent the mud burial of the settlements in the Sidoarjo Regency. The region is characterized by the presence of the Watukosek fault zone. This strike slip system originates from the Arjuno-Welirang volcanic complex and extends to the north east of the Java Island intersecting the Lusi crater. Therefore of particular interest are the faulted surveyed areas present around the Lusi crater inside the embankment. Results reveal a surprising accuracy for the collected mosaic. Multiple surveys are able to reveal the changes and the evolution of the fault through time and to indicate more active zones. In particular this type of survey can highlight the weakness zones and is thus useful to prevent potential geohazards in the area. The poster shows the aerial survey results, including a 3d-printed slice of LuSi, obtained combining 2500 16 Mp photographs. A 3d zoomed detail is also shown, evidencing the resolution that this technique can offer.

  11. The Activity of Major Faults and the Hydrothermal Alteration Zone at Tianchi Volcano of Changbaishan

    Institute of Scientific and Technical Information of China (English)

    Liu Mingjun; Gu Menglin; Sun Zhenguo; Wei Haiquan; Jin Bolu

    2004-01-01

    It is found by field investigation that the near horizontal top surface of the brown or brick-red hydrothermal alteration zone varies obviously in elevation at different sections of the same layer on the caldera's inner wall of Tianchi, with that at the north section near the Tianwen Peak about 110 m higher than that at the south near the Jiangjun Peak in Korea. The top surface of the hydrothermal alteration zone can be taken as key horizon to tectonic movement. The difference indicates that the total uplift height of the NW wall of the Liudaogou-TianchiJingfengshan fault, the principal fault trending NE at Tianchi, is bigger than that of the SE wall ever since the occurrence of hydrothermal alteration. This also explains why the topography in the northwest side of Tianchi is steeper and with more developed river system than in the southeast. The uplifting of the northeastern wall is bigger than that of the southwest along the principal NW-trend fault, namely, the Baishanzhen-Tianchi-Jince fault. It is observed from characters of hydrothermal alteration and the palaeoresiduum, that the recent vertical movement rate along the principal NE-trend fault is larger than that of the principal NW-trend fault. The two faults intersect at Tianchi, dividing the volcano into 4 blocks, with the uplift magnitudes decreasing successively in the order of the north, the west, the east and the south block. The biggest uplift of the north block corresponds well to the shallow magma batch in the north of Tianchi observed by DSS and telluric electromagnetic sounding, and etc.and they may be related with the causes.

  12. Mapping bathymetry in an active surf zone with the WorldView2 multispectral satellite

    Science.gov (United States)

    Trimble, S. M.; Houser, C.; Brander, R.; Chirico, P.

    2015-12-01

    Rip currents are strong, narrow seaward flows of water that originate in the surf zones of many global beaches. They are related to hundreds of international drownings each year, but exact numbers are difficult to calculate due to logistical difficulties in obtaining accurate incident reports. Annual average rip current fatalities are estimated to be ~100, 53 and 21 in the United States (US), Costa Rica, and Australia respectively. Current warning systems (e.g. National Weather Service) do not account for fine resolution nearshore bathymetry because it is difficult to capture. The method shown here could provide frequent, high resolution maps of nearshore bathymetry at a scale required for improved rip prediction and warning. This study demonstrates a method for mapping bathymetry in the surf zone (20m deep and less), specifically within rip channels, because rips form at topographically low spots in the bathymetry as a result of feedback amongst waves, substrate, and antecedent bathymetry. The methods employ the Digital Globe WorldView2 (WV2) multispectral satellite and field measurements of depth to generate maps of the changing bathymetry at two embayed, rip-prone beaches: Playa Cocles, Puerto Viejo de Talamanca, Costa Rica, and Bondi Beach, Sydney, Australia. WV2 has a 1.1 day pass-over rate with 1.84m ground pixel resolution of 8 bands, including 'yellow' (585-625 nm) and 'coastal blue' (400-450 nm). The data is used to classify bottom type and to map depth to the return in multiple bands. The methodology is tested at each site for algorithm consistency between dates, and again for applicability between sites.

  13. Soluble Collectin-12 (CL-12) Is a Pattern Recognition Molecule Initiating Complement Activation via the Alternative Pathway.

    Science.gov (United States)

    Ma, Ying Jie; Hein, Estrid; Munthe-Fog, Lea; Skjoedt, Mikkel-Ole; Bayarri-Olmos, Rafael; Romani, Luigina; Garred, Peter

    2015-10-01

    Soluble defense collagens including the collectins play important roles in innate immunity. Recently, a new member of the collectin family named collectin-12 (CL-12 or CL-P1) has been identified. CL-12 is highly expressed in umbilical cord vascular endothelial cells as a transmembrane receptor and may recognize certain bacteria and fungi, leading to opsonophagocytosis. However, based on its structural and functional similarities with soluble collectins, we hypothesized the existence of a fluid-phase analog of CL-12 released from cells, which may function as a soluble pattern-recognition molecule. Using recombinant CL-12 full length or CL-12 extracellular domain, we determined the occurrence of soluble CL-12 shed from in vitro cultured cells. Western blot showed that soluble recombinant CL-12 migrated with a band corresponding to ∼ 120 kDa under reducing conditions, whereas under nonreducing conditions it presented multimeric assembly forms. Immunoprecipitation and Western blot analysis of human umbilical cord plasma enabled identification of a natural soluble form of CL-12 having an electrophoretic mobility pattern close to that of shed soluble recombinant CL-12. Soluble CL-12 could recognize Aspergillus fumigatus partially through the carbohydrate-recognition domain in a Ca(2+)-independent manner. This led to activation of the alternative pathway of complement exclusively via association with properdin on A. fumigatus as validated by detection of C3b deposition and formation of the terminal complement complex. These results demonstrate the existence of CL-12 in a soluble form and indicate a novel mechanism by which the alternative pathway of complement may be triggered directly by a soluble pattern-recognition molecule.

  14. Screening for active small molecules in mitochondrial complex I deficient patient's fibroblasts, reveals AICAR as the most beneficial compound.

    Directory of Open Access Journals (Sweden)

    Anna Golubitzky

    Full Text Available Congenital deficiency of the mitochondrial respiratory chain complex I (CI is a common defect of oxidative phosphorylation (OXPHOS. Despite major advances in the biochemical and molecular diagnostics and the deciphering of CI structure, function assembly and pathomechanism, there is currently no satisfactory cure for patients with mitochondrial complex I defects. Small molecules provide one feasible therapeutic option, however their use has not been systematically evaluated using a standardized experimental system. In order to evaluate potentially therapeutic compounds, we set up a relatively simple system measuring different parameters using only a small amount of patient's fibroblasts, in glucose free medium, where growth is highly OXPOS dependent. Ten different compounds were screened using fibroblasts derived from seven CI patients, harboring different mutations.5-Aminoimidazole-4-carboxamide ribotide (AICAR was found to be the most beneficial compound improving growth and ATP content while decreasing ROS production. AICAR also increased mitochondrial biogenesis without altering mitochondrial membrane potential (Δψ. Fluorescence microscopy data supported increased mitochondrial biogenesis and activation of the AMP activated protein kinase (AMPK. Other compounds such as; bezafibrate and oltipraz were rated as favorable while polyphenolic phytochemicals (resverastrol, grape seed extract, genistein and epigallocatechin gallate were found not significant or detrimental. Although the results have to be verified by more thorough investigation of additional OXPHOS parameters, preliminary rapid screening of potential therapeutic compounds in individual patient's fibroblasts could direct and advance personalized medical treatment.

  15. Troglitazone, a PPAR-γ activator prevents endothelial cell adhesion molecule expression and lymphocyte adhesion mediated by TNF-α

    Directory of Open Access Journals (Sweden)

    Itoh Makoto

    2005-02-01

    Full Text Available Abstract Background Cytokine mediated induction of the mucosal addressin cell adhesion molecule-1(MAdCAM-1 expression is associated with the onset and progression of inflammatory bowel disease (IBD. Results Using western blotting and cell-based ELISA, we show in this study that troglitazone, an activator of the peroxisome proliferator-activated receptor-γ (PPAR-γ, widely used in the treatment of diabetes, has as well recently been highlighted as protective in models of inflammation and cancer. We found that troglitazone (10–40 μM, significantly reduced the TNF-α (1 ng/ml mediated induction of endothelial MAdCAM-1 in a dose-dependent manner, achieving a 34.7% to 98.4% reduction in induced MAdCAM-1. Trogliazone (20μM reduced TNF-α induced VCAM-1, ICAM-1 and E-selectin expression. Moreover, troglitazone significantly reduced α4β7-integrin dependent lymphocyte adhesion to TNF-α cultured endothelial cells. Conclusions These results suggest that PPAR-γ agonists like troglitazone may be useful in the clinical treatment of IBD.

  16. Roles of specific membrane lipid domains in EGF receptor activation and cell adhesion molecule stabilization in a developing olfactory system.

    Directory of Open Access Journals (Sweden)

    Nicholas J Gibson

    Full Text Available BACKGROUND: Reciprocal interactions between glial cells and olfactory receptor neurons (ORNs cause ORN axons entering the brain to sort, to fasciculate into bundles destined for specific glomeruli, and to form stable protoglomeruli in the developing olfactory system of an experimentally advantageous animal species, the moth Manduca sexta. Epidermal growth factor receptors (EGFRs and the cell adhesion molecules (IgCAMs neuroglian and fasciclin II are known to be important players in these processes. METHODOLOGY/PRINCIPAL FINDINGS: We report in situ and cell-culture studies that suggest a role for glycosphingolipid-rich membrane subdomains in neuron-glia interactions. Disruption of these subdomains by the use of methyl-beta-cyclodextrin results in loss of EGFR activation, depletion of fasciclin II in ORN axons, and loss of neuroglian stabilization in the membrane. At the cellular level, disruption leads to aberrant ORN axon trajectories, small antennal lobes, abnormal arrays of olfactory glomerul, and loss of normal glial cell migration. CONCLUSIONS/SIGNIFICANCE: We propose that glycosphingolipid-rich membrane subdomains (possible membrane rafts or platforms are essential for IgCAM-mediated EGFR activation and for anchoring of neuroglian to the cytoskeleton, both required for normal extension and sorting of ORN axons.

  17. Direct measurement and characterization of active photosynthesis zones inside biofuel producing and wastewater remediating microalgal biofilms

    Energy Technology Data Exchange (ETDEWEB)

    Bernstein, Hans C.; Kesaano, Maureen; Moll, Karen; Smith, Terence; Gerlach, Robin; Carlson, Ross; Miller, Charles D.; Peyton, Brent; Cooksey, Keith; Gardner, Robert D.; Sims, Ronald C.

    2014-03-01

    Abstract: Microalgal biofilm based technologies are of keen interest due to their high biomass concentrations and ability to utilize renewable resources, such as light and CO2. While photoautotrophic biofilms have long been used for wastewater remediation applications, biofuel production represents a relatively new and under-represented focus area. However, the direct measurement and characterization of fundamental parameters required for physiological analyses are challenging due to biofilm heterogeneity. This study evaluated oxygenic photosynthesis and biofuel precursor molecule production using a novel rotating algal biofilm reactor (RABR) operated at field- and laboratory-scales for wastewater remediation and biofuel production, respectively. Clear differences in oxygenic-photosynthesis, respiration and biofuel-precursor capacities were observed between the two systems and different conditions based on light and nitrogen availability. Nitrogen depletion was not found to have the same effect on lipid accumulation compared to prior planktonic studies. Physiological characterizations of these microalgal biofilms identify potential areas for future process optimization.

  18. Identifying active interplate and intraplate fault zones in the western Caribbean plate from seismic reflection data and the significance of the Pedro Bank fault zone in the tectonic history of the Nicaraguan Rise

    Science.gov (United States)

    Ott, B.; Mann, P.

    2015-12-01

    The offshore Nicaraguan Rise in the western Caribbean Sea is an approximately 500,000 km2 area of Precambrian to Late Cretaceous tectonic terranes that have been assembled during the Late Cretaceous formation of the Caribbean plate and include: 1) the Chortis block, a continental fragment; 2) the Great Arc of the Caribbean, a deformed Cretaceous arc, and 3) the Caribbean large igneous province formed in late Cretaceous time. Middle Eocene to Recent eastward motion of the Caribbean plate has been largely controlled by strike-slip faulting along the northern Caribbean plate boundary zone that bounds the northern margin of the Nicaraguan Rise. These faults reactivate older rift structures near the island of Jamaica and form the transtensional basins of the Honduran Borderlands near Honduras. Recent GPS studies suggest that small amount of intraplate motion within the current margin of error of GPS measurements (1-3 mm/yr) may occur within the center of the western Caribbean plate at the Pedro Bank fault zone and Hess Escarpment. This study uses a database of over 54,000 km of modern and vintage 2D seismic data, combined with earthquake data and results from previous GPS studies to define the active areas of inter- and intraplate fault zones in the western Caribbean. Intraplate deformation occurs along the 700-km-long Pedro Bank fault zone that traverses the center of the Nicaraguan Rise and reactivates the paleo suture zone between the Great Arc of the Caribbean and the Caribbean large igneous province. The Pedro Bank fault zone also drives active extension at the 200-km-long San Andres rift along the southwest margin of the Nicaraguan Rise. Influence of the Cocos Ridge indentor may be contributing to reactivation of faulting along the southwesternmost, active segment of the Hess Escarpment.

  19. Evidence of multistage late Quaternary strong earthquakes on typical segments of Longmenshan Active Fault Zone in Sichuan, China

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Investigation of offset landforms and trench excavation are important means to acquire the evidence of multistage activities of active faults. Here we present the result of fault trough investigation in Beichuan County and the Pingtong Town of Pingwu County along the Longmenshan Central Fault Belt, as well as the result from trench excavation at the platform foreslope in Hanwang Town of Mianzhu County on the Longmenshan Front Range Fault Belt. These results show that at least three fault activity events, including the Wenchuan earthquake, occurred in the Beichuan fault trough, at least two, including the Wenchuan earthquake, at Pingtong fault trough, and 2-3 paleoearthquakes in the Hanwang trench. Among these three localities, the times of the last strong earthquake prior to Wenchuan earthquake at Beichuan fault trough and Hanwang trench are close, approximately 6000 years ago, i.e., greater than 5.8 ka and smaller than 6.63 ka ago. This provides the evidence of synchronous activity of the Central Fault Belt and the Front Range Fault Belt of the Longmenshan Active Fault Zone during the previous strong earthquake activities prior to Wenchuan earthquake.

  20. Evidence of multistage late Quaternary strong earthquakes on typical segments of Longrnenshan Active Fault Zone in Sichuan,China

    Institute of Scientific and Technical Information of China (English)

    JIANG WaLi; XIE XinSheng; ZHANG JinFa; SUN ChangBin; HUANG Wei; SHENG Qiang; FENG XiYing

    2009-01-01

    Investigation of offset landforms and trench excavation are important means to acquire the evidence of multistage activities of active faults.Here we present the result of fault trough investigation in Beichuan County and the Pingtong Town of Pingwu County along the Longmenshan Central Fault Belt,as well as the result from trench excavation at the platform foreslope in Hanwang Town of Mianzhu County on the Longmenshan Front Range Fault Belt.These results show that at least three fault activity events,including the Wenchuan earthquake,occurred in the Beichuan fault trough,at least two,including the Wenchuan earthquake,at Pingtong fault trough,and 2-3 paleoearthquakes in the Hanwang trench.Among these three localities,the times of the last strong earthquake prior to Wenchuan earthquake at Beichuan fault trough and Hanwang trench are close,approximately 6000 years ago,i.e.,greater than 5.8 ka and smaller than 6.63 ka ago.This provides the evidence of synchronous activity of the Central Fault Belt and the Front Range Fault Belt of the Longmenshan Active Fault Zone during the previous strong earthquake activities prior to Wenchuan earthquake.

  1. 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

    Homophilic binding in trans of the neural cell adhesion molecule (NCAM) mediates adhesion between cells and leads, via activation of intracellular signaling cascades, to neurite outgrowth in primary neurons as well as in the neuronal cell line PC12. NCAM mediates neurite extension in PC12 cells...... 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...

  2. Activation of Relaxin Family Receptor 1 from Different Mammalian Species by Relaxin Peptide and Small-Molecule Agonist ML290.

    Science.gov (United States)

    Huang, Zaohua; Myhr, Courtney; Bathgate, Ross A D; Ho, Brian A; Bueno, Amaya; Hu, Xin; Xiao, Jingbo; Southall, Noel; Barnaeva, Elena; Agoulnik, Irina U; Marugan, Juan J; Ferrer, Marc; Agoulnik, Alexander I

    2015-01-01

    Relaxin peptide (RLN), which signals through the relaxin family peptide 1 (RXFP1) GPCR receptor, has shown therapeutic effects in an acute heart failure clinical trial. We have identified a small-molecule agonist of human RXFP1, ML290; however, it does not activate the mouse receptor. To find a suitable animal model for ML290 testing and to gain mechanistic insights into the interaction of various ligands with RXFP1, we have cloned rhesus macaque, pig, rabbit, and guinea pig RXFP1s and analyzed their activation by RLN and ML290. HEK293T cells expressing macaque or pig RXFP1 responded to relaxin and ML290 treatment as measured by an increase of cAMP production. Guinea pig RXFP1 responded to relaxin but had very low response to ML290 treatment only at highest concentrations used. The rabbit RXFP1 amino acid sequence was the most divergent, with a number of unique substitutions within the ectodomain and the seven-transmembrane domain (7TM). Two splice variants of rabbit RXFP1 derived through alternative splicing of the fourth exon were identified. In contrast to the other species, rabbit RXFP1s were activated by ML290, but not with human, pig, mouse, or rabbit RLNs. Using FLAG-tagged constructs, we have shown that both rabbit RXFP1 variants are expressed on the cell surface. No binding of human Eu-labeled RLN to rabbit RXFP1 was detected, suggesting that in this species, RXFP1 might be non-functional. We used chimeric rabbit-human and guinea pig-human constructs to identify regions important for RLN or ML290 receptor activation. Chimeras with the human ectodomain and rabbit 7TM domain were activated by RLN, whereas substitution of part of the guinea pig 7TM domain with the human sequence only partially restored ML290 activation, confirming the allosteric mode of action for the two ligands. Our data demonstrate that macaque and pig models can be used for ML290 testing. PMID:26347712

  3. Activation of Relaxin Family Receptor 1 from different mammalian species by relaxin peptide and small molecule agonist ML290

    Directory of Open Access Journals (Sweden)

    Zaohua eHuang

    2015-08-01

    Full Text Available Relaxin peptide (RLN, which signals through the relaxin family peptide 1 (RXFP1 GPCR receptor, has shown therapeutic effects in an acute heart failure clinical trial. We have identified a small molecule agonist of human RXFP1, ML290; however, it does not activate the mouse receptor. To find a suitable animal model for ML290 testing and to gain mechanistic insights into the interaction of various ligands with RXFP1, we have cloned rhesus macaque, pig, rabbit, and guinea pig RXFP1s and analyzed their activation by RLN and ML290. HEK293T cells expressing macaque or pig RXFP1 responded to relaxin and ML290 treatment as measured by an increase of cAMP production. Guinea pig RXFP1 responded to relaxin but had very low response to ML290 treatment only at highest concentrations used. The rabbit RXFP1 amino acid sequence was the most divergent, with a number of unique substitutions within the ectodomain and the 7-transmembrane domain (7TM. Two splice variants of rabbit RXFP1 derived through alternative splicing of the forth exon were identified. In contrast to the other species, rabbit RXFP1s were activated by ML290, but not with human, pig, mouse, or rabbit relaxins. Using FLAG-tagged constructs, we have shown that both rabbit RXFP1 variants are expressed on the cell surface. No binding of human Eu-labeled relaxin to rabbit RXFP1 was detected, suggesting that in this species RXFP1 might be non-functional. We used chimeric rabbit-human and guinea pig-human constructs to identify regions important for RLN or ML290 receptor activation. Chimeras with the human ectodomain and rabbit 7TM domain were activated by RLN, whereas substitution of part of the guinea pig 7TM domain with the human sequence only partially restored ML290 activation, confirming the allosteric mode of action for the two ligands. Our data demonstrate that macaque and pig models can be used for ML290 testing.

  4. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase.

    LENUS (Irish Health Repository)

    McSherry, Elaine A

    2012-02-01

    INTRODUCTION: The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. METHODS: MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and beta1-integrin, we examined activation of the beta1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and beta1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. RESULTS: JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the beta1-integrin substrate fibronectin. This was accompanied by reduced protein expression of beta1-integrin and its binding partners alphaV- and alpha5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and beta1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between

  5. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase.

    LENUS (Irish Health Repository)

    McSherry, Elaine A

    2011-03-23

    ABSTRACT: INTRODUCTION: The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. METHODS: MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and β1-integrin, we examined activation of the β1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and β1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. RESULTS: JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the β1-integrin substrate fibronectin. This was accompanied by reduced protein expression of β1-integrin and its binding partners αV- and α5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and β1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between JAM-A, AF

  6. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase

    LENUS (Irish Health Repository)

    McSherry, Elaine A

    2011-03-23

    Abstract Introduction The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. Methods MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and β1-integrin, we examined activation of the β1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and β1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. Results JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the β1-integrin substrate fibronectin. This was accompanied by reduced protein expression of β1-integrin and its binding partners αV- and α5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and β1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between JAM-A, AF-6

  7. Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the subventricular zone and ischaemic striatum after focal ischaemia

    Indian Academy of Sciences (India)

    ROSANA S LOPES; MARCELO M CARDOSO; ARTHUR O SAMPAIO; MARIO SANTOS BARBOSA Jr; CELICE C SOUZA; MICHELLE C DA SILVA; ELANE MAGNO N FERREIRA; MARCO AURELIOM FREIRE; RAFAEL RODRIGUES LIMA; WALACE GOMES-LEAL

    2016-09-01

    Neuroblasts from the subventricular zone (SVZ) migrate to striatum following stroke, but most of them die inthe ischaemic milieu and this can be related to exacerbated microglial activation. Here, we explored theeffects of the non-steroidal anti-inflammatory indomethacin on microglial activation, neuronal preservation andneuroblast migration following experimental striatal stroke in adult rats. Animals were submitted toendothelin-1 (ET-1)-induced focal striatal ischaemia and were treated with indomethacin or sterile saline(i.p.) for 7 days, being perfused after 8 or 14 days. Immunohistochemistry was performed to assess neuronalloss (anti-NeuN), microglial activation (anti-Iba1, ED1) and migrating neuroblasts (anti-DCX) by countingNeuN, ED1 and DCX-positive cells in the ischaemic striatum or SVZ. Indomethacin treatment reducedmicroglia activation and the number of ED1^{+} cells in both 8 and 14 days post injury as compared withcontrols. There was an increase in the number of DCX^{+} cells in both SVZ and striatum at the same survivaltimes. Moreover, there was a decrease in the number of NeuN^{+} cells in indomethacin-treated animals ascompared with the control group at 8 days but not after 14 days post injury. Our results suggest thatindomethacin treatment modulates microglia activation, contributing to increased neuroblast proliferation inthe SVZ and migration to the ischaemic striatum following stroke.

  8. Activation of cord T lymphocytes. III. Role of LFA-1/ICAM-1 and CD2/LFA-3 adhesion molecules in CD3-induced proliferative response.

    Science.gov (United States)

    Gerli, R; Agea, E; Muscat, C; Tognellini, R; Fiorucci, G; Spinozzi, F; Cernetti, C; Bertotto, A

    1993-04-15

    As cord T cells, a model of antigen (Ag)-unprimed cell, display a functional defect when stimulated through the CD3 molecule, the role of lymphocyte function-associated antigen 1(LFA-1)/intercellular adhesion molecule 1 (ICAM-1) and CD2/lymphocyte function-associated antigen 3 (LFA-3) receptor-ligand pairs in cord CD3-triggered T-cell activation was analyzed using specific monoclonal antibodies (mAb) against each adhesion molecule. The addition of anti-CD11a, anti-CD18, or anti-CD2 to both adult and cord peripheral blood mononuclear cells (PBMC) cultures led to a decrease in CD3-induced proliferation. In contrast, CD3-stimulated cord, but not adult, PBMC proliferation was markedly enhanced when anti-CD54 or anti-CD58 were added. Despite the fact that ICAM-1 and LFA-3 molecules were virtually absent on cord resting T cells, mAb against these two molecules boosted both mitogenesis of and interleukin (IL)-2 production by purified cord T cells stimulated with plastic immobilized anti-CD3. Cord T-cell supernatant levels of interferon-gamma (IFN-gamma) were undetectable with CD3 stimulation, slightly raised with CD58/CD3 costimulation, but normal when T cells were preincubated with IL-2 for 24 hr before being costimulated with anti-CD3/CD58. Evidence that IL-2 and IFN-gamma play a pivotal role in fully activating cord T cells came from the demonstration that IL-2 and IFN-gamma are able to bypass the CD3-proliferative defect through differential up-regulation of the adhesion molecules. It would, therefore, seem that ICAM-1 and LFA-3 molecules are crucially implicated in the CD3-activation pathway of Ag-unprimed T cells. PMID:7684326

  9. Active crustal deformation of the El Salvador Fault Zone (ESFZ) using GPS data: Implications in seismic hazard assessment

    Science.gov (United States)

    Staller, Alejandra; Benito, Belen; Jesús Martínez-Díaz, José; Hernández, Douglas; Hernández-Rey, Román; Alonso-Henar, Jorge

    2014-05-01

    El Salvador, Central America, is part of the Chortis block in the northwestern boundary of the Caribbean plate. This block is interacting with a diffuse triple junction point with the Cocos and North American plates. Among the structures that cut the Miocene to Pleistocene volcanic deposits stands out the El Salvador Fault Zone (ESFZ): It is oriented in N90º-100ºE direction, and it is composed of several structural segments that deform Quaternary deposits with right-lateral and oblique slip motions. The ESFZ is seismically active and capable of producing earthquakes such as the February 13, 2001 with Mw 6.6 (Martínez-Díaz et al., 2004), that seriously affected the population, leaving many casualties. This structure plays an important role in the tectonics of the Chortis block, since its motion is directly related to the drift of the Caribbean plate to the east and not with the partitioning of the deformation of the Cocos subduction (here not coupled) (Álvarez-Gómez et al., 2008). Together with the volcanic arc of El Salvador, this zone constitutes a weakness area that allows the motion of forearc block toward the NW. The geometry and the degree of activity of the ESFZ are not studied enough. However their knowledge is essential to understand the seismic hazard associated to this important seismogenic structure. For this reason, since 2007 a GPS dense network was established along the ESFZ (ZFESNet) in order to obtain GPS velocity measurements which are later used to explain the nature of strain accumulation on major faults along the ESFZ. The current work aims at understanding active crustal deformation of the ESFZ through kinematic model. The results provide significant information to be included in a new estimation of seismic hazard taking into account the major structures in ESFZ.

  10. Cytometric analysis of surface molecules of leucocytes and phagocytic activity of granulocytes and monocytes/macrophages in cows with pyometra.

    Science.gov (United States)

    Brodzki, P; Kostro, K; Brodzki, A; Niemczuk, K; Lisiecka, U

    2014-10-01

    Pyometra is a serious problem in dairy cow herds, causing large economic losses due to infertility. The development of pyometra depends mainly on the immunological status of the cow. The aim of the study was a comparative evaluation of selected indicators involving non-specific and specific immunity in cows with pyometra and in cows without inflammation of the uterus. The study was performed in 20 cows, which were divided into two groups: pyometra group and healthy group, each comprising 10 cows, based on the results of cytological and ultrasonographic tests. A flow cytometric analysis was performed for the surface molecules CD4, CD8, CD14, CD21, CD25 and CD4(+) CD25(+) on leucocytes, and the phagocytic activity was determined from granulocytes and monocytes/macrophages in the peripheral blood and uterine washings, respectively. It was demonstrated that the percentage of phagocytic granulocytes and monocytes/macrophages in both the peripheral blood and uterine washings was significantly lower in cows with pyometra compared with the healthy group (p pyometra group, along with a significantly higher (p pyometra may be caused by a bacterial infection and the presence of blocking agents (IL-10), released by the increasing number of CD8(+) lymphocytes what leads to the advanced inflammation of uterus. PMID:25124985

  11. Pseudomonas aeruginosa Biofilm Response and Resistance to Cold Atmospheric Pressure Plasma Is Linked to the Redox-Active Molecule Phenazine.

    Science.gov (United States)

    Mai-Prochnow, Anne; Bradbury, Mark; Ostrikov, Kostya; Murphy, Anthony B

    2015-01-01

    Pseudomonas aeruginosa is an important opportunistic pathogen displaying high antibiotic resistance. Its resistance is in part due to its outstanding ability to form biofilms on a range of biotic and abiotic surfaces leading to difficult-to-treat, often long-term infections. Cold atmospheric plasma (CAP) is a new, promising antibacterial treatment to combat antibiotic-resistant bacteria. Plasma is ionized gas that has antibacterial properties through the generation of a mix of reactive oxygen and nitrogen species (RONS), excited molecules, charged particles and UV photons. Our results show the efficient removal of P. aeruginosa biofilms using a plasma jet (kINPen med), with no viable cells detected after 5 min treatment and no attached biofilm cells visible with confocal microscopy after 10 min plasma treatment. Because of its multi-factorial action, it is widely presumed that the development of bacterial resistance to plasma is unlikely. However, our results indicate that a short plasma treatment (3 min) may lead to the emergence of a small number of surviving cells exhibiting enhanced resistance to subsequent plasma exposure. Interestingly, these cells also exhibited a higher degree of resistance to hydrogen peroxide. Whole genome comparison between surviving cells and control cells revealed 10 distinct polymorphic regions, including four belonging to the redox active, antibiotic pigment phenazine. Subsequently, the interaction between phenazine production and CAP resistance was demonstrated in biofilms of transposon mutants disrupted in different phenazine pathway genes which exhibited significantly altered sensitivity to CAP.

  12. Pseudomonas aeruginosa Biofilm Response and Resistance to Cold Atmospheric Pressure Plasma Is Linked to the Redox-Active Molecule Phenazine.

    Directory of Open Access Journals (Sweden)

    Anne Mai-Prochnow

    Full Text Available Pseudomonas aeruginosa is an important opportunistic pathogen displaying high antibiotic resistance. Its resistance is in part due to its outstanding ability to form biofilms on a range of biotic and abiotic surfaces leading to difficult-to-treat, often long-term infections. Cold atmospheric plasma (CAP is a new, promising antibacterial treatment to combat antibiotic-resistant bacteria. Plasma is ionized gas that has antibacterial properties through the generation of a mix of reactive oxygen and nitrogen species (RONS, excited molecules, charged particles and UV photons. Our results show the efficient removal of P. aeruginosa biofilms using a plasma jet (kINPen med, with no viable cells detected after 5 min treatment and no attached biofilm cells visible with confocal microscopy after 10 min plasma treatment. Because of its multi-factorial action, it is widely presumed that the development of bacterial resistance to plasma is unlikely. However, our results indicate that a short plasma treatment (3 min may lead to the emergence of a small number of surviving cells exhibiting enhanced resistance to subsequent plasma exposure. Interestingly, these cells also exhibited a higher degree of resistance to hydrogen peroxide. Whole genome comparison between surviving cells and control cells revealed 10 distinct polymorphic regions, including four belonging to the redox active, antibiotic pigment phenazine. Subsequently, the interaction between phenazine production and CAP resistance was demonstrated in biofilms of transposon mutants disrupted in different phenazine pathway genes which exhibited significantly altered sensitivity to CAP.

  13. Resonant activation in polymer translocation: new insights into the escape dynamics of molecules driven by an oscillating field.

    Science.gov (United States)

    Pizzolato, N; Fiasconaro, A; Adorno, D Persano; Spagnolo, B

    2010-08-04

    The translocation of molecules across cellular membranes or through synthetic nanopores is strongly affected by thermal fluctuations. In this work we study how the dynamics of a polymer in a noisy environment changes when the translocation process is driven by an oscillating electric field. An improved version of the Rouse model for a flexible polymer has been adopted to mimic the molecular dynamics, by taking into account the harmonic interactions between adjacent monomers and the excluded-volume effect by introducing a Lennard-Jones potential between all beads. A bending recoil torque has also been included in our model. The polymer dynamics is simulated in a two-dimensional domain by numerically solving the Langevin equations of motion. Thermal fluctuations are taken into account by introducing a Gaussian uncorrelated noise. The mean first translocation time of the polymer centre of inertia shows a minimum as a function of the frequency of the oscillating forcing field. This finding represents the first evidence of the resonant activation behaviour in the dynamics of polymer translocation.

  14. Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

    Science.gov (United States)

    Kevin, Dion A; Meujo, Damaris AF; Hamann, Mark T

    2016-01-01

    Background As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics. PMID:23480512

  15. Periradicular Tissue Responses to Biologically Active Molecules or MTA When Applied in Furcal Perforation of Dogs' Teeth

    Directory of Open Access Journals (Sweden)

    Anna Zairi

    2012-01-01

    Full Text Available The aim of this study was the comparative evaluation of inflammatory reactions and tissue responses to four growth factors, or mineral trioxide aggregate (MTA, or a zinc-oxide-eugenol-based cement (IRM as controls, when used for the repair of furcal perforations in dogs’ teeth. Results showed significantly higher inflammatory cell response in the transforming growth factorβ1 (TGFβ1 and zinc-oxide-eugenol-based cement (IRM groups and higher rates of epithelial proliferation in the TGFβ1, basic fibroblast growth factor (bFGF, and insulin growth factor-I (IGF-I groups compared to the MTA. Significantly higher rates of bone formation were found in the control groups compared to the osteogenic protein-1 (OP-1. Significantly higher rates of cementum formation were observed in the IGF-I and bFGF groups compared to the IRM. None of the biologically active molecules can be suggested for repairing furcal perforations, despite the fact that growth factors exerted a clear stimulatory effect on cementum formation and inhibited collagen capsule formation. MTA exhibited better results than the growth factors.

  16. 活化白细胞黏附分子与肿瘤%Activated leukocyte cell adhesion molecule and minors

    Institute of Scientific and Technical Information of China (English)

    柯少迎; 庄建良; 潘群雄

    2009-01-01

    Activated leukocyte cell adhesion molecule (ALCAM) is a member of immunoglobulin gene superfamily. It is manily expressed in leucocytes and thymic epithelial cells. ALCAM mediates both heterophilic (ALCAM-CD6) and homophilic(ALCAM-ALCAM) cell-cell interactions. Studies show that ALCAM is highly expressed on multiple tumor cells and plays a role in tumorigenesis and tumor progression. ALCAM expression is closely correlated with several human tumors, including breast cancer, esophageal carcinoma, colon carcinoma, o-varian caneer,hepatocellular carcinoma and malignant melanoma.%活化自细胞黏附分子(ALCAM)是免疫球蛋白基因超家族成员,主要表达在白细胞和胸腺上皮细胞.ALCAM在细胞间异嗜性黏附和同嗜性黏附中起重要作用.研究表明,ALCAM在多种肿瘤细胞表面高表达,参与肿瘤的发生发展,在人类肿瘤,ALCAM的表达与乳腺癌、食管癌、结肠癌、卵巢癌、肝癌及恶性黑色素瘤等密切相关.

  17. Land use influence on 3-D distribution of soil microbiological activity in forest-steppe zone of Central Russia

    Science.gov (United States)

    Vasenev, Viacheslav; Tembo, Alan; Sarzhanov, Dmirty; Sotnikova, Julia; Ryzhkov, Oleg; Lakeev, Pavel; Valentini, Riccardo

    2014-05-01

    Land use is the principal factor influencing soil environmental functions and quality. Quite a few studies on soil quality mainly focus on natural and agroecosystems. Much less is known about urban ecosystems, although the urbanization effect on soil quality can be considerable. Parameters of soil microbiological activity are very sensitive to land-use change. Microbial biomass carbon (Cmic), basal respiration (BR) and microbial metabolic coefficient (qCO2) are among most widely used parameters of soil microbiological activity. They are directly associated with such soil functions as fertility, microorganisms' habitat and participation in carbon cycle. So far, most of the studies focus on the effect of land-use change on the topsoil (0-10 cm) microbiological activity, averaged for different land-use types. Much less is known about changes in spatial variability and profile distribution of Cmic, BR and qCO2 in response to different land-use. Land-use influence on spatial and profile distribution of soil microbiological activity may differ between bioclimatic zones. Very fertile and rich in carbon Chernozemic soils (depth of the A horizon up to 1 m, carbon concentration up to 7-9%), dominating in forest-steppe zone are among the most sensitive to land-use change. This study aims to improve understanding of land-use influence on 3-D distribution of Cmic, BR and qCO2 in Central Chernozemic region of Russia. We observed three land-use types (fallow land, natural pasture and meadow) located in Kursk region and three contrast urban functional zone (industrial, residential and recreational) in Kursk city. Soil samples were collected by auguring in five replicas per land-use type, four layers each sampling point (0-10, 10-50, 50-100 and 100-150 cm). Cmic, BR and qCO2 as well as Corg, N and pHKCl were analyzed in all the samples. Cmic (µg C g-1 soil) was analyzed based on the substrate induced respiration (SIR) approach. qCO2 (μg CO2-C mg-1 Cmic h-1) was calculated as the

  18. Activated endothelial interleukin-1beta, -6, and -8 concentrations and intercellular adhesion molecule-1 expression are attenuated by lidocaine.

    LENUS (Irish Health Repository)

    Lan, Wei

    2012-02-03

    Endothelial cells play a key role in ischemia reperfusion injury. We investigated the effects of lidocaine on activated human umbilical vein endothelial cell (HUVEC) interleukin (IL)-1beta, IL-6, and IL-8 concentrations and intercellular adhesion molecule-1 (ICAM-1) expression. HUVECs were pretreated with different concentrations of lidocaine (0 to 0.5 mg\\/mL) for 60 min, thereafter tumor necrosis factor-alpha was added at a concentration of 2.5 ng\\/mL and the cells incubated for 4 h. Supernatants were harvested, and cytokine concentrations were analyzed by enzyme-linked immunosorbent assay. Endothelial ICAM-1 expression was analyzed by using flow cytometry. Differences were assessed using analysis of variance and post hoc unpaired Student\\'s t-test where appropriate. Lidocaine (0.5 mg\\/mL) decreased IL-1beta (1.89 +\\/- 0.11 versus 4.16 +\\/- 1.27 pg\\/mL; P = 0.009), IL-6 (65.5 +\\/- 5.14 versus 162 +\\/- 11.5 pg\\/mL; P < 0.001), and IL-8 (3869 +\\/- 785 versus 14,961 +\\/- 406 pg\\/mL; P < 0.001) concentrations compared with the control. IL-1beta, IL-6, and IL-8 concentrations in HUVECs treated with clinically relevant plasma concentrations of lidocaine (0.005 mg\\/mL) were similar to control. ICAM-1 expression on lidocaine-treated (0.05 mg\\/mL) HUVECs was less than on controls (198 +\\/- 52.7 versus 298 +\\/- 50.3; Mean Channel Fluorescence; P < 0.001). Activated endothelial IL-1beta, IL-6, and IL-8 concentrations and ICAM-1 expression are attenuated only by lidocaine at concentrations larger than clinically relevant concentrations.

  19. A heterocyclic molecule kartogenin induces collagen synthesis of human dermal fibroblasts by activating the smad4/smad5 pathway.

    Science.gov (United States)

    Wang, Jing; Zhou, Jia; Zhang, Ning; Zhang, Xiaoling; Li, Qingfeng

    2014-07-18

    Declined production of collagen by fibroblasts is one of the major causes of aging appearance. However, only few of compounds found in cosmetic products are able to directly increase collagen synthesis. A novel small heterocyclic compound called kartogenin (KGN) was found to stimulate collagen synthesis of mesenchymal stem cells (MSCs). So, we hypothesized and tested that if KGN could be applied to stimulate the collagen synthesis of fibroblasts. Human dermal fibroblasts in vitro were treated with various concentrations of KGN, with dimethyl sulfoxide (DMSO) serving as the negative control. Real-time reverse-transcription polymerase chain reaction, Western blot, and immunofluorescence analyses were performed to examine the expression of collagen and transforming growth factor beta (TGF-β) signaling pathway. The production of collagen was also tested in vivo by Masson's trichrome stain and immunohistochemistry in the dermis of mice administrated with KGN. Results showed that without obvious influence on fibroblasts' apoptosis and viability, KGN stimulated type-I collagen synthesis of fibroblasts at the mRNA and protein levels in a time-dependent manner, but KGN did not induce expression of α-skeletal muscle actin (α-sma) or matrix metallopeptidase1 (MMP1), MMP9 in vitro. Smad4/smad5 of the TGF-β signaling pathway was activated by KGN while MAPK signaling pathway remained unchanged. KGN also increased type-I collagen synthesis in the dermis of BALB/C mice. Our results indicated that KGN promoted the type-I collagen synthesis of dermal fibroblasts in vitro and in the dermis of mice through activation of the smad4/smad5 pathway. This molecule could be used in wound healing, tissue engineering of fibroblasts, or aesthetic and reconstructive procedures. PMID:24928394

  20. Electron-correlation effects in enhanced ionization of molecules: A time-dependent generalized-active-space configuration-interaction study

    Science.gov (United States)

    Chattopadhyay, S.; Bauch, S.; Madsen, L. B.

    2015-12-01

    We numerically study models of H2 and LiH molecules, aligned collinearly with the linear polarization of the external field, to elucidate the possible role of correlation in the enhanced-ionization (EI) phenomena. Correlation is considered at different levels of approximation with the time-dependent generalized-active-space configuration-interaction method. The results of our studies show that enhanced ionization occurs in multielectron molecules and that correlation is important, and they also demonstrate significant deviations between the results of the single-active-electron approximation and more accurate configuration-interaction methods. We further investigate the role of low-lying excited states in the EI phenomena. With the inclusion of correlation we show strong carrier-envelope-phase effects in the enhanced ionization of the asymmetric heteronuclear LiH -like molecule. The correlated calculation shows an intriguing feature of crossover in enhanced ionization with two carrier-envelope phases at critical internuclear separation.

  1. Electron correlation effects in enhanced-ionization of molecules:A time-dependent generalized-active-space configuration-interaction study

    CERN Document Server

    Chattopadhyay, S; Madsen, L B

    2015-01-01

    We numerically study models of $\\mathrm{H}_2$ and $\\mathrm{LiH}$ molecules, aligned collinearly with the linear polarization of the external field, to elucidate the possible role of correlation in the enhanced-ionization phenomena. Correlation is considered at different levels of approximation with the time-dependent generalized-active-space configuration-interaction method. The results of our studies show that enhanced ionization occurs in multielectron molecules, that correlation is important and they also demonstrate significant deviations between the results of the single-active-electron approximation and more accurate configuration-interaction methods. With the inclusion of correlation we show strong carrier-envelope-phase effects in the enhanced ionization of the asymmetric heteronuclear $\\mathrm{LiH}$-like molecule. The correlated calculation shows an intriguing feature of cross-over in enhanced ionization with two carrier-envelope-phases at critical inter-nuclear separation.

  2. Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Jingsong; Campobasso, Nino; Biju, Mangatt P.; Fisher, Kelly; Pan, Xiao-Qing; Cottom, Josh; Galbraith, Sarah; Ho, Thau; Zhang, Hong; Hong, Xuan; Ward, Paris; Hofmann, Glenn; Siegfried, Brett; Zappacosta, Francesca; Washio, Yoshiaki; Cao, Ping; Qu, Junya; Bertrand, Sophie; Wang, Da-Yuan; Head, Martha S.; Li, Hu; Moores, Sheri; Lai, Zhihong; Johanson, Kyung; Burton, George; Erickson-Miller, Connie; Simpson, Graham; Tummino, Peter; Copeland, Robert A.; Oliff, Allen (GSKPA)

    2014-10-02

    c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the {alpha}I helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the {alpha}I helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

  3. Effect of activated sludge in the bottom zone on biogenic sulfate reduction

    Energy Technology Data Exchange (ETDEWEB)

    Yagafarov, G.G.; Bikchentayeva, A.G.; Yagafarov, R.G.

    1981-01-01

    It is shown that sulfate destruction in the Arlansk group of fields is caused by infection of the formation by sulfate reducing bacteria in the drilling process and flooding by surface water. For the first time, the necessity is shown of considering the activated sludge formed from particles suspended in water and biocenosis of microorganisms during microbiological investigation of wells. It is suggested that biodecomposition of surfactants is possible only in the area of formation of activated sludge around the bottom of the injection well.

  4. Strontium-90 activity concentration in soil samples from the exclusion zone of the Fukushima daiichi nuclear power plant.

    Science.gov (United States)

    Sahoo, Sarata Kumar; Kavasi, Norbert; Sorimachi, Atsuyuki; Arae, Hideki; Tokonami, Shinji; Mietelski, Jerzy Wojciech; Łokas, Edyta; Yoshida, Satoshi

    2016-01-01

    The radioactive fission product (90)Sr has a long biological half-life (˜18 y) in the human body. Due to its chemical similarity to calcium it accumulates in bones and irradiates the bone marrow, causing its high radio-toxicity. Assessing (90)Sr is therefore extremely important in case of a nuclear disaster. In this work 16 soil samples were collected from the exclusion zone (nuclear power plant, to measure (90)Sr activity concentration using liquid scintillation counting. (137)Cs activity concentration was also measured with gamma-spectroscopy in order to investigate correlation with (90)Sr. The (90)Sr activity concentrations ranged from 3.0 ± 0.3 to 23.3 ± 1.5 Bq kg(-1) while the (137)Cs from 0.7 ± 0.1 to 110.8 ± 0.3 kBq kg(-1). The fact that radioactive contamination originated from the Fukushima nuclear accident was obvious due to the presence of (134)Cs. However, (90)Sr contamination was not confirmed in all samples although detectable amounts of (90)Sr can be expected in Japanese soils, as a background, stemming from global fallout due to the atmospheric nuclear weapon tests. Correlation analysis between (90)Sr and (137)Cs activity concentrations provides a potentially powerful tool to discriminate background (90)Sr level from its Fukushima contribution.

  5. Strontium-90 activity concentration in soil samples from the exclusion zone of the Fukushima daiichi nuclear power plant

    Science.gov (United States)

    Sahoo, Sarata Kumar; Kavasi, Norbert; Sorimachi, Atsuyuki; Arae, Hideki; Tokonami, Shinji; Mietelski, Jerzy Wojciech; Łokas, Edyta; Yoshida, Satoshi

    2016-04-01

    The radioactive fission product 90Sr has a long biological half-life (˜18 y) in the human body. Due to its chemical similarity to calcium it accumulates in bones and irradiates the bone marrow, causing its high radio-toxicity. Assessing 90Sr is therefore extremely important in case of a nuclear disaster. In this work 16 soil samples were collected from the exclusion zone (Fukushima Daiichi nuclear power plant, to measure 90Sr activity concentration using liquid scintillation counting. 137Cs activity concentration was also measured with gamma-spectroscopy in order to investigate correlation with 90Sr. The 90Sr activity concentrations ranged from 3.0 ± 0.3 to 23.3 ± 1.5 Bq kg-1 while the 137Cs from 0.7 ± 0.1 to 110.8 ± 0.3 kBq kg-1. The fact that radioactive contamination originated from the Fukushima nuclear accident was obvious due to the presence of 134Cs. However, 90Sr contamination was not confirmed in all samples although detectable amounts of 90Sr can be expected in Japanese soils, as a background, stemming from global fallout due to the atmospheric nuclear weapon tests. Correlation analysis between 90Sr and 137Cs activity concentrations provides a potentially powerful tool to discriminate background 90Sr level from its Fukushima contribution.

  6. Hair cells use active zones with different voltage dependence of Ca2+ influx to decompose sounds into complementary neural codes.

    Science.gov (United States)

    Ohn, Tzu-Lun; Rutherford, Mark A; Jing, Zhizi; Jung, Sangyong; Duque-Afonso, Carlos J; Hoch, Gerhard; Picher, Maria Magdalena; Scharinger, Anja; Strenzke, Nicola; Moser, Tobias

    2016-08-01

    For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca(2+) influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca(2+) influx ranged over ∼20 mV. Ca(2+) influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca(2+) channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca(2+) influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca(2+) influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca(2+) influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca(2+) channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs. PMID:27462107

  7. 78 FR 68026 - Foreign-Trade Zone (FTZ) 99-Wilmington, Delaware, Notification of Proposed Production Activity...

    Science.gov (United States)

    2013-11-13

    ... Production Activity, Noramco, Inc., (Pharmaceutical Intermediate), Wilmington, Delaware The Delaware Economic... Section 400.38 of the FTZ Board's regulations. The facility is used for the production of a pharmaceutical... to choose the duty rate during customs entry procedures that apply to the tapentadol...

  8. Direct observations of hydrothermal waters on the bottom of the Pacific Ocean (Galapagos active zone and Hess depession)

    Energy Technology Data Exchange (ETDEWEB)

    Gordeev, V.V.; Demina, L.L.

    1979-06-01

    Direct geochemical evidences of hydrothermal alteration of oceanic waters above active oceanic ridges were obtained. In axial part of Galapagos fault and in Hess depression the near-bottom waters having unusually high contents of Fe, Mn, Cu, and Zn in suspension and lowered contents of Fe, Cu, Zn, and Ni in solution (Mn was not detected in solution) were revealed. This is probably due to capture of dissolved metal by amorphous hydroxides of Fe and Mn. The length of the anomalous zone along meridional profile through the Carnegie ridge is near 100 km and its thickness above the bottom reachs 1000 m. Within Hess depression, where waters are more isolated, the alteration in metal concentrations in suspension and solution are detected at the distance 2000 to 5000 m from the bottom.

  9. Strontium-90 activity concentration in soil samples from the exclusion zone of the Fukushima daiichi nuclear power plant

    Science.gov (United States)

    Sahoo, Sarata Kumar; Kavasi, Norbert; Sorimachi, Atsuyuki; Arae, Hideki; Tokonami, Shinji; Mietelski, Jerzy Wojciech; Łokas, Edyta; Yoshida, Satoshi

    2016-04-01

    The radioactive fission product 90Sr has a long biological half-life (˜18 y) in the human body. Due to its chemical similarity to calcium it accumulates in bones and irradiates the bone marrow, causing its high radio-toxicity. Assessing 90Sr is therefore extremely important in case of a nuclear disaster. In this work 16 soil samples were collected from the exclusion zone (contamination originated from the Fukushima nuclear accident was obvious due to the presence of 134Cs. However, 90Sr contamination was not confirmed in all samples although detectable amounts of 90Sr can be expected in Japanese soils, as a background, stemming from global fallout due to the atmospheric nuclear weapon tests. Correlation analysis between 90Sr and 137Cs activity concentrations provides a potentially powerful tool to discriminate background 90Sr level from its Fukushima contribution.

  10. Exploring the Cross-sectional Association between Transit-Oriented Development Zoning and Active Travel and Transit Usage in the United States, 2010-2014

    Directory of Open Access Journals (Sweden)

    Emily eThrun

    2016-06-01

    Full Text Available Background: In response to traditional zoning codes that contribute to car-dependent, sprawling, and disconnected neighborhoods, communities are reforming their land use laws to create pedestrian-friendly areas that promote physical activity. One such reform is the adoption of transit-oriented developments or districts (TODs. TODs are higher-density, compact, mixed use areas located around transit stops that are designed to encourage walking.Purpose: To identify the characteristics of communities that have adopted TODs in their land use laws and examine if communities that have included TODs in their zoning codes are more likely to have adults that commute by any form of active transportation (i.e., walking, biking, or public transportation or by using public transportation specifically.Methods: Zoning codes effective as of 2010 were obtained for a purposeful sample of the largest 3,914 municipal jurisdictions located in 473 of the most populous US counties and consolidated cities within 48 states and the District of Columbia. They were evaluated to determine whether they included TOD districts or regulations using a coding tool developed by the study team. Descriptive statistics together with t-tests and Pearson’s chi-squared independence test were used to compare characteristics of jurisdictions with and without TOD zoning. Multivariate linear regressions were used to compute the adjusted association between TOD zoning and taking public or active transportation to work.Results: Jurisdictions with TOD zoning were located more in the South and West than non-TOD jurisdictions and were more populous, higher income, more racially diverse, and younger. Jurisdictions with TOD zoning had significantly higher percentages of occupied housing with no vehicle than those without TOD zoning. TOD zoning was associated with significantly higher rates of public transportation to work (β=2.10, 95% CI=0.88, 3.32 and active transportation to work (β=2.48, 95

  11. Late Quaternary Activity and Seismogenic Potential of the Gonave microplate: South Coast Fault Zone of Southern Jamaica

    Science.gov (United States)

    Benford, B.; Mann, P.; Prentice, C.; King, W.; Wiggins-Grandison, M.; Demets, C.; Tikoff, B.

    2008-12-01

    The South Coast fault zone (SCFZ) strikes east-west and forms a scarp as high as 600 m along the southern coast of Jamaica. It has been postulated that this fault acts as a left-lateral, strike-slip 'bypass' fault that truncates the large, right-stepping restraining bend formed between the Plantain Garden fault zone of southeastern Jamaica and the Duanvale-Walton fault zone of northwestern Jamaica. GPS measurements near the SCFZ show anomalously rotated vectors consistent with active left-lateral shear. Anomalous topography along the trace of the SCFZ includes two, doubly plunging anticlines: Kemp's Hill (119 m), an isolated high in the otherwise flat Vere Plain, and Round Hill (333 m), a larger high directly adjacent to the coast. Field work identified the most active trace of the SCFZ in a notch along the north flank of Round Hill; this trace can be extrapolated to the west along the coast and east that locally defines a low scarp in alluvium. Channel profiles constructed for six rivers and streams crossing the projected trace of the SCFZ show convex-upward morphologies, consistent with dominance of tectonic uplift over river downcutting. To better define the subsurface location of the SCFZ beneath the Vere Plain, a gravity survey network consisting of 327 stations and covering an areas of 500 km2 was performed using a Lacoste and Romberg G-meter. Differential GPS allowed centimeter-level elevation control for each station. Gravity corrections (elevation, latitude, instrument drift, and earth tides) were made using QC Tool software, and topographic and terrane corrections were made using both local topographic measurements and high-resolution SRTM data. An ~20 mgal negative gravity anomaly on the otherwise flat gravity field of the Vere Plain corresponds with the projected trace of the SCFZ across the Vere Plain and the locations of one river offset. We interpret that the SCFZ has down-to-the-south throw, which has led to thickening of Quaternary sediments south

  12. Estimation of ground water residence times in the Critical zone: insight from U activity ratios

    Science.gov (United States)

    Chabaux, Francois; Ackerer, Julien; Lucas, Yann; viville, Daniel

    2016-04-01

    The use of radioactive disequilibria as tracers and chronometers of weathering processes and related mass transfers has been recognized since the 60'. The development, over the last two decades, of analytical methods for measuring very precisely U-series nuclides (especially, 234U, 230Th and 226Ra) in environmental samples has opened up new scientific applications in Earth Surface Sciences. Here, we propose to present the potential of U activity ratios in surface waters as chronometer of water transfers at a watershed scale. This will be illustrated from studies performed at different scales, with the analysis of U activity ratios in surface waters from small watersheds (Strengbach and Ringelbach watersheds in the Vosges Mountain, France) but also from watersheds of much more regional extension (e.g., the Upper Rhine basin or the Ganges basin). These various studies show that variations of U activity ratios in surface waters are mainly associated with 234U-238U fractionations occurring during the water transfer within the bedrock, which intensity depends on two main parameters: the petro-physical characteristics of the aquifer, principally the geometry of water-rock interfaces and the duration of the water-rock interactions. This readily explains why different U activity ratios (UAR) can be observed in the different aquifers of a continental hydrosystem and hence why UAR can be used to trace the source of river waters. For a hydrological system developed on a substratum marked by fairly homogeneous petro-physical characteristics, the main parameter controlling the UAR in waters draining such a system would be the duration of the water-rock interactions. Variations of UAR in stream or spring waters of such a system can therefore be modeled using simple reactive transport model, which allows the estimation of both the dissolution rate of the bedrock and the residence time of the waters within the aquifer.

  13. Immunohistochemical expression of the oncogenic molecules active Stat3 and survivin in benign and malignant salivary gland tumors

    Science.gov (United States)

    Nikitakis, Nikolaos G.; Scheper, Mark A.; Papanicolaou, Vasileios S.; Sklavounou, Alexandra; Sauk, John J.

    2009-01-01

    Objective Signal transducer and activator of transcription 3 (Stat3) and survivin have been shown to exert oncogenic effects in various human neoplasms. The purpose of this study was to evaluate the expression of the tyrosine phosphorylated (active) Stat3 and survivin in various benign and malignant salivary gland tumors (SGTs). Study design Eighty-six SGTs (65 malignant and 21 benign tumors of various histopathologic subtypes) were immunohistochemically stained with anti-survivin or anti-phosphorylated tyrosine-705 (p-tyr) Stat3 antibodies. Immunohistochemical reactivity was graded in a semi-quantitative manner; a combined score of immunohistochemical positivity (0–6) was calculated for each tumor by adding the individual scores for percentage of tumor cells (0–3) and intensity of staining (0–3). Results Survivin was immunohistochemically detected in all studied benign and malignant SGTs; p-tyr Stat3 was also detected in the majority (91%) of SGTs. The average combined scores for survivin and p-tyr Stat3 immunohistochemical expression in the studied malignant SGTs was 4.40 and 3.35, respectively; the corresponding combined scores for survivin and p-tyr Stat3 in the studied benign SGTs were 4.37 and 3.22, respectively. No statistically significant differences (p>0.05) in p-tyr Stat3 or survivin expression were detected between the benign and malignant groups, or among the various examined histopathological subtypes of SGTs. In contrast, normal salivary gland elements in the vicinity of the studied tumors revealed only weak and focal survivin or p-tyr Stat3 immunoreactivity, mainly localized to ductal and mucous cells. Conclusions Our data indicate an almost universal expression of activated Stat3 and survivin in benign and malignant SGTs. Considering the well-established proliferative and anti-apoptotic properties of these molecules and their functional interrelationship, selective targeting techniques against Stat3 and/or survivin may represent promising

  14. A New Perspective of the Radio Bright Zone at The Galactic Center: Feedback from Nuclear Activities

    Science.gov (United States)

    Zhao, Jun-Hui; Morris, Mark R.; Goss, W. M.

    2016-02-01

    New observations of Sgr A have been carried out with the Jansky VLA in the B and C arrays using the broadband (2 GHz) continuum mode at 5.5 GHz. The field of view covers the central 13‧ (30 pc) region of the radio-bright zone at the Galactic center. Using the multi-scale and multi-frequency-synthesis (MS-MFS) algorithms in CASA, we have imaged Sgr A with a resolution of 1″, achieving an rms noise of 8 μJy beam-1, and a dynamic range of 100,000:1. Both previously known and newly identified radio features in this region are revealed, including numerous filamentary sources. The radio continuum image is compared with Chandra X-ray images, with a CN emission-line image obtained with the Submillimeter Array and with detailed Paschen-α images obtained with Hubble Space Telescope/NICMOS. We discuss several prominent features in the radio image. The “Sgr A west Wings” extend 2‧ (5 pc) from the NW and SE tips of the Sgr A west H ii region (the “Mini-spiral”) to positions located 2.9 and 2.4 arcmin to the northwest and southeast of Sgr A*, respectively. The NW wing, along with several other prominent features, including the previously identified “NW Streamers,” form an elongated radio lobe (NW lobe), oriented nearly perpendicular to the Galactic plane. This radio lobe, with a size of 6.‧3 × 3.‧2 (14.4 pc × 7.3 pc), has a known X-ray counterpart. In the outer region of the NW lobe, a row of three thermally emitting rings is observed. A field containing numerous amorphous radio blobs extends for a distance of ˜2 arcmin beyond the tip of the SE wing; these newly recognized features coincide with the SE X-ray lobe. Most of the amorphous radio blobs in the NW and SE lobes have Paschen-α counterparts. We propose that they have been produced by shock interaction of ambient gas concentrations with a collimated nuclear wind or an outflow that originated from within the circumnuclear disk (CND). We also discuss the possibility that the ionized wind or

  15. Multilayer stress from gravity and its tectonic implications in urban active fault zone: A case study in Shenzhen, South China

    Science.gov (United States)

    Xu, Chuang; Wang, Hai-hong; Luo, Zhi-cai; Ning, Jin-sheng; Liu, Hua-liang

    2015-03-01

    It is significant to identify urban active faults for human life and social sustainable development. The ordinary methods to detect active faults, such as geological survey, artificial seismic exploration, and electromagnetic exploration, are not convenient to be carried out in urban area with dense buildings. It is also difficult to supply information about vertical extension of the deeper faults by these methods. Gravity, reflecting the mass distribution of the Earth's interior, provides an alternative way to detect faults, which is more efficient and convenient for urban active fault detection than the aforementioned techniques. Based on the multi-scale decomposition of gravity anomalies, a novel method to invert multilayer horizontal tectonic stresses is proposed. The inverted multilayer stress fields are further used to infer the distribution and stability of the main faults. In order to validate our method, the multilayer stress fields in the Shenzhen fault zone are calculated as a case study. The calculated stress fields show that their distribution is controlled significantly by the strike of the main faults and can be used to derive depths of the faults. The main faults in Shenzhen may range from 4 km to 20 km in the depth. Each layer of the crust is nearly equipressure since the horizontal tectonic stress has small amplitude. It indicates that the main faults in Shenzhen are relatively stable and have no serious impact on planning and construction of the city.

  16. Could both vitamin D and geomagnetic activity impact serum levels of soluble cell adhesion molecules in young men?

    Science.gov (United States)

    Bleizgys, Andrius; Šapoka, Virginijus

    2016-07-01

    Vitamin D might have a role in diminishing endothelial dysfunction (ED). The initial aim was to test the hypothesis of reciprocity between levels of 25-hydroxyvitamin D (25(OH)D) and levels of soluble endothelial cell adhesion molecules (CAMs) that could serve as biomarkers of ED. Randomly selected men of age 20-39 were examined at February or March (cold season) and reexamined at August or September (warm season). Some lifestyle and anthropometrical data were recorded. Laboratory measurements, including those for serum levels of soluble CAMs—sICAM-1, sVCAM-1, sE-selectin and sP-selectin—were also performed. As some of the results were rather unexpected, indices of geomagnetic activity (GMA), obtained from the online database, were included in further analysis as a confounder. In 2012-2013, 130 men were examined in cold season, and 125 of them were reexamined in warm season. 25(OH)D levels were found to be significantly negatively associated with sVCAM-1 levels ( β = -0.15, p = 0.043 in warm season; β = -0.19, p = 0.007 for changes). Levels of sVCAM-1 and sICAM-1 from the same seasons were notably different between years and have changed in an opposite manner. Soluble P-selectin levels were higher at warm season in both years. GMA was positively associated with sVCAM-1 ( β = 0.17, p = 0.039 in cold season; β = 0.22, p = 0.002 for changes) and negatively with sICAM-1 ( β = -0.30. p Vitamin D might play a role in diminishing sVCAM-1 levels. Levels of sVCAM-1 and sICAM-1 were associated with the GMA; this implies a need for further research.

  17. Joint molecule resolution requires the redundant activities of MUS-81 and XPF-1 during Caenorhabditis elegans meiosis.

    Directory of Open Access Journals (Sweden)

    Nigel J O'Neil

    Full Text Available The generation and resolution of joint molecule recombination intermediates is required to ensure bipolar chromosome segregation during meiosis. During wild type meiosis in Caenorhabditis elegans, SPO-11-generated double stranded breaks are resolved to generate a single crossover per bivalent and the remaining recombination intermediates are resolved as noncrossovers. We discovered that early recombination intermediates are limited by the C. elegans BLM ortholog, HIM-6, and in the absence of HIM-6 by the structure specific endonuclease MUS-81. In the absence of both MUS-81 and HIM-6, recombination intermediates persist, leading to chromosome breakage at diakinesis and inviable embryos. MUS-81 has an additional role in resolving late recombination intermediates in C. elegans. mus-81 mutants exhibited reduced crossover recombination frequencies suggesting that MUS-81 is required to generate a subset of meiotic crossovers. Similarly, the Mus81-related endonuclease XPF-1 is also required for a subset of meiotic crossovers. Although C. elegans gen-1 mutants have no detectable meiotic defect either alone or in combination with him-6, mus-81 or xpf-1 mutations, mus-81;xpf-1 double mutants are synthetic lethal. While mus-81;xpf-1 double mutants are proficient for the processing of early recombination intermediates, they exhibit defects in the post-pachytene chromosome reorganization and the asymmetric disassembly of the synaptonemal complex, presumably triggered by crossovers or crossover precursors. Consistent with a defect in resolving late recombination intermediates, mus-81; xpf-1 diakinetic bivalents are aberrant with fine DNA bridges visible between two distinct DAPI staining bodies. We were able to suppress the aberrant bivalent phenotype by microinjection of activated human GEN1 protein, which can cleave Holliday junctions, suggesting that the DNA bridges in mus-81; xpf-1 diakinetic oocytes are unresolved Holliday junctions. We propose that the

  18. Could both vitamin D and geomagnetic activity impact serum levels of soluble cell adhesion molecules in young men?

    Science.gov (United States)

    Bleizgys, Andrius; Šapoka, Virginijus

    2015-11-01

    Vitamin D might have a role in diminishing endothelial dysfunction (ED). The initial aim was to test the hypothesis of reciprocity between levels of 25-hydroxyvitamin D (25(OH)D) and levels of soluble endothelial cell adhesion molecules (CAMs) that could serve as biomarkers of ED. Randomly selected men of age 20-39 were examined at February or March (cold season) and reexamined at August or September (warm season). Some lifestyle and anthropometrical data were recorded. Laboratory measurements, including those for serum levels of soluble CAMs—sICAM-1, sVCAM-1, sE-selectin and sP-selectin—were also performed. As some of the results were rather unexpected, indices of geomagnetic activity (GMA), obtained from the online database, were included in further analysis as a confounder. In 2012-2013, 130 men were examined in cold season, and 125 of them were reexamined in warm season. 25(OH)D levels were found to be significantly negatively associated with sVCAM-1 levels (β = -0.15, p = 0.043 in warm season; β = -0.19, p = 0.007 for changes). Levels of sVCAM-1 and sICAM-1 from the same seasons were notably different between years and have changed in an opposite manner. Soluble P-selectin levels were higher at warm season in both years. GMA was positively associated with sVCAM-1 (β = 0.17, p = 0.039 in cold season; β = 0.22, p = 0.002 for changes) and negatively with sICAM-1 (β = -0.30. p Vitamin D might play a role in diminishing sVCAM-1 levels. Levels of sVCAM-1 and sICAM-1 were associated with the GMA; this implies a need for further research.

  19. Could both vitamin D and geomagnetic activity impact serum levels of soluble cell adhesion molecules in young men?

    Science.gov (United States)

    Bleizgys, Andrius; Šapoka, Virginijus

    2016-07-01

    Vitamin D might have a role in diminishing endothelial dysfunction (ED). The initial aim was to test the hypothesis of reciprocity between levels of 25-hydroxyvitamin D (25(OH)D) and levels of soluble endothelial cell adhesion molecules (CAMs) that could serve as biomarkers of ED. Randomly selected men of age 20-39 were examined at February or March (cold season) and reexamined at August or September (warm season). Some lifestyle and anthropometrical data were recorded. Laboratory measurements, including those for serum levels of soluble CAMs—sICAM-1, sVCAM-1, sE-selectin and sP-selectin—were also performed. As some of the results were rather unexpected, indices of geomagnetic activity (GMA), obtained from the online database, were included in further analysis as a confounder. In 2012-2013, 130 men were examined in cold season, and 125 of them were reexamined in warm season. 25(OH)D levels were found to be significantly negatively associated with sVCAM-1 levels ( β = -0.15, p = 0.043 in warm season; β = -0.19, p = 0.007 for changes). Levels of sVCAM-1 and sICAM-1 from the same seasons were notably different between years and have changed in an opposite manner. Soluble P-selectin levels were higher at warm season in both years. GMA was positively associated with sVCAM-1 ( β = 0.17, p = 0.039 in cold season; β = 0.22, p = 0.002 for changes) and negatively with sICAM-1 ( β = -0.30. p < 0.001 in cold season) levels. Vitamin D might play a role in diminishing sVCAM-1 levels. Levels of sVCAM-1 and sICAM-1 were associated with the GMA; this implies a need for further research.

  20. Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity.

    OpenAIRE

    Turner, G D; Ly, V. C.; Nguyen, T.H.; Nguyen, H.P.; Bethell, D.; Wyllie, S.; Louwrier, K.; Fox, S B; Gatter, K C; Day, N P; Tran, T. H.; White, N J; Berendt, A R

    1998-01-01

    Fatal Plasmodium falciparum malaria is accompanied by systemic endothelial activation. To study endothelial activation directly during malaria and sepsis in vivo, the expression of cell adhesion molecules on dermal microvascular endothelium was examined in skin biopsies and correlated with plasma levels of soluble (circulating) ICAM-1, E-selectin, and VCAM-1 and the cytokine tumor necrosis factor (TNF)-alpha. Skin biopsies were obtained from 61 cases of severe malaria, 42 cases of uncomplicat...

  1. Serum levels of tumor necrosis factor-α and soluble adhesion molecules in relation to magnetic resonance imaging results and clinical activity in multiple sclerosis

    International Nuclear Information System (INIS)

    One direction of research in pathogenesis of multiple sclerosis (MS) has been to identify immunological markers associated with disease activity that are capable of predicting subsequent course of disease and are sensitive to intervention by immunomodulatory therapies. Adhesion molecules and tumor necrosis factor-α of the cytokine superfamily are associated with inflammation-mediated blood-brain barrier dysfunction and demyelination in the central nervous system (CNS). This study investigates the relationship between the serum level of soluble vascular adhesion molecule-1 (sVCAM), soluble intercellular adhesion molecule-1 (alCAM), tumor necrosis factor-α (TNF-α) and magnetic resonance imaging (MRI) activity in 18 patients with relapsing-remitting (RR) MS with different clinical activity. Patients with active gadolinium (Gd)-enhanced lesions on MRI showed a higher serum level of TNF-α, sVCA-1, slCAM-1 than RR MS patients without Gd-enhanced lesions. Control individuals (n=10) without MRI abnormalities had significantly lower serum levels of the above immunological parameters. These results suggest that serum levels of TNF-α and adhesion molecules slCAM-1 in RR MS patients are correlated with Gd-enhanced MRI and disease clinical activity and that they can be used as biological markers of disease activity. The soluble form of VCAM levels in peripheral blood did not correlate with disease activity and Gd-enhanced lesions of MRI. sVCAM as an early indicator of blood-brain barrier dysfunction may also serve as marker of beneficial activity in the relapsing phase of MS course. (authors)

  2. Inhibition of Dengue Virus Replication by a Class of Small-Molecule Compounds That Antagonize Dopamine Receptor D4 and Downstream Mitogen-Activated Protein Kinase Signaling

    OpenAIRE

    Smith, Jessica L.; Stein, David A.; Shum, David; Fischer, Matthew A.; Radu, Constantin; Bhinder, Bhavneet; Djaballah, Hakim; Nelson, Jay A.; Früh, Klaus; Hirsch, Alec J.

    2014-01-01

    Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. To date, no vaccines or antiviral therapeutics have been approved for combating DENV-associated disease. In this paper, we describe a class of tricyclic small-molecule compounds—dihydrodibenzothiepines (DHBTs), identified through high-throughput screening—with potent inhibitory activity against DENV serotype 2. SKI-417616, a highly active representative of ...

  3. Increase in electron transfer activity in photosystem Ⅱ of spinach thylakoids caused by conversion of phosphatidyl-glycerol to phosphatidic acid molecules

    Institute of Scientific and Technical Information of China (English)

    WU Feng; YANG Zhenle; LI Liangbi; KUANG Tingyun

    2003-01-01

    The techniques of oxygen electrode polarography, sodium dodecyl sulfate-polyacryamide gel electrophoresis (SDS-PAGE) and thin layer chromatography (TLC) were employed to investigate the effect of phospholipase D treatment on physiological function of spinach thylakoids. It was shown that the phospholipase D treatment on thylakoid resulted in the degradation of phosphatidylglycerol (PG) and occurrence of phosphatidic acid (PA). The changes of PG to PA molecules caused an increase in oxygen evolution in photosystem Ⅱ (PSⅡ), which was accompanied by an uncoupling effect on thylakoid membrane. It was revealed that the head-groups of PG molecules play an important role in the maintenance of the appropriate physiological activity of thylakoid membrane.

  4. Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity

    Science.gov (United States)

    Williamson, Iain; Lettice, Laura A.; Hill, Robert E.

    2016-01-01

    Limb-specific Shh expression is regulated by the (∼1 Mb distant) ZRS enhancer. In the mouse, limb bud-restricted spatiotemporal Shh expression occurs from ∼E10 to E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies of Shh/ZRS colocalisation only in the Shh-expressing regions of the limb bud, in a conformation consistent with enhancer-promoter loop formation. However, in all tissues and at all developmental stages analysed, Shh-ZRS spatial distances were still consistently shorter than those to a neural enhancer located between Shh and ZRS in the genome. 5C identified a topologically associating domain (TAD) over the Shh/ZRS genomic region and enriched interactions between Shh and ZRS throughout E11.5 embryos. Shh/ZRS colocalisation, therefore, correlates with the spatiotemporal domain of limb bud-specific Shh expression, but close Shh and ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate the expression of Shh. PMID:27402708

  5. Active flexural-slip faulting: A study from the Pamir-Tian Shan convergent zone, NW China

    Science.gov (United States)

    Li, Tao; Chen, Jie; Thompson, Jessica A.; Burbank, Douglas W.; Yang, Xiaodong

    2015-06-01

    The flexural-slip fault (FSF), a type of secondary fault generated by bed-parallel slip, occurs commonly and plays an important role in accommodating fold growth. Although the kinematics and mechanics of FSFs are well studied, relatively few field observations or geometric models explore its geomorphic expression. In the Pamir-Tian Shan convergent zone, NW China, suites of well-preserved FSF scarps displace fluvial terraces in the Mingyaole and Wulagen folds. Integrating interpretations of Google Earth images, detailed geologic and geomorphic mapping, and differential GPS measurements of terrace surfaces, we summarize geomorphic features that typify these faults and create kinematic models of active flexural-slip faulting. Our study indicates the following: (i) FSF scarps commonly occur near synclinal hinges, irrespective of whether (a) the dip direction of beds on either side of the hinge is unidirectional or in opposite directions, (b) the hinge is migrating or fixed, or (c) the hinge shape is narrow and angular or wide and curved. (ii) Active FSFs are likely to produce higher scarps on steeper beds, whereas lower or no topographic scarps typify gentler beds. (iii) Tilt angles of the terrace surface displaced above FSFs progressively decrease farther away from the hinge, with abrupt changes in slope coinciding with FSF scarps; the changes in tilt angle and scarp height have a predictable geometric relationship. (iv) Active FSFs can accommodate a significant fraction of total slip and play a significant role in folding deformation. (v) Active FSFs may be used to assess seismic hazards associated with active folds and associated blind thrusts.

  6. The influence of galvanic currents and voltage on the proliferation activity of lymphocytes and expression of cell surface molecules.

    Science.gov (United States)

    Podzimek, S; Hána, K; Miksovský, M; Pousek, L; Matucha, P; Meloun, M; Procházková, J

    2008-01-01

    Release of metal ions from dental metal fillings supported by galvanism can cause local or general pathological problems in sensitive and genetically susceptible individuals. We aimed to investigate in vitro lymphocyte responses and expression of surface molecules influenced by galvanic currents and voltage. Human peripheral blood lymphocytes were influenced by galvanic currents and voltages and lymphocyte proliferation was measured. Control samples were not exposed to the influence of galvanism. We also studied the expression of surface molecules by the FACS analysis. A 15-h and shorter influence of almost all tested currents and voltages caused a significant decrease in lymphocyte proliferation and the 15-h influence of 20 microA currents significantly increased expression of surface molecules CD 19, 11a/18, 19/69 and 19/95. An influence of 10 and 3 microA currents led to a significant decrease in the expression of surface molecules CD 3, 11a/18, 3/69 and 3/95 and to a significant increase in CD 19 expression. An 80 mV voltage influence led to a significant decrease in the expression of surface molecules CD 3, 11a/18, 3/69, 3/95, 19/69 and 19/95, and 200 and 300 mV voltages significantly decreased the expression of surface molecules CD 3, 19, 11a/18, 3/95 and 19/95 and significantly increased CD 19/69 expression. A long-lasting influence of galvanism can, in sensitive and genetically susceptible individuals, influence lymphocyte proliferation and surface molecule expression. The threshold for pathological values of 5 microA for galvanic currents and 100 mV for galvanic voltage was confirmed.

  7. Hygienic aspects of safety vital activity support of servicemen and their families on the contaminated zone

    International Nuclear Information System (INIS)

    Analysis of radiation-and-hygienic, radioecological and medical aspects of vital activity of servicemen and their families at the radioactive contaminated territories (RCT) after the Chernobyl NPP accident has shown that the life there is linked with the increased health risk. The paper presents the examination results of 2550 human beings, over 2100 samples of foods and of the environmental objects have been examined. The direct correlation link between the territory contamination density and Cs-137 content in foods was determined; additional radiation burden from foods through gastrointestinal tract was observed in case of the incorporated radiation of a human being. The values of dose radiation burden of the examined persons during their life at the RCT were estimated. The life at the RCT is linked with the morbidity,with growth of psychonoses, with the rearrangement of the immune system. 10 refs

  8. Enumerating molecules.

    Energy Technology Data Exchange (ETDEWEB)

    Visco, Donald Patrick, Jr. (, . Tennessee Technological University, Cookeville, TN); Faulon, Jean-Loup Michel; Roe, Diana C.

    2004-04-01

    This report is a comprehensive review of the field of molecular enumeration from early isomer counting theories to evolutionary algorithms that design molecules in silico. The core of the review is a detail account on how molecules are counted, enumerated, and sampled. The practical applications of molecular enumeration are also reviewed for chemical information, structure elucidation, molecular design, and combinatorial library design purposes. This review is to appear as a chapter in Reviews in Computational Chemistry volume 21 edited by Kenny B. Lipkowitz.

  9. Carbon Dioxide Activation by Scandium Atoms and Scandium Monoxide Molecules: Formation and Spectroscopic Characterization of ScCO3 and OCScCO3 in Solid Neon.

    Science.gov (United States)

    Zhang, Qingnan; Qu, Hui; Chen, Mohua; Zhou, Mingfei

    2016-01-28

    The reactions of carbon dioxide with scandium monoxide molecules and scandium atoms are investigated using matrix isolation infrared spectroscopy in solid neon. The species formed are identified by the effects of isotopic substitution on their infrared spectra as well as density functional calculations. The results show that the ground state ScO molecule reacts with carbon dioxide to form the carbonate complex ScCO3 spontaneously on annealing. The ground state Sc atom reacts with two carbon dioxide molecules to give the carbonate carbonyl complex OCScCO3 via the previously reported OScCO insertion intermediate on annealing. The observation of these spontaneous reactions is consistent with theoretical predictions that both the Sc + 2CO2 → OCScCO3 and ScO + CO2 → ScCO3 reactions are thermodynamically exothermic and are kinetically facile, requiring little or no activation energy.

  10. Carbon Dioxide Activation by Scandium Atoms and Scandium Monoxide Molecules: Formation and Spectroscopic Characterization of ScCO3 and OCScCO3 in Solid Neon.

    Science.gov (United States)

    Zhang, Qingnan; Qu, Hui; Chen, Mohua; Zhou, Mingfei

    2016-01-28

    The reactions of carbon dioxide with scandium monoxide molecules and scandium atoms are investigated using matrix isolation infrared spectroscopy in solid neon. The species formed are identified by the effects of isotopic substitution on their infrared spectra as well as density functional calculations. The results show that the ground state ScO molecule reacts with carbon dioxide to form the carbonate complex ScCO3 spontaneously on annealing. The ground state Sc atom reacts with two carbon dioxide molecules to give the carbonate carbonyl complex OCScCO3 via the previously reported OScCO insertion intermediate on annealing. The observation of these spontaneous reactions is consistent with theoretical predictions that both the Sc + 2CO2 → OCScCO3 and ScO + CO2 → ScCO3 reactions are thermodynamically exothermic and are kinetically facile, requiring little or no activation energy. PMID:26738558

  11. Activation of coherent lattice phonon following ultrafast molecular spin-state photo-switching: A molecule-to-lattice energy transfer

    Directory of Open Access Journals (Sweden)

    A. Marino

    2016-03-01

    Full Text Available We combine ultrafast optical spectroscopy with femtosecond X-ray absorption to study the photo-switching dynamics of the [Fe(PM-AzA2(NCS2] spin-crossover molecular solid. The light-induced excited spin-state trapping process switches the molecules from low spin to high spin (HS states on the sub-picosecond timescale. The change of the electronic state (<50 fs induces a structural reorganization of the molecule within 160 fs. This transformation is accompanied by coherent molecular vibrations in the HS potential and especially a rapidly damped Fe-ligand breathing mode. The time-resolved studies evidence a delayed activation of coherent optical phonons of the lattice surrounding the photoexcited molecules.

  12. Activation of type 1 cannabinoid receptor (CB1R promotes neurogenesis in murine subventricular zone cell cultures.

    Directory of Open Access Journals (Sweden)

    Sara Xapelli

    Full Text Available The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive, neurons and astrocytes. Stimulation of the CB1R by (R-(+-Methanandamide (R-m-AEA increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation, at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca(2+]i in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.

  13. Molecules in galaxies

    CERN Document Server

    Omont, Alain

    2007-01-01

    The main achievements, current developments and prospects of molecular studies in external galaxies are reviewed. They are put in the context of the results of several decades of studies of molecules in local interstellar medium, their chemistry and their importance for star formation. CO observations have revealed the gross structure of molecular gas in galaxies. Together with other molecules, they are among the best tracers of star formation at galactic scales. Our knowledge about molecular abundances in various local galactic environments is progressing. They trace physical conditions and metallicity, and they are closely related to dust processes and large aromatic molecules. Major recent developments include mega-masers, and molecules in Active Galactic Nuclei; millimetre emission of molecules at very high redshift; and infrared H2 emission as tracer of warm molecular gas, shocks and photodissociation regions. The advent of sensitive giant interferometers from the centimetre to sub-millimetre range, espe...

  14. Vadose zone microbial community structure and activity in metal/radionuclide contaminated sediments. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Balkwill, David L.

    2002-08-17

    This final technical report describes the research carried out during the final two months of the no-cost extension ending 11/14/01. The primary goals of the project were (1) to determine the potential for transformation of Cr(VI) (oxidized, mobile) to Cr(III) (reduced, immobile) under unsaturated conditions as a function of different levels and combinations of (a) chromium, (b) nitrate (co-disposed with Cr), and (c) molasses (inexpensive bioremediation substrate), and (2) to determine population structure and activity in experimental treatments by characterization of the microbial community by signature biomarker analysis and by RT-PCR and terminal restriction fragment length polymorphism (T-RFLP) and 16S ribosomal RNA genes. It was determined early in the one-year no-cost extension period that the T-RFLP approach was problematic in regard to providing information on the identities of microorganisms in the samples examined. As a result, it could not provide the detailed information on microbial community structure that was needed to assess the effects of treatments with chromium, nitrate, and/or molasses. Therefore, we decided to obtain the desired information by amplifying (using TR-PCR, with the same primers used for T-RFLP) and cloning 16S rRNA gene sequences from the same RNA extracts that were used for T-RFLP analysis. We also decided to use a restriction enzyme digest procedure (fingerprinting procedure) to place the clones into types. The primary focus of the research carried out during this report period was twofold: (a) to complete the sequencing of the clones, and (b) to analyze the clone sequences phylogenetically in order to determine the relatedness of the bacteria detected in the samples to each other and to previously described genera and species.

  15. Root Apex Transition Zone as Oscillatory Zone

    Directory of Open Access Journals (Sweden)

    Frantisek eBaluska

    2013-10-01

    Full Text Available Root apex of higher plants shows very high sensitivity to environmental stimuli. The root cap acts as the most prominent plant sensory organ; sensing diverse physical parameters such as gravity, light, humidity, oxygen and critical inorganic nutrients. However, the motoric responses to these stimuli are accomplished in the elongation region. This spatial discrepancy was solved when we have discovered and characterized the transition zone which is interpolated between the apical meristem and the subapical elongation zone. Cells of this zone are very active in the cytoskeletal rearrangements, endocytosis and endocytic vesicle recycling, as well as in electric activities. Here we discuss the oscillatory nature of the transition zone which, together with several other features of this zone, suggest that it acts as some kind of command centre. In accordance with the early proposal of Charles and Francis Darwins, cells of this root zone receive sensory information from the root cap and instruct the motoric responses of cells in the elongation zone.

  16. Pollution from organic contaminants in Greek marine areas, receiving anthropogenic pressures from intense activities in the coastal zone

    Science.gov (United States)

    Hatzianestis, Ioannis

    2014-05-01

    Polycyclic aromatic hydrocarbons (PAHs) are widespread pollutants in marine sediments, receiving the pressures from various anthropogenic activities in the coastal zone. Due to their mutagenic and carcinogenic behaviour, PAHs are classified as priority contaminants to be monitored in environmental quality control schemes. The purpose of this study was to determine the levels of PAHs in coastal areas of Greece directly influenced from the operation of major industrial units in the coastal zone, investigate their sources and evaluate their potential toxicity by comparison against effect - based sediment quality guidelines. Thirty two surface sediment samples were collected from three areas of the Hellenic coastline: a) Antikyra bay in Korinthiakos gulf, influenced from the operation of an alumina and aluminium production plant b) Larymna bay in Noth Evoikos gulf, influenced from the operation of a nickel production plant and c) Aliveri bay in South Evoikos Gulf, influenced from a cement production plant. In all the areas studied, aquaculture and fishing activities have been also developed in the coastal zone. PAH concentrations were determined by GC-MS, after soxhlet extraction and fractionation by silica column chromatography. PAH sources and origin were investigated by applying several isomeric ratio diagnostic criteria. The mean quotient Effect- Range Median (m-ERM) was used to evaluate the potential of adverse effects posed to benthic organisms. Three m-ERM-q values were used to differentiate the probability of observing toxicity and classify sites into four categories: sediments with m-ERMERM from 0.11 to 0.5 have a 21% probability of toxicity, those with m-ERM from 0.51 to 1.5 a 49% probability of toxicity, while sediments with m-ERM >1.5 have the highest probability (76%) of toxicity. Extremely high PAH concentrations more than 100,000 ng/g were found in the close vicinity of the alumina production plant in Antikyra bay. High levels of PAHs up to 22,000 ng

  17. Ventilation rates and activity levels of juvenile jumbo squid under metabolic suppression in the oxygen minimum zone.

    Science.gov (United States)

    Trübenbach, Katja; Pegado, Maria R; Seibel, Brad A; Rosa, Rui

    2013-02-01

    The Humboldt (jumbo) squid, Dosidicus gigas, is a part-time resident of the permanent oxygen minimum zone (OMZ) in the Eastern Tropical Pacific and, thereby, it encounters oxygen levels below its critical oxygen partial pressure. To better understand the ventilatory mechanisms that accompany the process of metabolic suppression in these top oceanic predators, we exposed juvenile D. gigas to the oxygen levels found in the OMZ (1% O(2), 1 kPa, 10 °C) and measured metabolic rate, activity cycling patterns, swimming mode, escape jet (burst) frequency, mantle contraction frequency and strength, stroke volume and oxygen extraction efficiency. In normoxia, metabolic rate varied between 14 and 29 μmol O(2) g(-1) wet mass h(-1), depending on the level of activity. The mantle contraction frequency and strength were linearly correlated and increased significantly with activity level. Additionally, an increase in stroke volume and ventilatory volume per minute was observed, followed by a mantle hyperinflation process during high activity periods. Squid metabolic rate dropped more than 75% during exposure to hypoxia. Maximum metabolic rate was not achieved under such conditions and the metabolic scope was significantly decreased. Hypoxia changed the relationship between mantle contraction strength and frequency from linear to polynomial with increasing activity, indicating that, under hypoxic conditions, the jumbo squid primarily increases the strength of mantle contraction and does not regulate its frequency. Under hypoxia, jumbo squid also showed a larger inflation period (reduced contraction frequency) and decreased relaxed mantle diameter (shortened diffusion pathway), which optimize oxygen extraction efficiency (up to 82%/34%, without/with consideration of 60% potential skin respiration). Additionally, they breathe 'deeply', with more powerful contractions and enhanced stroke volume. This deep-breathing behavior allows them to display a stable ventilatory volume per

  18. Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress.

    Science.gov (United States)

    Aggarwal, Monika; Sommers, Joshua A; Shoemaker, Robert H; Brosh, Robert M

    2011-01-25

    Modulation of DNA repair proteins by small molecules has attracted great interest. An in vitro helicase activity screen was used to identify molecules that modulate DNA unwinding by Werner syndrome helicase (WRN), mutated in the premature aging disorder Werner syndrome. A small molecule from the National Cancer Institute Diversity Set designated NSC 19630 [1-(propoxymethyl)-maleimide] was identified that inhibited WRN helicase activity but did not affect other DNA helicases [Bloom syndrome (BLM), Fanconi anemia group J (FANCJ), RECQ1, RecQ, UvrD, or DnaB). Exposure of human cells to NSC 19630 dramatically impaired growth and proliferation, induced apoptosis in a WRN-dependent manner, and resulted in elevated γ-H2AX and proliferating cell nuclear antigen (PCNA) foci. NSC 19630 exposure led to delayed S-phase progression, consistent with the accumulation of stalled replication forks, and to DNA damage in a WRN-dependent manner. Exposure to NSC 19630 sensitized cancer cells to the G-quadruplex-binding compound telomestatin or a poly(ADP ribose) polymerase (PARP) inhibitor. Sublethal dosage of NSC 19630 and the chemotherapy drug topotecan acted synergistically to inhibit cell proliferation and induce DNA damage. The use of this WRN helicase inhibitor molecule may provide insight into the importance of WRN-mediated pathway(s) important for DNA repair and the replicational stress response. PMID:21220316

  19. Domain movements of the enhancer-dependent sigma factor drive DNA delivery into the RNA polymerase active site: insights from single molecule studies.

    Science.gov (United States)

    Sharma, Amit; Leach, Robert N; Gell, Christopher; Zhang, Nan; Burrows, Patricia C; Shepherd, Dale A; Wigneshweraraj, Sivaramesh; Smith, David Alastair; Zhang, Xiaodong; Buck, Martin; Stockley, Peter G; Tuma, Roman

    2014-04-01

    Recognition of bacterial promoters is regulated by two distinct classes of sequence-specific sigma factors, σ(70) or σ(54), that differ both in their primary sequence and in the requirement of the latter for activation via enhancer-bound upstream activators. The σ(54) version controls gene expression in response to stress, often mediating pathogenicity. Its activator proteins are members of the AAA+ superfamily and use adenosine triphosphate (ATP) hydrolysis to remodel initially auto-inhibited holoenzyme promoter complexes. We have mapped this remodeling using single-molecule fluorescence spectroscopy. Initial remodeling is nucleotide-independent and driven by binding both ssDNA during promoter melting and activator. However, DNA loading into the RNA polymerase active site depends on co-operative ATP hydrolysis by the activator. Although the coupled promoter recognition and melting steps may be conserved between σ(70) and σ(54), the domain movements of the latter have evolved to require an activator ATPase.

  20. Introducing Bond-Line Organic Structures in High School Biology: An Activity that Incorporates Pleasant-Smelling Molecules

    Science.gov (United States)

    Rios, Andro C.; French, Gerald

    2011-01-01

    Chemical education occurs in settings other than just the chemistry classroom. High school biology courses are frequently where students are introduced to organic molecules and their importance to cellular chemistry. However, structural representations are often intimidating because students have not been introduced to the language. As part of a…

  1. Structure–activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1

    DEFF Research Database (Denmark)

    Bach, Anders; Stuhr-Hansen, Nicolai; Thorsen, Thor S.;

    2010-01-01

    Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with Ca-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure...

  2. Specificity and mechanism of action of alpha-helical membrane-active peptides interacting with model and biological membranes by single-molecule force spectroscopy.

    Science.gov (United States)

    Sun, Shiyu; Zhao, Guangxu; Huang, Yibing; Cai, Mingjun; Shan, Yuping; Wang, Hongda; Chen, Yuxin

    2016-01-01

    In this study, to systematically investigate the targeting specificity of membrane-active peptides on different types of cell membranes, we evaluated the effects of peptides on different large unilamellar vesicles mimicking prokaryotic, normal eukaryotic, and cancer cell membranes by single-molecule force spectroscopy and spectrum technology. We revealed that cationic membrane-active peptides can exclusively target negatively charged prokaryotic and cancer cell model membranes rather than normal eukaryotic cell model membranes. Using Acholeplasma laidlawii, 3T3-L1, and HeLa cells to represent prokaryotic cells, normal eukaryotic cells, and cancer cells in atomic force microscopy experiments, respectively, we further studied that the single-molecule targeting interaction between peptides and biological membranes. Antimicrobial and anticancer activities of peptides exhibited strong correlations with the interaction probability determined by single-molecule force spectroscopy, which illustrates strong correlations of peptide biological activities and peptide hydrophobicity and charge. Peptide specificity significantly depends on the lipid compositions of different cell membranes, which validates the de novo design of peptide therapeutics against bacteria and cancers. PMID:27363513

  3. Compound 13, an α1-selective small molecule activator of AMPK, inhibits Helicobacter pylori-induced oxidative stresses and gastric epithelial cell apoptosis

    International Nuclear Information System (INIS)

    Half of the world's population experiences Helicobacter pylori (H. pylori) infection, which is a main cause of gastritis, duodenal and gastric ulcer, and gastric cancers. In the current study, we investigated the potential role of compound 13 (C13), a novel α1-selective small molecule activator of AMP-activated protein kinase (AMPK), against H. pylori-induced cytotoxicity in cultured gastric epithelial cells (GECs). We found that C13 induced significant AMPK activation, evidenced by phosphorylation of AMPKα1 and ACC (acetyl-CoA carboxylase), in both primary and transformed GECs. Treatment of C13 inhibited H. pylori-induced GEC apoptosis. AMPK activation was required for C13-mediated GEC protection. Inhibition of AMPK kinase activity by the AMPK inhibitor Compound C, or silencing AMPKα1 expression by targeted-shRNAs, alleviated C13-induced GEC protective activities against H. pylori. Significantly, C13 inhibited H. pylori-induced reactive oxygen species (ROS) production in GECs. C13 induced AMPK-dependent expression of anti-oxidant gene heme oxygenase (HO-1) in GECs. Zinc protoporphyrin (ZnPP) and tin protoporphyrin (SnPP), two HO-1 inhibitors, not only suppressed C13-mediated ROS scavenging activity, but also alleviated its activity in GECs against H. pylori. Together, these results indicate that C13 inhibits H. pylori-induced ROS production and GEC apoptosis through activating AMPK–HO–1 signaling. - Highlights: • We synthesized compound 13 (C13), a α1-selective small molecule AMPK activator. • C13-induced AMPK activation requires α1 subunit in gastric epithelial cells (GECs). • C13 enhances Helicobacter pylori-induced pro-survival AMPK activation to inhibit GEC apoptosis. • C13 inhibits H. pylori-induced reactive oxygen species (ROS) production in GECs. • AMPK-heme oxygenase (HO-1) activation is required for C13-mediated anti-oxidant activity

  4. Compound 13, an α1-selective small molecule activator of AMPK, inhibits Helicobacter pylori-induced oxidative stresses and gastric epithelial cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hangyong; Zhu, Huanghuang; Lin, Zhou; Lin, Gang; Lv, Guoqiang, E-mail: lvguoqiangwuxivip@163.com

    2015-08-07

    Half of the world's population experiences Helicobacter pylori (H. pylori) infection, which is a main cause of gastritis, duodenal and gastric ulcer, and gastric cancers. In the current study, we investigated the potential role of compound 13 (C13), a novel α1-selective small molecule activator of AMP-activated protein kinase (AMPK), against H. pylori-induced cytotoxicity in cultured gastric epithelial cells (GECs). We found that C13 induced significant AMPK activation, evidenced by phosphorylation of AMPKα1 and ACC (acetyl-CoA carboxylase), in both primary and transformed GECs. Treatment of C13 inhibited H. pylori-induced GEC apoptosis. AMPK activation was required for C13-mediated GEC protection. Inhibition of AMPK kinase activity by the AMPK inhibitor Compound C, or silencing AMPKα1 expression by targeted-shRNAs, alleviated C13-induced GEC protective activities against H. pylori. Significantly, C13 inhibited H. pylori-induced reactive oxygen species (ROS) production in GECs. C13 induced AMPK-dependent expression of anti-oxidant gene heme oxygenase (HO-1) in GECs. Zinc protoporphyrin (ZnPP) and tin protoporphyrin (SnPP), two HO-1 inhibitors, not only suppressed C13-mediated ROS scavenging activity, but also alleviated its activity in GECs against H. pylori. Together, these results indicate that C13 inhibits H. pylori-induced ROS production and GEC apoptosis through activating AMPK–HO–1 signaling. - Highlights: • We synthesized compound 13 (C13), a α1-selective small molecule AMPK activator. • C13-induced AMPK activation requires α1 subunit in gastric epithelial cells (GECs). • C13 enhances Helicobacter pylori-induced pro-survival AMPK activation to inhibit GEC apoptosis. • C13 inhibits H. pylori-induced reactive oxygen species (ROS) production in GECs. • AMPK-heme oxygenase (HO-1) activation is required for C13-mediated anti-oxidant activity.

  5. To The Question Of Problems In The Legal Regulation Of The Lawful Activity In An Exclusive (Sea Economic Zone Of Ukraine

    Directory of Open Access Journals (Sweden)

    Tatyana V. Averochkina

    2014-06-01

    Full Text Available In the article current state of legislative instruments of lawful activity in the exclusive (sea economic zone of Ukraine is analyzed, gaps and possible ways of their overcoming are specified. An itemized analysis of the Law of Ukraine "About the exclusive (sea economic zone of Ukraine" is conducted, problems in some articles of the legal regulation are discussed, it is noted that they considerably complicate separate types of lawful activities in the considered area (freedom of the seas, construction, operation and use of artificial islands, installations and constructions, carrying out sea scientific researches. Carried-out analysis of current Ukrainian legislation on the exclusive economic zone showed that today there is a number of unresolved problems connected with the embodiment into the law-enforcement practice of the special Law norms, as a result, the United Nations Convention on the Law of the Sea of 1982 in Ukraine. The need of development and adoption of the number of subordinate normative legal acts in development of the Law of Ukraine "About the exclusive (sea economic zone of Ukraine" provisions is noted, namely: the procedure of freedoms of the sea in an economic zone, Order of artificial islands, installations and constructions construction, operation and use and the Order of sea scientific researches carrying out.

  6. Immunological network activation by low-dose rate irradiation. Analysis of cell populations and cell surface molecules in whole body irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Ina, Yasuhiro; Sakai, Kazuo [Central Research Inst. of Electric Power Industry, Low Dose Radiation Research Center, Komae, Tokyo (Japan)

    2003-07-01

    The effects of low-dose rate whole body irradiation on biodefense and immunological systems were investigated using female C57BL/6 (B6) mice. These B6 mice were exposed continuously to {gamma}-rays from a {sup 137}Cs source in the long-term low-dose rate irradiation facility at CRIEPI for 0 - 12 weeks at a dose rate of 0.95 mGy/hr. In the bone marrow, thymus, spleen, lymph nodes, and peripheral blood of the irradiated mice, changes in cell populations and cell surface molecules were examined. The cell surface functional molecules (CD3, CD4, CD8, CD19, CD45R/B220, ICAM-1, Fas, NK-1.1, CXCR4, and CCR5), and activation molecules (THAM, CD28, CD40, CD44H, CD70, B7-1, B7-2, OX-40 antigen, CTLA-4, CD30 ligand, and CD40 ligand) were analyzed by flow cytometry. The percentage of CD4{sup +} T cells and cell surface CD8 molecule expressions on the CD8{sup +} T cells increased significantly to 120-130% after 3 weeks of the irradiation, compared to non-irradiated control mice. On the other hand, the percentage of CD45R/B220{sup +} CD40{sup +} B cells, which is one of the immunological markers of inflammation, infection, tumor, and autoimmune disease, decreased significantly to 80-90% between the 3rd to 5th week of irradiation. There was no significant difference in other cell population rates and cell surface molecule expression. Furthermore, abnormal T cells bearing mutated T cell receptors induced by high-dose rate irradiation were not observed throughout this study. These results suggest that low-dose rate irradiation activates the immunological status of the whole body. (author)

  7. The contribution of phenolic acids to the anti-inflammatory activity of mushrooms: screening in phenolic extracts, individual parent molecules and synthesized glucuronated and methylated derivatives

    OpenAIRE

    Ayodele, Oludemi Taofiq; Calhelha, Ricardo C.; Heleno, Sandrina A.; Barros, Lillian; Martins, Anabela; Santos-Buelga, Celestino; Queiroz, Maria João R. P.; Isabel C. F. R. Ferreira

    2015-01-01

    In the present study, the ethanolic extracts of fourteen edible mushrooms were investigated for their anti-inflammatory potential in LPS (lipopolysaccharide) activated RAW 264.7 macrophages. Furthermore the extracts were chemically characterized in terms of phenolic acids and related compounds. The identified molecules (p-hydroxybenzoic, p-coumaric and cinnamic acids) and their glucuronated and methylated derivatives obtained by chemical synthesis were also evaluated for the same bioactivity,...

  8. Sorption Characteristics of Mixed Molecules of Glutaraldehyde from Water on Mesoporous Acid-Amine Modified Low-Cost Activated Carbon: Mechanism, Isotherm, and Kinetics

    OpenAIRE

    2015-01-01

    The environmental discharge of inefficiently treated waste solutions of the strong biocide glutaraldehyde (GA) from hospitals has potential toxic impact on aquatic organisms. The adsorption characteristics of mixed polarized monomeric and polymeric molecules of GA from water on mesoporous acid-amine modified low-cost activated carbon (AC) were investigated. It was found that the adsorption strongly depended on pH and surface chemistry. In acidic pH, the adsorption mechanism was elaborated to ...

  9. Crustal Structure Across the Okavango Rift Zone, Botswana: Initial Results From the PRIDE-SEISORZ Active-Source Seismic Profile

    Science.gov (United States)

    Canales, J. P.; Moffat, L.; Lizarralde, D.; Laletsang, K.; Harder, S. H.; Kaip, G.; Modisi, M.

    2015-12-01

    The PRIDE project aims to understand the processes of continental rift initiation and evolution by analyzing along-axis trends in the southern portion of the East Africa Rift System, from Botswana through Zambia and Malawi. The SEISORZ active-source seismic component of PRIDE focused on the Okavango Rift Zone (ORZ) in northwestern Botswana, with the main goal of imaging the crustal structure across the ORZ. This will allow us to estimate total crustal extension, determine the pattern and amount of thinning, assess the possible presence of melt within the rift zone, and assess the contrasts in crustal blocks across the rift, which closely follows the trend of a fold belt. In November 2014 we conducted a crustal-scale, 450-km-long seismic refraction/wide-angle reflection profile consisting of 19 sources (shots in 30-m-deep boreholes) spaced ~25 km apart from each other, and 900 receivers (IRIS/PASSCAL "Texan" dataloggers and 4.5Hz geophones) with ~500 m spacing. From NW to SE, the profile crosses several tectonic domains: the Congo craton, the Damara metamorphic belt and the Ghanzi-Chobe fold belt where the axis of the ORZ is located, and continues into the Kalahari craton. The record sections display clear crustal refraction (Pg) and wide-angle Moho reflection (PmP) phases for all 17 of the good-quality shots, and a mantle refraction arrival (Pn), with the Pg-PmP-Pn triplication appearing at 175 km offset. There are distinct changes in the traveltime and amplitude of these phases along the transect, and on either side of the axis, that seem to correlate with sharp transitions across tectonic terrains. Initial modeling suggests: (1) the presence of a sedimentary half-graben structure at the rift axis beneath the Okavango delta, bounded to the SE by the Kunyere-Thamalakane fault system; (2) faster crustal Vp in the domains to the NW of the ORZ; and (3) thicker crust (45-50 km) at both ends of the profile within the Congo and Kalahari craton domains than at the ORZ and

  10. Altered active zones, vesicle pools, nerve terminal conductivity, and morphology during experimental MuSK myasthenia gravis.

    Directory of Open Access Journals (Sweden)

    Vishwendra Patel

    Full Text Available Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK myasthenia gravis (MG. To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4% or complete (18% failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG.

  11. Response of the turbidity maximum zone in the Yangtze River Estuary due to human activities during the dry season.

    Science.gov (United States)

    Chen, Xiaofeng; Shen, Zhenyao; Yang, Ye

    2016-09-01

    The interaction between a river and the sea results in a turbidity maximum zone (TMZ) within the estuary, which has a great impact on the local ecosystem. In the Yangtze River Estuary, the magnitude and extent of the TMZ vary with water discharge. In this study, the cumulative human activity altered the water discharge regime from the river to the estuary. In the post-Three Gorges Dam (TGD) period, water discharge increased by 35.10 % at Datong in February compared with that in the pre-TGD period. The effects of water discharge variation on the characteristics of the TMZ were analyzed during spring and neap tidal periods using the three-dimensional environmental fluid dynamic code (EFDC) model. The area of the TMZ decreased by 3.11 and 17.39 % during neap and spring tides, respectively. In addition, the upper limit of the TMZ moved 11.68 km seaward during neap tide, whereas the upper limit of the TMZ in the upstream and downstream areas moved seaward 9.65 and 2.34 km, respectively, during spring tide. These findings suggest that the area and location of the TMZ are more sensitive to upstream runoff during spring tide than during neap tide. These changes in the TMZ will impact the biochemical processes in the Yangtze River Estuary. In the foreseeable future, the distribution characteristic of TMZ will inevitably change due to variations in the Yangtze River discharge resulting from new human activities (i.e., new dams), which are being constructed upstream in the Yangtze River system. PMID:27287491

  12. Activity-dependent endogenous taurine release facilitates excitatory neurotransmission in the neocortical marginal zone of neonatal rats

    Directory of Open Access Journals (Sweden)

    Taizhe eQian

    2014-02-01

    Full Text Available In the developing cerebral cortex, the marginal zone (MZ, consisting of early-generated neurons such as Cajal-Retzius cells, plays an important role in cell migration and lamination. There is accumulating evidence of widespread excitatory neurotransmission mediated by γ-aminobutyric acid (GABA in the MZ. Cajal-Retzius cells express not only GABAA receptors but also α2/β subunits of glycine receptors, and exhibit glycine receptor-mediated depolarization due to high [Cl−]i. However, the physiological roles of glycine receptors and their endogenous agonists during neurotransmission in the MZ are yet to be elucidated. To address this question, we performed optical imaging from the MZ using the voltage-sensitive dye JPW1114 on tangential neocortical slices of neonatal rats. A single electrical stimulus evoked an action-potential-dependent optical signal that spread radially over the MZ. The amplitude of the signal was not affected by glutamate receptor blockers, but was suppressed by either GABAA or glycine receptor antagonists. Combined application of both antagonists nearly abolished the signal. Inhibition of Na+, K+-2Cl− cotransporter by 20 µM bumetanide reduced the signal, indicating that this transporter contributes to excitation. Analysis of the interstitial fluid obtained by microdialysis from tangential neocortical slices with high-performance liquid chromatography revealed that GABA and taurine, but not glycine or glutamate, were released in the MZ in response to the electrical stimulation. The ambient release of taurine was reduced by the addition of a voltage-sensitive Na+ channel blocker. Immunohistochemistry and immunoelectron microscopy indicated that taurine was stored both in Cajal-Retzius and non-Cajal-Retzius cells in the MZ, but was not localized in presynaptic structures. Our results suggest that activity-dependent non-synaptic release of endogenous taurine facilitates excitatory neurotransmission through activation of

  13. Suppressive activity of a macrolide antibiotic, roxithromycin on co-stimulatory molecule expression on mouse splenocytes in vivo

    Directory of Open Access Journals (Sweden)

    K. Kawazu

    2000-01-01

    Full Text Available The influence of roxithromycin (RXM on the expression of co-stimulatory molecules, CD40, CD80 and CD86, was examined in vivo. When BALB/c mice were immunized intraperitoneally with two doses of dinitrophenylated ovalbumin (DNP-OVA at 1 week intervals, intraperitoneal administration of RXM at 250 μg/kg once a day for 14 days strongly suppressed IgE contents in sera obtained from mice 22 days after the first immunization. In addition, RXM treatment of mice suppressed endogenous IL–4 contents in aqueous spleen extracts, which were enhanced by DNP-OVA immunization. We next examined the influence of RXM on co-stimulatory molecule expression on splenic lymphocytes. RXM treatment of the immunized mice caused suppression of CD40 expression, but this treatment did not affect CD80 and CD86 expression.

  14. ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity.

    OpenAIRE

    Dubail, Johanne; Kesteloot, F.; Deroanne, Christophe; Motte, Patrick; Lambert, Vincent; Rakic, Jean-Marie; Lapiere, C.; Nusgens, Betty; Colige, Alain

    2010-01-01

    ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 st...

  15. Integrin Activation by Regulated Dimerization and Oligomerization of Platelet Endothelial Cell Adhesion Molecule (Pecam)-1 from within the Cell

    OpenAIRE

    Zhao, Tieming; Newman, Peter J.

    2001-01-01

    Platelet endothelial cell adhesion molecule (PECAM)-1 is a 130-kD transmembrane glycoprotein having six Ig homology domains within its extracellular domain and an immunoreceptor tyrosine–based inhibitory motif within its cytoplasmic domain. Previous studies have shown that addition of bivalent anti–PECAM-1 mAbs to the surface of T cells, natural killer cells, neutrophils, or platelets result in increased cell adhesion to immobilized integrin ligands. However, the mechanism by which this occur...

  16. Gab1 Acts as an Adapter Molecule Linking the Cytokine Receptor gp130 to ERK Mitogen-Activated Protein Kinase

    OpenAIRE

    Takahashi-Tezuka, Mariko; Yoshida, Yuichi; Fukada, Toshiyuki; Ohtani, Takuya; Yamanaka, Yojiro; Nishida, Keigo; NAKAJIMA, Koichi; Hibi, Masahiko; Hirano, Toshio

    1998-01-01

    Gab1 has structural similarities with Drosophila DOS (daughter of sevenless), which is a substrate of the protein tyrosine phosphatase Corkscrew. Both Gab1 and DOS have a pleckstrin homology domain and tyrosine residues, potential binding sites for various SH2 domain-containing adapter molecules when they are phosphorylated. We found that Gab1 was tyrosine phosphorylated in response to various cytokines, such as interleukin-6 (IL-6), IL-3, alpha interferon (IFN-α), and IFN-γ. Upon the stimula...

  17. Final Report - Montana State University - Microbial Activity and Precipitation at Solution-Solution Mixing Zones in Porous Media

    Energy Technology Data Exchange (ETDEWEB)

    Gerlach, Robin [Montana State University

    2014-10-31

    Background. The use of biological and chemical processes that degrade or immobilize contaminants in subsurface environments is a cornerstone of remediation technology. The enhancement of biological and chemical processes in situ, involves the transport, displacement, distribution and mixing of one or more reactive agents. Biological and chemical reactions all require diffusive transport of solutes to reaction sites at the molecular scale and accordingly, the success of processes at the meter-scale and larger is dictated by the success of phenomena that occur at the micron-scale. However, current understanding of scaling effects on the mixing and delivery of nutrients in biogeochemically dynamic porous media systems is limited, despite the limitations this imposes on the efficiency and effectiveness of the remediation challenges at hand. Objectives. We therefore proposed to experimentally characterize and computationally describe the growth, evolution, and distribution of microbial activity and mineral formation as well as changes in transport processes in porous media that receive two or more reactive amendments. The model system chosen for this project was based on a method for immobilizing 90Sr, which involves stimulating microbial urea hydrolysis with ensuing mineral precipitation (CaCO3), and co-precipitation of Sr. Studies at different laboratory scales were used to visualize and quantitatively describe the spatial relationships between amendment transport and consumption that stimulate the production of biomass and mineral phases that subsequently modify the permeability and heterogeneity of porous media. Biomass growth, activity, and mass deposition in mixing zones was investigated using two-dimensional micro-model flow cells as well as flow cells that could be analyzed using synchrotron-based x-ray tomography. Larger-scale flow-cell experiments were conducted where the spatial distribution of media properties, flow, segregation of biological activity and

  18. Activation of rape (Brassica napus L. embryo during seed germination. IV. Germinating embryo. The first zones of mitoses, starch and DNA synthesis and their expansion pattern

    Directory of Open Access Journals (Sweden)

    Mieczysław Kuraś

    2014-02-01

    Full Text Available The rape radicle is completely covered by the root cap. The successive lateral cell layers of the root cap are terminated by T-forming walls in the dermatogen layer in a statistically constant position. T-walls in dermatogen were utilized for delimitation of successive root sectors on longitudinal microtome sections at the succeeding germination stages. The length and the cell number of the corresponding sectors were studied and the starch and DNA synthesis sites as well as cell divisions localized. All these processes are initiated in a constant sequence and in specific embryo zones. The first symptom of activation of the embryo is starch synthesis. It begins in two centres: in the apical part of the radicle columella and in the hypoctyl dermalogen it moves deep into the cortex and in both directions along the columella the activation of starch synthesis shifts basipetally into the whole columella and the initial centre as well as the lateral parts of the root cap. From the hypocotyl dermatogen it moves into the cortex and in both directions along the embryo axis. In the root dermatogen and periblem the activation zone is first located in the basal sector and, then, gradually, in the lower ones. Just before germination the basal and apical zones of activation meet. Starch can then, be found throughout the root. During starch synthesis, in the basal part of the radicle. DNA synthesis and cell growth begin. In the root sectors which have already begun to grow and synthesize DNA, cell divisions start. The boundary of the dividing cells zone shifts acropetally at some distance above the lower boundary of DNA synthesis and the zone of cell premitotic growth. The acropetal shift of the mitotic activation zones can be described as wave expansion. Before the first mitotic wave reaches the promeristem it is followed by at least three acropetal waves, arising in the already activated basal sectors. and then the mitoses are asynchronised. Mitotic

  19. Influence of chloramine T iodination on the biological and immunological activity or the molecular radius of the human growth hormone molecule

    International Nuclear Information System (INIS)

    Potential alterations of the somatotropic activity of human growth hormone (hGH) resulting from Chloramine T labelling reaction, iodination up to 2.7 atoms/molecule and indirect radiation effects, have been studied. Three 2X2 factorial assays, performed in hypophysectomized rats, failed to reveal any significant difference (P greater than 0.05) in true growth promoting activity between hGH and (127-I)hGH, even after storing the latter with 125-I. Similar results were obtained applying a sensitive and precise gel filtration technique for Stokes Radius determination and radioimmunoassay

  20. Aplysia cell adhesion molecule and a novel protein kinase C activity in the postsynaptic neuron are required for presynaptic growth and initial formation of specific synapses

    OpenAIRE

    Hu, Jiang-Yuan; Chen, Yang; Bougie, Joanna K; Sossin, Wayne S.; Schacher, Samuel

    2010-01-01

    To explore the role of both Aplysia cell adhesion molecule (ApCAM) and activity of specific protein kinase C (PKC) isoforms in the initial formation of sensory neuron synapses with specific postsynaptic targets (L7 but not L11), we examined presynaptic growth, initial synapse formation, and the expression of the presynaptic neuropeptide sensorin following cell-specific reduction of ApCAM or of a novel PKC activity. Synapse formation between sensory neurons and L7 begins by 3 h after plating a...

  1. Single molecules and nanotechnology

    CERN Document Server

    Vogel, Horst

    2007-01-01

    This book focuses on recent advances in the rapidly evolving field of single molecule research. These advances are of importance for the investigation of biopolymers and cellular biochemical reactions, and are essential to the development of quantitative biology. Written by leading experts in the field, the articles cover a broad range of topics, including: quantum photonics of organic dyes and inorganic nanoparticles their use in detecting properties of single molecules the monitoring of single molecule (enzymatic) reactions single protein (un)folding in nanometer-sized confined volumes the dynamics of molecular interactions in biological cells The book is written for advanced students and scientists who wish to survey the concepts, techniques and results of single molecule research and assess them for their own scientific activities.

  2. Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule

    Science.gov (United States)

    Gaida, Matthias M.; Mayer, Christine; Dapunt, Ulrike; Stegmaier, Sabine; Schirmacher, Peter; Wabnitz, Guido H.; Hänsch, G. Maria

    2016-01-01

    T2R38 belongs to the family of bitter receptors and was initially detected in cells of the oral cavity. We now describe expression of T2R38 in tumor cells in patients with pancreatic cancer and in tumor-derived cell lines. T2R38 is localized predominantly intracellular in association with lipid droplets, particularly with the lipid droplet membrane. The receptor can be activated by the bona fide ligand for T2R38, phenylthiourea (PTU), and by N-acetyl-dodecanoyl homoserine (AHL-12), a quorum sensing molecule of Pseudomonas aeruginosa, the latter is the only known natural ligand for T2R38. In response to PTU or AHL-12, key transcription factors are activated including phosphorylation of the MAP kinases p38 and ERK1/2, and upregulation of NFATc1. Moreover, we found increased expression of the multi-drug resistance protein 1 (also known as ABCB1), a transmembrane transporter molecule, participating in shuttling of a plethora of drugs, such as chemotherapeutics or antibiotics. In conclusion, our data indicate a new, additional function of the taste receptor T2R38 beyond sensing ‘bitter’. Moreover, because T2R38 can be stimulated by a bacteria-derived signaling molecule the receptor could link microbiota and cancer. PMID:26862855

  3. Cardiotrophin-1 induces intercellular adhesion molecule-1 expression by nuclear factor κB activation in human umbilical vein endothelial cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background In addition to elevated concentrations of cytokines, patients with congestive heart failure (CHF) show endothelial dysfunction and increased plasma concentrations of adhesion molecules like intercellular adhesion molecule-1 (ICAM-1). Furthermore, the concentration of cardiotrophin-1 (CT-1) - a cytokine of the interleukin-6 superfamily - is increased in CHF. We tested the hypothesis whether CT-1 is able to induce ICAM-1 in human umbilical vein endothelial cells (HUVEC). Furthermore we examined the signalling mechanisms of CT-1 mediated ICAM-1 expression. Methods Confluent layers of HUVEC were incubated with increasing concentrations of CT-1 (5 to 100 ng/ml) for different periods. ICAM-1 mRNA was determined by real-time polymerase chain reaction (PCR) and ICAM-1 surface expression by fluorescence-activated cell sorter (FACS) analysis and soluble ICAM-1 (slCAM-1) in the culture supematant by enzyme linked immunosorbent assay (ELISA). To clarify the signalling pathway of CT-1 induced ICAM-1 expression we used various inhibitors of possible signal transducing molecules, electromobility shift assay (EMSA) and Western blot analysis. Results CT-1 induced ICAM-1 mRNA (1.8i-0.8 fold increase compared to unstimulated cells after 6 hours) and protein (1.4~-0.2 fold increase compared to unstimulated cells after 48 hours) in HUVEC in a time- and concentration-dependent manner. EMSA experiments show that CT-1 causes nuclear factor (NF) KB activation. Because parthenolide could inhibit CT-1 induced ICAM-1 expression NFKB activation is required in this pathway. CT-1 did not activate extraceUular signal regulated kinases (ERK), c-Jun N-terminal kinase (JNK) and p38. Conclusion CT-1 is able to induce ICAM-1 in endothelial cells by NFKB activation. These results may explain in part elevated ICAM-1 concentrations in patients with CHF and endothelial dysfunction.

  4. Water-soluble carbon monoxide-releasing molecules: helping to elucidate the vascular activity of the 'silent killer'.

    Science.gov (United States)

    Chatterjee, Prabal Kumar

    2004-06-01

    Carbon monoxide (CO) is formed during the degradation of haeme by haeme oxygenase (HO). As well as being an important signalling molecule and vasodilator, CO also possesses antihypertensive, anti-inflammatory and antiapoptotic qualities and protects against ischaemic tissue injury. Several approaches have been used to investigate the therapeutic potential of CO, ranging from direct administration of CO gas to the use of prodrugs, which generate CO upon metabolism. A novel approach involves the use of specific CO carriers, which will release measurable, controllable and effective amounts of CO into biological systems. Transitional metal carbonyls based around iron, manganese or ruthenium have recently been developed as CO-releasing molecules (CO-RMs) that, under appropriate conditions, will release CO. Such molecules have been shown to provide cardioprotection in both ex vivo and in vivo experiments. To date, CO-RMs have been largely incompatible with biological systems in that they are only soluble in organic solvents or have to be preactivated either by physical or chemical stimuli. However, the recent development of water-soluble CO-RMs has provided new opportunities to investigate the pharmacological and biological features of CO without such confounding influences. CORM-3, a novel water-soluble CO-RM, has recently been used to confirm the cardioprotective actions of CO. In this issue of British Journal of Pharmacology, Foresti and co-workers report that CORM-3 delivers CO, produces aortic vasodilation ex vivo and reduces blood pressure in vivo via modulation of the same cGMP and potassium channels utilised by endogenous and exogenous CO. These findings suggest that CORM-3 has the potential for use as a modulator of vascular function and hypertension. However, the use of water-soluble CO-RMs raises several questions of their own which will need to be addressed if CO-RMs are to be of future use therapeutically. PMID:15148242

  5. Neural progenitor cells isolated from the subventricular zone present hemichannel activity and form functional gap junctions with glial cells.

    Science.gov (United States)

    Talaverón, Rocío; Fernández, Paola; Escamilla, Rosalba; Pastor, Angel M; Matarredona, Esperanza R; Sáez, Juan C

    2015-01-01

    The postnatal subventricular zone (SVZ) lining the walls of the lateral ventricles contains neural progenitor cells (NPCs) that generate new olfactory bulb interneurons. Communication via gap junctions between cells in the SVZ is involved in NPC proliferation and in neuroblast migration towards the olfactory bulb. SVZ NPCs can be expanded in vitro in the form of neurospheres that can be used for transplantation purposes after brain injury. We have previously reported that neurosphere-derived NPCs form heterocellular gap junctions with host glial cells when they are implanted after mechanical injury. To analyze functionality of NPC-glial cell gap junctions we performed dye coupling experiments in co-cultures of SVZ NPCs with astrocytes or microglia. Neurosphere-derived cells expressed mRNA for at least the hemichannel/gap junction channel proteins connexin 26 (Cx26), Cx43, Cx45 and pannexin 1 (Panx1). Dye coupling experiments revealed that gap junctional communication occurred among neurosphere cells (incidence of coupling: 100%). Moreover, hemichannel activity was also detected in neurosphere cells as evaluated in time-lapse measurements of ethidium bromide uptake. Heterocellular coupling between NPCs and glial cells was evidenced in co-cultures of neurospheres with astrocytes (incidence of coupling: 91.0 ± 4.7%) or with microglia (incidence of coupling: 71.9 ± 6.7%). Dye coupling in neurospheres and in co-cultures was inhibited by octanol, a gap junction blocker. Altogether, these results suggest the existence of functional hemichannels and gap junction channels in postnatal SVZ neurospheres. In addition, they demonstrate that SVZ-derived NPCs can establish functional gap junctions with astrocytes or microglia. Therefore, cell-cell communication via gap junctions and hemichannels with host glial cells might subserve a role in the functional integration of NPCs after implantation in the damaged brain.

  6. Neural progenitor cells isolated from the subventricular zone present hemichannel activity and form functional gap junctions with glial cells

    Science.gov (United States)

    Talaverón, Rocío; Fernández, Paola; Escamilla, Rosalba; Pastor, Angel M.; Matarredona, Esperanza R.; Sáez, Juan C.

    2015-01-01

    The postnatal subventricular zone (SVZ) lining the walls of the lateral ventricles contains neural progenitor cells (NPCs) that generate new olfactory bulb interneurons. Communication via gap junctions between cells in the SVZ is involved in NPC proliferation and in neuroblast migration towards the olfactory bulb. SVZ NPCs can be expanded in vitro in the form of neurospheres that can be used for transplantation purposes after brain injury. We have previously reported that neurosphere-derived NPCs form heterocellular gap junctions with host glial cells when they are implanted after mechanical injury. To analyze functionality of NPC-glial cell gap junctions we performed dye coupling experiments in co-cultures of SVZ NPCs with astrocytes or microglia. Neurosphere-derived cells expressed mRNA for at least the hemichannel/gap junction channel proteins connexin 26 (Cx26), Cx43, Cx45 and pannexin 1 (Panx1). Dye coupling experiments revealed that gap junctional communication occurred among neurosphere cells (incidence of coupling: 100%). Moreover, hemichannel activity was also detected in neurosphere cells as evaluated in time-lapse measurements of ethidium bromide uptake. Heterocellular coupling between NPCs and glial cells was evidenced in co-cultures of neurospheres with astrocytes (incidence of coupling: 91.0 ± 4.7%) or with microglia (incidence of coupling: 71.9 ± 6.7%). Dye coupling in neurospheres and in co-cultures was inhibited by octanol, a gap junction blocker. Altogether, these results suggest the existence of functional hemichannels and gap junction channels in postnatal SVZ neurospheres. In addition, they demonstrate that SVZ-derived NPCs can establish functional gap junctions with astrocytes or microglia. Therefore, cell-cell communication via gap junctions and hemichannels with host glial cells might subserve a role in the functional integration of NPCs after implantation in the damaged brain. PMID:26528139

  7. Soluble Collectin-12 (CL-12) Is a Pattern Recognition Molecule Initiating Complement Activation via the Alternative Pathway

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Hein, Estrid; Munthe-Fog, Lea;

    2015-01-01

    and may recognize certain bacteria and fungi, leading to opsonophagocytosis. However, based on its structural and functional similarities with soluble collectins, we hypothesized the existence of a fluid-phase analog of CL-12 released from cells, which may function as a soluble pattern-recognition...... of the terminal complement complex. These results demonstrate the existence of CL-12 in a soluble form and indicate a novel mechanism by which the alternative pathway of complement may be triggered directly by a soluble pattern-recognition molecule....

  8. Age, tectonic evolution and origin of the Aswa Shear Zone in Uganda: Activation of an oblique ramp during convergence in the East African Orogen

    Science.gov (United States)

    Saalmann, K.; Mänttäri, I.; Nyakecho, C.; Isabirye, E.

    2016-05-01

    The Aswa Shear Zone (ASZ) is a major NW-SE trending structure of over 1000 km length in East Africa. In Uganda, the ASZ is a steeply NE-dipping, up to 11 km wide mylonitic shear zone that shows multiple stage brittle reactivation. On outcrop-scale, the fabric in the ASZ is characterized by a well-developed NW-SE striking and subvertical or steeply NE or SW dipping mylonitic foliation and a subhorizontal to moderately NW- or SE-plunging stretching lineation. Sinistral kinematics and fabric are very consistent along strike. The strain is heterogeneously distributed and partitioned into lens-shaped lower strain zones dominated by folding and characterized by pure shear, which are surrounded by high strain zones, some of them thick ultramylonites, with intense simple shear combined with flattening and strong transposition of pre-existing fabrics. Ductile shearing occurred during bulk E-W shortening, commenced at amphibolite facies conditions and continued with similar kinematics at greenschist and even lower grade conditions. A number of (sub-)parallel shear zones occur to the NE and SW of the main zone at a distance of up to 20-45 km. They show similar fabrics and kinematics and are thus related to activity along ASZ reflecting strain partitioning into simple shear and pure shear domains on a regional scale. Samples of mylonitic gneisses from the shear zone have been analyzed with U-Pb LA-MC-ICPMS and show Neoarchaean crystallisation ages between 2.66 and 2.61 Ga. Timing of ductile sinistral shearing is poorly constrained by lower intercept ages of 686 ± 62 and 640 ± 44 Ma. The fabric and structural relationship of the ca. 660 Ma Adjumani Granite exposed in the northern segment of ASZ suggest that the age of shear activity can be further limited to ca. 685 and 655 Ma. The Aswa Shear Zone is interpreted as an intra-cratonic, crustal-scale structure close to the northeastern margin of the Congo Craton, possibly inherited from previous continental extension. Early Aswa

  9. Upper plate deformation and seismic barrier in front of Nazca subduction zone: The Chololo Fault System and active tectonics along the Coastal Cordillera, southern Peru

    Science.gov (United States)

    Audin, Laurence; Lacan, Pierre; Tavera, Hernando; Bondoux, Francis

    2008-11-01

    The South America plate boundary is one of the most active subduction zone. The recent Mw = 8.4 Arequipa 2001 earthquake ruptured the subduction plane toward the south over 400 km and stopped abruptly on the Ilo Peninsula. In this exact region, the subduction seismic crisis induced the reactivation of continental fault systems in the coastal area. We studied the main reactivated fault system that trends perpendicular to the trench by detailed mapping of fault related-geomorphic features. Also, at a longer time scale, a recurrent Quaternary transtensive tectonic activity of the CFS is expressed by offset river gullies and alluvial fans. The presence of such extensional fault systems trending orthogonal to the trench along the Coastal Cordillera in southern Peru is interpreted to reflect a strong coupling between the two plates. In this particular case, stress transfer to the upper plate, at least along the coastal fringe, appears to have induced crustal seismic events that were initiated mainly during and after the 2001 earthquake. The seafloor roughness of the subducting plate is usually thought to be a cause of segmentation along subduction zones. However, after comparing and discussing the role of inherited structures within the upper plate to the subduction zone segmentation in southern Peru, we suggest that the continental structure itself may exert some feedback control on the segmentation of the subduction zone and thus participate to define the rupture pattern of major subduction earthquakes along the southern Peru continental margin.

  10. Assessing the previous activity at the source zone of the 2001 Bhuj earthquake based on the near-source and distant paleoseismological indicators

    Science.gov (United States)

    Rajendran, C. P.; Rajendran, Kusala; Thakkar, M.; Goyal, Bhanu

    2008-05-01

    The Mw 7.7 2001 Bhuj (Kachchh) earthquake was not associated with any primary surface rupture, but it produced secondary faulting, folding and liquefaction. This study highlights the potential of a secondary rupture and proxies like lateral spreads and sandblows in unraveling the past activity related to the 2001 source. Chronological constraints of an older lateral spread and far-field paleoliquefaction features, combined with archeological data, provide evidence for occurrences of two previous earthquakes at the 2001 source zone about 4000 and 9000 years, ago. Distinct stratigraphic evidence for at least one previous offset dated at 4424 ± 656 years could be detected at a stepover zone associated with a dextral secondary fault, reactivated during the 2001 earthquake. The studies imply longer interseismic intervals for the 2001 source zone, in comparison with the source zone of the 1819 earthquake located toward the northwestern part of the Rann of Kachchh. The spatial and temporal correlation of previous events derived on the basis of the available paleoseismic data from the region suggest not only repeated activity at the 2001 source, but possibility for additional potential sources in parts of Kachchh and Cambay basins. Although we infer a longer recurrence interval for the 2001 Bhuj earthquake source, our study points to the fact that these additional sources may have the potential to rupture in the future, considering the long elapsed time.

  11. Presence and patterns of alkaline phosphatase activity and phosphorus cycling in natural riparian zones under changing nutrient conditions

    Directory of Open Access Journals (Sweden)

    Peifang Wang

    2014-08-01

    Full Text Available Phosphorus (P is an important limiting nutrient in aquatic ecosystems and knowledge of P cycling is fundamental for reducing harmful algae blooms and other negative effects in water. Despite their importance, the characteristics of P cycling under changing nutrient conditions in shallow lakes were poorly investigated. In this study, in situ incubation experiments were conducted in a natural riparian zone in the main diversion channel used for water transfer into Lake Taihu (Wangyu River. Variations in microbial biomass, dissolved P fractions (organic and inorganic, and alkaline phosphatase activity (bulk APA and specific APA were determined after incubation with and without the addition of P and nitrogen (N (4 total water treatments: +P, +N, +NP, and control. Experiments were conducted during two seasons (late spring and early fall to account for natural differences in nutrient levels that may occur in situ. Our results demonstrated that low levels of DRP may not necessarily indicate P limitation. Phytoplankton exhibited “serial N limitation with P stress” in May, such that chlorophyll a (Chl a increased significantly with N addition, while the limiting nutrient shifted to P in October and phytoplankton biomass increased with P addition. Phytoplankton contributed greatly to APA production and was significantly influenced by P bioavailability, yet high levels of bulk APA were also not necessarily indicative of P limitation. In contrast to phytoplankton, bacteria were less P stressed. As a consequence of enhanced utilization of dissolved reactive P (DRP and dissolved organic P (DOP, +N treatment elevated APA significantly. By contrast, APA could be repressed to low values and phytoplankton converted a large portion of DRP to DOP with P addition. But this was not consistent with bacteria APA (bact-APA in the absence or presence of abundant phytoplankton biomass. The correlation between bulk APA and DRP was good at separate sites and discrepant

  12. Interaction between pregnancy zone protein and plasmin.

    Science.gov (United States)

    Poulsen, O M; Hau, J

    1988-01-01

    Pregnancy zone protein (PZP, alpha 2-PAG, SP3) was found to bind to plasmin in crossed affino-immunoelectrophoresis using sodium caseinate in the first dimension gel. The plasmin presence in the PZP-plasmin complex was confirmed by addition of antiserum against plasminogen to the gel. In crossed affino-immunoelectrophoresis using plasmin in the first dimension gel a non migrative PZP immunoreactive peak appeared, similar to the peak obtained with casein in the first dimension gel. Incubation of mixtures of PZP and plasmin also demonstrated complex formation between PZP and plasmin. The complex between PZP and plasmin could be precipitated not only by anti-PZP antibodies, but also by anti-plasminogen antibodies, confirming the interaction between the two molecules. The significance of the binding between plasmin and PZP remains to be elucidated, but it is tempting to speculate that PZP, present on the trophoblastic surface, immobilizes plasmin, rendering this molecule able to perform a local fibrinolytic activity.

  13. Crystal Structure of Liganded Rat Peroxisomal Multifunctional Enzyme Type 1: A FLEXIBLE MOLECULE WITH TWO INTERCONNECTED ACTIVE SITES*

    OpenAIRE

    Kasaragod, Prasad; Venkatesan, Rajaram; Kiema, Tiila R.; Hiltunen, J. Kalervo; Wierenga, Rik K.

    2010-01-01

    The crystal structure of the full-length rat peroxisomal multifunctional enzyme, type 1 (rpMFE1), has been determined at 2.8 Å resolution. This enzyme has three catalytic activities and two active sites. The N-terminal part has the crotonase fold, which builds the active site for the Δ3,Δ2-enoyl-CoA isomerase and the Δ2-enoyl-CoA hydratase-1 catalytic activities, and the C-terminal part has the (3S)-hydroxyacyl-CoA dehydrogenase fold and makes the (3S)-hydroxyacyl-CoA dehydrogenase active sit...

  14. Photochemical activation and reactivity of polynuclear transition-metal-complex molecules. Progress report, June 1981-May 31, 1982

    International Nuclear Information System (INIS)

    Significant results obtained during the year are summarized for the following programs: (1) reversible, two electron transfer at a single potential in binuclear complexes; (2) photophysics of polyketonate complexes; (3) synthetic strategies and characterization of heavy metal heterobinuclear complexes; (4) high yield synthesis of ligands capable of binding 3 and 4 metal ions per molecule. Electrochemical studies have uncovered a number of new binuclear metal complexes that undergo reversible two-electron reduction at single potential including Cu(II) complexes with two different coordination environments, mixed Ni(II), Cu(II) complexes and binuclear Ni(II) complexes. In each case the species that exhibit these electron transfer properties have been shown to be Na+ ion-paired complexes. Several new trinuclear molecular complexes have been prepared and characterized that contain two UO22+ ions and one transition metal ion. The electrochemistry, absorption spectra, and luminescence have been investigated

  15. Optimized geometry, vibration (IR and Raman spectra and nonlinear optical activity of p-nitroanilinium perchlorate molecule: A theoretical study

    Directory of Open Access Journals (Sweden)

    Tamer Ömer

    2016-03-01

    Full Text Available The molecular modeling of p-nitroanilinium perchlorate molecule was carried out by using B3LYP and HSEH1PBE levels of density functional theory (DFT. The IR and Raman spectra were simulated and the assignments of vibrational modes were performed on the basis of relative contribution of various internal co-ordinates. NBO analysis was performed to demonstrate charge transfer, conjugative interactions and the formation of intramolecular hydrogen bonding interactions within PNAPC. Obtained large dipole moment values showed that PNAPC is a highly polarizable complex, and the charge transfer occurs within PNAPC. Hydrogen bonding and charge transfer interactions were also displayed by small HOMO-LUMO gap and molecular electrostatic potential (MEP surface. The strong evidences that the material can be used as an efficient nonlinear optical (NLO material of PNAPC were demonstrated by considerable polarizability and hyperpolarizability values obtained at DFT levels.

  16. Identification of a novel Arabidopsis thaliana nitric oxide-binding molecule with guanylate cyclase activity in vitro

    KAUST Repository

    Mulaudzi, Takalani

    2011-09-01

    While there is evidence of nitric oxide (NO)-dependent signalling via the second messenger cyclic guanosine 3′,5′-monophosphate (cGMP) in plants, guanylate cyclases (GCs), enzymes that catalyse the formation of cGMP from guanosine 5′-triphosphate (GTP) have until recently remained elusive and none of the candidates identified to-date are NO-dependent. Using both a GC and heme-binding domain specific (H-NOX) search motif, we have identified an Arabidopsis flavin monooxygenase (At1g62580) and shown electrochemically that it binds NO, has a higher affinity for NO than for O 2 and that this molecule can generate cGMP from GTP in vitro in an NO-dependent manner. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  17. New design strategy for the two-photon active material based on push-pull substituted bisanthene molecule.

    Science.gov (United States)

    Chattopadhyaya, Mausumi; Alam, Md Mehboob; Chakrabarti, Swapan

    2011-03-31

    In the present work, we have critically examined the origin of strong two-photon transition probability of a donor-acceptor substituted bisanthene molecule that imitates a small piece of edge passivated (4, 4) graphene nanoribbon. In our calculations, we have considered -OMe, and -NH(2) as donors and -NO(2) as an acceptor. The one- and two-photon absorption parameters are evaluated using state-of-the-art linear and quadratic response theory, respectively, and all these calculations are carried out within the framework of time dependent density functional theory. To give a proper judgment on our findings, we have used the long-range corrected CAMB3LYP functional for all of the time dependent calculations. The present investigation reveals that the bisanthene molecule with three pairs of donor/acceptor moiety has a lower two-photon transition probability than that of a suitably designed bisanthene with only a single pair of donor/acceptor moiety. This in silico observation is consistent for all of the donor/acceptor moieties chosen in the present work. A comprehensive analysis at the two state model level of theory clearly offers us a verdict that by placing the donor/acceptor moiety in a suitable position of bisanthene, we can create a significant asymmetry in the electron density in the first excited state, which eventually leads to a significant difference in the ground and excited state dipole moment and is attributed to the higher two-photon transition probability of a particular bisanthene with a single pair of donor/acceptor moiety than bisanthene with three pairs of donor/acceptor.

  18. Jet-Cooled Laser Spectroscopy of a Jahn-Teller and Pseudo Jahn-Teller Active Molecule: the Nitrate Radical

    Science.gov (United States)

    Chen, Ming-Wei; Takematsu, Kana; Okumura, Mitchio; Miller, Terry A.

    2009-06-01

    Well-known as an important intermediate in atmospheric chemistry, the nitrate radical (NO_3) has been extensively studied both experimentally and theoretically. The three energetically lowest electronic states (tilde{X} ^{2}A_{2}^', tilde{A} ^{2}E^'', and tilde{B} ^{2}E^') are strongly coupled by vibronic interactions and hence it is a textbook molecule for understanding the coupling between nearby potential energy surfaces. Such coupling has been treated in considerable detail theoretically. However, corresponding experimental characterization of the interaction is much less detailed. The experimental results primarily consist of IR measurements of vibrational transitions in the ground state. In addition, the electronically forbidden tilde{A}-tilde{X} transition has been observed in ambient temperature CRDS studies. To understand both the Jahn-Teller and pseudo Jahn-Teller coupling in the molecule, further measurements are required with different selection rules and/or higher resolution to resolve the rotational structures of different transitions. In our group, a high-resolution (source Δν≈ 100 MHz in NIR region), jet-cooled CRDS system can be applied to rotationally resolve the electronically forbidden tilde{A}-tilde{X} transition. Furthermore, our high-resolution LIF/SEP system (source Δν≈ 100 MHz) can provide the direct, rotationally resolved measurements of the tilde{B}-tilde{X} and tilde{B}-tilde{A} transitions by operating in the LIF and SEP modes respectively. Such data can provide unambiguous spectral assignments in the tilde{X}, tilde{A} and tilde{B} states. J. F. Stanton, J. Chem. Phys., 126, 134309 (2007) K. Kawaguchi, E. Hirota, T. Ishiwata, and I. Tanaka, J. Chem. Phys., 93, 951 (1990) K. Kawaguchi, T. Ishiwata, E. Hirota, and I. Tanaka, Chem. Phys., 231, 193 (1998) A. Deev, J. Sommar, and M. Okumura, J. Chem. Phys., 122, 224305 (2005) S. Wu, P. Dupré, and T. A. Miller, Phys. Chem. Chem. Phys., 8, 1682, (2006)

  19. The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis.

    Science.gov (United States)

    Zhong, Ming-Chao; Veillette, André

    2013-11-01

    Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types.

  20. SLITHER: a web server for generating contiguous conformations of substrate molecules entering into deep active sites of proteins or migrating through channels in membrane transporters.

    Science.gov (United States)

    Lee, Po-Hsien; Kuo, Kuei-Ling; Chu, Pei-Ying; Liu, Eric M; Lin, Jung-Hsin

    2009-07-01

    Many proteins use a long channel to guide the substrate or ligand molecules into the well-defined active sites for catalytic reactions or for switching molecular states. In addition, substrates of membrane transporters can migrate to another side of cellular compartment by means of certain selective mechanisms. SLITHER (http://bioinfo.mc.ntu.edu.tw/slither/or http://slither.rcas.sinica.edu.tw/) is a web server that can generate contiguous conformations of a molecule along a curved tunnel inside a protein, and the binding free energy profile along the predicted channel pathway. SLITHER adopts an iterative docking scheme, which combines with a puddle-skimming procedure, i.e. repeatedly elevating the potential energies of the identified global minima, thereby determines the contiguous binding modes of substrates inside the protein. In contrast to some programs that are widely used to determine the geometric dimensions in the ion channels, SLITHER can be applied to predict whether a substrate molecule can crawl through an inner channel or a half-channel of proteins across surmountable energy barriers. Besides, SLITHER also provides the list of the pore-facing residues, which can be directly compared with many genetic diseases. Finally, the adjacent binding poses determined by SLITHER can also be used for fragment-based drug design.

  1. Upper plate deformation and seismic barrier in front of Nazca subduction zone : the Chololo Fault System and active tectonics along the Coastal Cordillera, southern Peru

    OpenAIRE

    Audin, Laurence; Lacan, P.; Tavera, H.; Bondoux, Francis

    2008-01-01

    The South America plate boundary is one of the most active subduction zone. The recent Mw=8.4 Arequipa 2001 earthquake ruptured the subduction plane toward the south over 400 km and stopped abruptly on the Ilo Peninsula. In this exact region, the subduction seismic crisis induced the reactivation of continental fault systems in the coastal area. We studied the main reactivated fault system that trends perpendicular to the trench by detailed mapping of fault related-geomorphic features. Also, ...

  2. A benzimidazole derivative small molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle

    DEFF Research Database (Denmark)

    Bultot, Laurent; Jensen, Thomas Elbenhardt; Lai, Yu-Chiang;

    2016-01-01

    AMP-activated protein kinase (AMPK) plays diverse roles and coordinates complex metabolic pathways for maintenance of energy homeostasis. This could be explained by the fact that AMPK exists as multiple heterotrimer complexes comprising a catalytic α subunit (α1, α2) and regulatory β (β1, β2) and...... treatments. The study demonstrates a utility of dual activator approach to achieve a greater activation of AMPK and downstream physiological responses in various cell types including skeletal muscle....

  3. Identification of EPAC (Exchange Protein Activated by cAMP) bioinformatically as a potential signalling biomarker in Cardiovascular Disease (CVD) and its molecular docking by a lead molecule.

    Science.gov (United States)

    Bala, Saranya; Pathak, Ravi Kant; Mishra, Vachaspati

    2011-01-01

    The present work delineates the combinatorial approach of firstly, creation of a centralized data-set comprising signalling proteins identified on the basis of altered expression, such as over-expression or repression of a set of signalling protein(s) leading to the cause of the disease, which is based on published reports screened through Pubmed and secondly, in the in silico creation of novel lead (drug) molecules and docking of identified signalling biomarkers using such drugs to investigate possibility of their future application in the model systems eventually. EPAC (Exchange Protein Activated by cAMP) emerges as a signalling biomarker in cases studied presently. Brefeldin, the known inhibitor of EPAC, though the mechanism yet unexplored, has been the molecule used as the pharmacophore for creation of lead drug molecule. Various modifications have been incorporated into the pharmacophore to increase the hydrophobic interactions for increasing the binding efficiency of the generated lead molecule. Side-chain modifications of the pharmacophore and refinement of data through firedock upon docking of EPAC with the modified pharmacophore yielded best results on the bases of atomic contact energy, van der Waal and partial electrostatic interactions as well as additional estimations of the binding free energy. Modifications of CH3 at C15 with COOH and H at C2 with OH in brefeldin showed the best docking results on the basis of protein-drug interaction parameters. The present work provides a clue in rational design of EPAC inhibitors which could be developed as drug lead in combating CVD. PMID:21738308

  4. Quantitative Structure-Activity Relationships of Noncompetitive Antagonists of the NMDA Receptor: A Study of a Series of MK801 Derivative Molecules Using Statistical Methods and Neural Network

    Directory of Open Access Journals (Sweden)

    T. Lakhlifi

    2003-04-01

    Full Text Available Abstract: From a series of 50 MK801 derivative molecules, a selected set of 44 compounds was submitted to a principal components analysis (PCA, a multiple regression analysis (MRA, and a neural network (NN. This study shows that the compounds' activity correlates reasonably well with the selected descriptors encoding the chemical structures. The correlation coefficients calculated by MRA and there after by NN, r = 0.986 and r = 0.974 respectively, are fairly good to evaluate a quantitative model, and to predict activity for MK801 derivatives. To test the performance of this model, the activities of the remained set of 6 compounds are deduced from the proposed quantitative model, by NN. This study proved that the predictive power of this model is relevant.

  5. Role of an expansin-like molecule in Dictyostelium morphogenesis and regulation of its gene expression by the signal transducer and activator of transcription protein Dd-STATa.

    Science.gov (United States)

    Ogasawara, Shun; Shimada, Nao; Kawata, Takefumi

    2009-02-01

    Expansins are proteins involved in plant morphogenesis, exerting their effects on cellulose to extend cell walls. Dictyostelium is an organism that possesses expansin-like molecules, but their functions are not known. In this study, we analyzed the expL7 (expansin-like 7) gene, which has been identified as a putative target of Dd-STATa, a Dictyostelium homolog of the metazoan signal transducer and activator of transcription (STAT) proteins. Promoter fragments of the expL7 were fused to a lacZ reporter and the expression patterns determined. As expected from the behavior of the endogenous expL7 gene, the expL7/lacZ fusion gene was downregulated in Dd-STATa null slugs. In the parental strain, the expL7 promoter was activated in the anterior tip region. Mutational analysis of the promoter identified a sequence that was necessary for expression in tip cells. In addition, an activator sequence for pstAB cells was identified. These sequences act in combination with the repressor region to prevent ectopic expL7 expression in the prespore and prestalk regions of the slug and culminant. Although the expL7 null mutant showed no phenotypic change, the expL7 overexpressor showed aberrant stalk formation. These results indicate that the expansin-like molecule is important for morphogenesis in Dictyostelium.

  6. Technical advance: soluble OX40 molecule mimics regulatory T cell modulatory activity on FcεRI-dependent mast cell degranulation.

    Science.gov (United States)

    Sibilano, Riccardo; Gri, Giorgia; Frossi, Barbara; Tripodo, Claudio; Suzuki, Ryo; Rivera, Juan; MacDonald, Andrew S; Pucillo, Carlo E

    2011-10-01

    Tregs play a central role in modulating FcεRI-dependent MC effector functions in the course of the allergic response. Cellular interaction depends on the constitutive expression of OX40 on Tregs and the OX40L counterpart on MCs. Study of OX40L signaling on MCs is hampered by the need of a highly purified molecule, which triggers OX40L specifically. We now report that sOX40 mimics the physiological activity of Treg interaction by binding to activated MCs. When treated with sOX40, activated MCs showed decreased degranulation and Ca(++) influx, whereas PLC-γ2 phosphorylation remained unaffected. Once injected into experimental animals, sOX40 not only located within the endothelium but also in parenchyma, where it could be found in close proximity and apparently bound to MCs. This soluble molecule triggers MC-OX40L without the requirement of Tregs, thus allowing study of OX40L signaling pathways in MCs and in other OX40L-expressing cell populations. Importantly, as sOX40 inhibits MC degranulation, it may provide an in vivo therapeutic tool in allergic disease. PMID:21653238

  7. Analysis of the pharmaceutical care activities practiced by private homeopathic pharmacies located in Rio de Janeiro North Zone

    Directory of Open Access Journals (Sweden)

    Tereza Aguiar

    2011-09-01

    Full Text Available The complexity of homeopathic treatment delegates to the Pharmacist the need and the responsibility of pharmaceutical care. This paper had the objective of verifying the practices of pharmaceutical care in homeopathy. The study was conducted in homeopathic pharmacies situated in Rio de Janeiro North Zone, during March and April, 2011, where 15 pharmacists were interviewed, with the help of a semi-open questionary self-administered. For the survey were investigated variables related to pharmaceutical: sex, age, nature of the institution where he graduated, having completed post-graduate and working ties. Information professionals for the pharmaceutical care were collected in 14 questions grouped into three areas: attitudes, perceptions and satisfaction. Attending the ethical aspects, the study was submitted to and approved by the Ethics Committee of University Estácio de Sá. The results demonstrated that 33% of the pharmacists have less than 5 years of professional practice, and 53% are specialists graduated by the Hahnemann’s Institutite of Brasil. All Pharmacists claim to orient patients, mostly during dispensation and through phone contacts. Most pharmacists oriented patients passively and actively. The elderly were pointed as the ones, who most often sought orientation. During dispensation of homeopathic drugs, all patients elicit some orientation. 67% of the pharmacies keep material for pharmaceutical guidance to the patients, usually leaflets. The verbal and written orientation was predominanted on homeopathic pharmacist. Posology and instructions of use for the pharmaceutical form dispensed were described as the most common doubts of the patients. Of all pharmacists interviewed, 67% pointed to self-medication practices in the pharmacy. The questions which measure the position and perception of the pharmacists related to pharmaceutical assistance scored over 3. The question which scored higher was related to

  8. [Autoradiographic investigations on postnatal proliferative activity of the telencephalic and diencephalic matrix-zones in the axolotl (Ambystoma mexicanum), with special references to the olfactory organ (author's transl)].

    Science.gov (United States)

    Richter, W; Kranz, D

    1981-01-01

    The localization and proliferative activity of the matrix-zones has been investigated in the telencephalon and in the diencephalon of 21 axolotls (Ambystoma mexicanum) by means of autoradiographs, after injection of tritiated thymidine at different stages of the postnatal life. There are no previous detailed autoradiographical reports on postnatal brain development in the axolotl. Matrix-zones (i.e. ventricular and subventricular zone) exist in the dorsal part and in the ventral part of the telencephalon, we have found these also in the diencephalon in the wall of the preoptic recessus and ventrally of the habenula. The quantitative part of this study indicates high values of the labeling-index in the early postnatal stages. Then, the labeling-index decreases, but also in 3 years old specimens labeled cells were observed in the matrix-zones of the telencephalon; therefore a few of proliferative capacity remains in the central nervous system of adult axolotls. Labeled cells were also found in the olfactory organ of early postnatal and adult axolotls; these are neuroblasts which have relevance for the regeneration of the forebrain.

  9. Small molecule antagonism of oxysterol-induced Epstein-Barr virus induced gene 2 (EBI2) activation

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Madsen, Christian M; Arfelt, Kristine N;

    2013-01-01

    682753A, which blocks oxysterol-induced G-protein activation, β-arrestin recruitment and B-cell chemotaxis. We furthermore demonstrate that activation triggers pertussis toxin-sensitive MAP kinase phosphorylation, which is also inhibited by GSK682753A. Thus, EBI2 signalling in B cells mediates key...

  10. : Seizure onset zone imaging

    OpenAIRE

    David, Olivier; Blauwblomme, Thomas; Job, Anne-Sophie; Chabardès, Stéphan; Hoffmann, Dominique,; Minotti, Lorella; Kahane, Philippe

    2011-01-01

    International audience Stereo-electroencephalography is used to localize the seizure onset zone and connected neuronal networks in surgical candidates suffering from intractable focal epilepsy. The concept of an epileptogenicity index has been proposed recently to represent the likelihood of various regions being part of the seizure onset zone. It quantifies low-voltage fast activity, the electrophysiological signature of seizure onset usually assessed visually by neurologists. Here, we re...

  11. Hadron Molecules

    CERN Document Server

    Gutsche, Thomas; Faessler, Amand; Lee, Ian Woo; Lyubovitskij, Valery E

    2010-01-01

    We discuss a possible interpretation of the open charm mesons $D_{s0}^*(2317)$, $D_{s1}(2460)$ and the hidden charm mesons X(3872), Y(3940) and Y(4140) as hadron molecules. Using a phenomenological Lagrangian approach we review the strong and radiative decays of the $D_{s0}^* (2317)$ and $D_{s1}(2460)$ states. The X(3872) is assumed to consist dominantly of molecular hadronic components with an additional small admixture of a charmonium configuration. Determing the radiative ($\\gamma J/\\psi$ and $\\gamma \\psi(2s)$) and strong ($J/\\psi 2\\pi $ and $ J/\\psi 3\\pi$) decay modes we show that present experimental observation is consistent with the molecular structure assumption of the X(3872). Finally we give evidence for molecular interpretations of the Y(3940) and Y(4140) related to the observed strong decay modes $J/\\psi + \\omega$ or $J/\\psi + \\phi$, respectively.

  12. Information flow during gene activation by signaling molecules: ethylene transduction in Arabidopsis cells as a study system

    Directory of Open Access Journals (Sweden)

    Díaz José

    2009-05-01

    Full Text Available Abstract Background We study root cells from the model plant Arabidopsis thaliana and the communication channel conformed by the ethylene signal transduction pathway. A basic equation taken from our previous work relates the probability of expression of the gene ERF1 to the concentration of ethylene. Results The above equation is used to compute the Shannon entropy (H or degree of uncertainty that the genetic machinery has during the decoding of the message encoded by the ethylene specific receptors embedded in the endoplasmic reticulum membrane and transmitted into the nucleus by the ethylene signaling pathway. We show that the amount of information associated with the expression of the master gene ERF1 (Ethylene Response Factor 1 can be computed. Then we examine the system response to sinusoidal input signals with varying frequencies to determine if the cell can distinguish between different regimes of information flow from the environment. Our results demonstrate that the amount of information managed by the root cell can be correlated with the frequency of the input signal. Conclusion The ethylene signaling pathway cuts off very low and very high frequencies, allowing a window of frequency response in which the nucleus reads the incoming message as a sinusoidal input. Out of this window the nucleus reads the input message as an approximately non-varying one. From this frequency response analysis we estimate: a the gain of the system during the synthesis of the protein ERF1 (~-5.6 dB; b the rate of information transfer (0.003 bits during the transport of each new ERF1 molecule into the nucleus and c the time of synthesis of each new ERF1 molecule (~21.3 s. Finally, we demonstrate that in the case of the system of a single master gene (ERF1 and a single slave gene (HLS1, the total Shannon entropy is completely determined by the uncertainty associated with the expression of the master gene. A second proposition shows that the Shannon entropy

  13. Atoms, molecules & elements

    CERN Document Server

    Graybill, George

    2007-01-01

    Young scientists will be thrilled to explore the invisible world of atoms, molecules and elements. Our resource provides ready-to-use information and activities for remedial students using simplified language and vocabulary. Students will label each part of the atom, learn what compounds are, and explore the patterns in the periodic table of elements to find calcium (Ca), chlorine (Cl), and helium (He) through hands-on activities.

  14. Activation of transcription factor AP-2 mediates UVA radiation- and singlet oxygen-induced expression of the human intercellular adhesion molecule 1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Grether-Beck, S.; Olaizola-Horn, S.; Schmitt, H.; Grewe, M. [Clinical and Experimental Photodermatology, Duesseldorf (Germany)] [and others

    1996-12-10

    UVA radiation is the major component of the UV solar spectrum that reaches the earth, and the therapeutic application of UVA radiation is increasing in medicine. Analysis of the cellular effects of UVA radiation has revealed that exposure of human cells to UVA radiation at physiological doses leads to increased gene expression and that this UVA response is primarily mediated through the generation of singlet oxygen. In this study, the mechanisms by which UVA radiation induces transcriptional activation of the human intercellular adhesion molecule 1 (ICAM-1) were examined. UVA radiation was capable of inducing activation of the human ICAM-1 promoter and increasing OCAM-1 mRNA and protein expression. These UVA radiation effects were inhibited by singlet oxygen quenchers, augmented by enhancement of singlet oxygen life-time, and mimicked in unirradiated cells by a singlet oxygen-generating system. UVA radiation as well as singlet oxygen-induced ICAM-1 promoter activation required activation of the transcription factor AP-2. Accordingly, both stimuli activated AP-2, and deletion of the putative AP-2-binding site abrogated ICAM-1 promoter activation in this system. This study identified the AP-2 site as the UVA radiation- and singlet oxygen-responsive element of the human ICAM-1 gene. The capacity of UVA radiation and/or singlet oxygen to induce human gene expression through activation of AP-2 indicates a previously unrecognized role of this transcription factor in the mammalian stress response. 38 refs., 3 figs., 3 tabs.

  15. Proteolysis of neuronal cell adhesion molecule by the tissue plasminogen activator-plasmin system after kainate injection in the mouse hippocampus.

    Science.gov (United States)

    Endo, A; Nagai, N; Urano, T; Takada, Y; Hashimoto, K; Takada, A

    1999-01-01

    Tissue plasminogen activator (tPA) is a serine protease that converts inactive plasminogen to the active protease plasmin and mediates extracellular metabolism. tPA is transcriptionally induced in the mouse hippocampus by pharmacological or electrical stimulation of neuronal activity and mediates excitotoxin-induced neuronal degeneration. Therefore, we hypothesized that tPA would be induced in the hippocampus after kainic acid (KA) injection into the lateral cerebral ventricle (LCV) and that the activated tPA-plasmin system would degrade the neuronal cell adhesion molecule (NCAM), which is a component of the extracellular matrix. In order to investigate this possibility, we first examined whether NCAM is a substrate for the tPA plasmin system by incubating mouse brain homogenates with tPA and plasminogen at 37 degrees C. Next, we examined the degradation of NCAM and the changes of tPA activity in the mouse hippocampus with immunohistochemical procedures and histological zymography after KA injection into both LCVs. As a result, we observed neuronal atrophy and a decrease of NCAM immunoreactivity along with an increase of tPA activity in the CA3 area of the hippocampus. These results suggest that activation of the tPA plasmin system after KA injection into the LCVs results in the degradation of NCAM in the CA3 area.

  16. Hybrid Molecules Containing a 7-Chloro-4-aminoquinoline Nucleus and a Substituted 2-Pyrazoline with Antiproliferative and Antifungal Activity.

    Science.gov (United States)

    Montoya, Alba; Quiroga, Jairo; Abonia, Rodrigo; Derita, Marcos; Sortino, Maximiliano; Ornelas, Alfredo; Zacchino, Susana; Insuasty, Braulio

    2016-01-01

    Twenty-four new hybrid analogues (15-38) containing 7-chloro-4-aminoquinoline and 2-pyrazoline N-heterocyclic fragments were synthesized. Twelve of the new compounds were evaluated against 58 human cancer cell lines by the U.S. National Cancer Institute (NCI). Compounds 25, 30, 31, 36, and 37 showed significant cytostatic activity, with the most outstanding GI50 values ranging from 0.05 to 0.95 µM. The hybrid compounds (15-38) were also evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. From the obtained results some structure-activity relationships were outlined. PMID:27472314

  17. Computational investigation and synthesis of a sol-gel imprinted material for sensing application of some biologically active molecules

    Energy Technology Data Exchange (ETDEWEB)

    Atta, Nada F., E-mail: Nada_fah1@yahoo.com [Department of Chemistry, Faculty of Science, University of Cairo, Post Code 12613, Giza (Egypt); Hamed, Maher M.; Abdel-Mageed, Ali M. [Department of Chemistry, Faculty of Science, University of Cairo, Post Code 12613, Giza (Egypt)

    2010-05-14

    A hybrid sol-gel material was molecularly imprinted with a group of neurotransmitters. Imprinted material is a sol-gel thin film that is spin coated on the surface of a glassy carbon electrode. Imprinted films were characterized electrochemically using cyclic voltammetry (CV) and the encapsulated molecules were extracted from the films and complementary molecular cavities are formed that enable their rebind. The films were tested in their corresponding template solutions for rebinding using square wave voltammetry (SWV). Computational approach for exploring the primary intermolecular forces between templates and hydrolyzed form of the precursor monomer, tetraethylorthosilicate (TEOS), were carried out using Hartree-Fock method (HF). Interaction energy values were computed for each adduct formed between a monomer and a template. Analysis of the optimized conformations of various adducts could explain the mode of interaction between the templates and the monomer units. We found that interaction via the amino group is the common mode among the studied compounds and the results are in good agreement with the electrochemical measurements.

  18. Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor.

    Science.gov (United States)

    Garg, Tarun; Bhandari, Saurav; Rath, Goutam; Goyal, Amit K

    2015-12-01

    Brain tumor is one of the most challenging diseases to treat. The major obstacle in the specific drug delivery to brain is blood-brain barrier (BBB). Mostly available anti-cancer drugs are large hydrophobic molecules which have limited permeability via BBB. Therefore, it is clear that the protective barriers confining the passage of the foreign particles into the brain are the main impediment for the brain drug delivery. Hence, the major challenge in drug development and delivery for the neurological diseases is to design non-invasive nanocarrier systems that can assist controlled and targeted drug delivery to the specific regions of the brain. In this review article, our major focus to treat brain tumor by study numerous strategies includes intracerebral implants, BBB disruption, intraventricular infusion, convection-enhanced delivery, intra-arterial drug delivery, intrathecal drug delivery, injection, catheters, pumps, microdialysis, RNA interference, antisense therapy, gene therapy, monoclonal/cationic antibodies conjugate, endogenous transporters, lipophilic analogues, prodrugs, efflux transporters, direct conjugation of antitumor drugs, direct targeting of liposomes, nanoparticles, solid-lipid nanoparticles, polymeric micelles, dendrimers and albumin-based drug carriers.

  19. Structural and Functional Characterization of a Single-chain Peptide-MHC Molecule that Modulates both Naive and Activated CD8plus T Cells

    Energy Technology Data Exchange (ETDEWEB)

    D Samanta; G Mukherjee; U Ramagopal; R Chaparro; S Nathenson; T DiLorenzo; S Almo

    2011-12-31

    Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8{sup +} T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8{sup +} T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK{sup d}.IGRP) by using the class I MHC molecule H-2K{sup d} and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP{sub 206-214}), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK{sup d}.IGRP tetramers bound specifically to cognate CD8{sup +} T cells. Tetramer binding induced death of naive T cells and in vitro- and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-{gamma} response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8{sup +} T cells makes them a potential intervention strategy in early and late stages of disease.

  20. A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth.

    Science.gov (United States)

    Yang, Tao; Massa, Stephen M; Tran, Kevin C; Simmons, Danielle A; Rajadas, Jayakumar; Zeng, Anne Y; Jang, Taichang; Carsanaro, Sara; Longo, Frank M

    2016-11-01

    Neurotrophin (NT) receptors are coupled to numerous signaling networks that play critical roles in neuronal survival and plasticity. Several non-peptide small molecule ligands have recently been reported that bind to and activate specific tropomyosin-receptor kinase (Trk) NT receptors, stimulate their downstream signaling, and cause biologic effects similar to, though not completely overlapping, those of the native NT ligands. Here, in silico screening, coupled with low-throughput neuronal survival screening, identified a compound, LM22B-10, that, unlike prior small molecule Trk ligands, binds to and activates TrkB as well as TrkC. LM22B-10 increased cell survival and strongly accelerated neurite outgrowth, superseding the effects of brain-derived neurotrophic factor (BDNF), NT-3 or the two combined. Additionally, unlike the NTs, LM22B-10 supported substantial early neurite outgrowth in the presence of inhibiting glycoproteins. Examination of the mechanisms of these actions suggested contributions of the activation of both Trks and differential interactions with p75(NTR), as well as a requirement for involvement of the Trk extracellular domain. In aged mice, LM22B-10 activated hippocampal and striatal TrkB and TrkC, and their downstream signaling, and increased hippocampal dendritic spine density. Thus, LM22B-10 may constitute a new tool for the study of TrkB and TrkC signaling and their interactions with p75(NTR), and provides groundwork for the development of ligands that stimulate unique combinations of Trk receptors and activity patterns for application to selected neuronal populations and deficits present in various disease states. PMID:27334657

  1. Circulating intercellular adhesion molecule-1 (ICAM-1) as an early and sensitive marker for virus-induced T cell activation

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Johansen, J; Marker, O;

    1995-01-01

    The effect of systemic virus infection on the level of circulating ICAM-1 (cICAM-1) in serum, and the role of virus-activated T cells in this context, were studied using the murine lymphocytic choriomeningitis virus infection as primary model system. A marked virus-induced elevation in cICAM-1...... in serum was revealed, the presence of which coincided with the phase of virus-induced T cell activation. However, high levels of cICAM-1 in serum were observed well before maximal T cell activation could be demonstrated. No increase in cICAM-1 was observed in the serum of infected T cell-deficient nude...... induce shedding of ICAM-1 into the circulation, and this parameter may be used as an early and sensitive marker for immune activation....

  2. Cleavage of human high molecular weight kininogen markedly enhances its coagulant activity. Evidence that this molecule exists as a procofactor.

    OpenAIRE

    Scott, C F; Silver, L D; Schapira, M; Colman, R W

    1984-01-01

    High molecular weight kininogen (HMW)-kininogen, the cofactor of contact-activated blood coagulation, accelerates the activation of Factor XII, prekallikrein, and Factor XI on a negatively charged surface. Although prekallikrein and Factor XI circulate as a complex with HMW-kininogen, no physical association has been demonstrated between Factor XII and HMW-kininogen, nor has the order of adsorption to surfaces of these proteins been fully clarified. In this report we explore the requirements ...

  3. Redox active molecules cytochrome c and vitamin C enhance heme-enzyme peroxidations by serving as non-specific agents for redox relay

    International Nuclear Information System (INIS)

    Highlights: ► At low concentrations, cytochrome c/vitamin C do not catalyze peroxidations. ► But low levels of cytochrome c/vitamin C enhance diverse heme peroxidase activities. ► Enhancement positively correlates to the concentration of peroxide in reaction. ► Reducible additives serve as non-specific agents for redox relay in the system. ► Insight into electron transfer processes in routine and oxidative-stress states. -- Abstract: We report that incorporation of very low concentrations of redox protein cytochrome c and redox active small molecule vitamin C impacted the outcome of one-electron oxidations mediated by structurally distinct plant/fungal heme peroxidases. Evidence suggests that cytochrome c and vitamin C function as a redox relay for diffusible reduced oxygen species in the reaction system, without invoking specific or affinity-based molecular interactions for electron transfers. The findings provide novel perspectives to understanding – (1) the promiscuous role of cytochrome b5 in the metabolism mediated by liver microsomal xenobiotic metabolizing systems and (2) the roles of antioxidant molecules in affording relief from oxidative stress.

  4. The Role of Sulfhydryl Reactivity of Small Molecules for the Activation of the KEAP1/NRF2 Pathway and the Heat Shock Response

    Directory of Open Access Journals (Sweden)

    Albena T. Dinkova-Kostova

    2012-01-01

    Full Text Available The KEAP1/NRF2 pathway and the heat shock response are two essential cytoprotective mechanisms that allow adaptation and survival under conditions of oxidative, electrophilic, and thermal stress by regulating the expression of elaborate networks of genes with versatile protective functions. The two pathways are independently regulated by the transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2 and heat shock factor 1 (HSF1, respectively. The activity of these transcriptional master regulators increases during conditions of stress and also upon encounter of small molecules (inducers, both naturally occurring as well as synthetically produced. Inducers have a common chemical property: the ability to react with sulfhydryl groups. The protein targets of such sulfhydryl-reactive compounds are equipped with highly reactive cysteine residues, which serve as sensors for inducers. The initial cysteine-sensed signal is further relayed to affect the expression of large networks of genes, which in turn can ultimately influence complex cell fate decisions such as life and death. The paper summarizes the multiple lines of experimental evidence demonstrating that the reactivity with sulfhydryl groups is a major determinant of the mechanism of action of small molecule dual activators of the KEAP1/NRF2 pathway and the heat shock response.

  5. Notch1 Signaling Modulates Neuronal Progenitor Activity in the Subventricular Zone in Response to Aging and Focal Ischemia

    OpenAIRE

    Sun, Fen; Mao, XiaoOu; Xie, Lin; Ding, Meiping; Shao, Bei; Jin, Kunlin

    2013-01-01

    Neurogenesis diminishes with aging and ischemia-induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that Notch1 signaling regulates neurogenesis in subventricular zone (SVZ) of young-adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat br...

  6. Magnetomineralogical changes along the Kohistan-Karakoram collision zone in North Pakistan: implications for variable thermochemical activities

    OpenAIRE

    ZAMAN, HAIDER; BAMOUSA, ABDULLAH O

    2015-01-01

    To identify remanence-carrying magnetic minerals and document their thermochemical behavior, detailed rock magnetic investigations were conducted on Cretaceous-Tertiary rocks collected from northwestern and northeastern Kohistan, northern Pakistan. Rock magnetic results from each area are clearly differentiated on the basis of site location. Detrital hematite is identified as a main magnetic carrier in red beds of northwestern Kohistan located at some distance from the Northern Suture Zone wi...

  7. Teaching with the Case Study Method to Promote Active Learning in a Small Molecule Crystallography Course for Chemistry Students

    Science.gov (United States)

    Campbell, Michael G.; Powers, Tamara M.; Zheng, Shao-Liang

    2016-01-01

    Implementing the case study method in a practical X-ray crystallography course designed for graduate or upper-level undergraduate chemistry students is described. Compared with a traditional lecture format, assigning small groups of students to examine literature case studies encourages more active engagement with the course material and…

  8. Optimized circuit design for flexible 8-bit RFID transponders with active layer of ink-jet printed small molecule semiconductors

    NARCIS (Netherlands)

    Kjellander, B.K.C.; Smaal, W.T.T.; Myny, K.; Genoe, J.; Dehaene, W.; Heremans, P.; Gelinck, G.H.

    2013-01-01

    We ink-jet print a blend of 6,13-bis(triisopropyl-silylethynyl)pentacene and polystyrene as the active layer for flexible circuits. The discrete ink-jet printed transistors exhibit a saturation mobility of 0.5 cm2 V -1 s-1. The relative spread in transistor characteristics can be very large. This sp

  9. Selective killing of gastric cancer cells by a small molecule targeting ROS-mediated ER stress activation.

    Science.gov (United States)

    Zou, Peng; Xia, Yiqun; Chen, Tongke; Zhang, Junru; Wang, Zhe; Chen, Wenbo; Chen, Minxiao; Kanchana, Karvannan; Yang, Shulin; Liang, Guang

    2016-06-01

    Gastric cancer is one of the leading causes of cancer mortality in the world. Curcumin is a natural product with multiple pharmacological activities, while its clinical application has been limited by the poor chemical stability. We have previously designed a series of curcumin derivatives with high stability and anticancer potentials. The present study aims to identify the anti-cancer effects and mechanisms of WZ26, an analog of curcumin, in gastric cancer cells. In vitro, WZ26 showed higher chemical stability and much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, the novel compound WZ26 induced ROS production, resulting in the activation of JNK-mitochondrial and ER stress apoptotic pathways. Blockage of ROS production totally reversed WZ26-induced JNK activation, Bcl-2/Bax decrease, ER stress activation, and final cell apoptosis in SGC-7901 cells. WZ26 also exhibited potent anti-tumor effects in human gastric cancer cell xenograft models. WZ26 could be considered as a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In addition, this study also demonstrated that ROS production could be act as a vital candidate pathway for inducing tumor cell apoptosis by targeting mitochondrial and ER stress-related death pathway. © 2015 Wiley Periodicals, Inc. PMID:26086416

  10. Magnetically separable nanocomposites with photocatalytic activity under visible light for the selective transformation of biomass-derived platform molecules

    Science.gov (United States)

    Novel magnetically separable TiO2-guanidine-(Ni,Co)Fe2O4 nanomaterials were prepared and characterised by a series of techniques including XRD, SEM, TEM, N2 physisorption as well as XPS and subsequently tested for their photocatalytic activities in the selective transformation of...

  11. Implementation of a high-throughput screen for identifying small molecules to activate the Keap1-Nrf2-ARE pathway.

    Directory of Open Access Journals (Sweden)

    Kai Connie Wu

    Full Text Available Nuclear factor erythroid 2-related factor 2 (Nrf2 is a transcription factor that induces a battery of cytoprotective genes involved in antioxidant defense through binding to Antioxidant Response Elements (ARE located in the promoter regions of these genes. To identify Nrf2 activators for the treatment of oxidative/electrophilic stress-induced diseases, the present study developed a high-throughput assay to evaluate Nrf2 activation using AREc32 cells that contain a luciferase gene under the control of ARE promoters. Of the 47,000 compounds screened, 238 (top 0.5% hits of the chemicals increased the luminescent signal more than 14.4-fold and were re-tested at eleven concentrations in a range of 0.01-30 µM. Of these 238 compounds, 231 (96% increased the luminescence signal in a concentration-dependent manner. Chemical structure relationship analysis of these 231 compounds indicated enrichment of four chemical scaffolds (diaryl amides and diaryl ureas, oxazoles and thiazoles, pyranones and thiapyranones, and pyridinones and pyridazinones. In addition, 30 of these 231 compounds were highly effective and/or potent in activating Nrf2, with a greater than 80-fold increase in luminescence, or an EC50 lower than 1.6 µM. These top 30 compounds were also screened in Hepa1c1c7 cells for an increase in Nqo1 mRNA, the prototypical Nrf2-target gene. Of these 30 compounds, 17 increased Nqo1 mRNA in a concentration-dependent manner. In conclusion, the present study documents the development, implementation, and validation of a high-throughput screen to identify activators of the Keap1-Nrf2-ARE pathway. Results from this screening identified Nrf2 activators, and provide novel insights into chemical scaffolds that might prevent oxidative/electrophilic stress-induced toxicity and carcinogenesis.

  12. Scorpionate-type coordination in MFU-4l metal-organic frameworks: small-molecule binding and activation upon the thermally activated formation of open metal sites.

    Science.gov (United States)

    Denysenko, Dmytro; Grzywa, Maciej; Jelic, Jelena; Reuter, Karsten; Volkmer, Dirk

    2014-06-01

    Postsynthetic metal and ligand exchange is a versatile approach towards functionalized MFU-4l frameworks. Upon thermal treatment of MFU-4l formates, coordinatively strongly unsaturated metal centers, such as zinc(II) hydride or copper(I) species, are generated selectively. Cu(I)-MFU-4l prepared in this way was stable under ambient conditions and showed fully reversible chemisorption of small molecules, such as O2, N2, and H2, with corresponding isosteric heats of adsorption of 53, 42, and 32 kJ mol(-1), respectively, as determined by gas-sorption measurements and confirmed by DFT calculations. Moreover, Cu(I)-MFU-4l formed stable complexes with C2H4 and CO. These complexes were characterized by FTIR spectroscopy. The demonstrated hydride transfer to electrophiles and strong binding of small gas molecules suggests these novel, yet robust, metal-organic frameworks with open metal sites as promising catalytic materials comprising earth-abundant metal elements.

  13. Molecule modification and antioxidant activity of EGC%EGC分子修饰及其抗氧化活性

    Institute of Scientific and Technical Information of China (English)

    刘金鹏; 蔡烈伟; 杜琪珍

    2012-01-01

    亲水性的表没食子儿茶素(ECC)是绿茶茶多酚的组成成分之一,采用氧杂Pictet-Spengler反应,通过嫁接酮类物质对表没食子儿茶素(EGC)进行了分子修饰,并对反应产物进行了抗氧化活性的研究。反应产物为脂溶性成分,且保持了较高的抗氧化活性。%Water-soluble EGC is one of the composition of green tea polyphenols. In this paper, Oxa- Pictet-Spengler reaction is use to modify EGC by grafting ketones, and studying the antioxidant activity of products. Products is liposoluble components, retaining fine antioxidant activity.

  14. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

    Science.gov (United States)

    Winter, Jon J G; Anderson, Malcolm; Blades, Kevin; Brassington, Claire; Breeze, Alexander L; Chresta, Christine; Embrey, Kevin; Fairley, Gary; Faulder, Paul; Finlay, M Raymond V; Kettle, Jason G; Nowak, Thorsten; Overman, Ross; Patel, S Joe; Perkins, Paula; Spadola, Loredana; Tart, Jonathan; Tucker, Julie A; Wrigley, Gail

    2015-03-12

    Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.

  15. Vasorelaxant activity of extracts obtained from Apium graveolens:Possible source for vasorelaxant molecules isolation with potential antihypertensive effect

    Institute of Scientific and Technical Information of China (English)

    Vergara-Galicia Jorge; Jimenez-Ramirez Luis ngel; Tun-Suarez Adrin; Aguirre-Crespo Francisco; Salazar-Gmez Anuar; Estrada-Soto Samuel; Sierra-Ovando ngel; Hernandez-Nuez Emmanuel

    2013-01-01

    Objective:To investigate the vasorelaxant effect of organic extracts from Apium graveolens (A. graveolens) which is a part of a group of plants subjected to pharmacological and phytochemical study with the purpose of offering it as an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects. Methods:An ex vivo method was employed to assess the vasorelaxant activity. This consisted of using rat aortic rings with and without endothelium precontracted with norepinephrine. Results:All extracts caused concentration-dependent relaxation in precontracted aortic rings with and without endothelium;the most active extracts were Dichloromethane and Ethyl Acetate extracts from A. graveolens. These results suggested that secondary metabolites responsible for the vasorelaxant activity belong to a group of compounds of medium polarity. Also, our evidence showed that effect induced by dichloromethane and ethyl acetate extracts from A. graveolens is mediated probably by calcium antagonism. Conclusions: A. graveolens represents an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects.

  16. Mesopelagic prokaryotic bulk and single-cell heterotrophic activity and community composition in the NW Africa-Canary Islands coastal-transition zone

    Science.gov (United States)

    Gasol, Josep M.; Alonso-Sáez, Laura; Vaqué, Dolors; Baltar, Federico; Calleja, Maria Ll.; Duarte, Carlos M.; Arístegui, Javier

    2009-12-01

    Mesopelagic prokaryotic communities have often been assumed to be relatively inactive in comparison to those from epipelagic waters, and therefore unresponsive to the presence of nearby upwelled waters. We have studied the zonal (shelf-ocean), latitudinal, and depth (epipelagic-mesopelagic) variability of microbial assemblages in the NW Africa-Canary Islands coastal-transition zone (CTZ). Vertical profiles of bacterial bulk and single-cell activity through the epi- and mesopelagic waters were combined with point measurements of bacterial respiration, leucine-to-carbon conversion factors and leucine-to-thymidine incorporation ratios. The overall picture that emerges from our study is that prokaryotes in the mesopelagic zone of this area are less abundant than in the epipelagic but have comparable levels of activity. The relationship between prokaryotes and heterotrophic nanoflagellates, their main predators, remains constant throughout the water column, further contradicting the assumption that deep ocean bacterial communities are mostly inactive. Both bulk and single-cell activity showed clear differences between stations, with higher mesopelagic activities closer to the shelf or affected by upwelling features. We also tested whether differences in microbial function between stations could be related to differences in bacterial community structure, and conclude that bacterial communities are very similar at similar depths in the deep ocean, even if the stations present order-of-magnitude differences in bacterial function.

  17. Enzymatic activities and arbuscular mycorrhizal colonization of Plantago lanceolata and Plantago major in a soil root zone under heavy metal stress.

    Science.gov (United States)

    Gucwa-Przepióra, Ewa; Nadgórska-Socha, Aleksandra; Fojcik, Barbara; Chmura, Damian

    2016-03-01

    The objectives of the present field study were to examine the soil enzyme activities in the soil root zones of Plantago lanceolata and Plantago major in different heavy metal contaminated stands. Moreover, the investigations concerned the intensity of root endophytic colonization and metal bioaccumulation in roots and shoots. The investigated Plantago species exhibited an excluder strategy, accumulating higher metal content in the roots than in the shoots. The heavy metal accumulation levels found in the two plantain species in this study were comparable to other plants suggested as phytostabilizers; therefore, the selected Plantago species may be applied in the phytostabilization of heavy metal contaminated areas. The lower level of soil enzymes (dehydrogenase, urease, acid, and alkaline phosphatase) as well as the higher bioavailability of metals in the root zone soil of the two plantain species were found in an area affected by smelting activity, where organic matter content in the soil was also the smallest. Mycorrhizal colonization on both species in the contaminated area was similar to colonization in non-contaminated stands. However, the lowest arbuscule occurrence and an absence of dark septate endophytes were found in the area affected by the smelting activity. It corresponded with the lowest plant cover observed in this stand. The assessment of enzyme activity, mycorrhizal colonization, and the chemical and physical properties of soils proved to be sensitive to differences between sites and between Plantago species. PMID:26531716

  18. Enzymatic activities and arbuscular mycorrhizal colonization of Plantago lanceolata and Plantago major in a soil root zone under heavy metal stress.

    Science.gov (United States)

    Gucwa-Przepióra, Ewa; Nadgórska-Socha, Aleksandra; Fojcik, Barbara; Chmura, Damian

    2016-03-01

    The objectives of the present field study were to examine the soil enzyme activities in the soil root zones of Plantago lanceolata and Plantago major in different heavy metal contaminated stands. Moreover, the investigations concerned the intensity of root endophytic colonization and metal bioaccumulation in roots and shoots. The investigated Plantago species exhibited an excluder strategy, accumulating higher metal content in the roots than in the shoots. The heavy metal accumulation levels found in the two plantain species in this study were comparable to other plants suggested as phytostabilizers; therefore, the selected Plantago species may be applied in the phytostabilization of heavy metal contaminated areas. The lower level of soil enzymes (dehydrogenase, urease, acid, and alkaline phosphatase) as well as the higher bioavailability of metals in the root zone soil of the two plantain species were found in an area affected by smelting activity, where organic matter content in the soil was also the smallest. Mycorrhizal colonization on both species in the contaminated area was similar to colonization in non-contaminated stands. However, the lowest arbuscule occurrence and an absence of dark septate endophytes were found in the area affected by the smelting activity. It corresponded with the lowest plant cover observed in this stand. The assessment of enzyme activity, mycorrhizal colonization, and the chemical and physical properties of soils proved to be sensitive to differences between sites and between Plantago species.

  19. The Novel Small Molecule Inhibitor, OSU-T315, Suppresses Vestibular Schwannoma and Meningioma Growth by Inhibiting PDK2 Function in the AKT Pathway Activation

    Science.gov (United States)

    Mercado-Pimentel, ME; Igarashi, S; Dunn, AM; Behbahani, M; Miller, C; Read, CM; Jacob, A

    2016-01-01

    Activation of PKB/AKT signaling, which requires PDK1 and PDK2 function, drives Vestibular Schwannoma (VS) and meningioma growth. PDK2 function is defined as a molecule that phosphorylates AKT-Ser473. Integrin-Linked Kinase (ILK) functions as PDK2 in PKB/AKT activation in many cancers; therefore, we hypothesized that OSU-T315, a small molecule ILK inhibitor, will inhibit the ILK-PDK2 function in PKB/AKT signaling activation in VS and meningioma cell growth. OSU-T315 decreased cell viability at IC50 < 2μM in VS (HEI193) and meningioma (Ben-Men-1) cell lines, in primary cells at < 3.5μM, while in normal primary Schwann cells at 7.1μM. OSU-T315 inhibits AKT signaling by decreasing phosphorylation at AKT-Ser473, AKT-Thr308, ILK-Ser246 and ILK-Thr173. In addition, OSU-T315 affected the phosphorylation or expression levels of AKT downstream proliferation effectors as well as autophagy markers. Flow cytometry shows that OSU-T315 increased the percentage of cells arrested at G2/M for both, HEI193 (39.99%) and Ben-Men-1 (26.96%) cells, compared to controls (21.54%, 8.47%). Two hours of OSU-T315 treatment increased cell death in both cell lines (34.3%, 9.1%) versus untreated (12.1%, 8.1%). Though longer exposure increased cell death in Ben-Men-1, TUNEL assays showed that OSU-T315 does not induce apoptosis. OSU-T315 was primarily cytotoxic for HEI193 and Ben-Men-1 inducing a dysregulated autophagy. Our studies suggest that OSU-T315 has translational potential as a chemotherapeutic agent against VS and meningioma.

  20. Towards single molecule switches.

    Science.gov (United States)

    Zhang, Jia Lin; Zhong, Jian Qiang; Lin, Jia Dan; Hu, Wen Ping; Wu, Kai; Xu, Guo Qin; Wee, Andrew T S; Chen, Wei

    2015-05-21

    The concept of using single molecules as key building blocks for logic gates, diodes and transistors to perform basic functions of digital electronic devices at the molecular scale has been explored over the past decades. However, in addition to mimicking the basic functions of current silicon devices, molecules often possess unique properties that have no parallel in conventional materials and promise new hybrid devices with novel functions that cannot be achieved with equivalent solid-state devices. The most appealing example is the molecular switch. Over the past decade, molecular switches on surfaces have been intensely investigated. A variety of external stimuli such as light, electric field, temperature, tunneling electrons and even chemical stimulus have been used to activate these molecular switches between bistable or even multiple states by manipulating molecular conformations, dipole orientations, spin states, charge states and even chemical bond formation. The switching event can occur either on surfaces or in break junctions. The aim of this review is to highlight recent advances in molecular switches triggered by various external stimuli, as investigated by low-temperature scanning tunneling microscopy (LT-STM) and the break junction technique. We begin by presenting the molecular switches triggered by various external stimuli that do not provide single molecule selectivity, referred to as non-selective switching. Special focus is then given to selective single molecule switching realized using the LT-STM tip on surfaces. Single molecule switches operated by different mechanisms are reviewed and discussed. Finally, molecular switches embedded in self-assembled monolayers (SAMs) and single molecule junctions are addressed. PMID:25757483

  1. The adjuvant activity of alphavirus replicons is enhanced by incorporating the microbial molecule flagellin into the replicon.

    Directory of Open Access Journals (Sweden)

    Maria L Knudsen

    Full Text Available Ligands of pattern recognition receptors (PRRs including Toll-like receptors (TLRs stimulate innate and adaptive immune responses and are considered as potent adjuvants. Combinations of ligands might act in synergy to induce stronger and broader immune responses compared to stand-alone ligands. Alphaviruses stimulate endosomal TLRs 3, 7 and 8 as well as the cytoplasmic PRR MDA-5, resulting in induction of a strong type I interferon (IFN response. Bacterial flagellin stimulates TLR5 and when delivered intracellularly the cytosolic PRR NLRC4, leading to secretion of proinflammatory cytokines. Both alphaviruses and flagellin have independently been shown to act as adjuvants for antigen-specific antibody responses. Here, we hypothesized that alphavirus and flagellin would act in synergy when combined. We therefore cloned the Salmonella Typhimurium flagellin (FliC gene into an alphavirus replicon and assessed its adjuvant activity on the antibody response against co-administered antigen. In mice immunized with recombinant alphavirus, antibody responses were greatly enhanced compared to soluble FliC or control alphavirus. Both IgG1 and IgG2a/c responses were increased, indicating an enhancement of both Th1 and Th2 type responses. The adjuvant activity of FliC-expressing alphavirus was diminished but not abolished in the absence of TLR5 or type I IFN signaling, suggesting the contribution of several signaling pathways and some synergistic and redundant activity of its components. Thus, we have created a recombinant adjuvant that stimulates multiple signaling pathways of innate immunity resulting in a strong and broad antibody response.

  2. Borreliacidal activity of Borrelia metal transporter A (BmtA binding small molecules by manganese transport inhibition

    Directory of Open Access Journals (Sweden)

    Wagh D

    2015-02-01

    Full Text Available Dhananjay Wagh,* Venkata Raveendra Pothineni,* Mohammed Inayathullah, Song Liu, Kwang-Min Kim, Jayakumar Rajadas Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA *These authors contributed equally to this work  Abstract: Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA, a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 µg/mL (250 µM. Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia.  Keywords: Lyme disease, BmtA, Borrelia burgdorferi, desloratadine, Bac Titer-Glo assay

  3. Sorption Characteristics of Mixed Molecules of Glutaraldehyde from Water on Mesoporous Acid-Amine Modified Low-Cost Activated Carbon: Mechanism, Isotherm, and Kinetics

    Directory of Open Access Journals (Sweden)

    Mukosha Lloyd

    2015-01-01

    Full Text Available The environmental discharge of inefficiently treated waste solutions of the strong biocide glutaraldehyde (GA from hospitals has potential toxic impact on aquatic organisms. The adsorption characteristics of mixed polarized monomeric and polymeric molecules of GA from water on mesoporous acid-amine modified low-cost activated carbon (AC were investigated. It was found that the adsorption strongly depended on pH and surface chemistry. In acidic pH, the adsorption mechanism was elaborated to involve chemical sorption of mainly hydroxyl GA monomeric molecules on acidic surface groups, while in alkaline pH, the adsorption was elaborated to involve both chemical and physical sorption of GA polymeric forms having mixed functional groups (aldehyde, carboxyl, and hydroxyl on acidic and amine surface groups. The optimum pH of adsorption was about 12 with significant contribution by cooperative adsorption, elucidated in terms of hydrogen bonding and aldol condensation. Freundlich and Dubinin-Radushkevich models were fitted to isotherm data. The adsorption kinetics was dependent on initial concentration and temperature and described by the Elovich model. The adsorption was endothermic, while the intraparticle diffusion model suggested significant contribution by film diffusion. The developed low-cost AC could be used to supplement the GA alkaline deactivation process for efficient removal of residual GA aquatic toxicity.

  4. Characterization of Active Hydrothermal Fluid Discharge and Recharge Zones in the Endeavour Axial Valley, Juan de Fuca Ridge

    Science.gov (United States)

    Salmi, M.; Hutnak, M.; Hearn, C.; Tivey, M.; Bjorklund, T.; Johnson, H. P.

    2012-12-01

    Sites where warm hydrothermal fluid vents at mid-ocean spreading centers are important for understanding a wide range of critical oceanic processes, but discharge zones represent a very limited portion of crustal fluid circulation pathways. Mapping the distribution of both fluid recharge and discharge sites within the axial valley provides wider insight into the larger scale features of hydrothermal circulation. Our 2011 survey consisted of 180 conductive heat flow stations within the Endeavour axial valley in roughly a 400 m by 1000 m grid, extending across the entire axial valley from the outer flank of the western boundary ridge to the eastern wall. Data acquisition used thermal blankets which measured conductive heat flow without requiring substantial sediment cover. A surprising result from this survey was zones of high heat flow extending across-strike, from the summit of the west valley wall across the entire axial valley floor. This trend was correlated with anomalously low seafloor magnetization from a near-bottom survey with the ROV JASON. Unexpectedly, over half of the axial valley floor was anomalously low at 1 W m-2. The areas of extremely low heat flow values are interpreted as being directly influenced by recharge zones. Based on MCS estimates of partial melt depth below the axial valley and the assumption of no fluid advection, the purely conductive heat flow for this region should be on the order of 1 W m-2.The observation that conductive heat flux is suppressed over large portions of the axial valley floor suggests that heat transfer within the crustal sub-surface fluid reservoir is widespread, and impacts a large portion of our survey area. The largely bi-modal distribution of high and low conductive heat flow, coupled with geophysical and video observations, suggest current Endeavour axial valley crustal fluid circulation models need to be re-evaluated.

  5. A new diamantane functionalized tris(aryloxide) ligand system for small molecule activation chemistry at reactive uranium complexes

    Energy Technology Data Exchange (ETDEWEB)

    Lam, O.P.; Heinemann, F.W.; Meyer, K. [Department of Chemistry and Pharmacy, Inorganic Chemistry, University Erlangen-Nuremberg, Erlangen (Germany); Lam, O.P. [University of California, San Diego, Department of Chemistry and Biochemistry, La Jolla, CA (United States)

    2010-06-15

    The diamantane functionalized triazacyclononane ligand ({sup Dia}ArOH){sub 3}tacn (L{sub 3}) has been synthesized and the reactivity of its U(III) metallated product [(({sup Dia}ArO){sub 3}tacn)U] (1) has been explored. Complex 1 promotes dichloromethane and azido-trimethyl-silane activation to generate U(IV) complex [(({sup Dia}ArO){sub 3}tacn)U(Cl)] (2) and U(V) complex [(({sup Dia}ArO){sub 3}tacn)U(NTMS)] (3), respectively. Spectroscopic investigations of complexes 1, 2, and 3 will be discussed, along with molecular structures where possible. (authors)

  6. A new diamantane functionalized tris(aryloxide) ligand system for small molecule activation chemistry at reactive uranium complexes

    International Nuclear Information System (INIS)

    The diamantane functionalized triazacyclononane ligand (DiaArOH)3tacn (L3) has been synthesized and the reactivity of its U(III) metallated product [((DiaArO)3tacn)U] (1) has been explored. Complex 1 promotes dichloromethane and azido-trimethyl-silane activation to generate U(IV) complex [((DiaArO)3tacn)U(Cl)] (2) and U(V) complex [((DiaArO)3tacn)U(NTMS)] (3), respectively. Spectroscopic investigations of complexes 1, 2, and 3 will be discussed, along with molecular structures where possible. (authors)

  7. The northwest trending north Boquerón Bay-Punta Montalva Fault Zone; A through going active fault system in southwestern Puerto Rico

    Science.gov (United States)

    Roig‐Silva, Coral Marie; Asencio, Eugenio; Joyce, James

    2013-01-01

    The North Boquerón Bay–Punta Montalva fault zone has been mapped crossing the Lajas Valley in southwest Puerto Rico. Identification of the fault was based upon detailed analysis of geophysical data, satellite images, and field mapping. The fault zone consists of a series of Cretaceous bedrock faults that reactivated and deformed Miocene limestone and Quaternary alluvial fan sediments. The fault zone is seismically active (local magnitude greater than 5.0) with numerous locally felt earthquakes. Focal mechanism solutions suggest strain partitioning with predominantly east–west left-lateral displacements with small normal faults striking mostly toward the northeast. Northeast-trending fractures and normal faults can be found in intermittent streams that cut through the Quaternary alluvial fan deposits along the southern margin of the Lajas Valley, an east–west-trending 30-km-long fault-controlled depression. Areas of preferred erosion within the alluvial fan trend toward the west-northwest parallel to the onland projection of the North Boquerón Bay fault. The North Boquerón Bay fault aligns with the Punta Montalva fault southeast of the Lajas Valley. Both faults show strong southward tilting of Miocene strata. On the western end, the Northern Boquerón Bay fault is covered with flat-lying Holocene sediments, whereas at the southern end the Punta Montalva fault shows left-lateral displacement of stream drainage on the order of a few hundred meters.

  8. Problems of Chernobyl Exclusion Zone

    International Nuclear Information System (INIS)

    The collection comprises the results of researches and design activity in the ChNPP exclusion zone, aimed at the development of technologies, equipment and devices for radioactive waste management and ChNPP accident clean-up, at studying the composition and structure of the Exclusion zone soil activity solid bearers, form transformation of the fission products of fuel fallout radionuclide composition in the ChNPP near zone, the spatial distribution of radionuclides and other radioecological issues.. Much attention is paid to medical and biological aspects of the accident influence on the flora, fauna and people's health, labour conditions and incidence of the workers of the Exclusion zone

  9. Activation of VCAM-1 and Its Associated Molecule CD44 Leads to Increased Malignant Potential of Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Pei-Chen Wang

    2014-02-01

    Full Text Available VCAM-1 (CD106, a transmembrane glycoprotein, was first reported to play an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1. In the present study, we observed that VCAM-1 expression can be induced in many breast cancer epithelial cells by cytokine stimulation in vitro and its up-regulation directly correlated with advanced clinical breast cancer stage. We found that VCAM-1 over-expression in the NMuMG breast epithelial cells controls the epithelial and mesenchymal transition (EMT program to increase cell motility rates and promote chemoresistance to doxorubicin and cisplatin in vitro. Conversely, in the established MDAMB231 metastatic breast cancer cell line, we confirmed that knockdown of endogenous VCAM-1 expression reduced cell proliferation and inhibited TGFβ1 or IL-6 mediated cell migration, and increased chemosensitivity. Furthermore, we demonstrated that knockdown of endogenous VCAM-1 expression in MDAMB231 cells reduced tumor formation in a SCID xenograft mouse model. Signaling studies showed that VCAM-1 physically associates with CD44 and enhances CD44 and ABCG2 expression. Our findings uncover the possible mechanism of VCAM-1 activation facilitating breast cancer progression, and suggest that targeting VCAM-1 is an attractive strategy for therapeutic intervention.

  10. Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages.

    Science.gov (United States)

    Leroux, Louis-Philippe; Dasanayake, Dayal; Rommereim, Leah M; Fox, Barbara A; Bzik, David J; Jardim, Armando; Dzierszinski, Florence S

    2015-04-01

    The obligate intracellular protozoan parasite Toxoplasma gondii interferes with major histocompatibility complex class II antigen presentation to dampen host CD4(+) T cell responses. While it is known that T. gondii inhibits major histocompatibility complex class II gene transcription and expression in infected host cells, the mechanism of this host manipulation is unknown. Here, we show that soluble parasite proteins inhibit IFNγ-induced expression of major histocompatibility complex class II on the surface of the infected cell in a dose-dependent response that was abolished by protease treatment. Subcellular fractionation of T. gondii tachyzoites revealed that the major histocompatibility complex class II inhibitory activity co-partitioned with rhoptries and/or dense granules. However, parasite mutants deleted for single rhoptries or dense granules genes (ROP1, 4/7, 14, 16 and 18 or GRA 2-9 and 12 knock-out strains) retained the ability to inhibit expression of major histocompatibility complex class II. In addition, excreted/secreted antigens released by extracellular tachyzoites displayed immunomodulatory activity characterized by an inhibition of major histocompatibility complex class II expression, and reduced expression and release of TNFα by macrophages. Tandem MS analysis of parasite excreted/secreted antigens generated a list of T. gondii secreted proteins that may participate in major histocompatibility complex class II inhibition and the modulation of host immune functions. PMID:25720921

  11. Orientating lipase molecules through surface chemical control for enhanced activity: A QCM-D and ToF-SIMS investigation.

    Science.gov (United States)

    Joyce, Paul; Kempson, Ivan; Prestidge, Clive A

    2016-06-01

    Bio-active materials consisting of lipase encapsulated within porous silica particles were engineered to control the adsorption kinetics and molecular orientation of lipase, which play critical roles in the digestion kinetics of triglycerides. The adsorption kinetics of Candida antartica lipase A (CalA) was monitored using quartz crystal microbalance with dissipation (QCM-D) and controlled by altering the hydrophobicity of a silica binding support. The extent of adsorption was 2-fold greater when CalA was adsorbed onto hydrophobic silica compared to hydrophilic silica. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) fragmentation patterns, in conjunction with multivariate statistics, demonstrated enhanced exposure of the lipase's catalytic domain, specifically the histidine group responsible for activity, when CalA was adsorbed on hydrophilic silica. Consequently, lipid digestion kinetics were enhanced when CalA was loaded in hydrophilic porous silica particles, i.e., a 2-fold increase in the pseudo-first-order rate constant for digestion when compared to free lipase. In contrast, digestion kinetics were inhibited when CalA was hosted in hydrophobic porous silica, i.e., a 5-fold decrease in pseudo-first-order rate constant for digestion when compared to free lipase. These findings provide valuable insights into the mechanism of lipase action which can be exploited to develop smarter food and drug delivery systems consisting of porous lipid-based materials.

  12. IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC-.

    Science.gov (United States)

    Yang, Yuzhe; Yee, Douglas

    2014-04-15

    Insulin-like growth factors (IGF) stimulate cell growth in part by increasing amino acid uptake. xCT (SLC7A11) encodes the functional subunit of the cell surface transport system xC(-), which mediates cystine uptake, a pivotal step in glutathione synthesis and cellular redox control. In this study, we show that IGF-I regulates cystine uptake and cellular redox status by activating the expression and function of xCT in estrogen receptor-positive (ER(+)) breast cancer cells by a mechanism that relies on the IGF receptor substrate-1 (IRS-1). Breast cancer cell proliferation mediated by IGF-I was suppressed by attenuating xCT expression or blocking xCT activity with the pharmacologic inhibitor sulfasalazine (SASP). Notably, SASP sensitized breast cancer cells to inhibitors of the type I IGF receptor (IGF-IR) in a manner reversed by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine. Thus, IGF-I promoted the proliferation of ER(+) breast cancer cells by regulating xC(-) transporter function to protect cancer cells from ROS in an IRS-1-dependent manner. Our findings suggest that inhibiting xC(-) transporter function may synergize with modalities that target the IGF-IR to heighten their therapeutic effects.

  13. Identification, mechanism of action, and antitumor activity of a small molecule inhibitor of hippo, TGF-β, and Wnt signaling pathways.

    Science.gov (United States)

    Basu, Dipanjan; Lettan, Robert; Damodaran, Krishnan; Strellec, Susan; Reyes-Mugica, Miguel; Rebbaa, Abdelhadi

    2014-06-01

    Embryonic signaling pathways, in particular those mediated by Wnt and TGF-β, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-β-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-β pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-β-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence. PMID:24694946

  14. Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain

    Science.gov (United States)

    Rivera, Patricia; Blanco, Eduardo; Bindila, Laura; Alen, Francisco; Vargas, Antonio; Rubio, Leticia; Pavón, Francisco J.; Serrano, Antonia; Lutz, Beat; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2015-01-01

    Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence. PMID:26483633

  15. Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules

    OpenAIRE

    1991-01-01

    Cytokines such as interleukin 1 (IL-1) promote adhesiveness in human umbilical vein endothelial cells for leukocytes including basophils, eosinophils, and neutrophils, and induce expression of adherence molecules including ICAM-1 (intercellular adhesion molecule-1), ELAM-1 (endothelial-leukocyte adhesion molecule-1), and VCAM-1 (vascular cell adhesion molecule-1). In the present study, blocking monoclonal antibodies (mAb) recognizing ICAM-1, ELAM-1, and VCAM-1 have been used to compare their ...

  16. Satellites of Xe transitions induced by infrared active vibrational modes of CF4 and C2F6 molecules.

    Science.gov (United States)

    Alekseev, Vadim A; Schwentner, Nikolaus

    2011-07-28

    Absorption and luminescence excitation spectra of Xe/CF(4) mixtures were studied in the vacuum UV region at high resolution using tunable synchrotron radiation. Pressure-broadened resonance bands and bands associated with dipole-forbidden states of the Xe atom due to collision-induced breakdown of the optical selection rules are reported. The spectra display in addition numerous satellite bands corresponding to transitions to vibrationally excited states of a Xe-CF(4) collisional complex. These satellites are located at energies of Xe atom transition increased by one quantum energy in the IR active v(3) vibrational mode of CF(4) (v(3) = 1281 cm(-1)). Satellites of both resonance and dipole-forbidden transitions were observed. Satellites of low lying resonance states are spectrally broad bands closely resembling in shape their parent pressure-broadened resonance bands. In contrast, satellites of dipole-forbidden states and of high lying resonance states are spectrally narrow bands (FWHM ∼10 cm(-1)). The satellites of dipole-forbidden states are orders of magnitude stronger than transitions to their parent states due to collision-induced breakdown of the optical selection rules. These satellites are attributed to a coupling of dipole-forbidden and resonance states induced by the electric field of the transient CF(4) (v(3) = 0 ↔ v(3) = 1) dipole. Similar satellites are present in spectra of Xe/C(2)F(6) mixtures where these bands are induced by the IR active v(10) mode of C(2)F(6). Transitions to vibrationally excited states of Xe-CF(4)(C(2)F(6)) collision pairs were also observed in two-photon LIF spectra.

  17. An isotopic study of the microbial activity in a vandose zone: A field and mesocosm laboratory study

    International Nuclear Information System (INIS)

    Isotope studies on carbon, nitrogen and sulphur can contribute to an increased understanding of biogeochemical and chemical processes occurring above and below the water table controlled by biotic, abiotic and hydraulic factors. Microbial induced respiration of organic material supported by oxidants such a dissolved oxygen, nitrate and sulphate increases pCO2 in relation to the atmosphere. As a result of microbial respiration, a diffusion controlled CO2 flux occurs in the vadose zone. Respiration and the hydraulic conditions in the vadose zone control the CO2 flux to the atmosphere and to the underlying water table. Further, at the interface to the water table (anoxic transition range), redox conditions can influence the oxidation state of the compounds. For that reason, carbon isotopes of soil CO2 gas and of the organic/inorganic carbon in soils were investigated in a mesocosm model and at an associated field site (natural scale) near Saskatoon, Canada. The models are equipped with gas and water sampling devices and with devices for controlling physicochemical parameters. Microbial processes have been investigated there for more than 900 d

  18. A Selective Assay to Detect Chitin and Biologically Active Nano-Machineries for Chitin-Biosynthesis with Their Intrinsic Chitin-Synthase Molecules

    Directory of Open Access Journals (Sweden)

    Hildgund Schrempf

    2010-09-01

    Full Text Available A new assay system for chitin has been developed. It comprises the chitin-binding protein ChbB in fusion with a His-tag as well as with a Strep-tag, the latter of which was chemically coupled to horseradish peroxidase. With the resulting complex, minimal quantities of chitin are photometrically detectable. In addition, the assay allows rapid scoring of the activity of chitin-synthases. As a result, a refined procedure for the rapid purification of yeast chitosomes (nano-machineries for chitin biosynthesis has been established. Immuno-electronmicroscopical studies of purified chitosomes, gained from a yeast strain carrying a chitin-synthase gene fused to that for GFP (green-fluorescence protein, has led to the in situ localization of chitin-synthase-GFP molecules within chitosomes.

  19. Activation energy of fractional vortices and spectroscopy of a vortex molecule in long Josephson junction; Aktivierungsenergie fraktionaler Flusswirbel und Spektroskopie an Vortex-Molekuelen in langen Josephsonkontakten

    Energy Technology Data Exchange (ETDEWEB)

    Buckenmaier, Kai

    2010-06-09

    This thesis is divided into two parts, the measurement of the activation energy of a fractional vortex and the spectroscopy of a vortex-molecule. Fractional vortices can be studied in long 0-{kappa} Josephson junctions, where a jump of the Josephson phase is created artificially with a pair of tiny current injectors. To compensate for this phase discontinuity, a {rho} vortex is formed. Here, {rho} describes the vortex's so called topological charge. The {rho} vortices are pinned at the discontinuity and they carry the fraction ({rho}/2).{phi}{sub 0} of magnetic flux, with the magnetic flux quantum {phi}{sub 0} 2.07.10{sup -15}. Two stable vortex configurations are possible, a direct Vortex and a complementary one. {rho} depends on the injector current. When the bias current of the junction exceeds a characteristic threshold, which dependents on {rho}, the Lorentz force is bigger than the pinning force of the vortex and a fluxon is pulled away. In this case a complementary ({rho}-2{pi}) vortex is left behind. This switching of the {rho} vortex and the resulting emission of a fluxon can be described as a Kramers like escape of a particle out of a tilted washboard potential. The washboard potential is tilted to the point where the barrier is small enough, so that the particle can escape via thermal or quantum fluctuations. In the case of thermal fluctuations the barrier height is called activation energy. The activation energy can be determined by measuring the junction's switching current statistics. In this thesis, the activation energy, necessary for the vortex escape, was measured as a function of {rho} and a homogenous external magnetic field perpendicular to the junction. The main focus was the investigation of 0-{pi} junctions. The temperature dependence of the activation energy was investigated, too. It turns out, that the transition-state-theory is convenient to describe the switching probability of the standard Nb-AlO{sub x}-Nb junctions at 4.2 K

  20. Dinamic changes of pro-inflammatory cytokines, adhesion molecules and lymphocytes activation markers as early indicators of diseases severity in patients with Dengue

    Directory of Open Access Journals (Sweden)

    Silvana Vielma

    2014-09-01

    Full Text Available Several immunopathogenic mechanisms have been proposed to explain the massive increase of vascular permeability observed in the severe forms of infection by Dengue Virus (DENV. Our aim was to determine the kinetic changes of inflammatory mediators (IL-8, TNF- α, soluble early lymphocyte activation markers (sIL-2R, sTNF-Rp75 and soluble fractions of cell adhesion molecules (sICAM-1 and sVCAM-1 as indicators for early recognition of disease severity in patients with laboratory-confirmed dengue. Twenty patients classified as Dengue±Warning Signs (D±WS and thirty patients with Severe Dengue (SD were included in the study. Serums of apparently healthy individuals were included as controls. Compared with normal subjects, D±WS cases did not show significant differences in the levels of IL-8 or TNF-α during the acute nor in the critical stages of the disease; however, in D±WS cases levels of sICAM-1 and sVCAM-1 were higher than controls during both phases; in contrast, significant increase of sTNF-p75 and sIL2R levels were observed during the critical phase of the disease. Compared with both dengue patients and controls, patients with SD showed significant rise in the levels of IL-8 and TNF-α during the critical phase of the disease and a significant increase in adhesion molecules were detected in both phases, but the highest levels of sVCAM-1 and sIL-2R were observed only during the acute stage of the disease. In conclusion, sIL-2R and sVCAM-1, as early markers of lymphocyte and endothelial activation, would serves as indicators of severity during the acute phase of dengue infection.

  1. Establishing the soundness of administrative spatial units for operationalising the active living potential of residential environments: an exemplar for designing optimal zones

    Directory of Open Access Journals (Sweden)

    Riva Mylène

    2008-07-01

    Full Text Available Abstract Background In health and place research, definitions of areas, area characteristics, and health outcomes should ideally be coherent with one another. Yet current approaches for delimiting areas mostly rely on spatial units "of convenience" such as census tracts. These areas may be homogeneous along socioeconomic conditions but heterogeneous along other environmental characteristics. This heterogeneity can lead to biased measurement of environment characteristics and misestimation of area effects on health. The objective of this study was to assess the soundness of census tracts as units of analysis for measuring the active living potential of environments, hypothesised to be associated with walking. Results Starting with data at the smallest census area level available, zones homogeneous along three indicators of active living potential, i.e. population density, land use mix, and accessibility to services were designed. Delimitation of zones ensued from statistical clustering of the smallest areas into seven clusters or "types of environment". Mapping of clusters into a GIS led to the delineation of 898 zones characterised by one of seven types of environment, corresponding to different levels of active living potential. Homogeneity of census tracts along indicators of active living potential varied. A greater proportion (83% of variation in accessibility to services was attributable to differences between census tracts suggesting within-tract homogeneity along this variable. However, census tracts were heterogeneous with respect to population density and land use mix where a greater proportion of the variation was attributable to within-tract differences. About 55% of tracts were characterised by a combination of three or more "types of environment" suggesting substantial within-tract heterogeneity in the active living potential of environments. Conclusion Soundness of census tracts for measuring active living potential may be limited

  2. Effect of androgen withdrawal on activation of ERKs and expression of cell cycle regulation molecules in human prostate carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    YE Ding-wei; LI Hui; TSENG Jane; CHAUVIN Priscilla; QIAN Song-xi; ZHENG Jia-fu; SUN Ying-hao; MA Yong-jiang

    2002-01-01

    Objective: To explore the possible mechanisms of growth regression of human androgen dependentprostate carcinoma cells caused by androgen withdrawal. Methods: After 24 h of treatment with 1×10-9mol/L dihydrotestosterone (DHT), the expression of phosphorylated ERK proteins and cell cycle regulationmolecules including CDK2, CDK4, CDK6 and P27kip1 in human androgen dependent prostate carcinoma cellline LNCaP was measured by Western blot analysis 0 h, 8 h and 24 h of after androgen withdrawal. Humanandrogen independent prostate carcinoma cell line PC-3 was also examined as control. Results: Down-regula-tion of phosphorylated ERK, CDK2, CDK4 and CDK6 and up-regulation of P27kip1 were found initially inLNCaP cell line 8 h after androgen withdrawal. The levels of phosphorylated ERK and CDKs decreased con-tinuously and reached the lowest after 24 h, while continuous elevation of P27kip1 was detected thereafter to 24h. No expression change of phosphorylated ERK, CDKs and P27kip1 were detected in PC-3 cell line. Conclu-sion: The androgen withdrawal can cause ERKs activation decrease and cell cycle regulation moleculeschanges, which may be one of the mechanisms for inhibited growth of androgen dependent prostate carcinomaafter androgen ablation by either operative or medicine methods.

  3. Zinc Chelation by a Small-Molecule Adjuvant Potentiates Meropenem Activity in Vivo against NDM-1-Producing Klebsiella pneumoniae.

    Science.gov (United States)

    Falconer, Shannon B; Reid-Yu, Sarah A; King, Andrew M; Gehrke, Sebastian S; Wang, Wenliang; Britten, James F; Coombes, Brian K; Wright, Gerard D; Brown, Eric D

    2015-11-13

    The widespread emergence of antibiotic drug resistance has resulted in a worldwide healthcare crisis. In particular, the extensive use of β-lactams, a highly effective class of antibiotics, has been a driver for pervasive β-lactam resistance. Among the most important resistance determinants are the metallo-β-lactamases (MBL), which are zinc-requiring enzymes that inactivate nearly all classes of β-lactams, including the last-resort carbapenem antibiotics. The urgent need for new compounds targeting MBL resistance mechanisms has been widely acknowledged; however, the development of certain types of compounds-namely metal chelators-is actively avoided due to host toxicity concerns. The work herein reports the identification of a series of zinc-selective spiro-indoline-thiadiazole analogues that, in vitro, potentiate β-lactam antibiotics against an MBL-carrying pathogen by withholding zinc availability. This study demonstrates the ability of one such analogue to inhibit NDM-1 in vitro and, using a mouse model of infection, shows that combination treatment of the respective analogue with meropenem results in a significant decrease in bacterial burden in contrast to animals that received antibiotic treatment alone. These results support the therapeutic potential of these chelators in overcoming antibiotic resistance. PMID:27623408

  4. Common catabolic enzyme patterns in a microplankton community of the Humboldt Current System off northern and central-south Chile: Malate dehydrogenase activity as an index of water-column metabolism in an oxygen minimum zone

    Science.gov (United States)

    González, R. R.; Quiñones, R. A.

    2009-07-01

    An extensive subsurface oxygen minimum zone off northern and central-south Chile, associated with the Peru-Chile undercurrent, has important effects on the metabolism of the organisms inhabiting therein. Planktonic species deal with the hypoxic and anoxic environments by relying on biochemical as well as physiological processes related to their anaerobic metabolisms. Here we characterize, for the first time, the potential enzymatic activities involved in the aerobic and anaerobic energy production pathways of microplanktonic organisms (catabolic pathways in the oxygen minimum zone. Malate dehydrogenase had the highest oxidizing activity of nicotinamide adenine dinucleotide (reduced form) in the batch of catabolic enzymatic activities assayed, including potential pyruvate oxidoreductases activity, the electron transport system, and dissimilatory nitrate reductase. Malate dehydrogenase correlated significantly with almost all the enzymes analyzed within and above the oxygen minimum zone, and also with the oxygen concentration and microplankton biomass in the water column of the Humboldt Current System, especially in the oxygen minimum zone off Iquique. These results suggest a possible specific pattern for the catabolic activity of the microplanktonic realm associated with the oxygen minimum zone spread along the Humboldt Current System off Chile. We hypothesize that malate dehydrogenase activity could be an appropriate indicator of microplankton catabolism in the oxygen minimum zone and adjacent areas.

  5. Race, Ethnicity, and Discriminatory Zoning

    OpenAIRE

    Allison Shertzer; Tate Twinam; Randall P. Walsh

    2014-01-01

    Zoning has been cited as a discriminatory policy tool by critics, who argue that ordinances are used to deter the entry of minority residents into majority neighborhoods through density restrictions (exclusionary zoning) and locate manufacturing activity in minority neighborhoods (environmental racism). However, identifying discrimination in these regulations is complicated by the fact that land use and zoning have been co-evolving for nearly a century in most American cities, rendering resid...

  6. Modulation of glucokinase by glucose, small-molecule activator and glucokinase regulatory protein: steady-state kinetic and cell-based analysis.

    Science.gov (United States)

    Bourbonais, Francis J; Chen, Jing; Huang, Cong; Zhang, Yanwei; Pfefferkorn, Jeffrey A; Landro, James A

    2012-02-01

    GK (glucokinase) is an enzyme central to glucose metabolism that displays positive co-operativity to substrate glucose. Small-molecule GKAs (GK activators) modulate GK catalytic activity and glucose affinity and are currently being pursued as a treatment for Type 2 diabetes. GK progress curves monitoring product formation are linear up to 1 mM glucose, but biphasic at 5 mM, with the transition from the lower initial velocity to the higher steady-state velocity being described by the rate constant kact. In the presence of a liver-specific GKA (compound A), progress curves at 1 mM glucose are similar to those at 5 mM, reflecting activation of GK by compound A. We show that GKRP (GK regulatory protein) is a slow tight-binding inhibitor of GK. Analysis of progress curves indicate that this inhibition is time dependent, with apparent initial and final Ki values being 113 and 12.8 nM respectively. When GK is pre-incubated with glucose and compound A, the inhibition observed by GKRP is time dependent, but independent of GKRP concentration, reflecting the GKA-controlled transition between closed and open GK conformations. These data are supported by cell-based imaging data from primary rat hepatocytes. This work characterizes the modulation of GK by a novel GKA that may enable the design of new and improved GKAs.

  7. Pharmacological modulation of histone demethylase activity by a small molecule isolated from subcritical water extracts of Sasa senanensis leaves prolongs the lifespan of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Nakagawa-Yagi Yuzo

    2012-07-01

    Full Text Available Abstract Background Extracts of Sasa senanensis Rehder are used in traditional Japanese medicine; however, little is known about the underlying mechanisms of their potential health benefits. Methods S. senanensis leaves were extracted with subcritical water. An active small-molecule was isolated using reversed-phase high-performance liquid chromatography (HPLC, and identified as 3,4-dihydroxybenzaldehyde (protocatechuic aldehyde or PA. The effects of PA on the activity of histone demethylase, the Drosophila melanogaster lifespan and gene expression in Drosophila S2 cells were investigated. Results PA inhibited the activity of Jumonji domain-containing protein 2A (JMJD2A histone demethylase in a dose-dependent manner with a half-maximal inhibitory concentration (IC50 of 11.6 μM. However, there was no effect on lysine-specific demethylase 1 (LSD1, histone deacetylase 1 (HDAC1 or HDAC8. PA significantly extended the lifespan of female, but not male, Drosophila. In Drosophila S2 cells, the eukaryotic translation initiation factor 4E binding protein (4E-BP was up-regulated by PA exposure. Conclusions Our findings provide insight into the possible relationship between the pharmacological modulation of histone demethylation and lifespan extension by PA; they might also be important in the development of alternative therapies for age-related disorders.

  8. 77 FR 63290 - Foreign-Trade Zone 61-San Juan, Puerto Rico; Authorization of Production Activity, Pfizer...

    Science.gov (United States)

    2012-10-16

    ... comment (77 FR 36997, 6/20/2012). The FTZ Board has determined that no further review of the activity is... Activity, Pfizer Pharmaceuticals, LLC (Subzone 61A), (Ibuprofen Pharmaceutical Products), Guayama, Puerto... notification of proposed production activity on behalf of Pfizer Pharmaceuticals, LLC (Subzone 61A) for...

  9. ALARA Review of the Activation/Repair of Fire Detectors in Zone Three at the 233-S Facility

    International Nuclear Information System (INIS)

    A formal as low as reasonably achievable (ALARA) review is required by BHI-SH-02, Vol. 1, Procedure 1.22, 'Planning Radiological Work', when radiological conditions exceed trigger levels. The level of contamination inside the viewing room meets this criterion. This ALARA review is for task instruction 1997-03-18-005-8.3.3 (mini task instruction to a living work package), 'Instructions for D ampersand D Support of Fire Detector Troubleshooting and Minor Maintenance Work at 233-S,' and DynCorp 2G-98-7207C, '233-S Reconnect Smoke Detectors Zone 3.' The Radiological Work Permit (RWP) request broke these two task instructions into four separate tasks. The four tasks identified in the RWP request were used to estimate airborne concentrations and the total exposure

  10. Lipopolysaccharide Binding Protein, Soluble-Intercellular Adhesion Molecule-1, Procalcitonin, and Protein C Activity and Clinical Outcome in Systemic Inflammatory Response Syndrome (SIRS or Sepsis Patients

    Directory of Open Access Journals (Sweden)

    Dewi Muliaty

    2009-04-01

    Full Text Available BACKGROUND: Biochemical markers may be used in diagnosis, prognostic and monitoring treatment and therapy for sepsis patients. In this study we used Lipopolysacharide Binding Protein (LBP, serum-Intercellular Adhesion Molecule-1 (ICAM-1, Procalcitonin (PCT and protein C activity. LBP is related to lipopolysachharide or gram-negative bacterial endotoxin which bound to LBP and induced inflammatory response. ICAM-1 is associated with endothelial dysfunction in response to systemic inflammatory and septic condition. PCT increased in bacterial infection and in severe systemic inflammatory. Role of Protein C is protecting the intravascular system to systemic inflammation, sepsis and the concomitant intravascular coagulopathy. The aim of this study was to examine the associations between levels of serum LBP, sICAM-1, PCT, and protein C activity with the clinical outcome of SIRS or sepsis patients. METHODS: We included 19 post surgery patients with SIRS criteria from intensive care unit (ICU and evaluated the level of LBP serum with Chemiliuminescent Enzyme Immunoassay (Diagnostic Product Co., ICAM-1 with ELISA (R&D System, PCT with immunochromatography (BRAHMS, protein C activity with chromogenic method (Dade Behring. We performed the samples serially at the first admission of patients and after 72 hours. Data were analysed by non-parametric with Wilcoxon test and Mann-Whitney test. Correlation study between biomarkers calculated by Kendall’s tau and Spearman’s rho. RESULTS: Of 19 patients, 9 (47,4% died and 10 (52,6% surviving. The level of LBP serum decreased after 72 hours in surviving-sepsis patients, and increased in nonsurviving sepsis patients with significant different levels at 72 hours examination (p0.05. In all patients were found high level of PCT serum since the first admission examination, decreasing levels were occurred significantly in surviving patients after 72 hours (p0.05 both in surviving and non-surviving patients. CONCLUSIONS

  11. The role of sexual vs. asexual recruitment of Artemisia wudanica in transition zone habitats between inter-dune lowlands and active dunes in Inner Mongolia, China

    Science.gov (United States)

    Wang, Yongcui; Alberto, Busso Carlos; Jiang, Deming; Ala, Musa; Li, Xuehua; Zhou, Quanlai; Lin, Jixiang; Ren, Guohua; Jia, Lian

    2016-04-01

    Artemisia wudanica is an endemic, perennial, pioneering psammophyte species in the sand dune ecosystems of western Horqin Sand Land in northern China. However, no studies have addressed how sexual and asexual reproduction modes of A. wudanica perform at the transitional zones between active dune inter-dune lowlands and active dunes. In early spring, quadrats were randomly set up in the study area to monitor surviving seedling and/or ramet density and frequency coming from sexual/asexual reproduction of A. wudanica. Iron sticks were inserted near each quadrat to determine wind erosion intensity (WE). Additionally, soil samples were collected nearby each quadrat to test for soil moisture (SM), organic matter (OM) and pH. Surviving seedlings of A. wudanica showed an inverse response in comparison with ramets to SM, OM and WE. Soil moisture showed the most positive effect, and WE the negative effect, on surviving, sexual reproduction seedlings. Contrarily, WE had the most positive effect, and SM the negative effect, on asexual reproduction ramets. This suggests that increases in SM and decreases in WE should benefit recruitment of A. wudanica seedlings. On the contrary, ramets coming from asexual reproduction showed a different response to environmental factors in transition zone habitats. While SM was not a key constraint for the survival of seedlings, they showed a better, positive response to wind erosion environments. Overall, various study environmental parameters could be improved to foster A. wudanica invasion and settlement in the plant community through different reproductive modes, thereby promoting vegetation restoration and rehabilitation.

  12. Photonic Molecule Lasers Revisited

    Science.gov (United States)

    Gagnon, Denis; Dumont, Joey; Déziel, Jean-Luc; Dubé, Louis J.

    2014-05-01

    Photonic molecules (PMs) formed by coupling two or more optical resonators are ideal candidates for the fabrication of integrated microlasers, photonic molecule lasers. Whereas most calculations on PM lasers have been based on cold-cavity (passive) modes, i.e. quasi-bound states, a recently formulated steady-state ab initio laser theory (SALT) offers the possibility to take into account the spectral properties of the underlying gain transition, its position and linewidth, as well as incorporating an arbitrary pump profile. We will combine two theoretical approaches to characterize the lasing properties of PM lasers: for two-dimensional systems, the generalized Lorenz-Mie theory will obtain the resonant modes of the coupled molecules in an active medium described by SALT. Not only is then the theoretical description more complete, the use of an active medium provides additional parameters to control, engineer and harness the lasing properties of PM lasers for ultra-low threshold and directional single-mode emission. We will extend our recent study and present new results for a number of promising geometries. The authors acknowledge financial support from NSERC (Canada) and the CERC in Photonic Innovations of Y. Messaddeq.

  13. Phenolic Molecules in Virgin Olive Oils: a Survey of Their Sensory Properties, Health Effects, Antioxidant Activity and Analytical Methods. An Overview of the Last Decade Alessandra

    Directory of Open Access Journals (Sweden)

    Giovanni Lercker

    2007-08-01

    Full Text Available Among vegetable oils, virgin olive oil (VOO has nutritional and sensory characteristics that to make it unique and a basic component of the Mediterranean diet. The importance of VOO is mainly attributed both to its high content of oleic acid a balanced contribution quantity of polyunsaturated fatty acids and its richness in phenolic compounds, which act as natural antioxidants and may contribute to the prevention of several human diseases. The polar phenolic compounds of VOO belong to different classes: phenolic acids, phenyl ethyl alcohols, hydroxy-isochromans, flavonoids, lignans and secoiridoids. This latter family of compounds is characteristic of Oleaceae plants and secoiridoids are the main compounds of the phenolic fraction. Many agronomical and technological factors can affect the presence of phenols in VOO. Its shelf life is higher than other vegetable oils, mainly due to the presence of phenolic molecules having a catechol group, such as hydroxytyrosol and its secoiridoid derivatives. Several assays have been used to establish the antioxidant activity of these isolated phenolic compounds. Typical sensory gustative properties of VOO, such as bitterness and pungency, have been attributed to secoiridoid molecules. Considering the importance of the phenolic fraction of VOO, high performance analytical methods have been developed to characterize its complex phenolic pattern. The aim of this review is to realize a survey on phenolic compounds of virgin olive oils bearing in mind their chemical-analytical, healthy and sensory aspects. In particular, starting from the basic studies, the results of researches developed in the last ten years will be focused.

  14. X-ray diffraction indicates that active cross-bridges bind to actin target zones in insect flight muscle.

    OpenAIRE

    Tregear, R T; Edwards, R J; Irving, T C; Poole, K J; Reedy, M C; Schmitz, H.; Towns-Andrews, E; Reedy, M K

    1998-01-01

    We report the first time-resolved study of the two-dimensional x-ray diffraction pattern during active contraction in insect flight muscle (IFM). Activation of demembranated Lethocerus IFM was triggered by 1.5-2.5% step stretches (risetime 10 ms; held for 1.5 s) giving delayed active tension that peaked at 100-200 ms. Bundles of 8-12 fibers were stretch-activated on SRS synchrotron x-ray beamline 16.1, and time-resolved changes in diffraction were monitored with a SRS 2-D multiwire detector. ...

  15. Role of T3 surface molecules in human T-cell activation: T3-dependent activation results in an increase in cytoplasmic free calcium.

    OpenAIRE

    Weiss, A; Imboden, J; Shoback, D; Stobo, J.

    1984-01-01

    The human T-cell leukemia, Jurkat, and a T3-negative mutant of Jurkat (S.5) were used to study the role of T3 in human T-cell activation. Incubation of Jurkat with phytohemagglutinin (PHA) resulted in the production of interleukin 2, which was markedly increased by the addition of phorbol 12-myristate 13-acetate (PMA). Antibodies reactive with T3 could activate Jurkat only if added together with PMA. However, S.5 cells failed to produce interleukin 2 in response to PHA and produced 1/16th the...

  16. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway

    DEFF Research Database (Denmark)

    Kolkova, K; Novitskaya, V; Pedersen, N;

    2000-01-01

    , inhibitors of the nonreceptor tyrosine kinase p59(fyn), PLC, PKC and MEK and an activator of PKC, phorbol-12-myristate-13-acetate (PMA). MEK2 transfection rescued cells treated with all inhibitors. The same was found for PMA treatment, except when cells concomitantly were treated with the MEK inhibitor....... Arachidonic acid rescued cells treated with antibodies to the FGF receptor or the PLC inhibitor, but not cells in which the activity of PKC, p59(fyn), FAK, Ras, or MEK was inhibited. Interaction of NCAM with a synthetic NCAM peptide ligand, known to induce neurite outgrowth, was shown to stimulate...

  17. The sequence of moderate-size earthquakes at the junction of the Ligurian basin and the Corsica margin (western Mediterranean): The initiation of an active deformation zone revealed?

    Science.gov (United States)

    Larroque, Christophe; Delouis, Bertrand; Sage, Françoise; Régnier, Marc; Béthoux, Nicole; Courboulex, Françoise; Deschamps, Anne

    2016-04-01

    A new seismically active zone is found in the southern part of the Ligurian basin, 80-km west of Corsica (western Mediterranean). The activity began in February 2011 with a foreshock (ML 4) and a mainshock (ML 5.3) 5 days later, followed by numerous aftershocks. We first analyze the fore- and mainshock in detail. We compare the results obtained using classical methods (linear location in a 1D medium and focal mechanisms from P and S polarities) and new approaches (non-linear location in a 3D medium and waveform modeling for determining the seismic moment and the focal mechanism). Both methods provided similar results for location, depth (in the range of 6-13 km) and focal mechanisms, which reveal reverse faulting with nodal planes oriented N-S and NE-SW. We then locate 27 of the aftershocks in the 3D model and find a 10-km-long NE-SW alignment with a depth between 7 and 16 km. In 2012 and 2013, three other moderate-size events (ML 3.8, 4 and 4.5) occurred and confirm that this zone is still active. The epicentral area is located in the oceanic domain of the Ligurian Basin. From analysis of the bathymetry and high-resolution multi-channel seismic profiles, no morphologic anomaly at surface and no inherited fault in the shallow ~ 4 km depth were imaged, which suggest that no significant deformation occurred in the area since 5 Ma. Thus, the structure(s) activated during the 2011-2013 sequence remain unknown. In light of these results, we point out a notable difference on both sides of the Ligurian Basin: the northern margin, close to the alpine chain, suffered strong earthquakes and large cumulated deformation since 5 Ma, while the southern margin, close to the Corsica-Sardinia continental block, is poorly deformed since 5 Ma.

  18. Activation of the Nrf2 Cell Defense Pathway by Ancient Foods: Disease Prevention by Important Molecules and Microbes Lost from the Modern Western Diet.

    Directory of Open Access Journals (Sweden)

    Donald R Senger

    Full Text Available The Nrf2 (NFE2L2 cell defense pathway protects against oxidative stress and disorders including cancer and neurodegeneration. Although activated modestly by oxidative stress alone, robust activation of the Nrf2 defense mechanism requires the additional presence of co-factors that facilitate electron exchange. Various molecules exhibit this co-factor function, including sulforaphane from cruciferous vegetables. However, natural co-factors that are potent and widely available from dietary sources have not been identified previously. The objectives of this study were to investigate support of the Nrf2 cell defense pathway by the alkyl catechols: 4-methylcatechol, 4-vinylcatechol, and 4-ethylcatechol. These small electrochemicals are naturally available from numerous sources but have not received attention. Findings reported here illustrate that these compounds are indeed potent co-factors for activation of the Nrf2 pathway both in vitro and in vivo. Each strongly supports expression of Nrf2 target genes in a variety of human cell types; and, in addition, 4-ethylcatechol is orally active in mice. Furthermore, findings reported here identify important and previously unrecognized sources of these compounds, arising from biotransformation of common plant compounds by lactobacilli that express phenolic acid decarboxylase. Thus, for example, Lactobacillus plantarum, Lactobacillus brevis, and Lactobacillus collinoides, which are consumed from a diet rich in traditionally fermented foods and beverages, convert common phenolic acids found in fruits and vegetables to 4-vinylcatechol and/or 4-ethylcatechol. In addition, all of the alkyl catechols are found in wood smoke that was used widely for food preservation. Thus, the potentially numerous sources of alkyl catechols in traditional foods suggest that these co-factors were common in ancient diets. However, with radical changes in food preservation, alkyl catechols have been lost from modern foods. The

  19. 77 FR 36997 - Foreign-Trade Zone 61-San Juan, PR; Notification of Proposed Production Activity; Pfizer...

    Science.gov (United States)

    2012-06-20

    ... 617