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Sample records for address specifically module

  1. Public Address Systems. Specifications - Installation - Operation.

    ERIC Educational Resources Information Center

    Palmer, Fred M.

    Provisions for public address in new construction of campus buildings (specifications, installations, and operation of public address systems), are discussed in non-technical terms. Consideration is given to microphones, amplifiers, loudspeakers and the placement and operation of various different combinations. (FS)

  2. Addressing the Mathematics-Specific Needs of Beginning Mathematics Teachers

    ERIC Educational Resources Information Center

    Britton, Edward

    2012-01-01

    Beginning mathematics teachers at the secondary level (middle and high school grades) have mathematics-specific needs that induction programs should address more substantially. However, a number of issues in how programs can accomplish this are more complex than often framed in discussions occurring in the induction programs and the field of…

  3. Design specifications for manufacturability of MCM-C multichip modules

    SciTech Connect

    Allen, C.; Blazek, R.; Desch, J.; Elarton, J.; Kautz, D.; Markley, D.; Morgenstern, H.; Stewart, R.; Warner, L.

    1995-06-01

    The scope of this document is to establish design guidelines for electronic circuitry packaged as multichip modules of the ceramic substrate variety, although many of these guidelines are applicable to other types of multichip modules. The guidelines begin with prerequisite information which must be developed between customer and designer of the multichip module. The core of the guidelines focuses on the many considerations that must be addressed during the multichip module design. The guidelines conclude with the resulting deliverables from the design which satisfy customer requirements and/or support the multichip module fabrication and testing processes. Considerable supporting information, checklists, and design constraints are captured in specific appendices and used as reference information in the main body text. Finally some real examples of multichip module design are presented.

  4. Addressing dual agency: getting specific about the expectations of professionalism.

    PubMed

    Tilburt, Jon C

    2014-01-01

    Professionalism requires that physicians uphold the best interests of patients while simultaneously insuring just use of health care resources. Current articulations of these obligations like the American Board of Internal Medicine (ABIM) Foundation's Physician Charter do not reconcile how these obligations fit together when they conflict. This is the problem of dual agency. The most common ways of dealing with dual agency: "bunkering"--physicians act as though societal cost issues are not their problem; "bailing"--physicians assume that they are merely agents of society and deliver care typically based on a strongly consequentialist public health ethic; or "balancing"--a vaguely specified attempt to uphold both patient welfare and societal need for judicious resource use simultaneously--all fail. Here I propose how the problem of dual agency might begin to be addressed with rigor and consistency. Without dealing with the dual agency problem and getting more specific about how to reconcile its norms when they conflict, the expectations of professionalism risk being written off as cute, nonbinding aphorisms from the medical profession. PMID:25127273

  5. Parallelized genetic optimization of spatial light modulator addressing for diffractive applications.

    PubMed

    Haist, Tobias; Lingel, Christian; Adler, Rodolfo; Osten, Wolfgang

    2014-03-01

    We describe a new technique for optimizing the addressing of spatial light modulators in dynamic holographic applications. The method utilizes 200 times parallelization using imaging of subholograms in combination with genetic optimization. Compared to a fixed linear addressing curve for all different gratings, the diffraction efficiency can be improved by up to 25% for a Holoeye Pluto LCoS modulator. PMID:24663371

  6. A Pipelined IP Address Lookup Module for 100 Gbps Line Rates and beyond

    NASA Astrophysics Data System (ADS)

    Teuchert, Domenic; Hauger, Simon

    New Internet services and technologies call for higher packet switching capacities in the core network. Thus, a performance bottleneck arises at the backbone routers, as forwarding of Internet Protocol (IP) packets requires to search the most specific entry in a forwarding table that contains up to several hundred thousand address prefixes. The Tree Bitmap algorithm provides a well-balanced solution in respect of storage needs as well as of search and update complexity. In this paper, we present a pipelined lookup module based on this algorithm, which allows for an easy adaption to diverse protocol and hardware constraints. We determined the pipelining degree required to achieve the throughput for a 100 Gbps router line card by analyzing a representative sub-unit for various configured sizes. The module supports IPv4 and IPv6 configurations providing this throughput, as we determined the performance of our design to achieve a processing rate of 178 million packets per second.

  7. Optogenetic approaches addressing extracellular modulation of neural excitability

    PubMed Central

    Ferenczi, Emily A.; Vierock, Johannes; Atsuta-Tsunoda, Kyoko; Tsunoda, Satoshi P.; Ramakrishnan, Charu; Gorini, Christopher; Thompson, Kimberly; Lee, Soo Yeun; Berndt, Andre; Perry, Chelsey; Minniberger, Sonja; Vogt, Arend; Mattis, Joanna; Prakash, Rohit; Delp, Scott; Deisseroth, Karl; Hegemann, Peter

    2016-01-01

    The extracellular ionic environment in neural tissue has the capacity to influence, and be influenced by, natural bouts of neural activity. We employed optogenetic approaches to control and investigate these interactions within and between cells, and across spatial scales. We began by developing a temporally precise means to study microdomain-scale interactions between extracellular protons and acid-sensing ion channels (ASICs). By coupling single-component proton-transporting optogenetic tools to ASICs to create two-component optogenetic constructs (TCOs), we found that acidification of the local extracellular membrane surface by a light-activated proton pump recruited a slow inward ASIC current, which required molecular proximity of the two components on the membrane. To elicit more global effects of activity modulation on ‘bystander’ neurons not under direct control, we used densely-expressed depolarizing (ChR2) or hyperpolarizing (eArch3.0, eNpHR3.0) tools to create a slow non-synaptic membrane current in bystander neurons, which matched the current direction seen in the directly modulated neurons. Extracellular protons played contributory role but were insufficient to explain the entire bystander effect, suggesting the recruitment of other mechanisms. Together, these findings present a new approach to the engineering of multicomponent optogenetic tools to manipulate ionic microdomains, and probe the complex neuronal-extracellular space interactions that regulate neural excitability. PMID:27045897

  8. Optogenetic approaches addressing extracellular modulation of neural excitability.

    PubMed

    Ferenczi, Emily A; Vierock, Johannes; Atsuta-Tsunoda, Kyoko; Tsunoda, Satoshi P; Ramakrishnan, Charu; Gorini, Christopher; Thompson, Kimberly; Lee, Soo Yeun; Berndt, Andre; Perry, Chelsey; Minniberger, Sonja; Vogt, Arend; Mattis, Joanna; Prakash, Rohit; Delp, Scott; Deisseroth, Karl; Hegemann, Peter

    2016-01-01

    The extracellular ionic environment in neural tissue has the capacity to influence, and be influenced by, natural bouts of neural activity. We employed optogenetic approaches to control and investigate these interactions within and between cells, and across spatial scales. We began by developing a temporally precise means to study microdomain-scale interactions between extracellular protons and acid-sensing ion channels (ASICs). By coupling single-component proton-transporting optogenetic tools to ASICs to create two-component optogenetic constructs (TCOs), we found that acidification of the local extracellular membrane surface by a light-activated proton pump recruited a slow inward ASIC current, which required molecular proximity of the two components on the membrane. To elicit more global effects of activity modulation on 'bystander' neurons not under direct control, we used densely-expressed depolarizing (ChR2) or hyperpolarizing (eArch3.0, eNpHR3.0) tools to create a slow non-synaptic membrane current in bystander neurons, which matched the current direction seen in the directly modulated neurons. Extracellular protons played contributory role but were insufficient to explain the entire bystander effect, suggesting the recruitment of other mechanisms. Together, these findings present a new approach to the engineering of multicomponent optogenetic tools to manipulate ionic microdomains, and probe the complex neuronal-extracellular space interactions that regulate neural excitability. PMID:27045897

  9. Software programs that address site-specific inventory characteristics issues.

    SciTech Connect

    Dare, J. H.; Cournoyer, M. E.

    2001-01-01

    The proper characterization of Hazardous, Mixed Low-Level, and Mixed Transuranic waste enhances productivity and safety. Hazardous material criteria that need to be considered include physical and health hazards inherent to the waste stream. Other factors that may influence characterization include: particulate diameter, complexing or chelating agent properties, lead, and mercury content, pressurized containers, and P-listed wastes. To meet these requirements are only a simple matter of generating a database with the proper fields. Manufactures and institutional databases bank huge sources of information, such as, work control documents, substance identification, container types, components of mixtures, physical property data, and regulatory data. In this report, utilization of commercially available software programs to take advantage of these resources in addressing waste characterization issues are presented. The application of user-friendly programs eliminates part of the tediousness associated with the complex requirements of certifying to general waste acceptance criteria with minimal impact on programmatic work. In other words, tapping into manufacturer and institutional database provides a way to take advantage of the combined expertise of these resources in managing a cost effective waste certification program as well as adding a quality assurance element to the program.

  10. An input-data page modulation scheme for content-addressable holographic digital data storage

    NASA Astrophysics Data System (ADS)

    John, Renu; Joseph, Joby; Singh, Kehar

    2005-05-01

    We implement a new modulation scheme for inputting digital data pages for content-addressable holographic data storage. This scheme, which is a modification of the hybrid ternary modulation (HTM) scheme, exploits the advantages of both pure phase modulation and hybrid ternary modulation. The technique of using binary phase data pages with equal number of 0 and π using twisted-nematic liquid crystal spatial light modulator reduces strong dc component and produces a more homogeneous spectral distribution at the recording plane. This technique should facilitate better recording of all spatial frequencies, and thus improve the discrimination capability of a content-addressable memory. In HTM, there are three states to represent binary bits, whereas in the proposed code, we use the two bright states with a difference of π for coding the binary data. The third state, which is a dark state, is used to code the undesired regions of the spatial light modulator (SLM) while performing a search operation using a small search argument. We also introduce a new balanced modulation code which is a modified version of the 8:12 modulation code to address the coding subtleties associated with phase-based data pages. The proposed technique enhances the discrimination capability of content search using small search arguments, thereby giving better results in associative recall in a holographic memory system, with very low number of false hits compared to the existing schemes. A comparative study is presented of discrimination ratio and SNR for the different modulation schemes.

  11. Optically addressed and submillisecond response phase only liquid crystal spatial light modulator

    NASA Astrophysics Data System (ADS)

    Zhao, Xiangjie; Duan, Jiazhu; Zhang, Dayong; Luo, Yongquan

    2014-10-01

    Liquid crystal based phase only spatial light modulator has attracted many research interests since last decades because of its superior advantage. Until now the liquid crystal spatial light modulator has been applied in many fields, but the response speed of nematic LC limited its further application. In this paper, an optically addressed phase only LC spatial light modulator was proposed based on polymer network liquid crystal. Morphology effect on the light scattering of PNLC was studied, which was mainly consisted of fiber and fiber bundles. The morphology nearly determined the light scattering and electro-optical property. Due to the high threshold voltage, to address the PNLC phase modulator was also concerned. Optical addressing method was proposed, in which BSO crystal was selected to replace one of the glass substrate. The response speed of PNLC was so fast that the reorientation of liquid crystal director will follow the change of effective voltage applied on LC layer, which was related with the voltage signal and especially with electron transport of photo-induced carriers due to diffusion and drift. The on state dynamic response of phase change was investigated. Based on this device, beam steering was also achieved by loading 488nm laser strip on the optical addressed phase only spatial light modulator.

  12. 46 CFR 107.317 - Addresses for submittal of plans, specifications, and calculations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Addresses for submittal of plans, specifications, and calculations. 107.317 Section 107.317 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS INSPECTION AND CERTIFICATION Plan Approval § 107.317 Addresses for submittal of plans, specifications,...

  13. Optically addressed spatial light modulators by MBE-grown nipi MQW structures

    NASA Technical Reports Server (NTRS)

    Maserjian, Joseph; Andersson, P. O.; Hancock, B. R.; Iannelli, J. M.; Eng, S. T.; Grunthaner, F. J.

    1989-01-01

    Promising approaches for achieving optically addressed spatial light modulators (O-SLMs) are investigated based on combining nipi and multiple quantum well structures. Theoretical aspects of photooptic effects achievable in such structures are treated. Test structures are grown by molecular beam epitaxy using two material systems. (In,Ga)As/GaAs and (Al,Ga)As/GaAs. Experiments show large optically controlled modulation of the absorption coefficient in the quantum well layers, a log power dependence on the control signal, millisecond and shorter time response, and generally predictable behavior. The results are encouraging for several different O-SLM device structures proposed.

  14. Technical Study Addresses a Key Challenge to Harmonizing U.S. and International PV Module Standards (Fact Sheet)

    SciTech Connect

    Not Available

    2012-07-01

    NREL builds community and industry support by addressing concerns voiced by key standards organizations. Photovoltaic (PV) manufacturers in the United States test the safety of their products using standards developed through consensus processes. Because U.S. PV module safety standards are not aligned with international standards, manufacturers must test their modules twice - and sometimes maintain separate product lines. By meeting with standards organizations such as the Solar ABCs and Underwriters Laboratories (UL), National Renewable Energy Laboratory (NREL) leaders have worked to identify different stakeholders priorities and concerns. UL, specifically, has expressed concern that the international standards do not address all possible risks. For example, new encapsulant materials could soften at high temperatures and frameless modules could slide apart, exposing live electrical parts or allowing glass to fall on a person below. The deformation of a solid material under the influence of mechanical stresses is known as 'creep.' Current module qualification tests are limited to 85 C, whereas modules can, for short times, reach 105 C outdoors. In response to UL's concern, NREL designed and executed an experiment to compare on-sun and accelerated rates of creep for modules fabricated with various encapsulants, including some that have low melting points. Objectives were to (1) evaluate the potential for creep in outdoor exposure, (2) provide guidance on the risks and design needs with thermoplastic materials, and (3) provide a basis for modifying standards to account for materials with potential to creep. The study tested experimental materials with eight representative encapsulants in both outdoor and indoor (chamber) exposure. The study found that modules with materials that were expected to creep did so in the indoor exposure, but not in most outdoor environments and mounting configurations. The results provide a basis for defining an accelerated test needed to

  15. Experiment module/support module interface specification for the reusable reentry satellite

    NASA Technical Reports Server (NTRS)

    1991-01-01

    This Interface Specification (IFS) identifies, defines, and controls the interface between the Reusable Reentry Satellite (RRS) Vehicle (RRV) Experiment Module (EM) and the Support Module (SM) equipment. Contained in this specification are the physical, functional, and environmental interface requirements for the SM and EM. This specification is tailored to the unique requirements of the EM associated with the Rodent Module. The addenda to this specification contain the requirements for alternate EM's.

  16. Experiment module/support module interface specification for the reusable reentry satellite

    NASA Astrophysics Data System (ADS)

    1991-02-01

    This Interface Specification (IFS) identifies, defines, and controls the interface between the Reusable Reentry Satellite (RRS) Vehicle (RRV) Experiment Module (EM) and the Support Module (SM) equipment. Contained in this specification are the physical, functional, and environmental interface requirements for the SM and EM. This specification is tailored to the unique requirements of the EM associated with the Rodent Module. The addenda to this specification contain the requirements for alternate EM's.

  17. Specific welds for test blanket modules

    NASA Astrophysics Data System (ADS)

    Rieth, Michael; Rey, Jörg

    2009-04-01

    Fabrication and assembling test blanket modules needs a variety of different welding techniques. Therefore, an evaluation of plate joining for breeder units by tungsten-inert-gas, laser, and electron beam welding was performed by qualification of relevant mechanical properties like hardness, charpy, and creep strength. The focus was laid on the study of post-weld heat treatments at lowest possible temperatures and for maximum recovery of the joints. The most important result is that thin EUROFER plates may be welded by EB or laser techniques without the necessity of post-welding heat treatments that include an austenitization step.

  18. Event-Specific Prevention: addressing college student drinking during known windows of risk.

    PubMed

    Neighbors, Clayton; Walters, Scott T; Lee, Christine M; Vader, Amanda M; Vehige, Tamara; Szigethy, Thomas; DeJong, William

    2007-11-01

    The unique drinking patterns of college students call for Event-Specific Prevention (ESP) strategies that address college student drinking associated with peak times and events. Despite limited research evaluating ESP, many college campuses are currently implementing programming for specific events. The present paper provides a review of existing literature related to ESP and offers practical guidance for research and practice. The prevention typology proposed by DeJong and Langford [DeJong, W. & Langford, L. M. (2002). A typology for campus-based alcohol prevention: Moving toward environmental management strategies. Journal of Studies on Alcohol, 140-147.] provides a framework for strategic planning, suggesting that programs and policies should address problems at the individual, group, institution, community, state, and society level, and that these interventions should focus on knowledge change, environmental change, health protection, and intervention and treatment services. From this typology, specific examples are provided for comprehensive program planning related to orientation/beginning of school year, homecoming, 21st birthday celebrations, spring break, and graduation. In addition, the University of Connecticut's efforts to address problems resulting from its annual Spring Weekend are described as an illustration of how advance planning by campus and community partners can produce a successful ESP effort. PMID:17616260

  19. Event-Specific Prevention: Addressing College Student Drinking During Known Windows of Risk

    PubMed Central

    Neighbors, Clayton; Walters, Scott T.; Lee, Christine M.; Vader, Amanda M.; Vehige, Tamara; Szigethy, Thomas; DeJong, William

    2007-01-01

    The unique drinking patterns of college students call for Event-Specific Prevention (ESP) strategies that address college student drinking associated with peak times and events. Despite limited research evaluating ESP, many college campuses are currently implementing programming for specific events. The present paper provides a review of existing literature related to ESP and offers practical guidance for research and practice. The prevention typology proposed by DeJong and Langford (2002) provides a framework for strategic planning, suggesting that programs and policies should address problems at the individual, group, institution, community, state, and society level, and that these interventions should focus on knowledge change, environmental change, health protection, and intervention and treatment services. From this typology, specific examples are provided for comprehensive program planning related to orientation/beginning of school year, homecoming, 21st birthday celebrations, spring break, and graduation. In addition, the University of Connecticut’s efforts to address problems resulting from its annual Spring Weekend are described as an illustration of how advance planning by campus and community partners can produce a successful ESP effort. PMID:17616260

  20. Patient specific tube current modulation for CT dose reduction

    NASA Astrophysics Data System (ADS)

    Jin, Yannan; Yin, Zhye; Yao, Yangyang; Wang, Hui; Wu, Mingye; Kalra, Mannudeep; De Man, Bruno

    2015-03-01

    Radiation exposure during CT imaging has drawn growing concern from academia, industry as well as the general public. Sinusoidal tube current modulation has been available in most commercial products and used routinely in clinical practice. To further exploit the potential of tube current modulation, Sperl et al. proposed a Computer-Assisted Scan Protocol and Reconstruction (CASPAR) scheme [6] that modulates the tube current based on the clinical applications and patient specific information. The purpose of this study is to accelerate the CASPAR scheme to make it more practical for clinical use and investigate its dose benefit for different clinical applications. The Monte Carlo simulation in the original CASPAR scheme was substituted by the dose reconstruction to accelerate the optimization process. To demonstrate the dose benefit, we used the CATSIM package generate the projection data and perform standard FDK reconstruction. The NCAT phantom at thorax position was used in the simulation. We chose three clinical cases (routine chest scan, coronary CT angiography with and without breast avoidance) and compared the dose level with different mA modulation schemes (patient specific, sinusoidal and constant mA) with matched image quality. The simulation study of three clinical cases demonstrated that the patient specific mA modulation could significantly reduce the radiation dose compared to sinusoidal modulation. The dose benefits depend on the clinical application and object shape. With matched image quality, for chest scan the patient specific mA profile reduced the dose by about 15% compared to the sinusoid mA modulation; for the organ avoidance scan the dose reduction to the breast was over 50% compared to the constant mA baseline.

  1. Vocal Imitation in Parrots Allows Addressing of Specific Individuals in a Dynamic Communication Network

    PubMed Central

    Balsby, Thorsten J. S.; Momberg, Jane Vestergaard; Dabelsteen, Torben

    2012-01-01

    Parrots in captivity are known for their ability to vocally imitate humans and recently it has been shown that wild-living orange-fronted conures are able to immediately imitate other individuals’ contact calls. The function of this exceptional ability to imitate remains unclear. However, orange–fronted conures live in fission-fusion flocks where they encounter many different individuals every day, and it is possible that their vocal imitation ability is a flexible means to address a specific individual within a flock. We tested this via playback to short-term captive wild conures. Test birds were placed together in pairs in outdoor aviaries to form simple flocks. To simulate imitation of a specific individual these pairs received playback of contact calls that primarily imitate one of the two birds. Overall, individuals that received simulated vocal imitations of its calls responded more frequently and faster than the other individual. This suggests that orange-fronted conures can use imitations of contact calls to address specific individuals of a flock. In the discussion we argue that the fission-fusion flock dynamics of many parrot species has been an important factor in evolving conures’ and other parrots’ exceptional ability to imitate. PMID:23185424

  2. Vocal imitation in parrots allows addressing of specific individuals in a dynamic communication network.

    PubMed

    Balsby, Thorsten J S; Momberg, Jane Vestergaard; Dabelsteen, Torben

    2012-01-01

    Parrots in captivity are known for their ability to vocally imitate humans and recently it has been shown that wild-living orange-fronted conures are able to immediately imitate other individuals' contact calls. The function of this exceptional ability to imitate remains unclear. However, orange-fronted conures live in fission-fusion flocks where they encounter many different individuals every day, and it is possible that their vocal imitation ability is a flexible means to address a specific individual within a flock. We tested this via playback to short-term captive wild conures. Test birds were placed together in pairs in outdoor aviaries to form simple flocks. To simulate imitation of a specific individual these pairs received playback of contact calls that primarily imitate one of the two birds. Overall, individuals that received simulated vocal imitations of its calls responded more frequently and faster than the other individual. This suggests that orange-fronted conures can use imitations of contact calls to address specific individuals of a flock. In the discussion we argue that the fission-fusion flock dynamics of many parrot species has been an important factor in evolving conures' and other parrots' exceptional ability to imitate. PMID:23185424

  3. Selective estrogen receptor modulators: tissue specificity and clinical utility

    PubMed Central

    Martinkovich, Stephen; Shah, Darshan; Planey, Sonia Lobo; Arnott, John A

    2014-01-01

    Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs. PMID:25210448

  4. Content-addressable Holographic Digital Data Storage Based on Hybrid Ternary Modulation with a Twisted-Nematic Liquid-Crystal Spatial Light Modulator

    NASA Astrophysics Data System (ADS)

    John, Renu; Joseph, Joby; Singh, Kehar

    We propose and demonstrate the use of hybrid ternary modulated digital pages for content-addressable holographic data storage. Display of binary data pages with equal number of ZEROs and ONEs by modulating both amplitude and phase of beams using twisted-nematic liquid crystal spatial light modulator, reduces strong de component and produces a more homogeneous spectral distribution at the recording plane. This technique facilitates better recording of all spatial frequencies, thus improving the discrimination capability of a content-addressable memory. Hence we get better results in associative recall in a holographic memory system, with very low number of false hits. An important advantage of the hybrid ternary modulation over pure phase data pages is that it offers a dark state for coding the undesired portion of the SLM while the search argument is small. The unique orientation of quarter wave plate and the analyzer blocks the light transmitted from OFF pixels leading to near total removal of dark signals. This in turn improves the system performance and reduces the number of false hits when the size of the search argument is small. Our experimental results show good discrimination capability and signal-to-noise ratio for a hybrid ternary modulation based content addressable memory.

  5. Spatiotemporal dynamics of early spatial and category-specific attentional modulations.

    PubMed

    Ioannides, Andreas A; Poghosyan, Vahe

    2012-04-15

    Different attention types select and focus brain resources on relevant sensory information. However, key questions remain unresolved: when and where cortical visual processing is first modulated by different types of attention? How do such modulatory effects spread thereafter? Here, we address these issues for spatial and category-specific types of attention using magnetoencephalography (MEG). First we identified the dynamics of visual attention-independent sensory processing to serve as a baseline framework for the attentional modulations of interest. We found that visual information is processed through the entire hierarchy of visual areas in at least two phases, in the 40-130 ms and 130-230 ms periods respectively. Spatial attention modulations were identified from the beginning of the initial stimulus-evoked response in the primary visual cortex ~70 ms post-stimulus. Category-specific attention modulated face processing beginning from the first face-specific response in high-level object-related areas ~100 ms post-stimulus, substantially earlier than previously reported for face-directed attention. Thus both attention types modulated responses during the first processing phase, beginning at the earliest brain area capable of coding the attentional target. Thereafter attentional effects propagated through the visual cortex together with the stimulus-evoked activity. Category-specific attention did not affect the first-phase responses in low-level strongly retinotopic visual areas, while the second-phase responses were enhanced when the stimulus was the response target and reduced when it was a distractor. Responses during both phases in high-level object-related areas were enhanced by category-specific attention independent of their target/distractor status. Spatial attention effects were stronger in low-level areas, whereas category-specific attention effects were stronger in high-level object-related areas. PMID:22342803

  6. Interfacing modules for integrating discipline specific structural mechanics codes

    NASA Technical Reports Server (NTRS)

    Endres, Ned M.

    1989-01-01

    An outline of the organization and capabilities of the Engine Structures Computational Simulator (Simulator) at NASA Lewis Research Center is given. One of the goals of the research at Lewis is to integrate various discipline specific structural mechanics codes into a software system which can be brought to bear effectively on a wide range of engineering problems. This system must possess the qualities of being effective and efficient while still remaining user friendly. The simulator was initially designed for the finite element simulation of gas jet engine components. Currently, the simulator has been restricted to only the analysis of high pressure turbine blades and the accompanying rotor assembly, although the current installation can be expanded for other applications. The simulator presently assists the user throughout its procedures by performing information management tasks, executing external support tasks, organizing analysis modules and executing these modules in the user defined order while maintaining processing continuity.

  7. Series-connected shaded modules to address partial shading conditions in SPV systems

    NASA Astrophysics Data System (ADS)

    Pareek, Smita; Dahiya, Ratna

    2016-03-01

    With the progress of technology and reduced cost of PV cells, the PV systems are being installed in many countries, including India. Even though this method of power generation has sufficient potential but its effective utilization is still lacking. This is because the output power of PV cells depends on many factors like insolation, temperature, climate conditions prevailing nearby, aging, using modules from different technologies/manufacturers or partial shading conditions. Among these factors, partial shading causes major reduction in output power despite the size of PV systems. As a result, the produced power is lower than the expected value. The connection of modules to each other has great impact on output power if they are prone to partial shading conditions. In this paper, PV arrays are investigated under partial shading conditions. The results show that partial shading losses can be minimized by connecting shaded modules in series rather than in parallel.

  8. Spatially addressable design of gradient index structures through spatial light modulator based holographic lithography

    SciTech Connect

    Ohlinger, Kris; Lutkenhaus, Jeff; Arigong, Bayaner; Zhang, Hualiang; Lin, Yuankun

    2013-12-07

    In this paper, we present an achievable gradient refractive index in bi-continuous holographic structures that are formed through five-beam interference. We further present a theoretic approach for the realization of gradient index devices by engineering the phases of the interfering beams with a pixelated spatial light modulator. As an example, the design concept of a gradient index Luneburg lens is verified through full-wave electromagnetic simulations. These five beams with desired phases can be generated through programming gray level super-cells in a diffractive spatial light modulator. As a proof-of-concept, gradient index structures are demonstrated using synthesized and gradient phase patterns displayed in the spatial light modulator.

  9. Polymeric membranes modulate human keratinocyte differentiation in specific epidermal layers.

    PubMed

    Salerno, Simona; Morelli, Sabrina; Giordano, Francesca; Gordano, Amalia; Bartolo, Loredana De

    2016-10-01

    In vitro models of human bioengineered skin substitutes are an alternative to animal experimentation for testing the effects and toxicity of drugs, cosmetics and pollutants. For the first time specific and distinct human epidermal strata were engineered by using membranes and keratinocytes. To this purpose, biodegradable membranes of chitosan (CHT), polycaprolactone (PCL) and a polymeric blend of CHT-PCL were prepared by phase-inversion technique and characterized in order to evaluate their morphological, physico-chemical and mechanical properties. The capability of membranes to modulate keratinocyte differentiation inducing specific interactions in epidermal membrane systems was investigated. The overall results demonstrated that the membrane properties strongly influence the cell morpho-functional behaviour of human keratinocytes, modulating their terminal differentiation, with the creation of specific epidermal strata or a fully proliferative epidermal multilayer system. In particular, human keratinocytes adhered on CHT and CHT-PCL membranes, forming the structure of the epidermal top layers, such as the corneum and granulosum strata, characterized by withdrawal or reduction from the cell cycle and cell proliferation. On the PCL membrane, keratinocytes developed an epidermal basal lamina, with high proliferating cells that stratified and migrated over time to form a complete differentiating epidermal multilayer system. PMID:27371895

  10. Characterization of submillisecond response optical addressing phase modulator based on low light scattering polymer network liquid crystal

    NASA Astrophysics Data System (ADS)

    Xiangjie, Zhao; Cangli, Liu; Jiazhu, Duan; Dayong, Zhang; Yongquan, Luo

    2015-01-01

    Optically addressed conventional nematic liquid crystal spatial light modulator has attracted wide research interests. But the slow response speed limited its further application. In this paper, polymer network liquid crystal (PNLC) was proposed to replace the conventional nematic liquid crystal to enhance the response time to the order of submillisecond. The maximum light scattering of the employed PNLC was suppressed to be less than 2% at 1.064 μm by optimizing polymerization conditions and selecting large viscosity liquid crystal as solvent. The occurrence of phase ripple phenomenon due to electron diffusion and drift in photoconductor was found to deteriorate the phase modulation effect of the optical addressed PNLC phase modulator. The wavelength effect and AC voltage frequency effect on the on state dynamic response of phase change was investigated by experimental methods. These effects were interpreted by electron diffusion and drift theory based on the assumption that free electron was inhomogeneously distributed in accordance with the writing beam intensity distribution along the incident direction. The experimental results indicated that the phase ripple could be suppressed by optimizing the wavelength of the writing beam and the driving AC voltage frequency when varying the writing beam intensity to generate phase change in 2π range. The modulation transfer function was also measured.

  11. Characterization of submillisecond response optical addressing phase modulator based on low light scattering polymer network liquid crystal

    SciTech Connect

    Xiangjie, Zhao E-mail: zxjdouble@gmail.com; Cangli, Liu; Jiazhu, Duan; Dayong, Zhang; Yongquan, Luo

    2015-01-07

    Optically addressed conventional nematic liquid crystal spatial light modulator has attracted wide research interests. But the slow response speed limited its further application. In this paper, polymer network liquid crystal (PNLC) was proposed to replace the conventional nematic liquid crystal to enhance the response time to the order of submillisecond. The maximum light scattering of the employed PNLC was suppressed to be less than 2% at 1.064 μm by optimizing polymerization conditions and selecting large viscosity liquid crystal as solvent. The occurrence of phase ripple phenomenon due to electron diffusion and drift in photoconductor was found to deteriorate the phase modulation effect of the optical addressed PNLC phase modulator. The wavelength effect and AC voltage frequency effect on the on state dynamic response of phase change was investigated by experimental methods. These effects were interpreted by electron diffusion and drift theory based on the assumption that free electron was inhomogeneously distributed in accordance with the writing beam intensity distribution along the incident direction. The experimental results indicated that the phase ripple could be suppressed by optimizing the wavelength of the writing beam and the driving AC voltage frequency when varying the writing beam intensity to generate phase change in 2π range. The modulation transfer function was also measured.

  12. Preparing teachers to address climate change with project-based instructional modules

    NASA Astrophysics Data System (ADS)

    Powers, S. E.; DeWaters, J.; Small, M.; Dhaniyala, S.

    2012-12-01

    Clarkson University's Project-Based Global Climate Change Education project funded by NASA has created and disseminated several instructional modules for middle and high school teachers. The modules were developed by a team of teachers and university students and faculty. Fundamental to these inquiry-based modules are questions about climate change or mitigation efforts, use of real-world data to explore historical climate changes, and review of IPCC model results to understand predictions of further changes over the next century. As an example, the Climate Connections module requires middle school students to investigate a geographic region, learn about the culture and likely carbon footprint, and then acquire and analyze data sets of historical and predicted temperature changes. The findings are then interpreted in relation to the impact of these changes on the region's culture. NOAA, NASA, IPCC and DOE databases are used extensively. The inquiry approach and core content included in these modules are well aligned with the new Framework for K-12 Science Education. The climate change science in these modules covers aspects of the disciplinary core subjects (dimension 3) and most of the cross cutting concepts (dimension 2). Our approach for inquiry and analysis are also authentic ways to include most of the science and engineering practices (dimension 1) included in the framework. Dissemination of the modules to teachers in New York State has been a joint effort by NYSERDA (New York State Energy Research and Development Authority) and Clarkson. Half-day and full-day workshops and week-long institutes provided opportunities to either introduce the modules and the basics of finding and using temperature data, or delve into the science concepts and integration of the modules into an instructional plan. A significant challenge has been identified by the workshop instructors - many science teachers lack the skills necessary to fully engage in the science and engineering

  13. Functional specification of the Performance Measurement (PM) module

    NASA Technical Reports Server (NTRS)

    Berliner, J. E.

    1980-01-01

    The design of the Performance Measurement Module is described with emphasis on what the PM Module would do, and what it would look like to the user. The PM Module as described could take several man-years to develop. An evolutionary approach to the implementation of the PM Module is presented which would provide an operational baseline PM Module within a few months.

  14. Sex-specific Immune Modulation of Primary Hypertension

    PubMed Central

    Sandberg, Kathryn; Ji, Hong; Hay, Meredith

    2015-01-01

    It is well known that the onset of essential hypertension occurs earlier in men than women. Numerous studies have shown sex differences in the vasculature, kidney and sympathetic nervous system contribute to this sex difference in the development of hypertension. The immune system also contributes to the development of hypertension; however, sex differences in immune system modulation of blood pressure (BP) and the development of hypertension has only recently begun to be explored. Here we review findings on the effect of one's sex on the immune system and specifically how these effects impact BP and the development of primary hypertension. We also propose a hypothesis for why mechanisms underlying inflammation-induced hypertension are sex-specific. These studies underscore the value of and need for studying both sexes in the basic science exploration of the pathophysiology of hypertension as well as other diseases. PMID:25498375

  15. 46 CFR 107.317 - Addresses for submittal of plans, specifications, and calculations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-MOBILE OFFSHORE DRILLING UNITS INSPECTION AND CERTIFICATION Plan Approval § 107.317 Addresses for...) The Officer in Charge, Marine Inspection, in the zone in which the unit is to be built or altered....

  16. Molecular beam epitaxy engineered III-V semiconductor structures for low-power optically addressed spatial light modulators

    NASA Technical Reports Server (NTRS)

    Larsson, Anders G.; Maserjian, Joseph

    1992-01-01

    Device approaches are investigated for optically addressed SLMs based on molecular-beam epitaxy (MBE) engineered III-V materials and structures. Strong photooptic effects can be achieved in periodically delta-doped multiple-quantum-well structures, but are still insufficient for high-contrast modulation with only single- or double-pass absorption through active layers of practical thickness. The asymmetric Fabry-Perot cavity approach is employed to permit extinction of light due to interference of light reflected from the front and back surfaces of the cavity. This approach is realized with an all-MBE-grown structure consisting of GaAs/AlAs quarter-wave stack reflector grown over the GaAs substrate as the high reflectance mirror and the GaAs surface as the low reflectance mirror. High-contrast modulation is achieved using a low-power InGaAs/GaAs quantum well laser for the control signal.

  17. To What Extent Is Criminal Justice Content Specifically Addressed in MSW Programs?

    ERIC Educational Resources Information Center

    Epperson, Matthew W.; Roberts, Leslie E.; Ivanoff, Andre; Tripodi, Stephen J.; Gilmer, Christy N.

    2013-01-01

    This study examined the extent to which criminal justice content is addressed in all CSWE-accredited MSW programs in the United States ("N"?=?192). Criminal justice content was measured in three areas: (1) dual or joint degree programs, (2) concentrations or specializations, and (3) coursework. Excluding social work and law classes, 22%…

  18. Smoking modulates language lateralization in a sex-specific way.

    PubMed

    Hahn, Constanze; Pogun, Sakire; Güntürkün, Onur

    2010-12-01

    Smoking affects a widespread network of neuronal functions by altering the properties of acetylcholinergic transmission. Recent studies show that nicotine consumption affects ascending auditory pathways and alters auditory attention, particularly in men. Here we show that smoking affects language lateralization in a sex-specific way. We assessed brain asymmetries of 90 healthy, right-handed participants using a classic consonant-vowel syllable dichotic listening paradigm in a 2×3 experimental design with sex (male, female) and smoking status (non-smoker, light smoker, heavy smoker) as between-subject factors. Our results revealed that male smokers had a significantly less lateralized response pattern compared to the other groups due to a decreased response rate of their right ear. This finding suggests a group-specific impairment of the speech dominant left hemisphere. In addition, decreased overall response accuracy was observed in male smokers compared to the other experimental groups. Similar adverse effects of smoking were not detected in women. Further, a significant negative correlation was detected between the severity of nicotine dependency and response accuracy in male but not in female smokers. Taken together, these results show that smoking modulates functional brain lateralization significantly and in a sexually dimorphic manner. Given that some psychiatric disorders have been associated with altered brain asymmetries and increased smoking prevalence, nicotinergic effects need to be specifically investigated in this context in future studies. PMID:20951712

  19. Cell-specific modulation of surfactant proteins by ambroxol treatment.

    PubMed

    Seifart, Carola; Clostermann, Ursula; Seifart, Ulf; Müller, Bernd; Vogelmeier, Claus; von Wichert, Peter; Fehrenbach, Heinz

    2005-02-15

    Ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanole hydrochloride], a mucolytic agent, was postulated to provide surfactant stimulatory properties and was previously used to prevent surfactant deficiency. Currently, the underlying mechanisms are not exactly clear. Because surfactant homeostasis is regulated by surfactant-specific proteins (SP), we analyzed protein amount and mRNA expression in whole lung tissue, isolated type II pneumocytes and bronchoalveolar lavage of Sprague-Dawley rats treated with ambroxol i.p. (75 mg/kg body weight, twice a day [every 12 h]). The methods used included competitive polymerase chain reaction (RT-PCR), Northern blotting, Western immunoblotting, and immunohistochemistry. In isolated type II pneumocytes of ambroxol-treated animals, SP-C protein and mRNA content were increased, whereas SP-A, -B and -D protein, mRNA, and immunoreactivity remained unaffected. However, ambroxol treatment resulted in a significant increase of SP-B and in a decrease of SP-D in whole lung tissue with enhanced immunostaining for SP-B in Clara Cells. SP-A and SP-D were significantly decreased in BAL fluid of ambroxol-treated animals. The data suggest that surfactant protein expression is modulated in a cell-specific manner by ambroxol, as type II pneumocytes exhibited an increase in SP-C, whereas Clara cells exhibited an increase in the immunoreactivity for SP-B accounting for the increased SP-B content of whole lung tissue. The results indicate that ambroxol may exert its positive effects, observed in the treatment of diseases related to surfactant deficiency, via modulation of surfactant protein expression. PMID:15694461

  20. Cell-specific modulation of surfactant proteins by ambroxol treatment

    SciTech Connect

    Seifart, Carola . E-mail: zwiebel@mailer.uni-marburg.de; Clostermann, Ursula; Seifart, Ulf

    2005-02-15

    Ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanole hydrochloride], a mucolytic agent, was postulated to provide surfactant stimulatory properties and was previously used to prevent surfactant deficiency. Currently, the underlying mechanisms are not exactly clear. Because surfactant homeostasis is regulated by surfactant-specific proteins (SP), we analyzed protein amount and mRNA expression in whole lung tissue, isolated type II pneumocytes and bronchoalveolar lavage of Sprague-Dawley rats treated with ambroxol i.p. (75 mg/kg body weight, twice a day [every 12 h]). The methods used included competitive polymerase chain reaction (RT-PCR), Northern blotting, Western immunoblotting, and immunohistochemistry. In isolated type II pneumocytes of ambroxol-treated animals, SP-C protein and mRNA content were increased, whereas SP-A, -B and -D protein, mRNA, and immunoreactivity remained unaffected. However, ambroxol treatment resulted in a significant increase of SP-B and in a decrease of SP-D in whole lung tissue with enhanced immunostaining for SP-B in Clara Cells. SP-A and SP-D were significantly decreased in BAL fluid of ambroxol-treated animals. The data suggest that surfactant protein expression is modulated in a cell-specific manner by ambroxol, as type II pneumocytes exhibited an increase in SP-C, whereas Clara cells exhibited an increase in the immunoreactivity for SP-B accounting for the increased SP-B content of whole lung tissue. The results indicate that ambroxol may exert its positive effects, observed in the treatment of diseases related to surfactant deficiency, via modulation of surfactant protein expression.

  1. Addressable, large-field second harmonic generation microscopy based on 2D acousto-optical deflector and spatial light modulator

    PubMed Central

    Shao, Yonghong; Liu, Honghai; Qin, Wan; Qu, Junle; Peng, Xiang; Niu, Hanben

    2013-01-01

    We present an addressable, large-field second harmonic generation microscope by combining a 2D acousto-optical deflector with a spatial light modulator. The SLM shapes an incoming mode-locked, near-infrared Ti:Sapphire laser beam into a multifocus array, which can be rapidly scanned by changing the incident angle of the laser beam using a 2D acousto-optical deflector. Compared to the single-beam-scan technique, the multifocus array scan can increase the scanning rate and the field-of-view size with the multi-region imaging ability. PMID:24307756

  2. Optical correlator using very-large-scale integrated circuit/ferroelectric-liquid-crystal electrically addressed spatial light modulators

    NASA Technical Reports Server (NTRS)

    Turner, Richard M.; Jared, David A.; Sharp, Gary D.; Johnson, Kristina M.

    1993-01-01

    The use of 2-kHz 64 x 64 very-large-scale integrated circuit/ferroelectric-liquid-crystal electrically addressed spatial light modulators as the input and filter planes of a VanderLugt-type optical correlator is discussed. Liquid-crystal layer thickness variations that are present in the devices are analyzed, and the effects on correlator performance are investigated through computer simulations. Experimental results from the very-large-scale-integrated / ferroelectric-liquid-crystal optical-correlator system are presented and are consistent with the level of performance predicted by the simulations.

  3. Phase control and fast start-up of a magnetron using modulation of an addressable faceted cathode

    SciTech Connect

    Browning, J. Fernandez-Gutierrez, S.; Lin, M. C.; Smithe, D. N.; Watrous, J.

    2014-06-09

    The use of an addressable, faceted cathode has been proposed as a method of modulating current injection in a magnetron to improve performance and control phase. To implement the controllable electron emission, five-sided and ten-sided faceted planar cathodes employing gated field emitters are considered as these emitters could be fabricated on flat substrates. For demonstration, the conformal finite-difference time-domain particle-in-cell simulation, as implemented in VORPAL, has been used to model a ten-cavity, rising sun magnetron using the modulated current sources and benchmarked against a typical continuous current source. For the modulated, ten-sided faceted cathode case, the electrons are injected from three emitter elements on each of the ten facets. Each emitter is turned ON and OFF in sequence at the oscillating frequency with five emitters ON at one time to drive the five electron spokes of the π-mode. The emitter duty cycle is then 1/6th the Radio-Frequency (RF) period. Simulations show a fast start-up time as low as 35 ns for the modulated case compared to 100 ns for the continuous current cases. Analysis of the RF phase using the electron spoke locations and the RF magnetic field components shows that the phase is controlled for the modulated case while it is random, as typical, for the continuous current case. Active phase control during oscillation was demonstrated by shifting the phase of the electron injection 180° after oscillations started. The 180° phase shift time was approximately 25 RF cycles.

  4. Increased Anatomical Specificity of Neuromodulation via Modulated Focused Ultrasound

    PubMed Central

    Mehić, Edin; Xu, Julia M.; Caler, Connor J.; Coulson, Nathaniel K.; Moritz, Chet T.; Mourad, Pierre D.

    2014-01-01

    Transcranial ultrasound can alter brain function transiently and nondestructively, offering a new tool to study brain function now and inform future therapies. Previous research on neuromodulation implemented pulsed low-frequency (250–700 kHz) ultrasound with spatial peak temporal average intensities (ISPTA) of 0.1–10 W/cm2. That work used transducers that either insonified relatively large volumes of mouse brain (several mL) with relatively low-frequency ultrasound and produced bilateral motor responses, or relatively small volumes of brain (on the order of 0.06 mL) with relatively high-frequency ultrasound that produced unilateral motor responses. This study seeks to increase anatomical specificity to neuromodulation with modulated focused ultrasound (mFU). Here, ‘modulated’ means modifying a focused 2-MHz carrier signal dynamically with a 500-kHz signal as in vibro-acoustography, thereby creating a low-frequency but small volume (approximately 0.015 mL) source of neuromodulation. Application of transcranial mFU to lightly anesthetized mice produced various motor movements with high spatial selectivity (on the order of 1 mm) that scaled with the temporal average ultrasound intensity. Alone, mFU and focused ultrasound (FUS) each induced motor activity, including unilateral motions, though anatomical location and type of motion varied. Future work should include larger animal models to determine the relative efficacy of mFU versus FUS. Other studies should determine the biophysical processes through which they act. Also of interest is exploration of the potential research and clinical applications for targeted, transcranial neuromodulation created by modulated focused ultrasound, especially mFU’s ability to produce compact sources of ultrasound at the very low frequencies (10–100s of Hertz) that are commensurate with the natural frequencies of the brain. PMID:24504255

  5. Education and Training to Address Specific Needs During the Career Progression of Surgeons.

    PubMed

    Sachdeva, Ajit K; Blair, Patrice Gabler; Lupi, Linda K

    2016-02-01

    Surgeons have specific education and training needs as they enter practice, progress through the core period of active practice, and then as they wind down their clinical work before retirement. These transitions and the career progression process, combined with the dynamic health care environment, present specific opportunities for innovative education and training based on practice-based learning and improvement, and continuous professional development methods. Cutting-edge technologies, blended models, simulation, mentoring, preceptoring, and integrated approaches can play critical roles in supporting surgeons as they provide the best surgical care throughout various phases of their careers. PMID:26612024

  6. Issue-Specific Barriers to Addressing Environmental Issues in the Classroom: An Exploratory Study

    ERIC Educational Resources Information Center

    Kim, Chankook; Fortner, Rosanne W.

    2006-01-01

    To explore issue-specific barriers to teaching environmental issues, the authors investigated secondary science teachers' perceived current and preferred teaching levels for 23 environmental issues and perceived barriers to teaching the selected issues. Subjects in this graduate project were 41 secondary science teachers self-selected to answer a…

  7. Enhancer-specific modulation of E protein activity.

    PubMed

    Markus, Maurice; Du, Zhimei; Benezra, Robert

    2002-02-22

    Homodimeric complexes of members of the E protein family of basic helix-loop-helix (bHLH) transcription factors are important for tissue-specific activation of genes in B lymphocytes (Bain, G., Gruenwald, S., and Murre, C. (1993) Mol. Cell Biol. 13, 3522-3529; Shen, C. P., and Kadesch, T. (1995) Mol. Cell Biol. 15, 4518-4524; Jacobs, Y., et al. (1994) Mol. Cell Biol. 14, 4087-4096; Wilson, R. B., et al. (1991) Mol. Cell Biol. 11, 6185-6191). These homodimers, however, have little activity on myogenic enhancers (Weintraub, H., Genetta, T., and Kadesch, T. (1994) Genes Dev. 8, 2203-2211). We report here the identification of a novel cis-acting transcriptional repression domain in the E protein family of bHLH transcription factors. This domain, the Rep domain, is present in each of the known vertebrate E proteins. Extensive mapping analysis demonstrates that this domain is an acidic region of 30 amino acids with a predicted loop structure. Fusion studies indicate that the Rep domain can repress both of the E protein transactivation domains (AD1 and AD2). Physiologically, the Rep domain plays a key role in maintaining E protein homodimers in an inactive state on myogenic enhancers. In addition, we demonstrate that Rep domain mediated repression of AD1 is a necessary for the function of MyoD-E protein heterodimeric complexes. These studies demonstrate that the Rep domain is important for modulating the transcriptional activity of E proteins and provide key insights into both the selectivity and mechanism of action of E protein containing bHLH protein complexes. PMID:11724804

  8. Addressing solar modulation and long-term uncertainties in scaling secondary cosmic rays for in situ cosmogenic nuclide applications [rapid communication

    NASA Astrophysics Data System (ADS)

    Lifton, Nathaniel A.; Bieber, John W.; Clem, John M.; Duldig, Marc L.; Evenson, Paul; Humble, John E.; Pyle, Roger

    2005-10-01

    Solar modulation affects the secondary cosmic rays responsible for in situ cosmogenic nuclide (CN) production the most at the high geomagnetic latitudes to which CN production rates are traditionally referenced. While this has long been recognized (e.g., D. Lal, B. Peters, Cosmic ray produced radioactivity on the Earth, in: K. Sitte (Ed.), Handbuch Der Physik XLVI/2, Springer-Verlag, Berlin, 1967, pp. 551-612 and D. Lal, Theoretically expected variations in the terrestrial cosmic ray production rates of isotopes, in: G.C. Castagnoli (Ed.), Proceedings of the Enrico Fermi International School of Physics 95, Italian Physical Society, Varenna 1988, pp. 216-233), these variations can lead to potentially significant scaling model uncertainties that have not been addressed in detail. These uncertainties include the long-term (millennial-scale) average solar modulation level to which secondary cosmic rays should be referenced, and short-term fluctuations in cosmic ray intensity measurements used to derive published secondary cosmic ray scaling models. We have developed new scaling models for spallogenic nucleons, slow-muon capture and fast-muon interactions that specifically address these uncertainties. Our spallogenic nucleon scaling model, which includes data from portions of 5 solar cycles, explicitly incorporates a measure of solar modulation ( S), and our fast- and slow-muon scaling models (based on more limited data) account for solar modulation effects through increased uncertainties. These models improve on previously published models by better sampling the observed variability in measured cosmic ray intensities as a function of geomagnetic latitude, altitude, and solar activity. Furthermore, placing the spallogenic nucleon data in a consistent time-space framework allows for a more realistic assessment of uncertainties in our model than in earlier ones. We demonstrate here that our models reasonably account for the effects of solar modulation on measured

  9. Operating characteristics of pixelated gray-scale optically addressed spatial light modulators incorporating the twisted smectic-C* liquid crystal effect

    NASA Astrophysics Data System (ADS)

    Yim, Louis W.; Davey, Anthony B.; Travis, Adrian R.

    1998-08-01

    An optically addressed spatial light modulator using the twisted smectic-C* liquid crystal effect in the light- modulating layer and an intrinsic hydrogenated amorphous silicon in the photosensitive layer is fabricated. The device incorporates a layer of pixelated aluminum mirrors, sandwiched between photosensitive and modulating layers, to increase the reflectivity of the modulated output read beam. The device is capable of achieving an intrinsic gray-scale optical output. A spatial resolution of 27 lp/mm (i.e., 54 lines/mm) at 50% modulation depth driving at 2.0 kHz and a maximum frame rate of 2.5 kHz at 80% modulation depth for which a frame cycle includes erase, write, and read operations have been demonstrated. Other operating characteristics, i.e., the sensitivity and contrast ratio, are reported.

  10. Target cell-specific modulation of neuronal activity by astrocytes

    NASA Astrophysics Data System (ADS)

    Kozlov, A. S.; Angulo, M. C.; Audinat, E.; Charpak, S.

    2006-06-01

    Interaction between astrocytes and neurons enriches the behavior of brain circuits. By releasing glutamate and ATP, astrocytes can directly excite neurons and modulate synaptic transmission. In the rat olfactory bulb, we demonstrate that the release of GABA by astrocytes causes long-lasting and synchronous inhibition of mitral and granule cells. In addition, astrocytes release glutamate, leading to a selective activation of granule-cell NMDA receptors. Thus, by releasing excitatory and inhibitory neurotransmitters, astrocytes exert a complex modulatory control on the olfactory network. glutamate | GABA | inhibition | olfactory bulb | synchronization

  11. Discovering Distinct Functional Modules of Specific Cancer Types Using Protein-Protein Interaction Networks

    PubMed Central

    Shen, Ru; Wang, Xiaosheng; Guda, Chittibabu

    2015-01-01

    Background. The molecular profiles exhibited in different cancer types are very different; hence, discovering distinct functional modules associated with specific cancer types is very important to understand the distinct functions associated with them. Protein-protein interaction networks carry vital information about molecular interactions in cellular systems, and identification of functional modules (subgraphs) in these networks is one of the most important applications of biological network analysis. Results. In this study, we developed a new graph theory based method to identify distinct functional modules from nine different cancer protein-protein interaction networks. The method is composed of three major steps: (i) extracting modules from protein-protein interaction networks using network clustering algorithms; (ii) identifying distinct subgraphs from the derived modules; and (iii) identifying distinct subgraph patterns from distinct subgraphs. The subgraph patterns were evaluated using experimentally determined cancer-specific protein-protein interaction data from the Ingenuity knowledgebase, to identify distinct functional modules that are specific to each cancer type. Conclusion. We identified cancer-type specific subgraph patterns that may represent the functional modules involved in the molecular pathogenesis of different cancer types. Our method can serve as an effective tool to discover cancer-type specific functional modules from large protein-protein interaction networks. PMID:26495282

  12. Design specifications for manufacturability of MCM-C multichip modules

    SciTech Connect

    Blazek, R.; Desch, J.; Kautz, D.; Morgenstern, H.

    1996-10-01

    A comprehensive guide for ceramic-based multichip modules (MCMS) has been developed by AlliedSignal Federal Manufacturing & Technologies (FM&T) to provide manufacturability information for its customers about how MCM designs can be affected by existing process and equipment capabilities. This guide extends beyond a listing of design rules by providing information about design layout, low- temperature cofired ceramic (LTCC) substrate fabrication, MCM assembly and electrical testing Electrical mechanical packaging, environmental, and producibility issues are reviewed. Examples of three MCM designs are shown in the form of packaging cross-sectional views, LTCC substrate layer allocations, and overall MCM photographs. The guide has proven to be an effective tool for enhancing communications between MCM designers and manufacturers and producing a microcircuit that meets design requirements within the limitations of process capabilities.

  13. Modules, Theories, or Islands of Expertise? Domain Specificity in Socialization

    ERIC Educational Resources Information Center

    Gelman, Susan A.

    2010-01-01

    The domain-specific approach to socialization processes presented by J. E. Grusec and M. Davidov (this issue) provides a compelling framework for integrating and interpreting a large and disparate body of research findings, and it generates a wealth of testable new hypotheses. At the same time, it introduces core theoretical questions regarding…

  14. Mimicking enzymatic systems: modulation of the performance of polymeric organocatalysts by ion-specific effects.

    PubMed

    Xu, Yun; Hua, Zan; Zhang, Jian; Yang, Jun; Cao, Zhonglin; Zhang, Dongyang; He, Lingxin; J Craig, Vincent S; Zhang, Guangzhao; Liu, Guangming

    2016-02-16

    Like natural enzymatic systems, our study has demonstrated that the activity of the polymeric organocatalysts can be modulated by ion-specific effects via the combination of anion-specific salting-in/out effects and anion-specific polarization of hydrogen bonding induced stabilization of the transition state. PMID:26880479

  15. Segment Specification for the Payload Segment of the Reusable Reentry Satellite: Rodent Module Version

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The Reusable Reentry Satellite (RRS) System is composed of the payload segment (PS), vehicle segment (VS), and mission support (MS) segments. This specification establishes the performance, design, development, and test requirements for the RRS Rodent Module (RM).

  16. Segment specification for the payload segment of the reusable reentry satellite: Rodent module version

    NASA Astrophysics Data System (ADS)

    1991-02-01

    The Reusable Reentry Satellite (RRS) System is composed of the payload segment (PS), vehicle segment (VS), and mission support (MS) segments. This specification establishes the performance, design, development, and test requirements for the RRS Rodent Module (RM).

  17. Neural Differentiation Modulates the Vertebrate Brain Specific Splicing Program

    PubMed Central

    Madgwick, Alicia; Fort, Philippe; Hanson, Peter S.; Thibault, Philippe; Gaudreau, Marie-Claude; Lutfalla, Georges; Möröy, Tarik; Abou Elela, Sherif; Chaudhry, Bill; Elliott, David J.; Morris, Christopher M.; Venables, Julian P.

    2015-01-01

    Alternative splicing patterns are known to vary between tissues but these patterns have been found to be predominantly peculiar to one species or another, implying only a limited function in fundamental neural biology. Here we used high-throughput RT-PCR to monitor the expression pattern of all the annotated simple alternative splicing events (ASEs) in the Reference Sequence Database, in different mouse tissues and identified 93 brain-specific events that shift from one isoform to another (switch-like) between brain and other tissues. Consistent with an important function, regulation of a core set of 9 conserved switch-like ASEs is highly conserved, as they have the same pattern of tissue-specific splicing in all vertebrates tested: human, mouse and zebrafish. Several of these ASEs are embedded within genes that encode proteins associated with the neuronal microtubule network, and show a dramatic and concerted shift within a short time window of human neural stem cell differentiation. Similarly these exons are dynamically regulated in zebrafish development. These data demonstrate that although alternative splicing patterns often vary between species, there is nonetheless a core set of vertebrate brain-specific ASEs that are conserved between species and associated with neural differentiation. PMID:25993117

  18. Disgust-specific modulation of early attention processes.

    PubMed

    van Hooff, Johanna C; van Buuringen, Melanie; El M'rabet, Ihsane; de Gier, Margot; van Zalingen, Lilian

    2014-10-01

    Although threatening images are known to attract and keep our attention, little is known about the existence of emotion-specific attention effects. In this study (N=46), characteristics of an anticipated, disgust-specific effect were investigated by means of a covert orienting paradigm incorporating pictures that were either disgust-evoking, fear-evoking, happiness-evoking or neutral. Attention adhesion to these pictures was measured by the time necessary to identify a peripheral target, presented 100, 200, 500, or 800 ms after picture onset. Main results showed that reaction times were delayed for targets following the disgust-evoking pictures by 100 and 200 ms, suggesting that only these pictures temporarily grabbed hold of participants' attention. These delays were similar for ignore- and attend-instructions, and they were not affected by the participants' anxiety levels or disgust sensitivity. The disgust-specific influence on early attention processes thus appeared very robust, occurring in the majority of participants and without contribution of voluntary- and strategic-attention processes. In contrast, a smaller and less reliable effect of all emotional (arousing) pictures was present in the form of delayed responding in the 100 ms cue-target interval. This effect was more transitory and apparent only in participants with relatively high state-anxiety scores. Practical and theoretical consequences of these findings are discussed. PMID:25226546

  19. Neural differentiation modulates the vertebrate brain specific splicing program.

    PubMed

    Madgwick, Alicia; Fort, Philippe; Hanson, Peter S; Thibault, Philippe; Gaudreau, Marie-Claude; Lutfalla, Georges; Möröy, Tarik; Abou Elela, Sherif; Chaudhry, Bill; Elliott, David J; Morris, Christopher M; Venables, Julian P

    2015-01-01

    Alternative splicing patterns are known to vary between tissues but these patterns have been found to be predominantly peculiar to one species or another, implying only a limited function in fundamental neural biology. Here we used high-throughput RT-PCR to monitor the expression pattern of all the annotated simple alternative splicing events (ASEs) in the Reference Sequence Database, in different mouse tissues and identified 93 brain-specific events that shift from one isoform to another (switch-like) between brain and other tissues. Consistent with an important function, regulation of a core set of 9 conserved switch-like ASEs is highly conserved, as they have the same pattern of tissue-specific splicing in all vertebrates tested: human, mouse and zebrafish. Several of these ASEs are embedded within genes that encode proteins associated with the neuronal microtubule network, and show a dramatic and concerted shift within a short time window of human neural stem cell differentiation. Similarly these exons are dynamically regulated in zebrafish development. These data demonstrate that although alternative splicing patterns often vary between species, there is nonetheless a core set of vertebrate brain-specific ASEs that are conserved between species and associated with neural differentiation. PMID:25993117

  20. Stream specificity and asymmetries in feature binding and content-addressable access in visual encoding and memory.

    PubMed

    Huynh, Duong L; Tripathy, Srimant P; Bedell, Harold E; Ögmen, Haluk

    2015-01-01

    Human memory is content addressable-i.e., contents of the memory can be accessed using partial information about the bound features of a stored item. In this study, we used a cross-feature cuing technique to examine how the human visual system encodes, binds, and retains information about multiple stimulus features within a set of moving objects. We sought to characterize the roles of three different features (position, color, and direction of motion, the latter two of which are processed preferentially within the ventral and dorsal visual streams, respectively) in the construction and maintenance of object representations. We investigated the extent to which these features are bound together across the following processing stages: during stimulus encoding, sensory (iconic) memory, and visual short-term memory. Whereas all features examined here can serve as cues for addressing content, their effectiveness shows asymmetries and varies according to cue-report pairings and the stage of information processing and storage. Position-based indexing theories predict that position should be more effective as a cue compared to other features. While we found a privileged role for position as a cue at the stimulus-encoding stage, position was not the privileged cue at the sensory and visual short-term memory stages. Instead, the pattern that emerged from our findings is one that mirrors the parallel processing streams in the visual system. This stream-specific binding and cuing effectiveness manifests itself in all three stages of information processing examined here. Finally, we find that the Leaky Flask model proposed in our previous study is applicable to all three features. PMID:26382005

  1. Specific ion modulated thermoresponse of poly(N-isopropylacrylamide) brushes.

    PubMed

    Humphreys, Ben A; Willott, Joshua D; Murdoch, Timothy J; Webber, Grant B; Wanless, Erica J

    2016-02-17

    The influence of specific anions on the equilibrium thermoresponse of poly(N-isopropylacrylamide) (pNIPAM) brushes has been studied using in situ ellipsometry, quartz crystal microbalance with dissipation (QCM-D) and static contact angle measurements between 20 and 45 °C in the presence of up to 250 mM acetate and thiocyanate anions in water. The thickness and changes in dissipation exhibited a broad swelling transition spanning approximately 15 °C from collapsed (high temperatures) to swollen conformation (low temperatures) while the brush surface wettability changed over approximately 2 °C. In the presence of the kosmotropic acetate anions, the measured lower critical solution temperature (LCST) by the three techniques was very similar and decreased linearly as a function of ionic strength. Conversely, increasing the concentration of the chaotropic thiocyanate anions raised the LCST of the pNIPAM brushes with variation in the measured LCST between the three techniques increasing with ionic strength. The thickness of the pNIPAM brush was seen to progressively increase with increasing thiocyanate concentration at all temperatures. It is proposed that specific ion binding of the chaotropic thiocyanate anion with pNIPAM amide moieties increases the electrostatic intra- and intermolecular repulsion within and between pNIPAM chains. This allows the brush to begin to swell at higher temperatures and to an overall greater extent. PMID:26840183

  2. Earth Observatory Satellite system definition study. Report 5: System design and specifications. Volume 4: Mission peculiar spacecraft segment and module specifications

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The specifications for the Earth Observatory Satellite (EOS) peculiar spacecraft segment and associated subsystems and modules are presented. The specifications considered include the following: (1) wideband communications subsystem module, (2) mission peculiar software, (3) hydrazine propulsion subsystem module, (4) solar array assembly, and (5) the scanning spectral radiometer.

  3. Cell Type-Specific Modulation of Respiratory Chain Supercomplex Organization.

    PubMed

    Sun, Dayan; Li, Bin; Qiu, Ruyi; Fang, Hezhi; Lyu, Jianxin

    2016-01-01

    Respiratory chain complexes are organized into large supercomplexes among which supercomplex In + IIIn + IVn is the only one that can directly transfer electrons from NADH to oxygen. Recently, it was reported that the formation of supercomplex In + IIIn + IVn in mice largely depends on their genetic background. However, in this study, we showed that the composition of supercomplex In + IIIn + IVn is well conserved in various mouse and human cell lines. Strikingly, we found that a minimal supercomplex In + IIIn, termed "lowest supercomplex" (LSC) in this study because of its migration at the lowest position close to complex V dimers in blue native polyacrylamide gel electrophoresis, was associated with complex IV to form a supercomplex In + IIIn + IVn in some, but not all of the human and mouse cells. In addition, we observed that the 3697G>A mutation in mitochondrial-encoded NADH dehydrogenase 1 (ND1) in one patient with Leigh's disease specifically affected the assembly of supercomplex In + IIIn + IVn containing LSC, leading to decreased cellular respiration and ATP generation. In conclusion, we showed the existence of LSC In + IIIn + IVn and impairment of this supercomplex causes disease. PMID:27338358

  4. Cell Type-Specific Modulation of Respiratory Chain Supercomplex Organization

    PubMed Central

    Sun, Dayan; Li, Bin; Qiu, Ruyi; Fang, Hezhi; Lyu, Jianxin

    2016-01-01

    Respiratory chain complexes are organized into large supercomplexes among which supercomplex In + IIIn + IVn is the only one that can directly transfer electrons from NADH to oxygen. Recently, it was reported that the formation of supercomplex In + IIIn + IVn in mice largely depends on their genetic background. However, in this study, we showed that the composition of supercomplex In + IIIn + IVn is well conserved in various mouse and human cell lines. Strikingly, we found that a minimal supercomplex In + IIIn, termed “lowest supercomplex” (LSC) in this study because of its migration at the lowest position close to complex V dimers in blue native polyacrylamide gel electrophoresis, was associated with complex IV to form a supercomplex In + IIIn + IVn in some, but not all of the human and mouse cells. In addition, we observed that the 3697G>A mutation in mitochondrial-encoded NADH dehydrogenase 1 (ND1) in one patient with Leigh’s disease specifically affected the assembly of supercomplex In + IIIn + IVn containing LSC, leading to decreased cellular respiration and ATP generation. In conclusion, we showed the existence of LSC In + IIIn + IVn and impairment of this supercomplex causes disease. PMID:27338358

  5. Practical guidelines addressing ethical issues pertaining to the curation of human locus-specific variation databases (LSDBs)

    PubMed Central

    Povey, Sue; Al Aqeel, Aida I; Cambon-Thomsen, Anne; Dalgleish, Raymond; den Dunnen, Johan T; Firth, Helen V; Greenblatt, Marc S; Barash, Carol Isaacson; Parker, Michael; Patrinos, George P; Savige, Judith; Sobrido, Maria-Jesus; Winship, Ingrid; Cotton, Richard GH

    2010-01-01

    More than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype to genotype, are a valuable source of information for clinicians, patients, and their families, as well as for basic research. The initiators of the Human Variome Project recently recognized that having access to some of the immense resources of unpublished information already present in diagnostic laboratories would provide critical data to help manage genetic disorders. However, there are significant ethical issues involved in sharing these data worldwide. An international working group presents second-generation guidelines addressing ethical issues relating to the curation of human LSDBs that provide information via a Web-based interface. It is intended that these should help current and future curators and may also inform the future decisions of ethics committees and legislators. These guidelines have been reviewed by the Ethics Committee of the Human Genome Organization (HUGO). Hum Mutat 31:–6, 2010. © 2010 Wiley-Liss, Inc. PMID:20683926

  6. 47 CFR 73.758 - System specifications for digitally modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 4 2013-10-01 2013-10-01 false System specifications for digitally modulated emissions in the HF broadcasting service. 73.758 Section 73.758 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES International Broadcast Stations § 73.758 System specifications...

  7. 47 CFR 73.758 - System specifications for digitally modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 4 2012-10-01 2012-10-01 false System specifications for digitally modulated emissions in the HF broadcasting service. 73.758 Section 73.758 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES International Broadcast Stations § 73.758 System specifications...

  8. Modulation of Automatic Semantic Priming by Feature-Specific Attention Allocation

    ERIC Educational Resources Information Center

    Spruyt, Adriaan; De Houwer, Jan; Hermans, Dirk

    2009-01-01

    We argue that the semantic analysis of task-irrelevant stimuli is modulated by feature-specific attention allocation. In line with this hypothesis, we found semantic priming of pronunciation responses to depend upon the extent to which participants focused their attention upon specific semantic stimulus dimensions. In Experiment 1, we examined the…

  9. Infrared to visible image up-conversion using optically addressed spatial light modulator utilizing liquid crystal and InGaAs photodiodes

    NASA Astrophysics Data System (ADS)

    Solodar, A.; Arun Kumar, T.; Sarusi, G.; Abdulhalim, I.

    2016-01-01

    Combination of InGaAs/InP heterojunction photodetector with nematic liquid crystal (LC) as the electro-optic modulating material for optically addressed spatial light modulator for short wavelength infra-red (SWIR) to visible light image conversion was designed, fabricated, and tested. The photodetector layer is composed of 640 × 512 photodiodes array based on heterojunction InP/InGaAs having 15 μm pitch on InP substrate and with backside illumination architecture. The photodiodes exhibit extremely low, dark current at room temperature, with optimum photo-response in the SWIR region. The photocurrent generated in the heterojunction, due to the SWIR photons absorption, is drifted to the surface of the InP, thus modulating the electric field distribution which modifies the orientation of the LC molecules. This device can be attractive for SWIR to visible image upconversion, such as for uncooled night vision goggles under low ambient light conditions.

  10. Block 4 solar cell module design and test specification for residential applications

    NASA Technical Reports Server (NTRS)

    1978-01-01

    Near-term design, qualification and acceptance requirements are provided for terrestrial solar cell modules suitable for incorporation in photovoltaic power sources (2 kW to 10 kW) applied to single family residential installations. Requirement levels and recommended design limits for selected performance criteria are specified for modules intended principally for rooftop installations. Modules satisfying the requirements of this specification fall into one of two categories, residential panel or residential shingle, both meeting general performance requirements plus additional category peculiar constraints.

  11. The construction of movement with behavior-specific and behavior-independent modules.

    PubMed

    Jing, Jian; Cropper, Elizabeth C; Hurwitz, Itay; Weiss, Klaudiusz R

    2004-07-14

    Growing evidence suggests that different forms of complex motor acts are constructed through flexible combinations of a small number of modules in interneuronal networks. It remains to be established, however, whether a module simply controls groups of muscles and functions as a computational unit for use in multiple behaviors (behavior independent) or whether a module controls multiple salient features that define one behavior and is used primarily for that behavior (behavior specific). We used the Aplysia feeding motor network to examine the two proposals by studying the functions of identifiable interneurons. We identified three types of motor programs that resemble three types of behaviors that Aplysia produce: biting, swallowing, and rejection. Two ingestive programs (biting, swallowing) are defined by two movement parameters of the feeding apparatus (the radula): one is the same in both programs (phasing of radula closure motoneurons relative to radula protraction-retraction), whereas the other parameter (protraction duration) is different in the two programs. In each program, these two parameters were specified together by an individual neuron, but the neurons in each were different (B40 for biting, B30 for swallowing). These findings support the existence of behavior-specific modules. Furthermore, neuron B51 was found to mediate a phase that can be flexibly added on to both ingestive and egestive-rejection programs, suggesting that B51 may be a behavior-independent module. The functional interpretation of the role played by these modules is supported by the patterns of synaptic connectivity that they make. Thus, both behavior-specific and behavior-independent modules are used to construct complex behaviors. PMID:15254087

  12. Earth Observatory Satellite system definition study. Report 5: System design and specifications. Volume 3: General purpose spacecraft segment and module specifications

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The specifications for the Earth Observatory Satellite (EOS) general purpose aircraft segment are presented. The satellite is designed to provide attitude stabilization, electrical power, and a communications data handling subsystem which can support various mission peculiar subsystems. The various specifications considered include the following: (1) structures subsystem, (2) thermal control subsystem, (3) communications and data handling subsystem module, (4) attitude control subsystem module, (5) power subsystem module, and (6) electrical integration subsystem.

  13. Modular glucuronoxylan-specific xylanase with a family CBM35 carbohydrate-binding module.

    PubMed

    Valenzuela, Susana Valeria; Diaz, Pilar; Pastor, F I Javier

    2012-06-01

    Xyn30D from the xylanolytic strain Paenibacillus barcinonensis has been identified and characterized. The enzyme shows a modular structure comprising a catalytic module family 30 (GH30) and a carbohydrate-binding module family 35 (CBM35). Like GH30 xylanases, recombinant Xyn30D efficiently hydrolyzed glucuronoxylans and methyl-glucuronic acid branched xylooligosaccharides but showed no catalytic activity on arabinose-substituted xylans. Kinetic parameters of Xyn30D were determined on beechwood xylan, showing a K(m) of 14.72 mg/ml and a k(cat) value of 1,510 min(-1). The multidomain structure of Xyn30D clearly distinguishes it from the GH30 xylanases characterized to date, which are single-domain enzymes. The modules of the enzyme were individually expressed in a recombinant host and characterized. The isolated GH30 catalytic module showed specific activity, mode of action on xylan, and kinetic parameters that were similar to those of the full-length enzyme. Computer modeling of the three-dimensional structure of Xyn30D showed that the catalytic module is comprised of a common (β/α)(8) barrel linked to a side-associated β-structure. Several derivatives of the catalytic module with decreasing deletions of this associated structure were constructed. None of them showed catalytic activity, indicating the importance of the side β-structure in the catalysis of Xyn30D. Binding properties of the isolated carbohydrate-binding module were analyzed by affinity gel electrophoresis, which showed that the CBM35 of the enzyme binds to soluble glucuronoxylans and arabinoxylans. Analysis by isothermal titration calorimetry showed that CBM35 binds to glucuronic acid and requires calcium ions for binding. Occurrence of a CBM35 in a glucuronoxylan-specific xylanase is a differential trait of the enzyme characterized. PMID:22447606

  14. Photochromic dithienylethene-containing triarylborane derivatives: facile approach to modulate photochromic properties with multi-addressable functions.

    PubMed

    Poon, Chun-Ting; Lam, Wai Han; Wong, Hok-Lai; Yam, Vivian Wing-Wah

    2015-01-26

    A series of dithienylethene-containing triarylboranes has been designed, synthesized, and characterized. The electrochemistry, photophysics, and photochromic behavior have also been studied. The photophysical and photochromic properties could be facilely tuned in this system by varying the thiophene spacers (thiophene, thienothiophene, and bithiophene) between the dithienylethene and the dimesitylboron (BMes2 ) or the position of the BMes2 substitution in the thiophene spacers. The absorption of closed form has been found to be more sensitive towards the structural modification upon incorporation of the BMes2 unit. Moreover, multi-addressable photochromic reactivity is obtained upon addition of Lewis base (F(-) ), which is due to the formation of boron-Lewis base adduct. The dependence of the photophysical and photochromic properties on the thiophene spacers and the position of the BMes2 substitution has been further supported by computational studies. PMID:25469818

  15. Targeted treatment of cancer with radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies

    PubMed Central

    Zimmerman, Jacquelyn W.; Jimenez, Hugo; Pennison, Michael J.; Brezovich, Ivan; Morgan, Desiree; Mudry, Albert; Costa, Frederico P.; Barbault, Alexandre; Pasche, Boris

    2013-01-01

    In the past century, there have been many attempts to treat cancer with low levels of electric and magnetic fields. We have developed noninvasive biofeedback examination devices and techniques and discovered that patients with the same tumor type exhibit biofeedback responses to the same, precise frequencies. Intrabuccal administration of 27.12 MHz radiofrequency (RF) electromagnetic fields (EMF), which are amplitude-modulated at tumor-specific frequencies, results in long-term objective responses in patients with cancer and is not associated with any significant adverse effects. Intrabuccal administration allows for therapeutic delivery of very low and safe levels of EMF throughout the body as exemplified by responses observed in the femur, liver, adrenal glands, and lungs. In vitro studies have demonstrated that tumor-specific frequencies identified in patients with various forms of cancer are capable of blocking the growth of tumor cells in a tissue- and tumor-specific fashion. Current experimental evidence suggests that tumor-specific modulation frequencies regulate the expression of genes involved in migration and invasion and disrupt the mitotic spindle. This novel targeted treatment approach is emerging as an appealing therapeutic option for patients with advanced cancer given its excellent tolerability. Dissection of the molecular mechanisms accounting for the anti-cancer effects of tumor-specific modulation frequencies is likely to lead to the discovery of novel pathways in cancer. PMID:24206915

  16. The 2011 Leona Tyler Award Address: The Relationship--And Its Relationship to the Common and Specific Factors of Psychotherapy

    ERIC Educational Resources Information Center

    Wampold, Bruce E.; Budge, Stephanie L.

    2012-01-01

    A debate exists about whether the common factors or specific ingredients are critical to producing the benefits of psychotherapy. A model of the relationship, based on evolved human characteristics related to healing, is presented that integrates common factors and specific ingredients. After the initial bond is formed, the relationship involves…

  17. Nuclear Technology. Course 26: Nondestructive Examination (NDE) Techniques I. Module 26-7, Radiographic Specifications and Code Requirements.

    ERIC Educational Resources Information Center

    Pelton, Rick; Espy, John

    This seventh in a series of seven modules for a course titled Nondestructive Examination (NDE) Techniques I describes radiographic specifications and code requirements. The module follows a typical format that includes the following sections: (1) introduction, (2) module prerequisites, (3) objectives, (4) notes to instructor/student, (5) subject…

  18. Institution-Specific Victimization Surveys: Addressing Legal and Practical Disincentives to Gender-Based Violence Reporting on College Campuses.

    PubMed

    Cantalupo, Nancy Chi

    2014-03-12

    This review brings together both the legal literature and original empirical research regarding the advisability of amending the Jeanne Clery Disclosure of Campus Security Policy and Campus Crime Statistics Act or creating new Department of Education regulations to mandate that all higher education institutions survey their students approximately every 5 years about students' experiences with sexual violence. Legal research conducted regarding the three relevant federal legal regimes show inconsistent incentives for schools to encourage victim reporting and proactively address sexual violence on campus. Moreover, the original research carried out for this article shows that the experience of institutions that have voluntarily conducted such surveys suggests many benefits not only for students, prospective students, parents, and the general public but also for schools themselves. These experiences confirm the practical viability of a mandated survey by the Department of Education. PMID:24626456

  19. 47 CFR 73.756 - System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 4 2011-10-01 2011-10-01 false System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service. 73.756 Section 73.756 Telecommunication FEDERAL... Stations § 73.756 System specifications for double-sideband (DBS) modulated emissions in the...

  20. 47 CFR 73.756 - System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 4 2014-10-01 2014-10-01 false System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service. 73.756 Section 73.756 Telecommunication FEDERAL... Stations § 73.756 System specifications for double-sideband (DBS) modulated emissions in the...

  1. 47 CFR 73.756 - System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 4 2013-10-01 2013-10-01 false System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service. 73.756 Section 73.756 Telecommunication FEDERAL... Stations § 73.756 System specifications for double-sideband (DBS) modulated emissions in the...

  2. 47 CFR 73.756 - System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 4 2012-10-01 2012-10-01 false System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service. 73.756 Section 73.756 Telecommunication FEDERAL... Stations § 73.756 System specifications for double-sideband (DBS) modulated emissions in the...

  3. Specificity of the Human Frequency Following Response for Carrier and Modulation Frequency Assessed Using Adaptation.

    PubMed

    Gockel, Hedwig E; Krugliak, Alexandra; Plack, Christopher J; Carlyon, Robert P

    2015-12-01

    The frequency following response (FFR) is a scalp-recorded measure of phase-locked brainstem activity to stimulus-related periodicities. Three experiments investigated the specificity of the FFR for carrier and modulation frequency using adaptation. FFR waveforms evoked by alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. The first experiment investigated peristimulus adaptation of the FFR for pure and complex tones as a function of stimulus frequency and fundamental frequency (F0). It showed more adaptation of the FFR in response to sounds with higher frequencies or F0s than to sounds with lower frequency or F0s. The second experiment investigated tuning to modulation rate in the FFR. The FFR to a complex tone with a modulation rate of 213 Hz was not reduced more by an adaptor that had the same modulation rate than by an adaptor with a different modulation rate (90 or 504 Hz), thus providing no evidence that the FFR originates mainly from neurons that respond selectively to the modulation rate of the stimulus. The third experiment investigated tuning to audio frequency in the FFR using pure tones. An adaptor that had the same frequency as the target (213 or 504 Hz) did not generally reduce the FFR to the target more than an adaptor that differed in frequency (by 1.24 octaves). Thus, there was no evidence that the FFR originated mainly from neurons tuned to the frequency of the target. Instead, the results are consistent with the suggestion that the FFR for low-frequency pure tones at medium to high levels mainly originates from neurons tuned to higher frequencies. Implications for the use and interpretation of the FFR are discussed. PMID:26162415

  4. Stimulus Specificity of Brain-Computer Interfaces Based on Code Modulation Visual Evoked Potentials

    PubMed Central

    Wei, Qingguo; Feng, Siwei; Lu, Zongwu

    2016-01-01

    A brain-computer interface (BCI) based on code modulated visual evoked potentials (c-VEP) is among the fastest BCIs that have ever been reported, but it has not yet been given a thorough study. In this study, a pseudorandom binary M sequence and its time lag sequences are utilized for modulation of different stimuli and template matching is adopted as the method for target recognition. Five experiments were devised to investigate the effect of stimulus specificity on target recognition and we made an effort to find the optimal stimulus parameters for size, color and proximity of the stimuli, length of modulation sequence and its lag between two adjacent stimuli. By changing the values of these parameters and measuring classification accuracy of the c-VEP BCI, an optimal value of each parameter can be attained. Experimental results of ten subjects showed that stimulus size of visual angle 3.8°, white, spatial proximity of visual angle 4.8° center to center apart, modulation sequence of length 63 bits and the lag of 4 bits between adjacent stimuli yield individually superior performance. These findings provide a basis for determining stimulus presentation of a high-performance c-VEP based BCI system. PMID:27243454

  5. Creating a lesson that addresses gender differences in physics testing a specific instructional technique in college level physics education

    NASA Astrophysics Data System (ADS)

    Lincoln, James J.

    Research-based instructional methods are applied in an effort to close the persistent gender gap in physics. Creating a short text on a limited topic using some of these methods could benefit female students specifically. A literature review showed research on the gender gap in physics and updated instructional methods for females. Two female physics students were interviewed and observations were conducted at a high performing all-girls school. A physics lab dialogue between two female physics students was recorded and analyzed, which informed the style and voice of the interactive dialogue lesson. An original written lesson intended to engage female physics students was created and tested on three classes of college-level physics students. The survey data, based on multiple choice and essay responses, measured the students' opinions of the lesson and their current textbook. Results showed the interactive lesson was preferred over the current text, and some students requested similar lessons.

  6. Specific ions modulate diffusion dynamics of hydration water on lipid membrane surfaces.

    PubMed

    Song, Jinsuk; Franck, John; Pincus, Philip; Kim, Mahn Won; Han, Songi

    2014-02-12

    Effects of specific ions on the local translational diffusion of water near large hydrophilic lipid vesicle surfaces were measured by Overhauser dynamic nuclear polarization (ODNP). ODNP relies on an unpaired electron spin-containing probe located at molecular or surface sites to report on the dynamics of water protons within ~10 Å from the spin probe, which give rise to spectral densities for electron-proton cross-relaxation processes in the 10 GHz regime. This pushes nuclear magnetic resonance relaxometry to more than an order of magnitude higher frequencies than conventionally feasible, permitting the measurement of water moving with picosecond to subnanosecond correlation times. Diffusion of water within ~10 Å of, i.e., up to ~3 water layers around the spin probes located on hydrophilic lipid vesicle surfaces is ~5 times retarded compared to the bulk water translational diffusion. This directly reflects on the activation barrier for surface water diffusion, i.e., how tightly water is bound to the hydrophilic surface and surrounding waters. We find this value to be modulated by the presence of specific ions in solution, with its order following the known Hofmeister series. While a molecular description of how ions affect the hydration structure at the hydrophilic surface remains to be answered, the finding that Hofmeister ions directly modulate the surface water diffusivity implies that the strength of the hydrogen bond network of surface hydration water is directly modulated on hydrophilic surfaces. PMID:24456096

  7. Design of LED-based reflector-array module for specific illuminance distribution

    NASA Astrophysics Data System (ADS)

    Chen, Enguo; Yu, Feihong

    2013-02-01

    This paper presents an efficient and practical design method for a LED based reflector-array lighting module. Improving on previous designs, this method could offer higher design freedom to achieve specific illuminance distribution for actual lighting application and deal with the LED light intensity distribution while shortening the design time. The detailed design description of the lighting system is thoroughly investigated. To demonstrate the effectiveness of this method, an ultra-compact reflector-array module, which produces a rectangular illumination area with a large aspect ratio, is specially designed to meet the high-demanding requirements of industrial lighting application. Design results show that most LED emitting energy could be collected into the required lighting region while higher-brightness and better-uniformity are simultaneously available within the focus region. It is expected that this method will have great potential for other lighting applications.

  8. Three dimensional patient-specific collagen architecture modulates cartilage responses in the knee joint during gait.

    PubMed

    Räsänen, Lasse P; Mononen, Mika E; Lammentausta, Eveliina; Nieminen, Miika T; Jurvelin, Jukka S; Korhonen, Rami K

    2016-08-01

    Site-specific variation of collagen fibril orientations can affect cartilage stresses in knee joints. However, this has not been confirmed by 3-D analyses. Therefore, we present a novel method for evaluation of the effect of patient-specific collagen architecture on time-dependent mechanical responses of knee joint cartilage during gait. 3-D finite element (FE) models of a human knee joint were created with the collagen architectures obtained from T2 mapped MRI (patient-specific model) and from literature (literature model). The effect of accuracy of the implementation of collagen fibril architecture into the model was examined by using a submodel with denser FE mesh. Compared to the literature model, fibril strains and maximum principal stresses were reduced especially in the superficial/middle regions of medial tibial cartilage in the patient-specific model after the loading response of gait (up to -413 and -26%, respectively). Compared to the more coarsely meshed joint model, the patient-specific submodel demonstrated similar strain and stress distributions but increased values particularly in the superficial cartilage regions (especially stresses increased >60%). The results demonstrate that implementation of subject-specific collagen architecture of cartilage in 3-D modulates location- and time-dependent mechanical responses of human knee joint cartilage. Submodeling with more accurate implementation of collagen fibril architecture alters cartilage stresses particularly in the superficial/middle tissue. PMID:26714834

  9. Combinatorial Modulation of Signaling Pathways Reveals Cell-Type-Specific Requirements for Highly Efficient and Synchronous iPSC Reprogramming

    PubMed Central

    Vidal, Simon E.; Amlani, Bhishma; Chen, Taotao; Tsirigos, Aristotelis; Stadtfeld, Matthias

    2014-01-01

    Summary The differentiated state of somatic cells provides barriers for the derivation of induced pluripotent stem cells (iPSCs). To address why some cell types reprogram more readily than others, we studied the effect of combined modulation of cellular signaling pathways. Surprisingly, inhibition of transforming growth factor β (TGF-β) together with activation of Wnt signaling in the presence of ascorbic acid allows >80% of murine fibroblasts to acquire pluripotency after 1 week of reprogramming factor expression. In contrast, hepatic and blood progenitors predominantly required only TGF-β inhibition or canonical Wnt activation, respectively, to reprogram at efficiencies approaching 100%. Strikingly, blood progenitors reactivated endogenous pluripotency loci in a highly synchronous manner, and we demonstrate that expression of specific chromatin-modifying enzymes and reduced TGF-β/mitogen-activated protein (MAP) kinase activity are intrinsic properties associated with the unique reprogramming response of these cells. Our observations define cell-type-specific requirements for the rapid and synchronous reprogramming of somatic cells. PMID:25358786

  10. Affinity maturation generates greatly improved xyloglucan-specific carbohydrate binding modules

    PubMed Central

    2009-01-01

    Background Molecular evolution of carbohydrate binding modules (CBM) is a new approach for the generation of glycan-specific molecular probes. To date, the possibility of performing affinity maturation on CBM has not been investigated. In this study we show that binding characteristics such as affinity can be improved for CBM generated from the CBM4-2 scaffold by using random mutagenesis in combination with phage display technology. Results Two modified proteins with greatly improved affinity for xyloglucan, a key polysaccharide abundant in the plant kingdom crucial for providing plant support, were generated. Both improved modules differ from other existing xyloglucan probes by binding to galactose-decorated subunits of xyloglucan. The usefulness of the evolved binders was verified by staining of plant sections, where they performed better than the xyloglucan-binding module from which they had been derived. They discriminated non-fucosylated from fucosylated xyloglucan as shown by their ability to stain only the endosperm, rich in non-fucosylated xyloglucan, but not the integument rich in fucosylated xyloglucan, on tamarind seed sections. Conclusion We conclude that affinity maturation of CBM selected from molecular libraries based on the CBM4-2 scaffold is possible and has the potential to generate new analytical tools for detection of plant carbohydrates. PMID:19878581

  11. Assembled modules technology for site-specific prolonged delivery of norfloxacin.

    PubMed

    Oliveira, Paulo Renato; Bernardi, Larissa Sakis; Strusi, Orazio Luca; Mercuri, Salvatore; Segatto Silva, Marcos A; Colombo, Paolo; Sonvico, Fabio

    2011-02-28

    The aim of this research was to design and study norfloxacin (NFX) release in floating conditions from compressed hydrophilic matrices of hydroxypropylmethylcellulose (HPMC) or poly(ethylene oxide) (PEO). Module assembling technology for drug delivery system manufacturing was used. Two differently cylindrical base curved matrix/modules, identified as female and male, were assembled in void configuration by friction interlocking their concave bases obtaining a floating release system. Drug release and floatation behavior of this assembly was investigated. Due to the higher surface area exposed to the release medium, faster release was observed for individual modules compared to their assembled configuration, independently on the polymer used and concentration. The release curves analyzed using the Korsmeyer exponential equation and Peppas & Sahlin binomial equation showed that the drug release was controlled both by drug diffusion and polymer relaxation or erosion mechanisms. However, convective transport was predominant with PEO and at low content of polymers. NFX release from PEO polymeric matrix was more erosion dependent than HPMC. The assembled systems were able to float in vitro for up to 240min, indicating that this drug delivery system of norfloxacin could provide gastro-retentive site-specific release for increasing norfloxacin bioavailability. PMID:21134427

  12. Ligand-specific and non-specific in vivo modulation of human epidermal cellular retinoic acid binding protein (CRABP).

    PubMed

    Hirschel-Scholz, S; Siegenthaler, G; Saurat, J H

    1989-04-01

    Retinoic acid (RA) is bound intracellularly by a specific, low molecular weight protein (CRABP), that is unrelated to its nuclear receptor and whose function and regulation are still unknown. In the present study we were able to obtain an in vivo modulation of CRABP by different stimuli in one of the major target organs of RA: the human skin. We found increased CRABP after daily application during 4 days of natural or synthetic retinoids (RA, acitretin, isotretinoin, Ro137410, retinol), that have either a high affinity to CRABP or can be transformed into RA. Only Ro150778 with no affinity and no reported transformation had no effect. No macro- or microscopical changes could be observed with any of the tested compounds. Induction of inflammatory and hyperproliferative changes in the skin by topical dithranol treatment, UVB irradiation or scotch tape stripping also induced a significant increase of CRABP 3 days after exposure. Topical diflucortolone showed not only a tendancy to decrease intrinsic CRABP levels, but significantly reduced the retinoid stimulated rise of CRABP. Thus we conclude that the increase of CRABP in a fully differentiated adult tissue seems to be a biological phenomenon following processes of inflammation and proliferation with a lag of several days, while retinoids seem to be able to induce such a rise independently of, or before, the appearance of such processes. Corticosteroids seem to be inhibitors of this reaction. We discuss the hypothesis that CRABP might function as an intracellular 'buffer' in the case of RA overload. PMID:2543582

  13. Cell-Specific Fine-Tuning of Neuronal Excitability by Differential Expression of Modulator Protein Isoforms

    PubMed Central

    Jepson, James; Sheldon, Amanda; Shahidullah, Mohammad; Fei, Hong; Koh, Kyunghee

    2013-01-01

    SLOB (SLOWPOKE-binding protein) modulates the Drosophila SLOWPOKE calcium-activated potassium channel. We have shown previously that SLOB deletion or RNAi knockdown decreases excitability of neurosecretory pars intercerebralis (PI) neurons in the adult Drosophila brain. In contrast, we found that SLOB deletion/knockdown enhances neurotransmitter release from motor neurons at the fly larval neuromuscular junction, suggesting an increase in excitability. Because two prominent SLOB isoforms, SLOB57 and SLOB71, modulate SLOWPOKE channels in opposite directions in vitro, we investigated whether divergent expression patterns of these two isoforms might underlie the differential modulation of excitability in PI and motor neurons. By performing detailed in vitro and in vivo analysis, we found strikingly different modes of regulatory control by the slob57 and slob71 promoters. The slob71, but not slob57, promoter contains binding sites for the Hunchback and Mirror transcriptional repressors. Furthermore, several core promoter elements that are absent in the slob57 promoter coordinately drive robust expression of a luciferase vector by the slob71 promoter in vitro. In addition, we visualized the expression patterns of the slob57 and slob71 promoters in vivo and found clear spatiotemporal differences in promoter activity. SLOB57 is expressed prominently in adult PI neurons, whereas larval motor neurons exclusively express SLOB71. In contrast, at the larval neuromuscular junction, SLOB57 expression appears to be restricted mainly to a subset of glial cells. Our results illustrate how the use of alternative transcriptional start sites within an ion channel modulator locus coupled with functionally relevant alternative splicing can be used to fine-tune neuronal excitability in a cell-specific manner. PMID:24133277

  14. Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons

    PubMed Central

    Nakajima, Miho; Görlich, Andreas; Heintz, Nathaniel

    2014-01-01

    SUMMARY Human imaging studies have revealed that intranasal administration of the “prosocial” hormone oxytocin (OT) activates the frontal cortex, and that this action of OT correlates with enhanced brain function in autism. Here we report the discovery of a population of somatostatin (Sst) positive, regular spiking interneurons that express the oxytocin receptor (OxtrINs). Silencing of OxtrINs in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice specifically during the sexually receptive phase of the estrous cycle. This sociosexual deficit was also present in mice in which the Oxtr gene was conditionally deleted from the mPFC, and in control mice infused with an Oxtr antagonist. Our data demonstrate a gender, cell type and state specific role for OT/Oxtr signaling in the mPFC, and identify a latent cortical circuit element that may modulate other complex social behaviors in response to OT. PMID:25303526

  15. Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways.

    PubMed

    Schaefer, Martin H; Yang, Jae-Seong; Serrano, Luis; Kiel, Christina

    2014-06-01

    Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors) and the output (transcription factors) layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types. PMID:24922536

  16. Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators.

    PubMed

    Zhan, Peng; Itoh, Yukihiro; Suzuki, Takayoshi; Liu, Xinyong

    2015-10-01

    Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition. PMID:26086931

  17. Species-Specific Chitin-Binding Module 18 Expansion in the Amphibian Pathogen Batrachochytrium dendrobatidis

    PubMed Central

    Abramyan, John; Stajich, Jason E.

    2012-01-01

    ABSTRACT Batrachochytrium dendrobatidis is the causative agent of chytridiomycosis, which is considered one of the driving forces behind the worldwide decline in populations of amphibians. As a member of the phylum Chytridiomycota, B. dendrobatidis has diverged significantly to emerge as the only pathogen of adult vertebrates. Such shifts in lifestyle are generally accompanied by various degrees of genomic modifications, yet neither its mode of pathogenicity nor any factors associated with it have ever been identified. Presented here is the identification and characterization of a unique expansion of the carbohydrate-binding module family 18 (CBM18), specific to B. dendrobatidis. CBM (chitin-binding module) expansions have been likened to the evolution of pathogenicity in a variety of fungus species, making this expanded group a prime candidate for the identification of potential pathogenicity factors. Furthermore, the CBM18 expansions are confined to three categories of genes, each having been previously implicated in host-pathogen interactions. These correlations highlight this specific domain expansion as a potential key player in the mode of pathogenicity in this unique fungus. The expansion of CBM18 in B. dendrobatidis is exceptional in its size and diversity compared to other pathogenic species of fungi, making this genomic feature unique in an evolutionary context as well as in pathogenicity. PMID:22718849

  18. Heterologous vaccination against human tuberculosis modulates antigen-specific CD4+ T-cell function.

    PubMed

    Dintwe, One B; Day, Cheryl L; Smit, Erica; Nemes, Elisa; Gray, Clive; Tameris, Michele; McShane, Helen; Mahomed, Hassan; Hanekom, Willem A; Scriba, Thomas J

    2013-09-01

    Heterologous prime-boost strategies hold promise for vaccination against tuberculosis. However, the T-cell characteristics required for protection are not known. We proposed that boost vaccines should induce long-lived functional and phenotypic changes to T cells primed by Bacille Calmette Guerin (BCG) and/or natural exposure to mycobacteria. We characterized changes among specific CD4(+) T cells after vaccination with the MVA85A vaccine in adults, adolescents, and children. CD4(+) T cells identified with Ag85A peptide-bearing HLA class II tetramers were characterized by flow cytometry. We also measured proliferative potential and cytokine expression of Ag85A-specific CD4(+) T cells. During the effector phase, MVA85A-induced specific CD4(+) T cells coexpressed IFN-γ and IL-2, skin homing integrins, and the activation marker CD38. This was followed by contraction and a transition to predominantly IL-2-expressing, CD45RA(-) CCR7(+) CD27(+) or CD45RA(+) CCR7(+) CD27(+) specific CD4(+) T cells. These surface phenotypes were similar to Ag85A-specific T cells prior to MVA85A. However, functional differences were observed postvaccination: specific proliferative capacity was markedly higher after 6-12 months than before vaccination. Our data suggest that MVA85A vaccination may modulate Ag85A-specific CD4(+) T-cell function, resulting in greater recall potential. Importantly, surface phenotypes commonly used as proxies for memory T-cell function did not associate with functional effects of vaccination. PMID:23737382

  19. Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression.

    PubMed

    Goodarzi, Hani; Nguyen, Hoang C B; Zhang, Steven; Dill, Brian D; Molina, Henrik; Tavazoie, Sohail F

    2016-06-01

    Transfer RNAs (tRNAs) are primarily viewed as static contributors to gene expression. By developing a high-throughput tRNA profiling method, we find that specific tRNAs are upregulated in human breast cancer cells as they gain metastatic activity. Through loss-of-function, gain-of-function, and clinical-association studies, we implicate tRNAGluUUC and tRNAArgCCG as promoters of breast cancer metastasis. Upregulation of these tRNAs enhances stability and ribosome occupancy of transcripts enriched for their cognate codons. Specifically, tRNAGluUUC promotes metastatic progression by directly enhancing EXOSC2 expression and enhancing GRIPAP1-constituting an "inducible" pathway driven by a tRNA. The cellular proteomic shift toward a pro-metastatic state mirrors global tRNA shifts, allowing for cell-state and cell-type transgene expression optimization through codon content quantification. TRNA modulation represents a mechanism by which cells achieve altered expression of specific transcripts and proteins. TRNAs are thus dynamic regulators of gene expression and the tRNA codon landscape can causally and specifically impact disease progression. PMID:27259150

  20. Alkylglycerols Modulate the Proliferation and Differentiation of Non-Specific Agonist and Specific Antigen-Stimulated Splenic Lymphocytes

    PubMed Central

    Qian, Linxi; Zhang, Mingshun; Wu, Shengmei; Zhong, Yan; Van Tol, Eric; Cai, Wei

    2014-01-01

    Alkylglycerols (AKGs) are ether-linked glycerols derived from shark liver oil and found in small amounts in human milk. Previous studies showed that oral AKGs administration significantly increased the immune response in mice. The aim of the present study was to investigate the in vitro immunomodulatory effect of AKGs on stimulating splenic lymphocyte responses. C57BL/6 mice were immunized with hepatitis B surface antigen (HBsAg). Splenic B cells were purified and stimulated with anti-BCR and anti-CD38. Meanwhile, splenic CD4+ T cells were purified and stimulated with anti-CD3 and anti-CD28. For antigen specific stimulation, the purified CD4+ T cells were cocultured with HBsAg -pulsed dendritic cells. The stimulated lymphocytes were treated with different concentrations of AKGs. The cell proliferation was assessed by [3H]-thymidine incorporation assay. The maturation of B cells was assessed by examining the germline (GL) transcription of IgG (γ1) mRNA expression, and the surface expressions of CD80/CD86 markers were examined by flow cytometry analysis. Th1/Th2 polarity was assessed by T-BET (Th1)/GATA-3 (Th2) flow cytometry assay and by characteristic cytokines ELISA assay (TNF-α and IFN-γ for Th1; IL-4 and IL-10 for Th2). It was found that AKGs significantly increased the BCR/CD38 -stimulated B cell proliferation. The T cell proliferation in response to CD3/CD28 or specific antigen stimulation was also increased by AKGs. The transcriptional level of IgG (γ1) and the expressions of CD80/CD86 molecules were markedly increased by AKGs in BCR/CD38 -stimulated B cells. Meanwhile, the results showed that AKGs increased the expression of T-BET transcriptional factor and the production of Th1 cytokines (TNF-α and IFN-γ) upon CD3/CD28 stimulation; whereas, levels of Th2 cytokines (IL-4 and IL-10) were decreased by AKGs. Our study demonstrated that AKGs can modulate immune responses by boosting the proliferation and maturation of murine lymphocytes in vitro. PMID

  1. Immunization with Immune Complexes Modulates the Fine Specificity of Antibody Responses to a Flavivirus Antigen

    PubMed Central

    Tsouchnikas, Georgios; Zlatkovic, Juergen; Jarmer, Johanna; Strauß, Judith; Vratskikh, Oksana; Kundi, Michael; Stiasny, Karin

    2015-01-01

    ABSTRACT The antibody response to proteins may be modulated by the presence of preexisting antigen-specific antibodies and the formation of immune complexes (ICs). Effects such as a general increase or decrease of the response as well as epitope-specific phenomena have been described. In this study, we investigated influences of IC immunization on the fine specificity of antibody responses in a structurally well-defined system, using the envelope (E) protein of tick-borne encephalitis (TBE) virus as an immunogen. TBE virus occurs in Europe and Asia and—together with the yellow fever, dengue, West Nile, and Japanese encephalitis viruses—represents one of the major human-pathogenic flaviviruses. Mice were immunized with a dimeric soluble form of E (sE) alone or in complex with monoclonal antibodies specific for each of the three domains of E, and the antibody response induced by these ICs was compared to that seen after immunization with sE alone. Immunoassays using recombinant domains and domain combinations of TBE virus sE as well as the distantly related West Nile virus sE allowed the dissection and quantification of antibody subsets present in postimmunization sera, thus generating fine-specificity patterns of the polyclonal responses. There were substantially different responses with two of the ICs, and the differences could be mechanistically related to (i) epitope shielding and (ii) antibody-mediated structural changes leading to dissociation of the sE dimer. The phenomena described may also be relevant for polyclonal responses upon secondary infections and/or booster immunizations and may affect antibody responses in an individual-specific way. IMPORTANCE Infections with flaviviruses such as yellow fever, dengue, Japanese encephalitis, West Nile, and tick-borne encephalitis (TBE) viruses pose substantial public health problems in different parts of the world. Antibodies to viral envelope protein E induced by natural infection or vaccination were shown to

  2. Identification of a novel family of carbohydrate-binding modules with broad ligand specificity

    PubMed Central

    Duan, Cheng-Jie; Feng, Yu-Liang; Cao, Qi-Long; Huang, Ming-Yue; Feng, Jia-Xun

    2016-01-01

    Most enzymes that act on carbohydrates include non-catalytic carbohydrate-binding modules (CBMs) that recognize and target carbohydrates. CBMs bring their appended catalytic modules into close proximity with the target substrate and increase the hydrolytic rate of enzymes acting on insoluble substrates. We previously identified a novel CBM (CBMC5614-1) at the C-terminus of endoglucanase C5614-1 from an uncultured microorganism present in buffalo rumen. In the present study, that the functional region of CBMC5614-1 involved in ligand binding was localized to 134 amino acids. Two representative homologs of CBMC5614-1, sharing the same ligand binding profile, targeted a range of β-linked polysaccharides that adopt very different conformations. Targeted substrates included soluble and insoluble cellulose, β-1,3/1,4-mixed linked glucans, xylan, and mannan. Mutagenesis revealed that three conserved aromatic residues (Trp-380, Tyr-411, and Trp-423) play an important role in ligand recognition and targeting. These results suggest that CBMC5614-1 and its homologs form a novel CBM family (CBM72) with a broad ligand-binding specificity. CBM72 members can provide new insight into CBM-ligand interactions and may have potential in protein engineering and biocatalysis. PMID:26765840

  3. Cell line specific modulation of connexin43 expression after exposure to ionizing radiation.

    PubMed

    Banaz-Yaşar, Ferya; Tischka, Rabea; Iliakis, George; Winterhager, Elke; Gellhaus, Alexandra

    2005-01-01

    Gap junctional intercellular communication plays a significant role in mediating radiation-induced bystander effects. However, the level of Cx43 itself is influenced by ionizing radiation, which could modify the bystander effect. Here we have investigated several cell lines for the modulation of Cx43 expression 24 h after irradiation with 5 Gy X-rays. The mouse endothelial cell line bEnd3 revealed a significantly elevated level of Cx43 already 15 min after exposure to X-rays, whereas human hybrid endothelial cells (EA.hy926) exhibited a transient downregulation of Cx43 mRNA. No obvious changes in the communication properties of the different cell lines could be observed after irradiation. The communication-deficient malignant human trophoblast cell line Jeg3 stably transfected with Cx43 did not reveal any induction of endogenous nor alteration in the exogenous Cx43 transcript level upon exposure to 5 Gy. Taken together, our data show a cell line specific modulation of Cx43 expression after exposure to X-rays. PMID:16531320

  4. Electrical brain stimulation improves cognitive performance by modulating functional connectivity and task-specific activation.

    PubMed

    Meinzer, Marcus; Antonenko, Daria; Lindenberg, Robert; Hetzer, Stefan; Ulm, Lena; Avirame, Keren; Flaisch, Tobias; Flöel, Agnes

    2012-02-01

    Excitatory anodal transcranial direct current stimulation (atDCS) can improve human cognitive functions, but neural underpinnings of its mode of action remain elusive. In a cross-over placebo ("sham") controlled study we used functional magnetic resonance imaging (fMRI) to investigate neurofunctional correlates of improved language functions induced by atDCS over a core language area, the left inferior frontal gyrus (IFG). Intrascanner transcranial direct current stimulation-induced changes in overt semantic word generation assessed behavioral modulation; task-related and task-independent (resting-state) fMRI characterized language network changes. Improved word-retrieval during atDCS was paralleled by selectively reduced task-related activation in the left ventral IFG, an area specifically implicated in semantic retrieval processes. Under atDCS, resting-state fMRI revealed increased connectivity of the left IFG and additional major hubs overlapping with the language network. In conclusion, atDCS modulates endogenous low-frequency oscillations in a distributed set of functionally connected brain areas, possibly inducing more efficient processing in critical task-relevant areas and improved behavioral performance. PMID:22302824

  5. Prdm13 regulates subtype specification of retinal amacrine interneurons and modulates visual sensitivity.

    PubMed

    Watanabe, Satoshi; Sanuki, Rikako; Sugita, Yuko; Imai, Wataru; Yamazaki, Ryoji; Kozuka, Takashi; Ohsuga, Mizuki; Furukawa, Takahisa

    2015-05-20

    Amacrine interneurons, which are highly diversified in morphological, neurochemical, and physiological features, play crucial roles in visual information processing in the retina. However, the specification mechanisms and functions in vision for each amacrine subtype are not well understood. We found that the Prdm13 transcriptional regulator is specifically expressed in developing and mature amacrine cells in the mouse retina. Most Prdm13-positive amacrine cells are Calbindin- and Calretinin-positive GABAergic or glycinergic neurons. Absence of Prdm13 significantly reduces GABAergic and glycinergic amacrines, resulting in a specific defect of the S2/S3 border neurite bundle in the inner plexiform layer. Forced expression of Prdm13 distinctively induces GABAergic and glycinergic amacrine cells but not cholinergic amacrine cells, whereas Ptf1a, an upstream transcriptional regulator of Prdm13, induces all of these subtypes. Moreover, Prdm13-deficient mice showed abnormally elevated spatial, temporal, and contrast sensitivities in vision. Together, these results show that Prdm13 regulates development of a subset of amacrine cells, which newly defines an amacrine subtype to negatively modulate visual sensitivities. Our current study provides new insights into mechanisms of the diversification of amacrine cells and their function in vision. PMID:25995483

  6. PLANT MICROBIOME. Salicylic acid modulates colonization of the root microbiome by specific bacterial taxa.

    PubMed

    Lebeis, Sarah L; Paredes, Sur Herrera; Lundberg, Derek S; Breakfield, Natalie; Gehring, Jase; McDonald, Meredith; Malfatti, Stephanie; Glavina del Rio, Tijana; Jones, Corbin D; Tringe, Susannah G; Dangl, Jeffery L

    2015-08-21

    Immune systems distinguish "self" from "nonself" to maintain homeostasis and must differentially gate access to allow colonization by potentially beneficial, nonpathogenic microbes. Plant roots grow within extremely diverse soil microbial communities but assemble a taxonomically limited root-associated microbiome. We grew isogenic Arabidopsis thaliana mutants with altered immune systems in a wild soil and also in recolonization experiments with a synthetic bacterial community. We established that biosynthesis of, and signaling dependent on, the foliar defense phytohormone salicylic acid is required to assemble a normal root microbiome. Salicylic acid modulates colonization of the root by specific bacterial families. Thus, plant immune signaling drives selection from the available microbial communities to sculpt the root microbiome. PMID:26184915

  7. A NEW ROLE FOR HIV NUCLEOCAPSID PROTEIN IN MODULATING THE SPECIFICITY OF PLUS STRAND PRIMING

    PubMed Central

    Jacob, Deena T.; DeStefano, Jeffrey J.

    2008-01-01

    The current study indicates a new role for HIV nucleocapsid protein (NC) in modulating the specificity of plus strand priming. RNase H cleavage by reverse transcriptase (RT) during minus strand synthesis gives rise to RNA fragments that could potentially be used as primers for synthesis of the plus strand, leading to the initiation of priming from multiple points as has been observed for other retroviruses. For HIV, the central and 3′ polypurine tracts (PPTs) are the major sites of plus strand initiation. Using reconstituted in vitro assays, results showed that NC greatly reduced the efficiency of extension of non-PPT RNA primers, but not PPT. Experiments mimicking HIV replication showed that RT generated and used both PPT and non-PPT RNAs to initiate “plus strand” synthesis, but non-PPT usage was strongly inhibited by NC. The results support a role for NC in specifying primer usage during plus strand synthesis. PMID:18632127

  8. Lineage-Specific Modulation of Interleukin 4 Signaling by Interferon Regulatory Factor 4

    PubMed Central

    Gupta, Sanjay; Jiang, Man; Anthony, Alissa; Pernis, Alessandra B.

    1999-01-01

    Interleukin (IL)-4 is an immunoregulatory cytokine that exerts distinct biological activities on different cell types. Our studies indicate that interferon regulatory factor (IRF)-4 is both a target and a modulator of the IL-4 signaling cascade. IRF-4 expression is strongly upregulated upon costimulation of B cells with CD40 and IL-4. Furthermore, we find that IRF-4 can interact with signal transducer and activator of transcription (Stat)6 and drive the expression of IL-4–inducible genes. The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6. Since expression of IRF-4 is mostly confined to lymphoid cells, these data provide a potential mechanism by which IL-4–inducible genes can be regulated in a lineage-specific manner. PMID:10601358

  9. REST and CoREST Modulate Neuronal Subtype Specification, Maturation and Maintenance

    PubMed Central

    Gokhan, Solen; Zheng, Deyou; Bergman, Aviv; Mehler, Mark F.

    2009-01-01

    Background The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a master regulator of neuronal gene expression. REST functions as a modular scaffold for dynamic recruitment of epigenetic regulatory factors including its primary cofactor, the corepressor for element-1-silencing transcription factor (CoREST), to genomic loci that contain the repressor element-1 (RE1) binding motif. While REST was initially believed to silence RE1 containing neuronal genes in neural stem cells (NSCs) and non-neuronal cells, emerging evidence shows an increasingly complex cell type- and developmental stage-specific repertoire of REST target genes and functions that include regulation of neuronal lineage maturation and plasticity. Methodology/Principal Findings In this study, we utilized chromatin immunoprecipitation on chip (ChIP-chip) analysis to examine REST and CoREST functions during NSC-mediated specification of cholinergic neurons (CHOLNs), GABAergic neurons (GABANs), glutamatergic neurons (GLUTNs), and medium spiny projection neurons (MSNs). We identified largely distinct but overlapping profiles of REST and CoREST target genes during neuronal subtype specification including a disproportionately high percentage that are exclusive to each neuronal subtype. Conclusions/Significance Our findings demonstrate that the differential deployment of REST and CoREST is an important regulatory mechanism that mediates neuronal subtype specification by modulating specific gene networks responsible for inducing and maintaining neuronal subtype identity. Our observations also implicate a broad array of factors in the generation of neuronal diversity including but not limited to those that mediate homeostasis, cell cycle dynamics, cell viability, stress responses and epigenetic regulation. PMID:19997604

  10. Serotonin modulates responses to species-specific vocalizations in the inferior colliculus.

    PubMed

    Hurley, Laura M; Pollak, George D

    2005-06-01

    Neuromodulators such as serotonin are capable of altering the neural processing of stimuli across many sensory modalities. In the inferior colliculus, a major midbrain auditory gateway, serotonin alters the way that individual neurons respond to simple tone bursts and linear frequency modulated sweeps. The effects of serotonin are complex, and vary among neurons. How serotonin transforms the responses to spectrotemporally complex sounds of the type normally heard in natural settings has been poorly examined. To explore this issue further, the effects of iontophoretically applied serotonin on the responses of individual inferior colliculus neurons to a variety of recorded species-specific vocalizations were examined. These experiments were performed in the Mexican free-tailed bat, a species that uses a rich repertoire of vocalizations for the purposes of communication as well as echolocation. Serotonin frequently changed the number of recorded calls that were capable of evoking a response from individual neurons, sometimes increasing (15% of serotonin-responsive neurons), but usually decreasing (62% of serotonin-responsive neurons), this number. A functional consequence of these serotonin-evoked changes would be to change the population response to species-specific vocalizations. PMID:15830241

  11. Startle reflex hyporeactivity in Parkinson's disease: an emotion-specific or arousal-modulated deficit?

    PubMed Central

    Miller, K.M.; Okun, M.S.; Marsiske, M.; Fennell, E.B.; Bowers, D.

    2009-01-01

    We previously reported that patients with Parkinson's disease (PD) demonstrate reduced psychophysiologic reactivity to unpleasant pictures as indexed by diminished startle eyeblink magnitude (Bowers et al., 2006). In the present study, we tested the hypothesis that this hyporeactivity was primarily driven by diminished reactivity to fear-eliciting stimuli as opposed to other types of aversive pictures. This hypothesis was based on previous evidence suggesting amygdalar abnormalities in PD patients coupled with the known role of the amygdala in fear processing. To test this hypothesis, 24 patients with Parkinson's disease and 24 controls viewed standardized sets of emotional pictures that depicted fear, disgust (mutilations, contaminations), pleasant, and neutral contents. Startle eyeblinks were elicited while subjects viewed these emotional pictures. Results did not support the hypothesis of a specific deficit to fear pictures. Instead, the PD patients had reduced reactivity to mutilation pictures relative to other types of negative pictures in the context of normal subjective ratings. Further analyses revealed that controls displayed a pattern of increased startle eyeblink magnitude for “high arousal” versus “low arousal” negative pictures, regardless of picture category, whereas startle eyeblink magnitude in the PD group did not vary by arousal level. These results suggest that previous findings of decreased aversion-modulated startle is driven by reduced reactivity to highly arousing negative stimuli rather than to a specific category (i.e., fear or disgust) of emotion stimuli. PMID:19428424

  12. Computationally designed liver-specific transcriptional modules and hyperactive factor IX improve hepatic gene therapy

    PubMed Central

    Nair, Nisha; Rincon, Melvin Y.; Evens, Hanneke; Sarcar, Shilpita; Dastidar, Sumitava; Samara-Kuko, Emira; Ghandeharian, Omid; Man Viecelli, Hiu; Thöny, Beat; De Bleser, Pieter; Chuah, Marinee K.

    2014-01-01

    The development of the next-generation gene therapy vectors for hemophilia requires using lower and thus potentially safer vector doses and augmenting their therapeutic efficacy. We have identified hepatocyte-specific transcriptional cis-regulatory modules (CRMs) by using a computational strategy that increased factor IX (FIX) levels 11- to 15-fold. Vector efficacy could be enhanced by combining these hepatocyte-specific CRMs with a synthetic codon-optimized hyperfunctional FIX-R338L Padua transgene. This Padua mutation boosted FIX activity up to sevenfold, with no apparent increase in thrombotic risk. We then validated this combination approach using self-complementary adenoassociated virus serotype 9 (scAAV9) vectors in hemophilia B mice. This resulted in sustained supraphysiologic FIX activity (400%), correction of the bleeding diathesis at clinically relevant, low vector doses (5 × 1010 vector genomes [vg]/kg) that are considered safe in patients undergoing gene therapy. Moreover, immune tolerance could be induced that precluded induction of inhibitory antibodies to FIX upon immunization with recombinant FIX protein. PMID:24637359

  13. The essential mycobacterial amidotransferase GatCAB is a modulator of specific translational fidelity.

    PubMed

    Su, Hong-Wei; Zhu, Jun-Hao; Li, Hao; Cai, Rong-Jun; Ealand, Christopher; Wang, Xun; Chen, Yu-Xiang; Kayani, Masood Ur Rehman; Zhu, Ting F; Moradigaravand, Danesh; Huang, Hairong; Kana, Bavesh D; Javid, Babak

    2016-01-01

    Although regulation of translation fidelity is an essential process(1-7), diverse organisms and organelles have differing requirements of translational accuracy(8-15), and errors in gene translation serve an adaptive function under certain conditions(16-20). Therefore, optimal levels of fidelity may vary according to context. Most bacteria utilize a two-step pathway for the specific synthesis of aminoacylated glutamine and/or asparagine tRNAs, involving the glutamine amidotransferase GatCAB(21-25), but it had not been appreciated that GatCAB may play a role in modulating mistranslation rates. Here, by using a forward genetic screen, we show that the mycobacterial GatCAB enzyme complex mediates the translational fidelity of glutamine and asparagine codons. We identify mutations in gatA that cause partial loss of function in the holoenzyme, with a consequent increase in rates of mistranslation. By monitoring single-cell transcription dynamics, we demonstrate that reduced gatCAB expression leads to increased mistranslation rates, which result in enhanced rifampicin-specific phenotypic resistance. Consistent with this, strains with mutations in gatA from clinical isolates of Mycobacterium tuberculosis show increased mistranslation, with associated antibiotic tolerance, suggesting a role for mistranslation as an adaptive strategy in tuberculosis. Together, our findings demonstrate a potential role for the indirect tRNA aminoacylation pathway in regulating translational fidelity and adaptive mistranslation. PMID:27564922

  14. Block 4 solar cell module design and test specification for intermediate load center applications

    NASA Technical Reports Server (NTRS)

    1978-01-01

    Requirements for performance of terrestrial solar cell modules intended for use in various test applications are established. During the 1979-80 time period, such applications are expected to be in the 20 to 500 kilowatt size range. A series of characterization and qualification tests necessary to certify the module design for production, and the necessary performance test for acceptance of modules are specified.

  15. Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner

    PubMed Central

    Espinosa, Felipe; Xuan, Zhong; Liu, Shunan; Powell, Craig M.

    2015-01-01

    Together with its presynaptic partner Neurexin 1 (Nxn1), Neuroligin 1 (NL1) participates in synapse specification and synapse maintenance. We and others have shown that NL1 can also modulate glutamatergic synaptic function in the central nervous system of rodent models. These molecular/cellular changes can translate into altered animal behaviors that are thought to be analogous to symptomatology of neuropsychiatric disorders. For example, in dorsal striatum of NL1 deletion mice, we previously reported that the ratio N-methyl-D-aspartate receptor (NMDAR) mediated synaptic currents to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) mediated synaptic currents (NMDA/AMPA) is reduced in medium spiny neuron (MSNs). Importantly, this reduction in NMDA/AMPA ratio correlated with increased repetitive grooming. The striatum is the input nucleus of the basal ganglia (BG). Classical models of this circuitry imply that there are two principal pathways that render distinct and somewhat opposite striatal outputs critical to the function of these nuclei in modulating motor behavior. Thus, we set out to better characterize the effects of NL1 deletion on direct and indirect pathways of the dorsal striatum by genetically labeling MSNs participating in the direct and indirect pathways. We demonstrate that a decrease in NMDAR-mediated currents is limited to MSNs of the direct pathway. Furthermore, the decrease in NMDAR-mediated currents is largely due to a reduction in function of NMDARs containing the GluN2A subunit. In contrast, indirect pathway MSNs in NL1 knockout (KO) mice showed a reduction in the frequency of miniature excitatory neurotransmission not observed in the direct pathway. Thus, NL1 deletion differentially affects direct and indirect pathway MSNs in dorsal striatum. These findings have potential implications for striatal function in NL1 KO mice. PMID:26283958

  16. Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism

    PubMed Central

    Moyer, Adam L.; Wagner, Kathryn R.

    2015-01-01

    Background The transforming growth factor β (TGF-β) signaling pathways modulate skeletal muscle growth, regeneration, and cellular metabolism. Several recent gene expression studies have shown that inhibition of myostatin and TGF-β1 signaling consistently leads to a significant reduction in expression of Mss51, also named Zmynd17. The function of mammalian Mss51 is unknown although a putative homolog in yeast is a mitochondrial translational activator. Objective The objective of this work was to characterize mammalian Mss51. Methods Quantitative RT-PCR and immunoblot of subcellular fractionation were used to determine expression patterns and localization of Mss51. The CRISPR/Cas9 system was used to reduce expression of Mss51 in C2C12 myoblasts and the function of Mss51 was evaluated in assays of proliferation, differentiation and cellular metabolism. Results Mss51 was predominantly expressed in skeletal muscle and in those muscles dominated by fast-twitch fibers. In vitro, its expression was upregulated upon differentiation of C2C12 myoblasts into myotubes. Expression of Mss51 was modulated in response to altered TGF-β family signaling. In human muscle, Mss51 localized to the mitochondria. Its genetic disruption resulted in increased levels of cellular ATP, β-oxidation, glycolysis, and oxidative phosphorylation. Conclusions Mss51 is a novel, skeletal muscle-specific gene and a key target of myostatin and TGF-β1 signaling. Unlike myostatin, TGF-β1 and IGF-1, Mss51 does not regulate myoblast proliferation or differentiation. Rather, Mss51 appears to be one of the effectors of these growth factors on metabolic processes including fatty acid oxidation, glycolysis and oxidative phosphorylation. PMID:26634192

  17. Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64+ cells

    PubMed Central

    Vogel, Stephanie; Grabski, Elena; Buschjäger, Daniela; Klawonn, Frank; Döring, Marius; Wang, Junxi; Fletcher, Erika; Bechmann, Ingo; Witte, Torsten; Durisin, Martin; Schraven, Burkhart; Mangsbo, Sara M.; Schönfeld, Kurt; Czeloth, Niklas; Kalinke, Ulrich

    2015-01-01

    Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64+ monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients’ inflamed joints that comprised enhanced numbers of CD64+ cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64+ cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64+ cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions. PMID:26670584

  18. Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64(+) cells.

    PubMed

    Vogel, Stephanie; Grabski, Elena; Buschjäger, Daniela; Klawonn, Frank; Döring, Marius; Wang, Junxi; Fletcher, Erika; Bechmann, Ingo; Witte, Torsten; Durisin, Martin; Schraven, Burkhart; Mangsbo, Sara M; Schönfeld, Kurt; Czeloth, Niklas; Kalinke, Ulrich

    2015-01-01

    Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64(+) monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients' inflamed joints that comprised enhanced numbers of CD64(+) cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64(+) cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64(+) cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions. PMID:26670584

  19. Understanding How Noncatalytic Carbohydrate Binding Modules Can Display Specificity for Xyloglucan*

    PubMed Central

    Luís, Ana S.; Venditto, Immacolata; Temple, Max J.; Rogowski, Artur; Baslé, Arnaud; Xue, Jie; Knox, J. Paul; Prates, José A.M.; Ferreira, Luís M. A.; Fontes, Carlos M. G. A.; Najmudin, Shabir; Gilbert, Harry J.

    2013-01-01

    Plant biomass is central to the carbon cycle and to environmentally sustainable industries exemplified by the biofuel sector. Plant cell wall degrading enzymes generally contain noncatalytic carbohydrate binding modules (CBMs) that fulfil a targeting function, which enhances catalysis. CBMs that bind β-glucan chains often display broad specificity recognizing β1,4-glucans (cellulose), β1,3-β1,4-mixed linked glucans and xyloglucan, a β1,4-glucan decorated with α1,6-xylose residues, by targeting structures common to the three polysaccharides. Thus, CBMs that recognize xyloglucan target the β1,4-glucan backbone and only accommodate the xylose decorations. Here we show that two closely related CBMs, CBM65A and CBM65B, derived from EcCel5A, a Eubacterium cellulosolvens endoglucanase, bind to a range of β-glucans but, uniquely, display significant preference for xyloglucan. The structures of the two CBMs reveal a β-sandwich fold. The ligand binding site comprises the β-sheet that forms the concave surface of the proteins. Binding to the backbone chains of β-glucans is mediated primarily by five aromatic residues that also make hydrophobic interactions with the xylose side chains of xyloglucan, conferring the distinctive specificity of the CBMs for the decorated polysaccharide. Significantly, and in contrast to other CBMs that recognize β-glucans, CBM65A utilizes different polar residues to bind cellulose and mixed linked glucans. Thus, Gln106 is central to cellulose recognition, but is not required for binding to mixed linked glucans. This report reveals the mechanism by which β-glucan-specific CBMs can distinguish between linear and mixed linked glucans, and show how these CBMs can exploit an extensive hydrophobic platform to target the side chains of decorated β-glucans. PMID:23229556

  20. Specific regulation of male rat liver cytosolic estrogen receptor by the modulator of the glucocorticoid receptor.

    PubMed

    Celiker, M Y; Haas, A; Saunders, D; Litwack, G

    1993-08-31

    Modulator is a novel low-molecular-weight organic compound that regulates activities of glucocorticoid and mineralocorticoid receptors as well as protein kinase C. In this study we show that male rat liver cytosolic estrogen receptor activation is inhibited by modulator in a dose-dependent manner. Fifty percent inhibition is obtained with 1 unit/ml modulator purified from bovine liver which is within the physiological concentration for modulator. However, sheep uterine cytosolic estrogen and androgen receptors are insensitive to regulation by modulator. Exogenous sodium molybdate treatment inhibits activation of all of these receptors of liver or uterus origin in an identical manner, further differentiating the effects of modulator and the molybdate anion. PMID:8363596

  1. SOX11 MODULATES BRAIN-DERIVED NEUROTROPHIC FACTOR EXPRESSION IN AN EXON PROMOTER-SPECIFIC MANNER

    PubMed Central

    Salerno, Kathleen M.; Jing, Xiaotang; Diges, Charlotte M.; Cornuet, Pamela K.; Glorioso, Joseph C.; Albers, Kathryn M.

    2011-01-01

    Sox11 is a high mobility group (HMG) containing transcription factor that is significantly elevated in peripheral neurons in response to nerve injury. In vitro and in vivo studies support a central role for Sox11 in adult neuron growth and survival following injury. Brain-derived neurotrophic factor (BDNF) is a pleiotropic growth factor that has effects on neuronal survival, differentiation, synaptic plasticity and regeneration. BDNF transcription is elevated in the DRG following nerve injury in parallel with Sox11 allowing for the possible regulation by Sox11. To begin to assess the possible influence of Sox11 we used reverse transcriptase PCR assays to determine the relative expression of the nine (I-IXa) noncoding exons and one coding exon (exon IX) of the BDNF gene after sciatic nerve axotomy in the mouse. Exons with upstream promoter regions containing the Sox binding motif 5′-AACAAAG-3′ (I, IV, VII and VIII) were increased at 1d or 3d following axotomy. Exons 1 and IV showed the greatest increase and only exon 1 remained elevated at 3d. Luciferase assays showed that Sox11 could activate the most highly regulated exons, I and IV, and that this activation was reduced by mutation of putative Sox binding sites. Exon expression in injured DRG neurons had some overlap with Neuro2a cells that overexpress Sox11, showing elevation in exon IV and VII transcripts. These findings indicate cell type and contextual specificity of Sox11 in modulation of BDNF transcription. PMID:22331573

  2. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

    PubMed Central

    Fernández-Suárez, María E.; Escolà-Gil, Joan C.; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A.; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [3H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [3H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  3. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport.

    PubMed

    Fernández-Suárez, María E; Escolà-Gil, Joan C; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  4. Electro-acupuncture at different acupoints modulating the relative specific brain functional network

    NASA Astrophysics Data System (ADS)

    Fang, Jiliang; Wang, Xiaoling; Wang, Yin; Liu, Hesheng; Hong, Yang; Liu, Jun; Zhou, Kehua; Wang, Lei; Xue, Chao; Song, Ming; Liu, Baoyan; Zhu, Bing

    2010-11-01

    Objective: The specific brain effects of acupoint are important scientific concern in acupuncture. However, previous acupuncture fMRI studies focused on acupoints in muscle layer on the limb. Therefore, researches on acupoints within connective tissue at trunk are warranted. Material and Methods: Brain effects of acupuncture on abdomen at acupoints Guanyuan (CV4) and Zhongwan (CV12) were tested using fMRI on 21 healthy volunteers. The data acquisition was performed at resting state, during needle retention, electroacupuncture (EA) and post-EA resting state. Needling sensations were rated after every electroacupuncture (EA) procedure. The needling sensations and the brain functional activity and connectivity were compared between CV4 and CV12 using SPSS, SPM2 and the local and remote connectivity maps. Results and conclusion: EA at CV4 and CV12 induced apparent deactivation effects in the limbic-paralimbic-neocortical network. The default mode of the brain was modified by needle retention and EA, respectively. The functional brain network was significantly changed post EA. However, the minor differences existed between these two acupoints. The results demonstrated similarity between functional brain network mode of acupuncture modulation and functional circuits of emotional and cognitive regulation. Acupuncture may produce analgesia, anti-anxiety and anti-depression via the limbic-paralimbic-neocortical network (LPNN).

  5. Evolution of lineage-specific functions in ancient cis-regulatory modules.

    PubMed

    Pauls, Stefan; Goode, Debbie K; Petrone, Libero; Oliveri, Paola; Elgar, Greg

    2015-11-01

    Morphological evolution is driven both by coding sequence variation and by changes in regulatory sequences. However, how cis-regulatory modules (CRMs) evolve to generate entirely novel expression domains is largely unknown. Here, we reconstruct the evolutionary history of a lens enhancer located within a CRM that not only predates the lens, a vertebrate innovation, but bilaterian animals in general. Alignments of orthologous sequences from different deuterostomes sub-divide the CRM into a deeply conserved core and a more divergent flanking region. We demonstrate that all deuterostome flanking regions, including invertebrate sequences, activate gene expression in the zebrafish lens through the same ancient cluster of activator sites. However, levels of gene expression vary between species due to the presence of repressor motifs in flanking region and core. These repressor motifs are responsible for the relatively weak enhancer activity of tetrapod flanking regions. Ray-finned fish, however, have gained two additional lineage-specific activator motifs which in combination with the ancient cluster of activators and the core constitute a potent lens enhancer. The exploitation and modification of existing regulatory potential in flanking regions but not in the highly conserved core might represent a more general model for the emergence of novel regulatory functions in complex CRMs. PMID:26538567

  6. A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain.

    PubMed

    Hildebrand, Michael E; Smith, Paula L; Bladen, Chris; Eduljee, Cyrus; Xie, Jennifer Y; Chen, Lina; Fee-Maki, Molly; Doering, Clint J; Mezeyova, Janette; Zhu, Yongbao; Belardetti, Francesco; Pajouhesh, Hassan; Parker, David; Arneric, Stephen P; Parmar, Manjeet; Porreca, Frank; Tringham, Elizabeth; Zamponi, Gerald W; Snutch, Terrance P

    2011-04-01

    Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics. PMID:21349638

  7. The GHKL ATPase MORC1 Modulates Species-Specific Plant Immunity in Solanaceae.

    PubMed

    Manosalva, Patricia; Manohar, Murli; Kogel, Karl-Heinz; Kang, Hong-Gu; Klessig, Daniel F

    2015-08-01

    The microrchidia (MORC) proteins, a subset of the GHKL ATPase superfamily, were recently described as components involved in transcriptional gene silencing and plant immunity in Arabidopsis. To assess the role of MORC1 during resistance to Phytophthora infestans in solanaceous species, we altered the expression of the corresponding MORC1 homologs in potato, tomato, and Nicotiana benthamiana. Basal resistance to P. infestans was compromised in StMORC1-silenced potato and enhanced in overexpressing lines, indicating that StMORC1 positively affects immunity. By contrast, silencing SlMORC1 expression in tomato or NbMORC1 expression in N. benthamiana enhanced basal resistance to this oomycete pathogen. In addition, silencing SlMORC1 further enhanced resistance conferred by two resistance genes in tomato. Transient expression of StMORC1 in N. benthamiana accelerated cell death induced by infestin1 (INF1), whereas SlMORC1 or NbMORC1 suppressed it. Domain-swapping and mutational analyses indicated that the C-terminal region dictates the species-specific effects of the solanaceous MORC1 proteins on INF1-induced cell death. This C-terminal region also was required for homodimerization and phosphorylation of recombinant StMORC1 and SlMORC1, and its transient expression induced spontaneous cell death in N. benthamiana. Thus, this C-terminal region likely plays important roles in both determining and modulating the biological activity of MORC1 proteins. PMID:25822715

  8. Frequency Band-Specific Electrical Brain Stimulation Modulates Cognitive Control Processes

    PubMed Central

    van Driel, Joram; Sligte, Ilja G.; Linders, Jara; Elport, Daniel; Cohen, Michael X

    2015-01-01

    A large body of findings has tied midfrontal theta-band (4–8 Hz) oscillatory activity to adaptive control mechanisms during response conflict. Thus far, this evidence has been correlational. To evaluate whether theta oscillations are causally involved in conflict processing, we applied transcranial alternating current stimulation (tACS) in the theta band to a midfrontal scalp region, while human subjects performed a spatial response conflict task. Conflict was introduced by incongruency between the location of the target stimulus and the required response hand. As a control condition, we used alpha-band (8–12 Hz) tACS over the same location. The exact stimulation frequencies were determined empirically for each subject based on a pre-stimulation EEG session. Behavioral results showed general conflict effects of slower response times (RT) and lower accuracy for high conflict trials compared to low conflict trials. Importantly, this conflict effect was reduced specifically during theta tACS, which was driven by slower response times on low conflict trials. These results show how theta tACS can modulate adaptive cognitive control processes, which is in accordance with the view of midfrontal theta oscillations as an active mechanism for cognitive control. PMID:26405801

  9. Muscle-specific modulation of vestibular reflexes with increased locomotor velocity and cadence.

    PubMed

    Dakin, Christopher J; Inglis, John Timothy; Chua, Romeo; Blouin, Jean-Sébastien

    2013-07-01

    Vestibular information is one of the many sensory signals used to stabilize the body during locomotion. When locomotor velocity increases, the influence of these signals appears to wane. It is unclear whether vestibular signals are globally attenuated with velocity or are influenced by factors such as whether a muscle is contributing to balance control. Here we investigate how vestibular sensory signals influence muscles of the leg during locomotion and what causes their attenuation with increasing locomotor velocity. We hypothesized that 1) vestibular signals influence the activity of all muscles engaged in the maintenance of medio-lateral stability during locomotion and 2) increases in both cadence and velocity would be associated with attenuation of these signals. We used a stochastic vestibular stimulus and recorded electromyographic signals from muscles of the ankle, knee, and hip. Participants walked using two cadences (52 and 78 steps/min) and two walking velocities (0.4 and 0.8 m/s). We observed phase-dependent modulation of vestibular influence over ongoing muscle activity in all recorded muscles. Within a stride, reversals of the muscle responses were observed in the biceps femoris, tibialis anterior, and rectus femoris. Vestibular-muscle coupling decreases with increases in both cadence and walking velocity. These results show that the observed vestibular suppression is muscle- and phase dependent. We suggest that the phase- and muscle-specific influence of vestibular signals on locomotor activity is organized according to each muscle's functional role in body stabilization during locomotion. PMID:23576695

  10. Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling

    PubMed Central

    McCabe, NP; De, S; Vasanji, A; Brainard, J; Byzova, TV

    2009-01-01

    The management of pain and morbidity owing to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the αvβ3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that αvβ3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional αvβ3 enabled tumor growth in bone (incidence: 4/4), whereas αvβ3 (—), inactive or constitutively active mutants of αvβ3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated αvβ3 (either inactive of constitutively active), but not those lacking β3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for β3 integrin, we next demonstrated that αvβ3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated αvβ3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development. PMID:17369840

  11. Identification of tissue-specific cis-regulatory modules based on interactions between transcription factors

    PubMed Central

    Yu, Xueping; Lin, Jimmy; Zack, Donald J; Qian, Jiang

    2007-01-01

    Background Evolutionary conservation has been used successfully to help identify cis-acting DNA regions that are important in regulating tissue-specific gene expression. Motivated by increasing evidence that some DNA regulatory regions are not evolutionary conserved, we have developed an approach for cis-regulatory region identification that does not rely upon evolutionary sequence conservation. Results The conservation-independent approach is based on an empirical potential energy between interacting transcription factors (TFs). In this analysis, the potential energy is defined as a function of the number of TF interactions in a genomic region and the strength of the interactions. By identifying sets of interacting TFs, the analysis locates regions enriched with the binding sites of these interacting TFs. We applied this approach to 30 human tissues and identified 6232 putative cis-regulatory modules (CRMs) regulating 2130 tissue-specific genes. Interestingly, some genes appear to be regulated by different CRMs in different tissues. Known regulatory regions are highly enriched in our predicted CRMs. In addition, DNase I hypersensitive sites, which tend to be associated with active regulatory regions, significantly overlap with the predicted CRMs, but not with more conserved regions. We also find that conserved and non-conserved CRMs regulate distinct gene groups. Conserved CRMs control more essential genes and genes involved in fundamental cellular activities such as transcription. In contrast, non-conserved CRMs, in general, regulate more non-essential genes, such as genes related to neural activity. Conclusion These results demonstrate that identifying relevant sets of binding motifs can help in the mapping of DNA regulatory regions, and suggest that non-conserved CRMs play an important role in gene regulation. PMID:17996093

  12. Light has a specific role in modulating Arabidopsis gene expression at low temperature

    PubMed Central

    Soitamo, Arto J; Piippo, Mirva; Allahverdiyeva, Yagut; Battchikova, Natalia; Aro, Eva-Mari

    2008-01-01

    Background Light and temperature are the key abiotic modulators of plant gene expression. In the present work the effect of light under low temperature treatment was analyzed by using microarrays. Specific attention was paid to the up and down regulated genes by using promoter analysis. This approach revealed putative regulatory networks of transcription factors behind the induction or repression of the genes. Results Induction of a few oxidative stress related genes occurred only under the Cold/Light treatment including genes encoding iron superoxide dismutase (FeSOD) and glutathione-dependent hydrogen peroxide peroxidases (GPX). The ascorbate dependent water-water cycle genes showed no response to Cold/Light or Cold/Dark treatments. Cold/Light specifically induced genes encoding protective molecules like phenylpropanoids and photosynthesis-related carotenoids also involved in the biosynthesis of hormone abscisic acid (ABA) crucial for cold acclimation. The enhanced/repressed transcript levels were not always reflected on the respective protein levels as demonstrated by dehydrin proteins. Conclusion Cold/Light up regulated twice as many genes as the Cold/Dark treatment and only the combination of light and low temperature enhanced the expression of several genes earlier described as cold-responsive genes. Cold/Light-induced genes included both cold-responsive transcription factors and several novel ones containing zinc-finger, MYB, NAC and AP2 domains. These are likely to function in concert in enhancing gene expression. Similar response elements were found in the promoter regions of both the transcription factors and their target genes implying a possible parallel regulation or amplification of the environmental signals according to the metabolic/redox state in the cells. PMID:18230142

  13. Zeaxanthin protects plant photosynthesis by modulating chlorophyll triplet yield in specific light-harvesting antenna subunits.

    PubMed

    Dall'Osto, Luca; Holt, Nancy E; Kaligotla, Shanti; Fuciman, Marcel; Cazzaniga, Stefano; Carbonera, Donatella; Frank, Harry A; Alric, Jean; Bassi, Roberto

    2012-12-01

    Plants are particularly prone to photo-oxidative damage caused by excess light. Photoprotection is essential for photosynthesis to proceed in oxygenic environments either by scavenging harmful reactive intermediates or preventing their accumulation to avoid photoinhibition. Carotenoids play a key role in protecting photosynthesis from the toxic effect of over-excitation; under excess light conditions, plants accumulate a specific carotenoid, zeaxanthin, that was shown to increase photoprotection. In this work we genetically dissected different components of zeaxanthin-dependent photoprotection. By using time-resolved differential spectroscopy in vivo, we identified a zeaxanthin-dependent optical signal characterized by a red shift in the carotenoid peak of the triplet-minus-singlet spectrum of leaves and pigment-binding proteins. By fractionating thylakoids into their component pigment binding complexes, the signal was found to originate from the monomeric Lhcb4-6 antenna components of Photosystem II and the Lhca1-4 subunits of Photosystem I. By analyzing mutants based on their sensitivity to excess light, the red-shifted triplet-minus-singlet signal was tightly correlated with photoprotection in the chloroplasts, suggesting the signal implies an increased efficiency of zeaxanthin in controlling chlorophyll triplet formation. Fluorescence-detected magnetic resonance analysis showed a decrease in the amplitude of signals assigned to chlorophyll triplets belonging to the monomeric antenna complexes of Photosystem II upon zeaxanthin binding; however, the amplitude of carotenoid triplet signal does not increase correspondingly. Results show that the high light-induced binding of zeaxanthin to specific proteins plays a major role in enhancing photoprotection by modulating the yield of potentially dangerous chlorophyll-excited states in vivo and preventing the production of singlet oxygen. PMID:23066020

  14. Zeaxanthin Protects Plant Photosynthesis by Modulating Chlorophyll Triplet Yield in Specific Light-harvesting Antenna Subunits*

    PubMed Central

    Dall'Osto, Luca; Holt, Nancy E.; Kaligotla, Shanti; Fuciman, Marcel; Cazzaniga, Stefano; Carbonera, Donatella; Frank, Harry A.; Alric, Jean; Bassi, Roberto

    2012-01-01

    Plants are particularly prone to photo-oxidative damage caused by excess light. Photoprotection is essential for photosynthesis to proceed in oxygenic environments either by scavenging harmful reactive intermediates or preventing their accumulation to avoid photoinhibition. Carotenoids play a key role in protecting photosynthesis from the toxic effect of over-excitation; under excess light conditions, plants accumulate a specific carotenoid, zeaxanthin, that was shown to increase photoprotection. In this work we genetically dissected different components of zeaxanthin-dependent photoprotection. By using time-resolved differential spectroscopy in vivo, we identified a zeaxanthin-dependent optical signal characterized by a red shift in the carotenoid peak of the triplet-minus-singlet spectrum of leaves and pigment-binding proteins. By fractionating thylakoids into their component pigment binding complexes, the signal was found to originate from the monomeric Lhcb4–6 antenna components of Photosystem II and the Lhca1–4 subunits of Photosystem I. By analyzing mutants based on their sensitivity to excess light, the red-shifted triplet-minus-singlet signal was tightly correlated with photoprotection in the chloroplasts, suggesting the signal implies an increased efficiency of zeaxanthin in controlling chlorophyll triplet formation. Fluorescence-detected magnetic resonance analysis showed a decrease in the amplitude of signals assigned to chlorophyll triplets belonging to the monomeric antenna complexes of Photosystem II upon zeaxanthin binding; however, the amplitude of carotenoid triplet signal does not increase correspondingly. Results show that the high light-induced binding of zeaxanthin to specific proteins plays a major role in enhancing photoprotection by modulating the yield of potentially dangerous chlorophyll-excited states in vivo and preventing the production of singlet oxygen. PMID:23066020

  15. Photosensitive biosensor array system using optical addressing without an addressing circuit on array biochips

    NASA Astrophysics Data System (ADS)

    Ahn, Chang-Geun; Ah, Chil Seong; Kim, Tae-Youb; Park, Chan Woo; Yang, Jong-Heon; Kim, Ansoon; Sung, Gun Yong

    2010-09-01

    This paper introduces a photosensitive biosensor array system with a simple photodiode array that detects photocurrent changes caused by reactions between probe and target molecules. Using optical addressing, the addressing circuit on the array chip is removed for low-cost application, and real cell addressing is achieved using an externally located computer-controllable light-emitting diode array module. The fabricated biosensor array chip shows a good dynamic range of 1-100 ng/mL under prostate-specific antigen detection, with an on-chip resolution of roughly 1 ng/mL.

  16. Addressing healthcare.

    PubMed

    Daly, Rich

    2013-02-11

    Though President Barack Obama has rarely made healthcare references in his State of the Union addresses, health policy experts are hoping he changes that strategy this year. "The question is: Will he say anything? You would hope that he would, given that that was the major issue he started his presidency with," says Dr. James Weinstein, left, of the Dartmouth-Hitchcock health system. PMID:23487896

  17. 47 CFR 73.756 - System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 4 2010-10-01 2010-10-01 false System specifications for double-sideband (DBS) modulated emissions in the HF broadcasting service. 73.756 Section 73.756 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES International Broadcast Stations § 73.756...

  18. 47 CFR 73.757 - System specifications for single-sideband (SSB) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 4 2010-10-01 2010-10-01 false System specifications for single-sideband (SSB) modulated emissions in the HF broadcasting service. 73.757 Section 73.757 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES International Broadcast Stations § 73.757...

  19. 47 CFR 73.757 - System specifications for single-sideband (SSB) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 4 2013-10-01 2013-10-01 false System specifications for single-sideband (SSB) modulated emissions in the HF broadcasting service. 73.757 Section 73.757 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES International Broadcast Stations § 73.757...

  20. 47 CFR 73.757 - System specifications for single-sideband (SSB) modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 4 2012-10-01 2012-10-01 false System specifications for single-sideband (SSB) modulated emissions in the HF broadcasting service. 73.757 Section 73.757 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES International Broadcast Stations § 73.757...

  1. Tissue-specific modulation of mitochondrial DNA segregation by a defect in mitochondrial division.

    PubMed

    Jokinen, Riikka; Marttinen, Paula; Stewart, James B; Neil Dear, T; Battersby, Brendan J

    2016-02-15

    Mitochondria are dynamic organelles that divide and fuse by remodeling an outer and inner membrane in response to developmental, physiological and stress stimuli. These events are coordinated by conserved dynamin-related GTPases. The dynamics of mitochondrial morphology require coordination with mitochondrial DNA (mtDNA) to ensure faithful genome transmission, however, this process remains poorly understood. Mitochondrial division is linked to the segregation of mtDNA but how it affects cases of mtDNA heteroplasmy, where two or more mtDNA variants/mutations co-exist in a cell, is unknown. Segregation of heteroplasmic human pathogenic mtDNA mutations is a critical factor in the onset and severity of human mitochondrial diseases. Here, we investigated the coupling of mitochondrial morphology to the transmission and segregation of mtDNA in mammals by taking advantage of two genetically modified mouse models: one with a dominant-negative mutation in the dynamin-related protein 1 (Drp1 or Dnm1l) that impairs mitochondrial fission and the other, heteroplasmic mice segregating two neutral mtDNA haplotypes (BALB and NZB). We show a tissue-specific response to mtDNA segregation from a defect in mitochondrial fission. Only mtDNA segregation in the hematopoietic compartment is modulated from impaired Dnm1l function. In contrast, no effect was observed in other tissues arising from the three germ layers during development and in mtDNA transmission through the female germline. Our data suggest a robust organization of a heteroplasmic mtDNA segregating unit across mammalian cell types that can overcome impaired mitochondrial division to ensure faithful transmission of the mitochondrial genome. PMID:26681804

  2. Functionally relevant motions of haloalkane dehalogenases occur in the specificity-modulating cap domains

    PubMed Central

    Otyepka, Michal; Damborský, Jiří

    2002-01-01

    One-nanosecond molecular dynamics trajectories of three haloalkane dehalogenases (DhlA, LinB, and DhaA) are compared. The main domain was rigid in all three dehalogenases, whereas the substrate specificity-modulating cap domains showed considerably higher mobility. The functionally relevant motions were spread over the entire cap domain in DhlA, whereas they were more localized in LinB and DhaA. The highest amplitude of essential motions of DhlA was noted in the α4′-helix-loop-α4-helix region, formerly proposed to participate in the large conformation change needed for product release. The highest amplitude of essential motions of LinB and DhaA was observed in the random coil before helix 4, linking two domains of these proteins. This flexibility is the consequence of the modular composition of haloalkane dehalogenases. Two members of the catalytic triad, that is, the nucleophile and the base, showed a very high level of rigidity in all three dehalogenases. This rigidity is essential for their function. One of the halide-stabilizing residues, important for the catalysis, shows significantly higher flexibility in DhlA compared with LinB and DhaA. Enhanced flexibility may be required for destabilization of the electrostatic interactions during the release of the halide ion from the deeply buried active site of DhlA. The exchange of water molecules between the enzyme active site and bulk solvent was very different among the three dehalogenases. The differences could be related to the flexibility of the cap domains and to the number of entrance tunnels. PMID:11967377

  3. A retrospective analysis for patient-specific quality assurance of volumetric-modulated arc therapy plans

    SciTech Connect

    Li, Guangjun; Wu, Kui; Peng, Guang; Zhang, Yingjie; Bai, Sen

    2014-01-01

    Volumetric-modulated arc therapy (VMAT) is now widely used clinically, as it is capable of delivering a highly conformal dose distribution in a short time interval. We retrospectively analyzed patient-specific quality assurance (QA) of VMAT and examined the relationships between the planning parameters and the QA results. A total of 118 clinical VMAT cases underwent pretreatment QA. All plans had 3-dimensional diode array measurements, and 69 also had ion chamber measurements. Dose distribution and isocenter point dose were evaluated by comparing the measurements and the treatment planning system (TPS) calculations. In addition, the relationship between QA results and several planning parameters, such as dose level, control points (CPs), monitor units (MUs), average field width, and average leaf travel, were also analyzed. For delivered dose distribution, a gamma analysis passing rate greater than 90% was obtained for all plans and greater than 95% for 100 of 118 plans with the 3%/3-mm criteria. The difference (mean ± standard deviation) between the point doses measured by the ion chamber and those calculated by TPS was 0.9% ± 2.0% for all plans. For all cancer sites, nasopharyngeal carcinoma and gastric cancer have the lowest and highest average passing rates, respectively. From multivariate linear regression analysis, the dose level (p = 0.001) and the average leaf travel (p < 0.001) showed negative correlations with the passing rate, and the average field width (p = 0.003) showed a positive correlation with the passing rate, all indicating a correlation between the passing rate and the plan complexity. No statistically significant correlation was found between MU or CP and the passing rate. Analysis of the results of dosimetric pretreatment measurements as a function of VMAT plan parameters can provide important information to guide the plan parameter setting and optimization in TPS.

  4. Is sensory-specific satiety for a bitter-sweet infusion modulated by context?

    PubMed

    Garcia-Burgos, David; Secchiari, Florencia; Calviño, Amalia

    2015-03-01

    The sensory-affective attributes of beverages have an important influence on a given intake and successive consumptions because of sensory-specific satiety (SSS; defined as a decrease in pleasantness ratings of a food eaten relative to uneaten foods). No studies have, however, investigated how multiple sessions of SSS for familiar drinks over a period of several days up to a week may change their pleasantness and how these hedonic-related judgments are affected by the context during SSS testing. With twenty-six participants, the present study explored the medium lasting and contextual effects of repeated SSS sessions for a bitter-sweet infusion on olfactory and flavour pleasantness over the course of three exposures in either a laboratory or a cafeteria setting. The results showed olfactory and flavour SSS for the infusion following each consumption in both the artificial and the natural setting. More interestingly, despite the failure to detect medium-term SSS (i.e., a greater decrease in pleasantness ratings of a food eaten relative to uneaten foods after repeated SSS sessions over several days as compared to the first SSS session), a contextual modulation of olfactory SSS was observed with a lesser overall magnitude in the cafeteria compared to the laboratory setting. To the best of our knowledge, the impact of eating location on the development of satiation and the differential contextual sensitivity of SSS for orthonasal odours and flavours has not been reported previously. The implications of potential environmental control of SSS are considered in this study. PMID:25542889

  5. Improved Sequence Learning with Subthalamic Nucleus Deep Brain Stimulation: Evidence for Treatment-Specific Network Modulation

    PubMed Central

    Mure, Hideo; Tang, Chris C.; Argyelan, Miklos; Ghilardi, Maria-Felice; Kaplitt, Michael G.; Dhawan, Vijay; Eidelberg, David

    2015-01-01

    We used a network approach to study the effects of anti-parkinsonian treatment on motor sequence learning in humans. Eight Parkinson’s disease (PD) patients with bilateral subthalamic nucleus (STN) deep brain stimulation underwent H2 15Opositron emission tomography (PET) imaging to measure regional cerebral blood flow (rCBF) while they performed kinematically matched sequence learning and movement tasks at baseline and during stimulation. Network analysis revealed a significant learning-related spatial covariance pattern characterized by consistent increases in subject expression during stimulation (p = 0.008, permutation test). The network was associated with increased activity in the lateral cerebellum, dorsal premotor cortex, and parahippocampal gyrus, with covarying reductions in the supplementary motor area (SMA) and orbitofrontal cortex. Stimulation-mediated increases in network activity correlated with concurrent improvement in learning performance (p < 0.02). To determine whether similar changes occurred during dopaminergic pharmacotherapy, we studied the subjects during an intravenous levodopa infusion titrated to achieve a motor response equivalent to stimulation. Despite consistent improvement in motor ratings during infusion, levodopa did not alter learning performance or network activity. Analysis of learning-related rCBF in network regions revealed improvement in baseline abnormalities with STN stimulation but not levodopa. These effects were most pronounced in the SMA. In this region, a consistent rCBF response to stimulation was observed across subjects and trials (p = 0.01), although the levodopa response was not significant. These findings link the cognitive treatment response in PD to changes in the activity of a specific cerebello-premotor cortical network. Selective modulation of overactive SMA–STN projection pathways may underlie the improvement in learning found with stimulation. PMID:22357863

  6. Neural control of rhythmic, cyclical human arm movement: task dependency, nerve specificity and phase modulation of cutaneous reflexes

    PubMed Central

    Zehr, E Paul; Kido, Aiko

    2001-01-01

    The organization and pattern of cutaneous reflex modulation during rhythmic cyclical movements of the human upper limbs has received much less attention than that afforded the lower limb. Our working hypothesis is that control mechanisms underlying the modulation of cutaneous reflex amplitude during rhythmic arm movement are similar to those that control reflex modulation in the leg. Thus, we hypothesized that cutaneous reflexes would show task dependency and nerve specificity in the upper limb during rhythmic cyclical arm movement as has been demonstrated in the human lower limb. EMG was recorded from 10 muscles crossing the human shoulder, elbow and wrist joints while bilateral whole arm rhythmic cyclical movements were performed on a custom-made, hydraulic apparatus. Cutaneous reflexes were evoked with trains (5× 1.0 ms pulses at 300 Hz) of electrical stimulation delivered at non-noxious intensities (∼2× threshold for radiating parasthesia) to the superficial radial, median and ulnar nerves innervating the hand. Cutaneous reflexes were typically modulated with the movement cycle (i.e. phase dependency was observed). There was evidence for nerve specificity of cutaneous reflexes during rhythmic movement of the upper limbs. Task-dependent modulation was also seen as cutaneous reflexes were of larger amplitude or inhibitory (reflex reversal) during arm cycling as compared to static contraction. While there are some differences in the patterns of cutaneous reflex modulation seen between the arms and legs, it is concluded that cutaneous reflexes are modulated similarly in the upper and lower limbs implicating similar motor control mechanisms. PMID:11744775

  7. Low frequency steady-state brain responses modulate large scale functional networks in a frequency-specific means.

    PubMed

    Wang, Yi-Feng; Long, Zhiliang; Cui, Qian; Liu, Feng; Jing, Xiu-Juan; Chen, Heng; Guo, Xiao-Nan; Yan, Jin H; Chen, Hua-Fu

    2016-01-01

    Neural oscillations are essential for brain functions. Research has suggested that the frequency of neural oscillations is lower for more integrative and remote communications. In this vein, some resting-state studies have suggested that large scale networks function in the very low frequency range (<1 Hz). However, it is difficult to determine the frequency characteristics of brain networks because both resting-state studies and conventional frequency tagging approaches cannot simultaneously capture multiple large scale networks in controllable cognitive activities. In this preliminary study, we aimed to examine whether large scale networks can be modulated by task-induced low frequency steady-state brain responses (lfSSBRs) in a frequency-specific pattern. In a revised attention network test, the lfSSBRs were evoked in the triple network system and sensory-motor system, indicating that large scale networks can be modulated in a frequency tagging way. Furthermore, the inter- and intranetwork synchronizations as well as coherence were increased at the fundamental frequency and the first harmonic rather than at other frequency bands, indicating a frequency-specific modulation of information communication. However, there was no difference among attention conditions, indicating that lfSSBRs modulate the general attention state much stronger than distinguishing attention conditions. This study provides insights into the advantage and mechanism of lfSSBRs. More importantly, it paves a new way to investigate frequency-specific large scale brain activities. PMID:26512872

  8. Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes

    PubMed Central

    Healy, Luke M; Sheridan, Graham K; Pritchard, Adam J; Rutkowska, Aleksandra; Mullershausen, Florian; Dev, Kumlesh K

    2013-01-01

    Background and Purpose The sphingosine 1-phosphate receptor subtype 1 (S1P1R) is modulated by phosphorylated FTY720 (pFTY720), which causes S1P1R internalization preventing lymphocyte migration thus limiting autoimmune response. Studies indicate that internalized S1P1Rs continue to signal, maintaining an inhibition of cAMP, thus raising question whether the effects of pFTY720 are due to transient initial agonism, functional antagonism and/or continued signalling. To further investigate this, the current study first determined if continued S1P1R activation is pathway specific. Experimental Approach Using human and rat astrocyte cultures, the effects of S1P1R activation on cAMP, pERK and Ca2+ signalling was investigated. In addition, to examine the role of S1P1R redistribution on these events, a novel biologic (MNP301) that prevented pFTY720-mediated S1P1R redistribution was engineered. Key Results The data showed that pFTY720 induced long-lasting S1P1R redistribution and continued cAMP signalling in rat astrocytes. In contrast, pFTY720 induced a transient increase of Ca2+ in astrocytes and subsequent antagonism of Ca2+ signalling. Notably, while leaving pFTY720-induced cAMP signalling intact, the novel MNP301 peptide attenuated S1P1R-mediated Ca2+ and pERK signalling in cultured rat astrocytes. Conclusions and Implications These findings suggested that pFTY720 causes continued cAMP signalling that is not dependent on S1P1R redistribution and induces functional antagonism of Ca2+ signalling after transient stimulation. To our knowledge, this is the first report demonstrating that pFTY720 causes continued signalling in one pathway (cAMP) versus functional antagonism of another pathway (Ca2+) and which also suggests that redistributed S1P1Rs may have differing signalling properties from those expressed at the surface. PMID:23587004

  9. Ion-specific modulation of protein interactions: Anion-induced, reversible oligomerization of a fusion protein

    PubMed Central

    Gokarn, Yatin R; Fesinmeyer, R Matthew; Saluja, Atul; Cao, Shawn; Dankberg, Jane; Goetze, Andrew; Remmele, Richard L; Narhi, Linda O; Brems, David N

    2009-01-01

    Ions can significantly modulate the solution interactions of proteins. We aim to demonstrate that the salt-dependent reversible heptamerization of a fusion protein called peptibody A or PbA is governed by anion-specific interactions with key arginyl and lysyl residues on its peptide arms. Peptibody A, an E. coli expressed, basic (pI = 8.8), homodimer (65.2 kDa), consisted of an IgG1-Fc with two, C-terminal peptide arms linked via penta-glycine linkers. Each peptide arm was composed of two, tandem, active sequences (SEYQGLPPQGWK) separated by a spacer (GSGSATGGSGGGASSGSGSATG). PbA was monomeric in 10 mM acetate, pH 5.0 but exhibited reversible self-association upon salt addition. The sedimentation coefficient (sw) and hydrodynamic diameter (DH) versus PbA concentration isotherms in the presence of 140 mM NaCl (A5N) displayed sharp increases in sw and DH, reaching plateau values of 9 s and 16 nm by 10 mg/mL PbA. The DH and sedimentation equilibrium data in the plateau region (>12 mg/mL) indicated the oligomeric ensemble to be monodisperse (PdI = 0.05) with a z-average molecular weight (Mz) of 433 kDa (stoichiometry = 7). There was no evidence of reversible self-association for an IgG1-Fc molecule in A5N by itself or in a mixture containing fluorescently labeled IgG1-Fc and PbA, indicative of PbA self-assembly being mediated through its peptide arms. Self-association increased with pH, NaCl concentration, and anion size (I− > Br− > Cl− > F−) but could be inhibited using soluble Trp-, Phe-, and Leu-amide salts (Trp > Phe > Leu). We propose that in the presence of salt (i) anion binding renders PbA self-association competent by neutralizing the peptidyl arginyl and lysyl amines, (ii) self-association occurs via aromatic and hydrophobic interactions between the..xx..xxx..xx.. motifs, and (iii) at >10 mg/mL, PbA predominantly exists as heptameric clusters. PMID:19177361

  10. Holographic content addressable storage

    NASA Astrophysics Data System (ADS)

    Chao, Tien-Hsin; Lu, Thomas; Reyes, George

    2015-03-01

    We have developed a Holographic Content Addressable Storage (HCAS) architecture. The HCAS systems consists of a DMD (Digital Micromirror Array) as the input Spatial Light Modulator (SLM), a CMOS (Complementary Metal-oxide Semiconductor) sensor as the output photodetector and a photorefractive crystal as the recording media. The HCAS system is capable of performing optical correlation of an input image/feature against massive reference data set stored in the holographic memory. Detailed system analysis will be reported in this paper.

  11. Inaugural address

    NASA Astrophysics Data System (ADS)

    Joshi, P. S.

    2014-03-01

    From jets to cosmos to cosmic censorship P S Joshi Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India E-mail: psj@tifr.res.in 1. Introduction At the outset, I should like to acknowledge that part of the title above, which tries to capture the main flavour of this meeting, and has been borrowed from one of the plenary talks at the conference. When we set out to make the programme for the conference, we thought of beginning with observations on the Universe, but then we certainly wanted to go further and address deeper questions, which were at the very foundations of our inquiry, and understanding on the nature and structure of the Universe. I believe, we succeeded to a good extent, and it is all here for you in the form of these Conference Proceedings, which have been aptly titled as 'Vishwa Mimansa', which could be possibly translated as 'Analysis of the Universe'! It is my great pleasure and privilege to welcome you all to the ICGC-2011 meeting at Goa. The International Conference on Gravitation and Cosmology (ICGC) series of meetings are being organized by the Indian Association for General Relativity and Gravitation (IAGRG), and the first such meeting was planned and conducted in Goa in 1987, with subsequent meetings taking place at a duration of about four years at various locations in India. So, it was thought appropriate to return to Goa to celebrate the 25 years of the ICGC meetings. The recollections from that first meeting have been recorded elsewhere here in these Proceedings. The research and teaching on gravitation and cosmology was initiated quite early in India, by V V Narlikar at the Banares Hindu University, and by N R Sen in Kolkata in the 1930s. In course of time, this activity grew and gained momentum, and in early 1969, at the felicitation held for the 60 years of V V Narlikar at a conference in Ahmedabad, P C Vaidya proposed the formation of the IAGRG society, with V V Narlikar being the first President. This

  12. Opening addresses.

    PubMed

    Chukudebelu, W O; Lucas, A O; Ransome-kuti, O; Akinla, O; Obayi, G U

    1988-01-01

    The theme of the 3rd International Conference of the Society of Gynecology and Obstetrics of Nigeria (SOGON) held October 26, 1986 in Enugu was maternal morbidity and mortality in Africa. The opening addresses emphasize the high maternal mortality rate in Africa and SOGON's dedication to promoting women's health and welfare. In order to reduce maternal mortality, the scope of this problem must be made evident by gathering accurate mortality rates through maternity care monitoring and auditing. Governments, health professionals, educators, behavioral scientists, and communication specialists have a responsibility to improve maternal health services in this country. By making the population aware of this problem through education, measures can be taken to reduce the presently high maternal mortality rates. Nigerian women are physically unprepared for childbirth; therefore, balanced diets and disease prevention should be promoted. Since about 40% of deliveries are unmanaged, training for traditional birth attendants should be provided. Furthermore, family planning programs should discourage teenage pregnancies, encourage birth spacing and small families, and promote the use of family planning techniques among men. The problem of child bearing and rearing accompanied by hard work should also be investigated. For practices to change so that maternal mortality rates can be reduced, attitudes must be changed such that the current rates are viewed as unacceptable. PMID:12179275

  13. Modulating role of pheromonal cues from oestrus-specific urine on 3-methylcholanthrene-induced male reproductive toxicity.

    PubMed

    Suriyakalaa, U; Gayathiri, R; SankarGanesh, D; Kokilavani, P; Sukirtha, R; Ramachandran, R; Kamalakkannan, S; Achiraman, S

    2016-09-01

    Polyaromatic hydrocarbons (PAHs) are persistent organic pollutants that contribute to endocrine/gonadal disruption. This study was designed to investigate the endocrine modulating role of pheromones in alleviating the reproductive toxic effects of 3-MC (3-methylcholanthrene), one of the common PAHs, in rat model. The rats were injected intraperitoneally with 3-MC at a dose of 25 mg kg(-1) BW. The serum levels of testosterone and other biochemical parameters were altered to significant levels in 3-MC-treated rats and oestrus-specific urine exposure restored all these effects to near normal. Although testis weight did not indicate any significant change, sperm and spermatid counts were significantly reduced in 3-MC-treated rats, which became normal in oestrus-urine-exposed rats. Hence, this study suggests that oestrus-specific urinary pheromones have the potential to modulate the endocrine system and alleviate the male reproductive toxic effects produced by 3-MC. PMID:26715617

  14. Opening Address

    NASA Astrophysics Data System (ADS)

    Yamada, T.

    2014-12-01

    Ladies and Gentlemen, it is my great honor and pleasure to present an opening address of the 3rd International Workshop on "State of the Art in Nuclear Cluster Physics"(SOTANCP3). On the behalf of the organizing committee, I certainly welcome all your visits to KGU Kannai Media Center belonging to Kanto Gakuin University, and stay in Yokohama. In particular, to whom come from abroad more than 17 countries, I would appreciate your participations after long long trips from your homeland to Yokohama. The first international workshop on "State of the Art in Nuclear Cluster Physics", called SOTANCP, was held in Strasbourg, France, in 2008, and the second one was held in Brussels, Belgium, in 2010. Then the third workshop is now held in Yokohama. In this period, we had the traditional 10th cluster conference in Debrecen, Hungary, in 2012. Thus we have the traditional cluster conference and SOTANCP, one after another, every two years. This obviously shows our field of nuclear cluster physics is very active and flourishing. It is for the first time in about 10 years to hold the international workshop on nuclear cluster physics in Japan, because the last cluster conference held in Japan was in Nara in 2003, about 10 years ago. The president in Nara conference was Prof. K. Ikeda, and the chairpersons were Prof. H. Horiuchi and Prof. I. Tanihata. I think, quite a lot of persons in this room had participated at the Nara conference. Since then, about ten years passed. So, this workshop has profound significance for our Japanese colleagues. The subjects of this workshop are to discuss "the state of the art in nuclear cluster physics" and also discuss the prospect of this field. In a couple of years, we saw significant progresses of this field both in theory and in experiment, which have brought better and new understandings on the clustering aspects in stable and unstable nuclei. I think, the concept of clustering has been more important than ever. This is true also in the

  15. Presidential address.

    PubMed

    Vohra, U

    1993-07-01

    The Secretary of India's Ministry of Health and Family Welfare serves as Chair of the Executive Council of the International Institute for Population Sciences in Bombay. She addressed its 35th convocation in 1993. Global population stands at 5.43 billion and increases by about 90 million people each year. 84 million of these new people are born in developing countries. India contributes 17 million new people annually. The annual population growth rate in India is about 2%. Its population size will probably surpass 1 billion by the 2000. High population growth rates are a leading obstacle to socioeconomic development in developing countries. Governments of many developing countries recognize this problem and have expanded their family planning programs to stabilize population growth. Asian countries that have done so and have completed the fertility transition include China, Japan, Singapore, South Korea, and Thailand. Burma, Malaysia, North Korea, Sri Lanka, and Vietnam have not yet completed the transition. Afghanistan, Bangladesh, Iran, Nepal, and Pakistan are half-way through the transition. High population growth rates put pressure on land by fragmenting finite land resources, increasing the number of landless laborers and unemployment, and by causing considerable rural-urban migration. All these factors bring about social stress and burden civic services. India has reduced its total fertility rate from 5.2 to 3.9 between 1971 and 1991. Some Indian states have already achieved replacement fertility. Considerable disparity in socioeconomic development exists among states and districts. For example, the states of Bihar, Madhya Pradesh, Rajasthan, and Uttar Pradesh have female literacy rates lower than 27%, while that for Kerala is 87%. Overall, infant mortality has fallen from 110 to 80 between 1981 and 1990. In Uttar Pradesh, it has fallen from 150 to 98, while it is at 17 in Kerala. India needs innovative approaches to increase contraceptive prevalence rates

  16. 47 CFR 73.758 - System specifications for digitally modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...) For digitally modulated emissions, the Digital Radio Mondiale (DRM) standard shall be employed. Both digital audio broadcasting and datacasting are authorized. The RF requirements for the DRM system are... require that the digital spectral power density (and total power) be lower by several dB than is...

  17. 47 CFR 73.758 - System specifications for digitally modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...) For digitally modulated emissions, the Digital Radio Mondiale (DRM) standard shall be employed. Both digital audio broadcasting and datacasting are authorized. The RF requirements for the DRM system are... require that the digital spectral power density (and total power) be lower by several dB than is...

  18. 47 CFR 73.758 - System specifications for digitally modulated emissions in the HF broadcasting service.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) For digitally modulated emissions, the Digital Radio Mondiale (DRM) standard shall be employed. Both digital audio broadcasting and datacasting are authorized. The RF requirements for the DRM system are... require that the digital spectral power density (and total power) be lower by several dB than is...

  19. Welcome Address

    NASA Astrophysics Data System (ADS)

    Kiku, H.

    2014-12-01

    Ladies and Gentlemen, It is an honor for me to present my welcome address in the 3rd International Workshop on "State of the Art in Nuclear Cluster Physics"(SOTANCP3), as the president of Kanto Gakuin University. Particularly to those from abroad more than 17 countries, I am very grateful for your participation after long long trips from your home to Yokohama. On the behalf of the Kanto Gakuin University, we certainly welcome your visit to our university and stay in Yokohama. First I would like to introduce Kanto Gakuin University briefly. Kanto Gakuin University, which is called KGU, traces its roots back to the Yokohama Baptist Seminary founded in 1884 in Yamate, Yokohama. The seminary's founder was Albert Arnold Bennett, alumnus of Brown University, who came to Japan from the United States to establish a theological seminary for cultivating and training Japanese missionaries. Now KGU is a major member of the Kanto Gakuin School Corporation, which is composed of two kindergartens, two primary schools, two junior high schools, two senior high schools as well as KGU. In this university, we have eight faculties with graduate school including Humanities, Economics, Law, Sciences and Engineering, Architecture and Environmental Design, Human and Environmental Studies, Nursing, and Law School. Over eleven thousands students are currently learning in our university. By the way, my major is the geotechnical engineering, and I belong to the faculty of Sciences and Engineering in my university. Prof. T. Yamada, here, is my colleague in the same faculty. I know that the nuclear physics is one of the most active academic fields in the world. In fact, about half of the participants, namely, more than 50 scientists, come from abroad in this conference. Moreover, I know that the nuclear physics is related to not only the other fundamental physics such as the elementary particle physics and astrophysics but also chemistry, medical sciences, medical cares, and radiation metrology

  20. Gene-Specific Assessment of Guanine Oxidation as an Epigenetic Modulator for Cardiac Specification of Mouse Embryonic Stem Cells

    PubMed Central

    Park, Joonghoon; Park, Jong Woo; Oh, Hawmok; Maria, Fernanda S.; Kang, Jaeku; Tian, Xiuchun

    2016-01-01

    Epigenetics have essential roles in development and human diseases. Compared to the complex histone modifications, epigenetic changes on mammalian DNA are as simple as methylation on cytosine. Guanine, however, can be oxidized as an epigenetic change which can undergo base-pair transversion, causing a genetic difference. Accumulating evidence indicates that reactive oxygen species (ROS) are important signaling molecules for embryonic stem cell (ESC) differentiation, possibly through transient changes on genomic DNA such as 7,8-dihydro-8-oxoguanine (8-oxoG). Technical limitations on detecting such DNA modifications, however, restrict the investigation of the role of 8-oxoG in ESC differentiation. Here, we developed a Hoogsteen base pairing-mediated PCR-sequencing assay to detect 8-oxoG lesions that can subsequently cause G to T transversions during PCR. We then used this assay to assess the epigenetic and transient 8-oxoG formation in the Tbx5 gene of R1 mouse ESCs subjected to oxidative stress by removing 2-mercaptoethanol (2ME) from the culture media. To our surprise, significantly higher numbers of 8-oxoG-mediated G∙C to C∙G transversion, not G∙C to T∙A, were detected at 7th and 9th base position from the transcription start site of exon 1 of Tbx5 in ESCs in the (-)2ME than (+)2ME group (p < 0.05). This was consistent with the decrease in the amount of amplifiable of DNA harboring the 8-oxoG lesions at the Tbx5 promoter region in the oxidative stressed ESCs. The ESCs responded to oxidative stress, possibly through the epigenetic effects of guanine oxidation with decreased proliferation (p < 0.05) and increased formation of beating embryoid bodies (EBs; p < 0.001). Additionally, the epigenetic changes of guanine induced up-regulation of Ogg1 and PolB, two base excision repairing genes for 8-oxoG, in ESCs treated with (-)2ME (p < 0.01). Together, we developed a gene-specific and direct quantification assay for guanine oxidation. Using oxidative stressed

  1. Waste Receiving and Processing Facility Module 1 Data Management System Software Requirements Specification

    SciTech Connect

    Brann, E.C. II

    1994-09-09

    This document provides the software requirements for Waste Receiving and Processing (WRAP) Module 1 Data Management System (DMS). The DMS is one of the plant computer systems for the new WRAP 1 facility (Project W-026). The DMS will collect, store and report data required to certify the low level waste (LLW) and transuranic (TRU) waste items processed at WRAP 1 as acceptable for shipment, storage, or disposal.

  2. Waste Receiving and Processing Facility Module 1 Data Management System software requirements specification

    SciTech Connect

    Rosnick, C.K.

    1996-04-19

    This document provides the software requirements for Waste Receiving and Processing (WRAP) Module 1 Data Management System (DMS). The DMS is one of the plant computer systems for the new WRAP 1 facility (Project W-0126). The DMS will collect, store and report data required to certify the low level waste (LLW) and transuranic (TRU) waste items processed at WRAP 1 as acceptable for shipment, storage, or disposal.

  3. President's Address

    PubMed Central

    Moore, John

    1928-01-01

    The paper recalls how matters veterinary were regarded forty-six years ago, what has been achieved since, and future progress is reflected. The paper is divided into parts relating respectively to: (a) medicine; (b) surgery (c) teaching and research; (d) administration. Formerly, glanders and farcy, and rabies, though acknowledged as contagious and specific, were also believed to be of spontaneous origin. Experiences with regard to these two diseases, and the mallein test for glanders, are related. The discovery of the Bacillus anthracis led to the development of veterinary research, but for some time confusion existed. Tuberculosis was believed to be endogenous and the result of the absorption of caseous products of a previous inflammation. Treatment of “milk fever” in cows by udder inflation and biochemistry in relation to that disease are considered. The advance in veterinary surgery stands out most prominently; in canine practice, operations are now attempted which were never thought possible in the early days. Allusion is made to the recent formidable operations for the cure of “windsucking” in horses, and for traumatic pericarditis in bovines. The powers of observance of the old practitioners in diagnosing lameness, and some of the old methods of treatment for lameness, are supported. The great progress in veterinary research is referred to, also its advantages from an imperial point of view. The causative agents of those diseases which are at present ultravisible, particularly foot-and-mouth disease, will probably be found, and better methods of prevention result. In training, thorough instruction in animal physiology, animal nutrition and biochemistry is advocated, also affiliation of veterinary colleges to universities, the individuality of such colleges, and the one-portal system of qualification being maintained. PMID:19986709

  4. Eye movement preparation causes spatially-specific modulation of auditory processing: New evidence from event-related brain potentials

    PubMed Central

    Gherri, Elena; Driver, Jon; Eimer, Martin

    2009-01-01

    To investigate whether saccade preparation can modulate processing of auditory stimuli in a spatially-specific fashion, ERPs were recorded for a Saccade task, in which the direction of a prepared saccade was cued, prior to an imperative auditory stimulus indicating whether to execute or withhold that saccade. For comparison, we also ran a conventional Covert Attention task, where the same cue now indicated the direction for a covert endogenous attentional shift prior to an auditory target-nontarget discrimination. Lateralised components previously observed during cued shifts of attention (ADAN, LDAP) did not differ significantly across tasks, indicating commonalities between auditory spatial attention and oculomotor control. Moreover, in both tasks, spatially-specific modulation of auditory processing was subsequently found, with enhanced negativity for lateral auditory nontarget stimuli at cued versus uncued locations. This modulation started earlier and was more pronounced for the Covert Attention task, but was also reliably present in the Saccade task, demonstrating that the effects of covert saccade preparation on auditory processing can be similar to effects of endogenous covert attentional orienting, albeit smaller. These findings provide new evidence for similarities but also some differences between oculomotor preparation and shifts of endogenous spatial attention. They also show that saccade preparation can affect not just vision, but also sensory processing of auditory events. PMID:18614157

  5. Modulation of antigen presentation by autoreactive B cell clones specific for GAD65 from a type I diabetic patient

    PubMed Central

    BANGA, J P; MOORE, J K; DUHINDAN, N; MADEC, A M; VAN ENDERT, P M; ORGIAZZI, J; ENDL, J

    2004-01-01

    We used a GAD65-specific human B–T cell line cognate system in vitro to investigate the modulation of GAD65 presentation by autoantibody, assessed in a proliferation assay. Generally, if the T cell determinant overlaps or resides within the antibody epitope, effects of presentation are blunted while if they are distant can lead to potent presentation. For three different autoreactive B–T cell line cognate pairs, the modulation of GAD65 presentation followed the mode of overlapping or distant epitopes with resultant potent or undetectable presentation. However, other cognate pairs elicited variability in this pattern of presentation. Notably, one B cell line, DPC, whose antibody epitope did not overlap with the T cell determinants, was consistently poor in presenting GAD65. Using the fluorescent dye Alexa Fluor 647 conjugated to GAD65 to study receptor-mediated antigen endocytosis showed that all the antigen-specific B cell clones were efficient in intracellular accumulation of the antigen. Additionally, multicolour immunofluorescence microscopy showed that the internalized GAD65/surface IgG complexes were rapidly targeted to a perinuclear compartment in all GAD-specific B cell clones. This analysis also demonstrated that HLA-DM expression was reduced strongly in DPC compared to the stimulatory B cell clones. Thus the capability of antigen-specific B cells to capture and present antigen to human T cell lines is dependent on the spatial relationship of B and T cell epitopes as well other factors which contribute to the efficiency of presentation. PMID:14678267

  6. Waste Receiving and Processing, Module 2A, feed specification: Revision 1

    SciTech Connect

    Kruger, O.L.; Sheriff, M.L.

    1994-11-14

    Detailed descriptions of the various mixed low-level waste feed streams that will be processed in the Waste Receiving and Processing Facility, Module 2A (WRAP 2A) are provided. Feed stream descriptions are based on available reports, the solid waste information tracking system database, and the 1993 solid waste forecast data. Available chemical and physical attributes, radionuclide data, waste codes, and packaging information are shown for 15 feed streams. The information sources and methodology for obtaining projections for WRAP 2A expected feed stream volumes also are described.

  7. Auditory imagery modulates frequency-specific areas in the human auditory cortex.

    PubMed

    Oh, Jihoon; Kwon, Jae Hyung; Yang, Po Song; Jeong, Jaeseung

    2013-02-01

    Neural responses in early sensory areas are influenced by top-down processing. In the visual system, early visual areas have been shown to actively participate in top-down processing based on their topographical properties. Although it has been suggested that the auditory cortex is involved in top-down control, functional evidence of topographic modulation is still lacking. Here, we show that mental auditory imagery for familiar melodies induces significant activation in the frequency-responsive areas of the primary auditory cortex (PAC). This activation is related to the characteristics of the imagery: when subjects were asked to imagine high-frequency melodies, we observed increased activation in the high- versus low-frequency response area; when the subjects were asked to imagine low-frequency melodies, the opposite was observed. Furthermore, we found that A1 is more closely related to the observed frequency-related modulation than R in tonotopic subfields of the PAC. Our findings suggest that top-down processing in the auditory cortex relies on a mechanism similar to that used in the perception of external auditory stimuli, which is comparable to early visual systems. PMID:22905820

  8. Interface specifications for the SCR (a-7e) Extended Computer Module

    SciTech Connect

    Parnas, D.L.; Weiss, D.M.; Clements, P.C.; Britton, K.H.

    1983-01-01

    This document describes the programmer interface to a computing machine partially implemented in software. The Extended Computer is part of NRL's Software Cost Reduction (SCR) project, to demonstrate the feasibility of applying advanced software engineering techniques to complex real-time systems in order to simplify maintenance. The Extended Computer allows code portability among avionics computers by providing extensible addressing, uniform i/o and data access, representation-independent data types, uniform event signalling, a standard subprogram invocation mechanism, and parallel process capability. The purpose of the Extended Computer is to allow the remainder of the software to remain unchanged when the host computer is changed or replaced.

  9. States Address Achievement Gaps.

    ERIC Educational Resources Information Center

    Christie, Kathy

    2002-01-01

    Summarizes 2 state initiatives to address the achievement gap: North Carolina's report by the Advisory Commission on Raising Achievement and Closing Gaps, containing an 11-point strategy, and Kentucky's legislation putting in place 10 specific processes. The North Carolina report is available at www.dpi.state.nc.us.closingthegap; Kentucky's…

  10. Limb-specific autonomic dysfunction in complex regional pain syndrome modulated by wearing prism glasses.

    PubMed

    Moseley, G Lorimer; Gallace, Alberto; Di Pietro, Flavia; Spence, Charles; Iannetti, Gian Domenico

    2013-11-01

    In unilateral upper-limb complex regional pain syndrome (CRPS), the temperature of the hands is modulated by where the arms are located relative to the body midline. We hypothesized that this effect depends on the perceived location of the hands, not on their actual location, nor on their anatomical alignment. In 2 separate cross-sectional randomized experiments, 10 (6 female) unilateral CRPS patients wore prism glasses that laterally shifted the visual field by 20°. Skin temperature was measured before and after 9-minute periods in which the position of one hand was changed. Placing the affected hand on the healthy side of the body midline increased its temperature (Δ°C=+0.47 ± 0.14°C), but not if prism glasses made the hand appear to be on the body midline (Δ°C=+0.07 ± 0.06°C). Similarly, when prism glasses made the affected hand appear to be on the healthy side of the body midline, even though it was not, the affected hand warmed up (Δ°C=+0.28 ± 0.14°C). When prism glasses made the healthy hand appear to be on the affected side of the body midline, even though it was not, the healthy hand cooled down (Δ°C=-0.30 ± 0.15°C). Friedman's analysis of variance and Wilcoxon pairs tests upheld the results (P<0.01 for all). We conclude that, in CRPS, cortical mechanisms responsible for encoding the perceived location of the limbs in space modulate the temperature of the hands. PMID:23886518

  11. Attention modulates specificity effects in spoken word recognition: Challenges to the time-course hypothesis.

    PubMed

    Theodore, Rachel M; Blumstein, Sheila E; Luthra, Sahil

    2015-07-01

    Findings in the domain of spoken word recognition have indicated that lexical representations contain both abstract and episodic information. It has been proposed that processing time determines when each source of information is recruited, with increased processing time being required to access lower-frequency episodic instantiations. The time-course hypothesis of specificity effects has thus identified a strong role for retrieval mechanisms mediating the use of abstract versus episodic information. Here we conducted three recognition memory experiments to examine whether the findings previously attributed to retrieval mechanisms might instead reflect attention during encoding. The results from Experiment 1 showed that talker-specificity effects emerged when subjects attended to the individual speakers, but not when they attended to lexical characteristics, during encoding, even though processing times at retrieval were equivalent. The results from Experiment 2 showed that talker-specificity effects emerged when listeners attended to talker gender but not when they attended to syntactic characteristics, even though the processing times at retrieval were significantly longer in the latter condition. The results from Experiment 3 showed no talker-specificity effects when all listeners attended to lexical characteristics, even when processing at retrieval was slowed by the addition of background noise. Collectively, these results suggest that when processing time during retrieval is decoupled from encoding factors, it fails to predict the emergence of talker-specificity effects. Rather, attention during encoding appears to be the putative variable. PMID:25824889

  12. Attention modulates specificity effects in spoken word recognition: Challenges to the time-course hypothesis

    PubMed Central

    Theodore, Rachel M.; Blumstein, Sheila E.; Luthra, Sahil

    2015-01-01

    Findings in the domain of spoken word recognition indicate that lexical representations contain both abstract and episodic information. It has been proposed that processing time determines when each source of information is recruited, with increased processing time required to access lower-frequency episodic instantiations. The time-course hypothesis of specificity effects thus identifies a strong role for retrieval mechanisms mediating the use of abstract versus episodic information. Here we conducted three recognition memory experiments to examine whether findings previously attributed to retrieval mechanisms might reflect attention during encoding. Results from Experiment 1 showed that talker-specificity effects emerged when subjects attended to individual speakers during encoding, but not when they attended to lexical characteristics during encoding, even though processing time at retrieval was equivalent. Results from Experiment 2 showed that talker-specificity effects emerged when listeners attended to talker gender but not when they attended to syntactic characteristics, even though processing time at retrieval was significantly longer in the latter condition. Results from Experiment 3 showed no talker-specificity effects when attending to lexical characteristics even when processing at retrieval was slowed by the addition of background noise. Collectively, these results suggest that when processing time during retrieval is decoupled from encoding factors, it fails to predict the emergence of talker-specificity effects. Rather, attention during encoding appears to be the putative variable. PMID:25824889

  13. Hypocretin neuron-specific transcriptome profiling identifies the sleep modulator Kcnh4a

    PubMed Central

    Yelin-Bekerman, Laura; Elbaz, Idan; Diber, Alex; Dahary, Dvir; Gibbs-Bar, Liron; Alon, Shahar; Lerer-Goldshtein, Tali; Appelbaum, Lior

    2015-01-01

    Sleep has been conserved throughout evolution; however, the molecular and neuronal mechanisms of sleep are largely unknown. The hypothalamic hypocretin/orexin (Hcrt) neurons regulate sleep\\wake states, feeding, stress, and reward. To elucidate the mechanism that enables these various functions and to identify sleep regulators, we combined fluorescence cell sorting and RNA-seq in hcrt:EGFP zebrafish. Dozens of Hcrt-neuron–specific transcripts were identified and comprehensive high-resolution imaging revealed gene-specific localization in all or subsets of Hcrt neurons. Clusters of Hcrt-neuron–specific genes are predicted to be regulated by shared transcription factors. These findings show that Hcrt neurons are heterogeneous and that integrative molecular mechanisms orchestrate their diverse functions. The voltage-gated potassium channel Kcnh4a, which is expressed in all Hcrt neurons, was silenced by the CRISPR-mediated gene inactivation system. The mutant kcnh4a (kcnh4a-/-) larvae showed reduced sleep time and consolidation, specifically during the night, suggesting that Kcnh4a regulates sleep. DOI: http://dx.doi.org/10.7554/eLife.08638.001 PMID:26426478

  14. An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females.

    PubMed

    Correa, Stephanie M; Newstrom, David W; Warne, James P; Flandin, Pierre; Cheung, Clement C; Lin-Moore, Alexander T; Pierce, Andrew A; Xu, Allison W; Rubenstein, John L; Ingraham, Holly A

    2015-01-01

    Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting the development of Nkx2-1(+) VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons coexpressing ERα and Tac1. Unexpectedly, two responses controlled by ERα(+) neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses. PMID:25543145

  15. An Estrogen-Responsive Module in the Ventromedial Hypothalamus Selectively Drives Sex-Specific Activity in Females

    PubMed Central

    Correa, Stephanie M.; Newstrom, David W.; Warne, James P.; Flandin, Pierre; Cheung, Clement C.; Lin-Moore, Alexander T.; Pierce, Andrew A.; Xu, Allison W.; Rubenstein, John L.; Ingraham, Holly A.

    2015-01-01

    Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting development of Nkx2-1+ VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons co-expressing ERα and Tac1. Unexpectedly, two responses controlled by ERα neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses. PMID:25543145

  16. Lineage-specific variations in the trigger loop modulate RNA proofreading by bacterial RNA polymerases

    PubMed Central

    Esyunina, Daria; Turtola, Matti; Pupov, Danil; Bass, Irina; Klimašauskas, Saulius; Belogurov, Georgiy; Kulbachinskiy, Andrey

    2016-01-01

    RNA cleavage by bacterial RNA polymerase (RNAP) has been implicated in transcriptional proofreading and reactivation of arrested transcription elongation complexes but its molecular mechanism is less understood than the mechanism of nucleotide addition, despite both reactions taking place in the same active site. RNAP from the radioresistant bacterium Deinococcus radiodurans is characterized by highly efficient intrinsic RNA cleavage in comparison with Escherichia coli RNAP. We find that the enhanced RNA cleavage activity largely derives from amino acid substitutions in the trigger loop (TL), a mobile element of the active site involved in various RNAP activities. The differences in RNA cleavage between these RNAPs disappear when the TL is deleted, or in the presence of GreA cleavage factors, which replace the TL in the active site. We propose that the TL substitutions modulate the RNA cleavage activity by altering the TL folding and its contacts with substrate RNA and that the resulting differences in transcriptional proofreading may play a role in bacterial stress adaptation. PMID:26733581

  17. GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters

    PubMed Central

    Ramesh, Sunita A.; Tyerman, Stephen D.; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A.; Ryan, Peter R.; Gillham, Matthew

    2015-01-01

    The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms. PMID:26219411

  18. Congruency sequence effect in cross-task context: evidence for dimension-specific modulation.

    PubMed

    Lee, Jaeyong; Cho, Yang Seok

    2013-11-01

    The congruency sequence effect refers to a reduced congruency effect after incongruent trials relative to congruent trials. This modulation is thought to be, at least in part, due to the control mechanisms resolving conflict. The present study examined the nature of the control mechanisms by having participants perform two different tasks in an alternating way. When participants performed horizontal and vertical Simon tasks in Experiment 1A, and horizontal and vertical spatial Stroop task in Experiment 1B, no congruency sequence effect was obtained between the task congruencies. When the Simon task and spatial Stroop task were performed with different response sets in Experiment 2, no congruency sequence effect was obtained. However, in Experiment 3, in which the participants performed the horizontal Simon and spatial Stroop tasks with an identical response set, a significant congruency sequence effect was obtained between the task congruencies. In Experiment 4, no congruency sequence effect was obtained when participants performed two tasks having different task-irrelevant dimensions with the identical response set. The findings suggest inhibitory processing between the task-irrelevant dimension and response mode after conflict. PMID:24184348

  19. Establishing an optimized patient-specific verification program for volumetric modulated arc therapy.

    PubMed

    Serna, Alfredo; Mata, Fernando; Puchades, Vicente

    2013-01-01

    Quality assurance (QA) of volumetric modulated arc therapy (VMAT) increases the workload significantly. We compared the results from 4 verification methods to establish an efficient VMAT QA. Planning for VMAT treatments was carried out for 40 consecutive patients. Pretreatment verifications were carried out with ion chamber array Physikalish-Technische Werkstätten (PTW729), electronic portal dosimetry (EPID), ion chamber measurements, and independent dose calculation with Diamond program. 2D analyses were made using the gamma analysis (3mm distance to agreement and 3% dose difference relative to maximum, 10% dose threshold). Average point dose difference calculated by Eclipse relative to ion chamber measurements and Diamond were 0.1%±0.9% and 0.6%±2.2%, respectively. Average pass rate for PTW729 was 99.2%±1.9% and 98.3%±1.3% for EPID. The total required time (linac occupancy time given in parentheses) for each QA method was: PTW729 43.5 minutes (26.5 minutes), EPID 14.5 minutes (2.5 minutes), ion chamber 34.5 minutes (26.5 minutes), and Diamond 12.0 minutes (0 minute). The results were consistent and allowed us to establish an optimized protocol, considering safety and accuracy as well as workload, consisting of 2 verification methods: EPID 2D analysis and independent dose calculation. PMID:23540493

  20. Establishing an optimized patient-specific verification program for volumetric modulated arc therapy

    SciTech Connect

    Serna, Alfredo; Mata, Fernando; Puchades, Vicente

    2013-10-01

    Quality assurance (QA) of volumetric modulated arc therapy (VMAT) increases the workload significantly. We compared the results from 4 verification methods to establish an efficient VMAT QA. Planning for VMAT treatments was carried out for 40 consecutive patients. Pretreatment verifications were carried out with ion chamber array Physikalish-Technische Werkstätten (PTW729), electronic portal dosimetry (EPID), ion chamber measurements, and independent dose calculation with Diamond program. 2D analyses were made using the gamma analysis (3 mm distance to agreement and 3% dose difference relative to maximum, 10% dose threshold). Average point dose difference calculated by Eclipse relative to ion chamber measurements and Diamond were 0.1%±0.9% and 0.6%±2.2%, respectively. Average pass rate for PTW729 was 99.2%±1.9% and 98.3%±1.3% for EPID. The total required time (linac occupancy time given in parentheses) for each QA method was: PTW729 43.5 minutes (26.5 minutes), EPID 14.5 minutes (2.5 minutes), ion chamber 34.5 minutes (26.5 minutes), and Diamond 12.0 minutes (0 minute). The results were consistent and allowed us to establish an optimized protocol, considering safety and accuracy as well as workload, consisting of 2 verification methods: EPID 2D analysis and independent dose calculation.

  1. Subject-specific modulation of local field potential spectral power during brain-machine interface control in primates

    NASA Astrophysics Data System (ADS)

    So, Kelvin; Dangi, Siddharth; Orsborn, Amy L.; Gastpar, Michael C.; Carmena, Jose M.

    2014-04-01

    Objective. Intracortical brain-machine interfaces (BMIs) have predominantly utilized spike activity as the control signal. However, an increasing number of studies have shown the utility of local field potentials (LFPs) for decoding motor related signals. Currently, it is unclear how well different LFP frequencies can serve as features for continuous, closed-loop BMI control. Approach. We demonstrate 2D continuous LFP-based BMI control using closed-loop decoder adaptation, which adapts decoder parameters to subject-specific LFP feature modulations during BMI control. We trained two macaque monkeys to control a 2D cursor in a center-out task by modulating LFP power in the 0-150 Hz range. Main results. While both monkeys attained control, they used different strategies involving different frequency bands. One monkey primarily utilized the low-frequency spectrum (0-80 Hz), which was highly correlated between channels, and obtained proficient performance even with a single channel. In contrast, the other monkey relied more on higher frequencies (80-150 Hz), which were less correlated between channels, and had greater difficulty with control as the number of channels decreased. We then restricted the monkeys to use only various sub-ranges (0-40, 40-80, and 80-150 Hz) of the 0-150 Hz band. Interestingly, although both monkeys performed better with some sub-ranges than others, they were able to achieve BMI control with all sub-ranges after decoder adaptation, demonstrating broad flexibility in the frequencies that could potentially be used for LFP-based BMI control. Significance. Overall, our results demonstrate proficient, continuous BMI control using LFPs and provide insight into the subject-specific spectral patterns of LFP activity modulated during control.

  2. Silver Nanoclusters with Specific Ion Recognition Modulated by Ligand Passivation toward Fluorimetric and Colorimetric Copper Analysis and Biological Imaging

    PubMed Central

    Sun, Zongzhao; Li, Shuying; Jiang, Yao; Qiao, Yuchun; Zhang, Liyan; Xu, Lulu; Liu, Jinghui; Qi, Wei; Wang, Hua

    2016-01-01

    Silver nanoclusters were synthesized and passivated by glutathione (GSH) ligand, with high aqueous stability and powerful red fluorescence and UV-vis yellow colour. Importantly, the specific recognition of the AgNCs was modulated from Hg2+ ions to Cu2+ ions upon the GSH passivation, of which the unique GSH-Cu2+ chelating reaction could conduct the fluorescence quenching of AgNCs. Strong UV-vis absorbance of GSH-passivated AgNCs could also be realized depending on the Cu2+ levels. Moreover, the Cu2+-induced loss of fluorescence and UV-vis absorbance of GSH-passivated AgNCs could be well restored by using stronger Cu2+ chelating agent. A simultaneous and reversible fluorimetric and colorimetric sensing method was thereby developed for probing Cu2+ ions in blood with high sensitivity and selectivity. Subsequently, the fluorescence-trackable imaging for live tissues and cells was demonstrated towards the analysis Cu2+ ions using GSH-passivated AgNCs as the fluorescent probes. This study indicates that the use of functional ligands like GSH could not only modulate the specific ion recognition of AgNCs, but also endow them the high aqueous stability and powerful red fluorescence towards the wide applications for ion sensing and biological imaging in the complicated media like blood. PMID:26847593

  3. Silver Nanoclusters with Specific Ion Recognition Modulated by Ligand Passivation toward Fluorimetric and Colorimetric Copper Analysis and Biological Imaging

    NASA Astrophysics Data System (ADS)

    Sun, Zongzhao; Li, Shuying; Jiang, Yao; Qiao, Yuchun; Zhang, Liyan; Xu, Lulu; Liu, Jinghui; Qi, Wei; Wang, Hua

    2016-02-01

    Silver nanoclusters were synthesized and passivated by glutathione (GSH) ligand, with high aqueous stability and powerful red fluorescence and UV-vis yellow colour. Importantly, the specific recognition of the AgNCs was modulated from Hg2+ ions to Cu2+ ions upon the GSH passivation, of which the unique GSH-Cu2+ chelating reaction could conduct the fluorescence quenching of AgNCs. Strong UV-vis absorbance of GSH-passivated AgNCs could also be realized depending on the Cu2+ levels. Moreover, the Cu2+-induced loss of fluorescence and UV-vis absorbance of GSH-passivated AgNCs could be well restored by using stronger Cu2+ chelating agent. A simultaneous and reversible fluorimetric and colorimetric sensing method was thereby developed for probing Cu2+ ions in blood with high sensitivity and selectivity. Subsequently, the fluorescence-trackable imaging for live tissues and cells was demonstrated towards the analysis Cu2+ ions using GSH-passivated AgNCs as the fluorescent probes. This study indicates that the use of functional ligands like GSH could not only modulate the specific ion recognition of AgNCs, but also endow them the high aqueous stability and powerful red fluorescence towards the wide applications for ion sensing and biological imaging in the complicated media like blood.

  4. Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation

    PubMed Central

    Day, Trevor A; Wilson, Richard J A

    2007-01-01

    Inputs from central (brainstem) and peripheral (carotid body) respiratory chemoreceptors are coordinated to protect blood gases against potentially deleterious fluctuations. However, the mathematics of the steady-state interaction between chemoreceptors has been difficult to ascertain. Further, how this interaction affects time-dependent phenomena (in which chemoresponses depend upon previous experience) is largely unknown. To determine how central PCO2 modulates the response to peripheral chemostimulation in the rat, we utilized an in situ arterially perfused, vagotomized, decerebrate preparation, in which central and peripheral chemoreceptors were perfused separately (i.e. dual perfused preparation (DPP)). We carried out two sets of experiments: in Experiment 1, we alternated steady-state brainstem PCO2 between 25 and 50 Torr in each preparation, and applied specific carotid body hypoxia (60 Torr PO2 and 40 Torr PCO2) under both conditions; in Experiment 2, we applied four 5 min bouts (separated by 5 min) of specific carotid body hypoxia (60 Torr PO2 and 40 Torr PCO2) while holding the brainstem at either 30 Torr or 50 Torr PCO2. We demonstrate that the level of brainstem PCO2 modulates (a) the magnitude of the phrenic responses to a single step of specific carotid body hypoxia and (b) the magnitude of time-dependent phenomena. We report that the interaction between chemoreceptors is negative (i.e. hypo-additive), whereby a lower brainstem PCO2 augments phrenic responses resulting from specific carotid body hypoxia. A negative interaction may underlie the pathophysiology of central sleep apnoea in populations that are chronically hypocapnic. PMID:17082232

  5. From specificity to sensitivity: affective states modulate visual working memory for emotional expressive faces.

    PubMed

    Maran, Thomas; Sachse, Pierre; Furtner, Marco

    2015-01-01

    Previous findings suggest that visual working memory (VWM) preferentially remembers angry looking faces. However, the meaning of facial actions is construed in relation to context. To date, there are no studies investigating the role of perceiver-based context when processing emotional cues in VWM. To explore the influence of affective context on VWM for faces, we conducted two experiments using both a VWM task for emotionally expressive faces and a mood induction procedure. Affective context was manipulated by unpleasant (Experiment 1) and pleasant (Experiment 2) IAPS pictures in order to induce an affect high in motivational intensity (defensive or appetitive, respectively) compared to a low arousal control condition. Results indicated specifically increased sensitivity of VWM for angry looking faces in the neutral condition. Enhanced VWM for angry faces was prevented by inducing affects of high motivational intensity. In both experiments, affective states led to a switch from specific enhancement of angry expressions in VWM to an equally sensitive representation of all emotional expressions. Our findings demonstrate that emotional expressions are of different behavioral relevance for the receiver depending on the affective context, supporting a functional organization of VWM along with flexible resource allocation. In VWM, stimulus processing adjusts to situational requirements and transitions from a specifically prioritizing default mode in predictable environments to a sensitive, hypervigilant mode in exposure to emotional events. PMID:26379609

  6. From specificity to sensitivity: affective states modulate visual working memory for emotional expressive faces

    PubMed Central

    Maran, Thomas; Sachse, Pierre; Furtner, Marco

    2015-01-01

    Previous findings suggest that visual working memory (VWM) preferentially remembers angry looking faces. However, the meaning of facial actions is construed in relation to context. To date, there are no studies investigating the role of perceiver-based context when processing emotional cues in VWM. To explore the influence of affective context on VWM for faces, we conducted two experiments using both a VWM task for emotionally expressive faces and a mood induction procedure. Affective context was manipulated by unpleasant (Experiment 1) and pleasant (Experiment 2) IAPS pictures in order to induce an affect high in motivational intensity (defensive or appetitive, respectively) compared to a low arousal control condition. Results indicated specifically increased sensitivity of VWM for angry looking faces in the neutral condition. Enhanced VWM for angry faces was prevented by inducing affects of high motivational intensity. In both experiments, affective states led to a switch from specific enhancement of angry expressions in VWM to an equally sensitive representation of all emotional expressions. Our findings demonstrate that emotional expressions are of different behavioral relevance for the receiver depending on the affective context, supporting a functional organization of VWM along with flexible resource allocation. In VWM, stimulus processing adjusts to situational requirements and transitions from a specifically prioritizing default mode in predictable environments to a sensitive, hypervigilant mode in exposure to emotional events. PMID:26379609

  7. Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479.

    PubMed

    Furuya, Kazuyuki; Yamamoto, Noriko; Ohyabu, Yuki; Morikyu, Teruyuki; Ishige, Hirohide; Albers, Michael; Endo, Yasuhisa

    2013-01-01

    Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, β-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues. PMID:23449329

  8. Predicting tissue specific cis-regulatory modules in the human genome using pairs of co-occurring motifs

    PubMed Central

    2012-01-01

    Background Researchers seeking to unlock the genetic basis of human physiology and diseases have been studying gene transcription regulation. The temporal and spatial patterns of gene expression are controlled by mainly non-coding elements known as cis-regulatory modules (CRMs) and epigenetic factors. CRMs modulating related genes share the regulatory signature which consists of transcription factor (TF) binding sites (TFBSs). Identifying such CRMs is a challenging problem due to the prohibitive number of sequence sets that need to be analyzed. Results We formulated the challenge as a supervised classification problem even though experimentally validated CRMs were not required. Our efforts resulted in a software system named CrmMiner. The system mines for CRMs in the vicinity of related genes. CrmMiner requires two sets of sequences: a mixed set and a control set. Sequences in the vicinity of the related genes comprise the mixed set, whereas the control set includes random genomic sequences. CrmMiner assumes that a large percentage of the mixed set is made of background sequences that do not include CRMs. The system identifies pairs of closely located motifs representing vertebrate TFBSs that are enriched in the training mixed set consisting of 50% of the gene loci. In addition, CrmMiner selects a group of the enriched pairs to represent the tissue-specific regulatory signature. The mixed and the control sets are searched for candidate sequences that include any of the selected pairs. Next, an optimal Bayesian classifier is used to distinguish candidates found in the mixed set from their control counterparts. Our study proposes 62 tissue-specific regulatory signatures and putative CRMs for different human tissues and cell types. These signatures consist of assortments of ubiquitously expressed TFs and tissue-specific TFs. Under controlled settings, CrmMiner identified known CRMs in noisy sets up to 1:25 signal-to-noise ratio. CrmMiner was 21-75% more precise than a

  9. Neuroactive substances specifically modulate rhythmic body contractions in the nerveless metazoon Tethya wilhelma (Demospongiae, Porifera)

    PubMed Central

    Ellwanger, Kornelia; Nickel, Michael

    2006-01-01

    Background Sponges (Porifera) are nerve- and muscleless metazoa, but display coordinated motor reactions. Therefore, they represent a valuable phylum to investigate coordination systems, which evolved in a hypothetical Urmetazoon prior to the central nervous system (CNS) of later metazoa. We have chosen the contractile and locomotive species Tethya wilhelma (Demospongiae, Hadromerida) as a model system for our research, using quantitative analysis based on digital time lapse imaging. In order to evaluate candidate coordination pathways, we extracorporeally tested a number of chemical messengers, agonists and antagonists known from chemical signalling pathways in animals with CNS. Results Sponge body contraction of T. wilhelma was induced by caffeine, glycine, serotonine, nitric oxide (NO) and extracellular cyclic adenosine monophosphate (cAMP). The induction by glycine and cAMP followed patterns varying from other substances. Induction by cAMP was delayed, while glycine lead to a bi-phasic contraction response. The frequency of the endogenous contraction rhythm of T. wilhelma was significantly decreased by adrenaline and NO, with the same tendency for cAMP and acetylcholine. In contrast, caffeine and glycine increased the contraction frequency. The endogenous rhythm appeared irregular during application of caffeine, adrenaline, NO and cAMP. Caffeine, glycine and NO attenuated the contraction amplitude. All effects on the endogenous rhythm were neutralised by the washout of the substances from the experimental reactor system. Conclusion Our study demonstrates that a number of chemical messengers, agonists and antagonists induce contraction and/or modulate the endogenous contraction rhythm and amplitude of our nerveless model metazoon T. wilhelma. We conclude that a relatively complex system of chemical messengers regulates the contraction behaviour through auto- and paracrine signalling, which is presented in a hypothetical model. We assume that adrenergic

  10. Modulation of mouse Leydig cell steroidogenesis through a specific arginine-vasopressin receptor

    SciTech Connect

    Tahri-Joutei, A.; Pointis, G.

    1988-01-01

    Characterization of specific vasopressin binding sites was investigated in purified mouse Leydig cells using tritiated arginine-vasopressin. Binding of radioligand was saturable, time- and temperature-dependent and reversible. (/sup 3/H)-AVP was found to bind to a single class of sites with high affinity and low capacity. Binding displacements with specific selection analogs of AVP indicated the presence of V/sub 1/ subtype receptors on Leydig cells. The ability of AVP to displace (/sup 3/H)-AVP binding was greater than LVP and oxytocin. The unrelated peptides, somatostatin and substance P, were less potent, while neurotensin and LHRH did not displace (/sup 3/H)-AVP binding. The time-course effects of AVP-pretreatment on basal and hCG-stimulated testosterone and cAMP accumulations were studied in primary culture of Leydig cells. Basal testosterone accumulation was significantly increased by a 24 h AVP-pretreatment of Leydig cells. This effect was potentiated by the phosphodiesterase inhibitor (MIX) and was concomitantly accompanied by a slight but significant increase in cAMP accumulation. AVP-pretreatment of the cells for 72 h had no effect on basal testosterone accumulation, but exerted a marked inhibitory effect on the hCG-stimulated testosterone accumulation. This reduction of testosterone accumulation occurred even in the presence of MIX and was not accompanied by any significant change of cAMP levels.

  11. The apelinergic system: sexual dimorphism and tissue-specific modulations by obesity and insulin resistance in female mice.

    PubMed

    Butruille, Laura; Drougard, Anne; Knauf, Claude; Moitrot, Emmanuelle; Valet, Philippe; Storme, Laurent; Deruelle, Philippe; Lesage, Jean

    2013-08-01

    It has been proposed that the apelinergic system (apelin and its receptor APJ) may be a promising therapeutic target in obesity-associated insulin resistance syndrome. However, due to the extended tissue-distribution of this system, the therapeutic use of specific ligands for APJ may target numerous tissues resulting putatively to collateral deleterious effects. To unravel specific tissular dysfunctions of this system under obesity and insulin-resistance conditions, we measured the apelinemia and gene-expression level of both apelin (APL) and APJ in 12-selected tissues of insulin-resistant obese female mice fed with a high fat (HF) diet. In a preliminary study, we compared between adult male and female mice, the circadian plasma apelin variation and the effect of fasting on apelinemia. No significant differences were found for these parameters suggesting that the apelinemia is not affected by the sex. Moreover, plasma apelin level was not modulated during the four days of the estrous cycle in females. In obese and insulin-resistant HF female mice, plasma apelin concentration after fasting was not modified but, the gene-expression level of the APL/APJ system was augmented in the white adipose tissue (WAT) and reduced in the brown adipose tissue (BAT), the liver and in kidneys. BAT apelin content was reduced in HF female mice. Our data suggest that the apelinergic system may be implicated into specific dysfunctions of these tissues under obesity and diabetes and that, pharmacologic modulations of this system may be of interest particularly in the treatment of adipose, liver and renal dysfunctions that occur during these pathologies. PMID:23747606

  12. Evaluation of the first year of the Oxpal Medlink: A web-based partnership designed to address specific challenges facing medical education in the occupied Palestinian territories

    PubMed Central

    Ali, Mohammad A; Ali, Adam M; Patel, Ishita; MacGregor, Thomas; Shankar, Sushma; Cahill, Thomas J; Finlayson, Alexander ET; Mahmud, Imran

    2014-01-01

    Objectives To (1) evaluate educational needs of clinical students at Al-Quds University Medical School in the West Bank; (2) address these needs where possible using synchronous distance learning, with clinicians in Oxford providing case-based tutorials to undergraduates in the West Bank via an online platform (WizIQ) and (3) assess the impact of this education. Design Review of online OxPal Medlink database for tutorials held between March 2012 and April 2013. Needs assessment and evaluation of student and tutor experiences through online questionnaires, focus groups and semi-structured interviews. Setting Oxford University Hospitals, Oxford, UK, and Al-Quds University Medical School, Abu Dies, Palestine. Participants Doctors at Oxford University Hospitals and fourth-, fifth- and sixth-year medical students and faculty members at Al-Quds Medical School. Main outcome measures Number of tutorials, student participation, student-rated satisfaction and qualitative feedback from tutors and students. Results Students demonstrated strong theoretical knowledge but struggled to apply this in presentation-based scenarios. Between March 2012 and April 2013, 90 tutorials were delivered to 60 students. Feedback: >95% respondents rated tutorials as ‘Excellent’ or ‘Good’ and ‘Very’ or ‘Fairly’ relevant to their future practice in Palestine. Students reported the programme had modified their approach to patients but requested better synchronization with concurrent attachments and clarification of learning outcomes. Conclusions OxPal Medlink is a novel, web-based distance-learning partnership designed to overcome some of the challenges to local medical education in the occupied Palestinian territories. Evaluation of the first year indicates teaching is relevant to local practice and of high quality. This approach may have the potential to strengthen local capacity for medical education. PMID:25057373

  13. FGF signaling restricts hematopoietic stem cell specification via modulation of the BMP pathway

    PubMed Central

    Pouget, Claire; Peterkin, Tessa; Simões, Filipa Costa; Lee, Yoonsung; Traver, David; Patient, Roger

    2015-01-01

    SUMMARY Hematopoietic stem cells (HSCs) are produced during embryogenesis from the floor of the dorsal aorta. The localization of HSCs is dependent upon the presence of instructive signals on the ventral side of the vessel. The nature of the extrinsic molecular signals that control the aortic hematopoietic niche is currently poorly understood. Here we demonstrate a novel requirement for FGF signaling in the specification of aortic hemogenic endothelium. Our results demonstrate that FGF signaling normally acts to repress BMP activity in the subaortic mesenchyme through transcriptional inhibition of bmp4, as well as through activation of two BMP antagonists, noggin2 and gremlin1a. Taken together, these findings demonstrate a key role for FGF signaling in establishment of the developmental HSC niche via its regulation of BMP activity in the subaortic mesenchyme. These results should help inform strategies to recapitulate the development of HSCs in vitro from pluripotent precursors. PMID:25429520

  14. GABAA-Mediated Inhibition Modulates Stimulus-Specific Adaptation in the Inferior Colliculus

    PubMed Central

    Pérez-González, David; Hernández, Olga; Covey, Ellen; Malmierca, Manuel S.

    2012-01-01

    The ability to detect novel sounds in a complex acoustic context is crucial for survival. Neurons from midbrain through cortical levels adapt to repetitive stimuli, while maintaining responsiveness to rare stimuli, a phenomenon called stimulus-specific adaptation (SSA). The site of origin and mechanism of SSA are currently unknown. We used microiontophoretic application of gabazine to examine the role of GABAA-mediated inhibition in SSA in the inferior colliculus, the midbrain center for auditory processing. We found that gabazine slowed down the process of adaptation to high probability stimuli but did not abolish it, with response magnitude and latency still depending on the probability of the stimulus. Blocking GABAA receptors increased the firing rate to high and low probability stimuli, but did not completely equalize the responses. Together, these findings suggest that GABAA-mediated inhibition acts as a gain control mechanism that enhances SSA by modifying the responsiveness of the neuron. PMID:22479591

  15. HypE-specific Nanobodies as Tools to Modulate HypE-mediated Target AMPylation

    PubMed Central

    Truttmann, Matthias C.; Wu, Qin; Stiegeler, Sarah; Duarte, Joao N.; Ingram, Jessica; Ploegh, Hidde L.

    2015-01-01

    The covalent addition of mono-AMP to target proteins (AMPylation) by Fic domain-containing proteins is a poorly understood, yet highly conserved post-translational modification. Here, we describe the generation, evaluation, and application of four HypE-specific nanobodies: three that inhibit HypE-mediated target AMPylation in vitro and one that acts as an activator. All heavy chain-only antibody variable domains bind HypE when expressed as GFP fusions in intact cells. We observed localization of HypE at the nuclear envelope and further identified histones H2–H4, but not H1, as novel in vitro targets of the human Fic protein. Its role in histone modification provides a possible link between AMPylation and regulation of gene expression. PMID:25678711

  16. A Space Oddity: Geographic and Specific Modulation of Migration in Eudyptes Penguins

    PubMed Central

    Thiebot, Jean-Baptiste; Cherel, Yves; Crawford, Robert J. M.; Makhado, Azwianewi B.; Trathan, Philip N.; Pinaud, David; Bost, Charles-André

    2013-01-01

    Post-breeding migration in land-based marine animals is thought to offset seasonal deterioration in foraging or other important environmental conditions at the breeding site. However the inter-breeding distribution of such animals may reflect not only their optimal habitat, but more subtle influences on an individual’s migration path, including such factors as the intrinsic influence of each locality’s paleoenvironment, thereby influencing animals’ wintering distribution. In this study we investigated the influence of the regional marine environment on the migration patterns of a poorly known, but important seabird group. We studied the inter-breeding migration patterns in three species of Eudyptes penguins (E. chrysolophus, E. filholi and E. moseleyi), the main marine prey consumers amongst the World’s seabirds. Using ultra-miniaturized logging devices (light-based geolocators) and satellite tags, we tracked 87 migrating individuals originating from 4 sites in the southern Indian Ocean (Marion, Crozet, Kerguelen and Amsterdam Islands) and modelled their wintering habitat using the MADIFA niche modelling technique. For each site, sympatric species followed a similar compass bearing during migration with consistent species-specific latitudinal shifts. Within each species, individuals breeding on different islands showed contrasting migration patterns but similar winter habitat preferences driven by sea-surface temperatures. Our results show that inter-breeding migration patterns in sibling penguin species depend primarily on the site of origin and secondly on the species. Such site-specific migration bearings, together with similar wintering habitat used by parapatrics, support the hypothesis that migration behaviour is affected by the intrinsic characteristics of each site. The paleo-oceanographic conditions (primarily, sea-surface temperatures) when the populations first colonized each of these sites may have been an important determinant of subsequent

  17. The modulation of tissue-specific gene expression in rat nasal chondrocyte cultures by bioactive glasses.

    PubMed

    Asselin, Audrey; Hattar, Susan; Oboeuf, Martine; Greenspan, David; Berdal, Ariane; Sautier, Jean-Michel

    2004-11-01

    Since bone repair may occur, following endochondral ossification, we have investigated the behaviour of chondrocytes isolated from nasal septum cartilage of foetal rats and cultured up to 21 days in the presence of a melt-derived bioactive glass (Bioglass 45S5) and a less reactive glass with 60 wt% silica content (60S). In both cultures, chondrocytes proliferate and form typical cartilaginous nodules on day 5 of cultures. However, on day 12, the nodules in contact with 45S5 granules became darker than in 60S cultures, corresponding to the emergence of matrix biomineralization. Transmission electron microscopy showed a collagen-rich matrix composed of densely packed fibres and mineralized foci formed of needle-shaped crystals in contact with an electron-dense layer located at the periphery of the material. The specific activity of alkaline phosphatase was significant higher in 45S5 cultures on day 15 than in 60S cultures. Real time RT-PCR was used to monitor gene expression levels of specific chondrogenic markers. The transcription factor Sox9 was expressed throughout the culture period, but with no significant differences between the two kinds of cultures. In contrast, Runx2 expression was higher in experiment cultures on day 12. Type II collagen mRNA and aggrecan, showed an almost similar expression pattern with a strong expression at the beginning of cultures but higher in experiment cultures. Indian hedgehog was strongly expressed between day 9 and 12 with a significant stimulation in 45S5 cultures. Similarly, type X collagen mRNA seemed to be up-regulated in 45S5 cultures on day 20. In conclusion, this study shows hat 45S5 Bioglass has the ability to support the growth of chondrocytes and to stimulate some chondrogenic molecular markers. PMID:15159078

  18. A space oddity: geographic and specific modulation of migration in Eudyptes penguins.

    PubMed

    Thiebot, Jean-Baptiste; Cherel, Yves; Crawford, Robert J M; Makhado, Azwianewi B; Trathan, Philip N; Pinaud, David; Bost, Charles-André

    2013-01-01

    Post-breeding migration in land-based marine animals is thought to offset seasonal deterioration in foraging or other important environmental conditions at the breeding site. However the inter-breeding distribution of such animals may reflect not only their optimal habitat, but more subtle influences on an individual's migration path, including such factors as the intrinsic influence of each locality's paleoenvironment, thereby influencing animals' wintering distribution. In this study we investigated the influence of the regional marine environment on the migration patterns of a poorly known, but important seabird group. We studied the inter-breeding migration patterns in three species of Eudyptes penguins (E. chrysolophus, E. filholi and E. moseleyi), the main marine prey consumers amongst the World's seabirds. Using ultra-miniaturized logging devices (light-based geolocators) and satellite tags, we tracked 87 migrating individuals originating from 4 sites in the southern Indian Ocean (Marion, Crozet, Kerguelen and Amsterdam Islands) and modelled their wintering habitat using the MADIFA niche modelling technique. For each site, sympatric species followed a similar compass bearing during migration with consistent species-specific latitudinal shifts. Within each species, individuals breeding on different islands showed contrasting migration patterns but similar winter habitat preferences driven by sea-surface temperatures. Our results show that inter-breeding migration patterns in sibling penguin species depend primarily on the site of origin and secondly on the species. Such site-specific migration bearings, together with similar wintering habitat used by parapatrics, support the hypothesis that migration behaviour is affected by the intrinsic characteristics of each site. The paleo-oceanographic conditions (primarily, sea-surface temperatures) when the populations first colonized each of these sites may have been an important determinant of subsequent migration

  19. Pulmonary collectins modulate strain-specific influenza a virus infection and host responses.

    PubMed

    Hawgood, Samuel; Brown, Cynthia; Edmondson, Jess; Stumbaugh, Amber; Allen, Lennell; Goerke, Jon; Clark, Howard; Poulain, Francis

    2004-08-01

    Collectins are secreted collagen-like lectins that bind, agglutinate, and neutralize influenza A virus (IAV) in vitro. Surfactant proteins A and D (SP-A and SP-D) are collectins expressed in the airway and alveolar epithelium and could have a role in the regulation of IAV infection in vivo. Previous studies have shown that binding of SP-D to IAV is dependent on the glycosylation of specific sites on the HA1 domain of hemagglutinin on the surface of IAV, while the binding of SP-A to the HA1 domain is dependent on the glycosylation of the carbohydrate recognition domain of SP-A. Here, using SP-A and SP-D gene-targeted mice on a common C57BL6 background, we report that viral replication and the host response as measured by weight loss, neutrophil influx into the lung, and local cytokine release are regulated by SP-D but not SP-A when the IAV is glycosylated at a specific site (N165) on the HA1 domain. SP-D does not protect against IAV infection with a strain lacking glycosylation at N165. With the exception of a small difference on day 2 after infection with X-79, we did not find any significant difference in viral load in SP-A(-/-) mice with either IAV strain, although small differences in the cytokine responses to IAV were detected in SP-A(-/-) mice. Mice deficient in both SP-A and SP-D responded to IAV similarly to mice deficient in SP-D alone. Since most strains of IAV currently circulating are glycosylated at N165, SP-D may play a role in protection from IAV infection. PMID:15280465

  20. Addressing the Question of Disorder-Specific Risk Factors of Internet Addiction: A Comparison of Personality Traits in Patients with Addictive Behaviors and Comorbid Internet Addiction

    PubMed Central

    Müller, K. W.; Koch, A.; Dickenhorst, U.; Beutel, M. E.; Duven, E.; Wölfling, K.

    2013-01-01

    Uncontrolled use of the internet has been reported to affect the lives of some users in a negative way. According to epidemiological studies, about 1% of the general population is showing signs of internet addiction. Since internet addiction is becoming a growing health concern, research on potential risk factors is becoming more important in order to develop strategies for prevention and to adopt therapeutic treatment. Although there are some studies investigating personality traits in internet addiction, most of these studies are based on samples of healthy subjects. In this research project, we compared personality profiles of a sample of patients in different rehabilitation centers. 70 patients with an addiction disorder that additionally met the criteria for internet addiction were compared to 48 patients suffering from alcohol dependence. Besides Big Five personality traits, we also assessed depressive symptoms. It was shown that patients with comorbid internet addiction can be discriminated from other patients by higher neuroticism and lower extraversion as well as lower conscientiousness. After controlling for depressive symptoms, lower conscientiousness especially turned out to be a disorder-specific risk factor. As internet addiction is related to unique patterns of personality traits and can be discriminated from alcohol dependence, treatment approaches are needed that meet the specific requirements of patients with internet addiction. PMID:23865056

  1. The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans.

    PubMed

    Grants, Jennifer M; Ying, Lisa T L; Yoda, Akinori; You, Charlotte C; Okano, Hideyuki; Sawa, Hitoshi; Taubert, Stefan

    2016-02-01

    Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinase-dependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals. PMID:26715664

  2. Specific modulation of spinal and cortical excitabilities during lengthening and shortening submaximal and maximal contractions in plantar flexor muscles.

    PubMed

    Duclay, Julien; Pasquet, Benjamin; Martin, Alain; Duchateau, Jacques

    2014-12-15

    This study investigated the influence of the torque produced by plantar flexor muscles on cortical and spinal excitability during lengthening and shortening voluntary contractions. To that purpose, modulations of motor-evoked potential (MEP) and Hoffmann (H) reflex were compared in the soleus (SOL) and medial gastrocnemius (MG) during anisometric submaximal and maximal voluntary contraction (MVC) of the plantar flexor muscles. For the submaximal shortening and lengthening contractions, the target torque was set at 50% of their respective MVC force. The results indicate that the amplitudes of both MEP and H-reflex responses, normalized to the maximal M wave, were significantly (P < 0.05) lower during lengthening compared with shortening submaximal contraction. For these two parameters, the reduction reached, respectively, 22.1 and 31.9% for the SOL and 34.5 and 29.3% for the MG. During MVC, normalized MEP and H reflex of the SOL were both reduced significantly by 19.9% (P < 0.05) and 29.9% (P < 0.001) during lengthening and shortening contraction, respectively, whereas no significant change (P > 0.05) was observed for MG. In addition, the silent period in the ongoing electromyogram (EMG) activity following the MEP was significantly (P < 0.01) briefer during lengthening than shortening contractions but did not differ (P > 0.05) between contraction intensities and muscles. Together, these results indicate that cortical and spinal mechanisms involved in the modulation of muscle activation during shortening and lengthening contractions differ between synergistic muscles according to the torque produced. Data further document previous studies reporting that the specific modulation of muscle activation during lengthening contraction is not torque dependent. PMID:25324516

  3. Plasma protein corona modulates the vascular wall interaction of drug carriers in a material and donor specific manner.

    PubMed

    Sobczynski, Daniel J; Charoenphol, Phapanin; Heslinga, Michael J; Onyskiw, Peter J; Namdee, Katawut; Thompson, Alex J; Eniola-Adefeso, Omolola

    2014-01-01

    The nanoscale plasma protein interaction with intravenously injected particulate carrier systems is known to modulate their organ distribution and clearance from the bloodstream. However, the role of this plasma protein interaction in prescribing the adhesion of carriers to the vascular wall remains relatively unknown. Here, we show that the adhesion of vascular-targeted poly(lactide-co-glycolic-acid) (PLGA) spheres to endothelial cells is significantly inhibited in human blood flow, with up to 90% reduction in adhesion observed relative to adhesion in simple buffer flow, depending on the particle size and the magnitude and pattern of blood flow. This reduced PLGA adhesion in blood flow is linked to the adsorption of certain high molecular weight plasma proteins on PLGA and is donor specific, where large reductions in particle adhesion in blood flow (>80% relative to buffer) is seen with ∼60% of unique donor bloods while others exhibit moderate to no reductions. The depletion of high molecular weight immunoglobulins from plasma is shown to successfully restore PLGA vascular wall adhesion. The observed plasma protein effect on PLGA is likely due to material characteristics since the effect is not replicated with polystyrene or silica spheres. These particles effectively adhere to the endothelium at a higher level in blood over buffer flow. Overall, understanding how distinct plasma proteins modulate the vascular wall interaction of vascular-targeted carriers of different material characteristics would allow for the design of highly functional delivery vehicles for the treatment of many serious human diseases. PMID:25229244

  4. Input-Specific Gain Modulation by Local Sensory Context Shapes Cortical and Thalamic Responses to Complex Sounds.

    PubMed

    Williamson, Ross S; Ahrens, Misha B; Linden, Jennifer F; Sahani, Maneesh

    2016-07-20

    Sensory neurons are customarily characterized by one or more linearly weighted receptive fields describing sensitivity in sensory space and time. We show that in auditory cortical and thalamic neurons, the weight of each receptive field element depends on the pattern of sound falling within a local neighborhood surrounding it in time and frequency. Accounting for this change in effective receptive field with spectrotemporal context improves predictions of both cortical and thalamic responses to stationary complex sounds. Although context dependence varies among neurons and across brain areas, there are strong shared qualitative characteristics. In a spectrotemporally rich soundscape, sound elements modulate neuronal responsiveness more effectively when they coincide with sounds at other frequencies, and less effectively when they are preceded by sounds at similar frequencies. This local-context-driven lability in the representation of complex sounds-a modulation of "input-specific gain" rather than "output gain"-may be a widespread motif in sensory processing. PMID:27346532

  5. Specific binding of Clostridium perfringens enterotoxin fragment to Claudin-b and modulation of zebrafish epidermal barrier.

    PubMed

    Zhang, Jingjing; Ni, Chen; Yang, Zhenguo; Piontek, Anna; Chen, Huapu; Wang, Sijie; Fan, Yiming; Qin, Zhihai; Piontek, Joerg

    2015-08-01

    Claudins (Cldn) are the major components of tight junctions (TJs) sealing the paracellular cleft in tissue barriers of various organs. Zebrafish Cldnb, the homolog of mammalian Cldn4, is expressed at epithelial cell-cell contacts and is important for regulating epidermal permeability. The bacterial toxin Clostridium perfringens enterotoxin (CPE) has been shown to bind to a subset of mammalian Cldns. In this study, we used the Cldn-binding C-terminal domain of CPE (194-319 amino acids, cCPE 194-319 ) to investigate its functional role in modulating zebrafish larval epidermal barriers. In vitro analyses show that cCPE 194-319 removed Cldn4 from epithelial cells and disrupted the monolayer tightness, which could be rescued by the removal of cCPE 194-319. Incubation of zebrafish larvae with cCPE 194-319 removed Cldnb specifically from the epidermal cell membrane. Dye diffusion analysis with 4-kDa fluorescent dextran indicated that the permeability of the epidermal barrier increased due to cCPE 194-319 incubation. Electron microscopic investigation revealed reversible loss of TJ integrity by Cldnb removal. Collectively, these results suggest that cCPE 194-319 could be used as a Cldnb modulator to transiently open the epidermal barrier in zebrafish. In addition, zebrafish might be used as an in vivo system to investigate the capability of cCPE to enhance drug delivery across tissue barriers. PMID:25869230

  6. Sensorimotor enhancement in mouse mutants lacking the Purkinje cell-specific Gi/o modulator, Pcp2(L7)

    PubMed Central

    Iscru, Emilia; Serinagaoglu, Yelda; Schilling, Karl; Tian, Jinbin; Bowers-Kidder, Stephanie L.; Zhang, Rui; Morgan, James I.; DeVries, A. Courtney; Nelson, Randy J.; Zhu, Michael X.; Oberdick, John

    2009-01-01

    Pcp2(L7) is a GoLoco domain protein specifically and abundantly expressed in cerebellar Purkinje cells. It has been hypothesized to “tune” Gi/o-coupled receptor modulation of physiological effectors, including the P-type Ca2+ channel. We have analyzed a mouse mutant in which the Pcp2(L7) gene was inactivated and find significant anatomical, behavioral and electrophysiological changes. Anatomically, we observed mild cerebellar hypoplasia. Behaviorally, the mutants were altered in modalities atypical for a traditional cerebellar mutant, and oddly, all of these changes could be considered functional enhancements. This includes increased asymptotic performance in gross motor learning, increased rate of acquisition in tone-conditioned fear, and enhanced pre-pulse inhibition of the acoustic startle response. Electrophysiological analysis of Purkinje cells in the mutants reveals depression of the complex spike waveform that may underlie the behavioral changes. Based on these observations we suggest that the Pcp2(L7) protein acts as a sensorimotor damper that modulates time- and sense-dependent changes in motor responses. PMID:18930827

  7. Modality-specific alpha modulations facilitate long-term memory encoding in the presence of distracters.

    PubMed

    Jiang, Haiteng; van Gerven, Marcel A J; Jensen, Ole

    2015-03-01

    It has been proposed that long-term memory encoding is not only dependent on engaging task-relevant regions but also on disengaging task-irrelevant regions. In particular, oscillatory alpha activity has been shown to be involved in shaping the functional architecture of the working brain because it reflects the functional disengagement of specific regions in attention and memory tasks. We here ask if such allocation of resources by alpha oscillations generalizes to long-term memory encoding in a cross-modal setting in which we acquired the ongoing brain activity using magnetoencephalography. Participants were asked to encode pictures while ignoring simultaneously presented words and vice versa. We quantified the brain activity during rehearsal reflecting subsequent memory in the different attention conditions. The key finding was that successful long-term memory encoding is reflected by alpha power decreases in the sensory region of the to-be-attended modality and increases in the sensory region of the to-be-ignored modality to suppress distraction during rehearsal period. Our results corroborate related findings from attention studies by demonstrating that alpha activity is also important for the allocation of resources during long-term memory encoding in the presence of distracters. PMID:25244116

  8. Maternal Microbe-Specific Modulation of Inflammatory Response in Extremely Low-Gestational-Age Newborns

    PubMed Central

    Fichorova, Raina N.; Onderdonk, Andrew B.; Yamamoto, Hidemi; Delaney, Mary L.; DuBois, Andrea M.; Allred, Elizabeth; Leviton, Alan

    2011-01-01

    The fetal response to intrauterine inflammatory stimuli appears to contribute to the onset of preterm labor as well as fetal injury, especially affecting newborns of extremely low gestational age. To investigate the role of placental colonization by specific groups of microorganisms in the development of inflammatory responses present at birth, we analyzed 25 protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section in the 23rd to 27th gestation weeks. Bacteria were detected in placentas and characterized by culture techniques. Odds ratios for having protein concentrations in the top quartile for gestation age for individual and groups of microorganisms were calculated. Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to those of infectious facultative anaerobes. Prevotella and Gardnerella species, anaerobic streptococci, peptostreptococci, and genital mycoplasmas each appeared to be associated with a different pattern of elevated blood levels of inflammation-related proteins. Lactobacillus was associated with low odds of an inflammatory response. This study provides evidence that microorganisms colonizing the placenta provoke distinctive newborn inflammatory responses and that Lactobacillus may suppress these responses. PMID:21264056

  9. Gender-specific modulation of neural mechanisms underlying social reward processing by Autism Quotient.

    PubMed

    Barman, Adriana; Richter, Sylvia; Soch, Joram; Deibele, Anna; Richter, Anni; Assmann, Anne; Wüstenberg, Torsten; Walter, Henrik; Seidenbecher, Constanze I; Schott, Björn H

    2015-11-01

    Autism spectrum disorder refers to a neurodevelopmental condition primarily characterized by deficits in social cognition and behavior. Subclinically, autistic features are supposed to be present in healthy humans and can be quantified using the Autism Quotient (AQ). Here, we investigated a potential relationship between AQ and neural correlates of social and monetary reward processing, using functional magnetic resonance imaging in young, healthy participants. In an incentive delay task with either monetary or social reward, reward anticipation elicited increased ventral striatal activation, which was more pronounced during monetary reward anticipation. Anticipation of social reward elicited activation in the default mode network (DMN), a network previously implicated in social processing. Social reward feedback was associated with bilateral amygdala and fusiform face area activation. The relationship between AQ and neural correlates of social reward processing varied in a gender-dependent manner. In women and, to a lesser extent in men, higher AQ was associated with increased posterior DMN activation during social reward anticipation. During feedback, we observed a negative correlation of AQ and right amygdala activation in men only. Our results suggest that social reward processing might constitute an endophenotype for autism-related traits in healthy humans that manifests in a gender-specific way. PMID:25944965

  10. The Matching Relation and Situation-Specific Bias Modulation in Professional Football Play Selection

    PubMed Central

    Stilling, Stephanie T; Critchfield, Thomas S

    2010-01-01

    The utility of a quantitative model depends on the extent to which its fitted parameters vary systematically with environmental events of interest. Professional football statistics were analyzed to determine whether play selection (passing versus rushing plays) could be accounted for with the generalized matching equation, and in particular whether variations in play selection across game situations would manifest as changes in the equation's fitted parameters. Statistically significant changes in bias were found for each of five types of game situations; no systematic changes in sensitivity were observed. Further analyses suggested relationships between play selection bias and both turnover probability (which can be described in terms of punishment) and yards-gained variance (which can be described in terms of variable-magnitude reinforcement schedules). The present investigation provides a useful demonstration of association between face-valid, situation-specific effects in a domain of everyday interest, and a theoretically important term of a quantitative model of behavior. Such associations, we argue, are an essential focus in translational extensions of quantitative models. PMID:21119855

  11. Root hair-specific expansins modulate root hair elongation in rice.

    PubMed

    ZhiMing, Yu; Bo, Kang; XiaoWei, He; ShaoLei, Lv; YouHuang, Bai; WoNa, Ding; Ming, Chen; Hyung-Taeg, Cho; Ping, Wu

    2011-06-01

    Root hair growth requires intensive cell-wall modification. This study demonstrates that root hair-specific expansin As, a sub-clade of the cell wall-loosening expansin proteins, are required for root hair elongation in rice (Oryza sativa L.). We identified a gene encoding EXPA17 (OsEXPA17) from a rice mutant with short root hairs. Promoter::reporter transgenic lines exhibited exclusive OsEXPA17 expression in root hair cells. The OsEXPA17 mutant protein (OsexpA17) contained a point mutation, causing a change in the amino acid sequence (Gly104→Arg). This amino acid alteration is predicted to disrupt a highly conserved disulfide bond in the mutant. Suppression of OsEXPA17 by RNA interference further confirmed requirement for the gene in root hair elongation. Complementation of the OsEXPA17 mutant with other root hair EXPAs (OsEXPA30 and Arabidopsis EXPA7) can restore root hair elongation, indicating functional conservation of these root hair EXPAs in monocots and dicots. These results demonstrate that members of the root hair EXPA sub-clade play a crucial role in root hair cell elongation in Graminaceae. PMID:21309868

  12. Sulfasalazine and mesalamine modulate beryllium-specific lymphocyte proliferation and inflammatory cytokine production.

    PubMed

    Dobis, Dave R; Sawyer, Richard T; Gillespie, May M; Newman, Lee S; Maier, Lisa A; Day, Brian J

    2010-10-01

    Occupational exposure to beryllium (Be) results in Be sensitization (BeS) that can progress to pulmonary granulomatous inflammation associated with chronic Be disease (CBD). Be-specific lymphocytes are present in the blood of patients with BeS and in the blood and lungs of patients with CBD. Sulfasalazine and its active metabolite, mesalamine, are clinically used to ameliorate chronic inflammation associated with inflammatory bowel disease. We tested whether sulfasalazine or mesalamine could decrease Be-stimulated peripheral blood mononuclear cell (PBMC) proliferation in subjects with CBD and BeS and Be-induced cytokine production in CBD bronchoalveolar lavage (BAL) cells. CBD (n = 25), BeS (n = 12) and healthy normal control (n = 6) subjects were enrolled and ex vivo proliferation and cytokine production were assessed in the presence of Be and sulfasalazine or mesalamine. Be-stimulated PBMC proliferation was inhibited by treatment with either sulfasalazine or mesalamine. Be-stimulated CBD BAL cell IFN-γ and TNF-α cytokine production was decreased by treatment with sulfasalazine or mesalamine. Our data suggest that both sulfasalazine and mesalamine interfere with Be-stimulated PBMC proliferation in CBD and BeS and dampens Be-stimulated CBD BAL cell proinflammatory cytokine production. These studies demonstrate that sulfasalazine and mesalamine can disrupt inflammatory pathways critical to the pathogenesis of chronic granulomatous inflammation in CBD, and may serve as novel therapy for human granulomatous lung diseases. PMID:19901345

  13. Chondrocytes-Specific Expression of Osteoprotegerin Modulates Osteoclast Formation in Metaphyseal Bone.

    PubMed

    Wang, Baoli; Jin, Hongting; Shu, Bing; Mira, Ranim R; Chen, Di

    2015-01-01

    Bone marrow stromal cells/osteoblasts were originally thought to be the major player in regulating osteoclast differentiation through expressing RANKL/OPG cytokines. Recent studies have established that chondrocytes also express RANKL/OPG and support osteoclast formation. Till now, the in vivo function of chondrocyte-produced OPG in osteoclast formation and postnatal bone growth has not been directly investigated. In this study, chondrocyte-specific Opg transgenic mice were generated by using type II collagen promoter. The Col2-Opg transgenic mice showed delayed formation of secondary ossification center and localized increase of bone mass in proximal metaphysis of tibiae. TRAP staining showed that osteoclast numbers were reduced in both secondary ossification center and proximal metaphysis. This finding was further confirmed by in vitro chondrocyte/spleen cell co-culture assay. In contrast, the mineral apposition rates were not changed in Col2-Opg transgenic mice. TUNEL staining revealed more apoptotic hypertrophic chondrocytes in the growth plate of Col2-Opg mice. Flow cytometry analysis showed fewer RANK-expressing cells in the marrow of Col2a1-Opg mice, suggesting the role of OPG in blocking the differentiation of early mesenchymal progenitors into RANK-expressing pre-osteoclasts. Our results demonstrated that OPG expression in chondrocyte increases bone mass in the proximal metaphysis of tibiae through negative regulation of osteoclast formation. PMID:26329493

  14. Chondrocytes-Specific Expression of Osteoprotegerin Modulates Osteoclast Formation in Metaphyseal Bone

    PubMed Central

    Wang, Baoli; Jin, Hongting; Shu, Bing; Mira, Ranim R.; Chen, Di

    2015-01-01

    Bone marrow stromal cells/osteoblasts were originally thought to be the major player in regulating osteoclast differentiation through expressing RANKL/OPG cytokines. Recent studies have established that chondrocytes also express RANKL/OPG and support osteoclast formation. Till now, the in vivo function of chondrocyte-produced OPG in osteoclast formation and postnatal bone growth has not been directly investigated. In this study, chondrocyte-specific Opg transgenic mice were generated by using type II collagen promoter. The Col2-Opg transgenic mice showed delayed formation of secondary ossification center and localized increase of bone mass in proximal metaphysis of tibiae. TRAP staining showed that osteoclast numbers were reduced in both secondary ossification center and proximal metaphysis. This finding was further confirmed by in vitro chondrocyte/spleen cell co-culture assay. In contrast, the mineral apposition rates were not changed in Col2-Opg transgenic mice. TUNEL staining revealed more apoptotic hypertrophic chondrocytes in the growth plate of Col2-Opg mice. Flow cytometry analysis showed fewer RANK-expressing cells in the marrow of Col2a1-Opg mice, suggesting the role of OPG in blocking the differentiation of early mesenchymal progenitors into RANK-expressing pre-osteoclasts. Our results demonstrated that OPG expression in chondrocyte increases bone mass in the proximal metaphysis of tibiae through negative regulation of osteoclast formation. PMID:26329493

  15. Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs

    PubMed Central

    HOHL, TOBIAS M.

    2013-01-01

    The pulmonary innate immune system clears inhaled A spergillus fumigatus conidia (spores) from terminal airways. Failure to control conidial germination in immune compromised hosts can result in hyphal tissue invasion and fatal disease. Insight into the molecular recognition of A. fumigatus by host leukocytes indicates that the innate immune system exploits obligate changes in fungal cell wall composition that occur at the first stage of germination, conidial swelling. Germinating spores activate at least two host signal transduction pathways. Surface exposure of fungal β-(1,3) glucan, a polysaccharide constituent of the fungal cell wall, triggers dectin-1 signaling by host phagocytes. Spore germination leads to the induction of Toll-like receptor (TLR) signaling as well. This stage-specific recognition mechanism focuses host antifungal responses on cells with the potential for tissue invasion and may serve to limit potentially deleterious effects of inflammation in space and time. Fungal β-(1,3) glucan not only activates host innate immune responses but also represents the target of echinocandin drugs. The activity of echinocandin drugs has largely been understood on the basis of pharmacologic growth inhibition of yeast and moulds, resulting in lysis of yeast cells and stunting of dysmorphic hyphae. The recognition that fungal β-1,3 glucan activates dectin-1 signaling suggests that echinocandin drugs may exert immune modulatory effects by altering innate immune responses to drug-treated fungal cells, a view supported by recent data from studies on C. albicans, A. fumigatus, and non-Aspergillus moulds. PMID:18608931

  16. Schistosoma mansoni Hemozoin Modulates Alternative Activation of Macrophages via Specific Suppression of Retnla Expression and Secretion

    PubMed Central

    Truscott, Martha; Evans, D. Andrew; Gunn, Matt

    2013-01-01

    The trematode Schistosoma mansoni is one of the etiological agents of schistosomiasis, a key neglected tropical disease responsible for an estimated annual loss of 70 million disability-adjusted life years. Hematophagy represents the primary nutrient acquisition pathway of this parasite, but digestion of hemoglobin also liberates toxic heme. Schistosomes detoxify heme via crystallization into hemozoin, which is subsequently regurgitated into the host's circulation. Here we demonstrate that during experimental schistosomiasis, hemozoin accumulating in the mouse liver is taken up by phagocytes at a time coincident with the development of the egg-induced T-helper 2 (Th2) granulomatous immune response. Furthermore, the uptake of hemozoin also coincides with the hepatic expression of markers of alternative macrophage activation. Alternatively activated macrophages are a key effector cell population associated with protection against schistosomiasis, making hemozoin well placed to play an important immunomodulatory role in this disease. To systematically explore this hypothesis, S. mansoni hemozoin was purified and added to in vitro bone marrow-derived macrophage cultures concurrently exposed to cytokines chosen to reflect the shifting state of macrophage activation in vivo. Macrophages undergoing interleukin-4 (IL-4)-induced alternative activation in the presence of hemozoin developed a phenotype specifically lacking in Retnla, a characteristic alternatively activated macrophage product associated with regulation of Th2 inflammatory responses. As such, in addition to its important detoxification role during hematophagy, we propose that schistosome hemozoin also provides a potent immunomodulatory function in the coevolved network of host-parasite relationships during schistosomiasis. PMID:23090958

  17. Affinity maturation of anti-(4-hydroxy-3-nitrophenyl)acetyl antibodies accompanies a modulation of antigen specificity.

    PubMed

    Oda, Masayuki; Azuma, Takachika

    2016-02-01

    Anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies bearing λ1 chains are known to possess fine specificity, referred to as heterocliticity, which causes these antibodies to bind to hapten analogues such as (4-hydroxy-3-iodo-5-nitrophenyl)acetyl (NIP) and (4-hydroxy-3,5-dinitrophenyl)acetyl (NNP) with higher affinity than to the autologous hapten, NP. They also show preferential binding to the phenolate form of hapten than to the phenolic form. We address here the question of whether affinity maturation accompanies in the fine specificity of these antibodies by analyzing the interaction between NP1-, NIP1-, or NNP1-hen egg lysozyme and anti-NP antibodies that possess different association constants to NP using a surface plasmon resonance biosensor. We measured interactions at various pH values and found that heterocliticity as well as preferential binding to the phenolate form of hapten were most prominent in a germline antibody having immature affinity and that fine specificity becomes less evident, i.e., anti-NP antibodies become more specific to the immunizing antigen, NP during the process of affinity maturation. PMID:26688069

  18. Proteome-wide Light/Dark Modulation of Thiol Oxidation in Cyanobacteria Revealed by Quantitative Site-specific Redox Proteomics*

    PubMed Central

    Guo, Jia; Nguyen, Amelia Y.; Dai, Ziyu; Su, Dian; Gaffrey, Matthew J.; Moore, Ronald J.; Jacobs, Jon M.; Monroe, Matthew E.; Smith, Richard D.; Koppenaal, David W.; Pakrasi, Himadri B.; Qian, Wei-Jun

    2014-01-01

    Reversible protein thiol oxidation is an essential regulatory mechanism of photosynthesis, metabolism, and gene expression in photosynthetic organisms. Herein, we present proteome-wide quantitative and site-specific profiling of in vivo thiol oxidation modulated by light/dark in the cyanobacterium Synechocystis sp. PCC 6803, an oxygenic photosynthetic prokaryote, using a resin-assisted thiol enrichment approach. Our proteomic approach integrates resin-assisted enrichment with isobaric tandem mass tag labeling to enable site-specific and quantitative measurements of reversibly oxidized thiols. The redox dynamics of ∼2,100 Cys-sites from 1,060 proteins under light, dark, and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (a photosystem II inhibitor) conditions were quantified. In addition to relative quantification, the stoichiometry or percentage of oxidation (reversibly oxidized/total thiols) for ∼1,350 Cys-sites was also quantified. The overall results revealed broad changes in thiol oxidation in many key biological processes, including photosynthetic electron transport, carbon fixation, and glycolysis. Moreover, the redox sensitivity along with the stoichiometric data enabled prediction of potential functional Cys-sites for proteins of interest. The functional significance of redox-sensitive Cys-sites in NADP-dependent glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin (AhpC/TSA family protein Sll1621), and glucose 6-phosphate dehydrogenase was further confirmed with site-specific mutagenesis and biochemical studies. Together, our findings provide significant insights into the broad redox regulation of photosynthetic organisms. PMID:25118246

  19. Proteome-wide light/dark modulation of thiol oxidation in cyanobacteria revealed by quantitative site-specific redox proteomics.

    PubMed

    Guo, Jia; Nguyen, Amelia Y; Dai, Ziyu; Su, Dian; Gaffrey, Matthew J; Moore, Ronald J; Jacobs, Jon M; Monroe, Matthew E; Smith, Richard D; Koppenaal, David W; Pakrasi, Himadri B; Qian, Wei-Jun

    2014-12-01

    Reversible protein thiol oxidation is an essential regulatory mechanism of photosynthesis, metabolism, and gene expression in photosynthetic organisms. Herein, we present proteome-wide quantitative and site-specific profiling of in vivo thiol oxidation modulated by light/dark in the cyanobacterium Synechocystis sp. PCC 6803, an oxygenic photosynthetic prokaryote, using a resin-assisted thiol enrichment approach. Our proteomic approach integrates resin-assisted enrichment with isobaric tandem mass tag labeling to enable site-specific and quantitative measurements of reversibly oxidized thiols. The redox dynamics of ∼2,100 Cys-sites from 1,060 proteins under light, dark, and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (a photosystem II inhibitor) conditions were quantified. In addition to relative quantification, the stoichiometry or percentage of oxidation (reversibly oxidized/total thiols) for ∼1,350 Cys-sites was also quantified. The overall results revealed broad changes in thiol oxidation in many key biological processes, including photosynthetic electron transport, carbon fixation, and glycolysis. Moreover, the redox sensitivity along with the stoichiometric data enabled prediction of potential functional Cys-sites for proteins of interest. The functional significance of redox-sensitive Cys-sites in NADP-dependent glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin (AhpC/TSA family protein Sll1621), and glucose 6-phosphate dehydrogenase was further confirmed with site-specific mutagenesis and biochemical studies. Together, our findings provide significant insights into the broad redox regulation of photosynthetic organisms. PMID:25118246

  20. Crystal structures of human tissue kallikrein 4: activity modulation by a specific zinc binding site.

    PubMed

    Debela, Mekdes; Magdolen, Viktor; Grimminger, Valerie; Sommerhoff, Christian; Messerschmidt, Albrecht; Huber, Robert; Friedrich, Rainer; Bode, Wolfram; Goettig, Peter

    2006-10-01

    Human tissue kallikrein 4 (hK4) belongs to a 15-member family of closely related serine proteinases. hK4 is predominantly expressed in prostate, activates hK3/PSA, and is up-regulated in prostate and ovarian cancer. We have identified active monomers of recombinant hK4 besides inactive oligomers in solution. hK4 crystallised in the presence of zinc, nickel, and cobalt ions in three crystal forms containing cyclic tetramers and octamers. These structures display a novel metal site between His25 and Glu77 that links the 70-80 loop with the N-terminal segment. Micromolar zinc as present in prostatic fluid inhibits the enzymatic activity of hK4 against fluorogenic substrates. In our measurements, wild-type hK4 exhibited a zinc inhibition constant (IC50) of 16 microM including a permanent residual activity, in contrast to the zinc-independent mutants H25A and E77A. Since the Ile16 N terminus of wild-type hK4 becomes more accessible for acetylating agents in the presence of zinc, we propose that zinc affects the hK4 active site via the salt-bridge formed between the N terminus and Asp194 required for a functional active site. hK4 possesses an unusual 99-loop that creates a groove-like acidic S2 subsite. These findings explain the observed specificity of hK4 for the P1 to P4 substrate residues. Moreover, hK4 shows a negatively charged surface patch, which may represent an exosite for prime-side substrate recognition. PMID:16950394

  1. Self-regulation of circumscribed brain activity modulates spatially selective and frequency specific connectivity of distributed resting state networks

    PubMed Central

    Vukelić, Mathias; Gharabaghi, Alireza

    2015-01-01

    The mechanisms of learning involved in brain self-regulation have still to be unveiled to exploit the full potential of this methodology for therapeutic interventions. This skill of volitionally changing brain activity presumably resembles motor skill learning which in turn is accompanied by plastic changes modulating resting state networks. Along these lines, we hypothesized that brain regulation and neurofeedback would similarly modify intrinsic networks at rest while presenting a distinct spatio-temporal pattern. High-resolution electroencephalography preceded and followed a single neurofeedback training intervention of modulating circumscribed sensorimotor low β-activity by kinesthetic motor imagery in eleven healthy participants. The participants were kept in the deliberative phase of skill acquisition with high demands for learning self-regulation through stepwise increases of task difficulty. By applying the corrected imaginary part of the coherency function, we observed increased functional connectivity of both the primary motor and the primary somatosensory cortex with their respective contralateral homologous cortices in the low β-frequency band which was self-regulated during feedback. At the same time, the primary motor cortex—but none of the surrounding cortical areas—showed connectivity to contralateral supplementary motor and dorsal premotor areas in the high β-band. Simultaneously, the neurofeedback target displayed a specific increase of functional connectivity with an ipsilateral fronto-parietal network in the α-band while presenting a de-coupling with contralateral primary and secondary sensorimotor areas in the very same frequency band. Brain self-regulation modifies resting state connections spatially selective to the neurofeedback target of the dominant hemisphere. These are anatomically distinct with regard to the cortico-cortical connectivity pattern and are functionally specific with regard to the time domain of coherent activity

  2. Self-regulation of circumscribed brain activity modulates spatially selective and frequency specific connectivity of distributed resting state networks.

    PubMed

    Vukelić, Mathias; Gharabaghi, Alireza

    2015-01-01

    The mechanisms of learning involved in brain self-regulation have still to be unveiled to exploit the full potential of this methodology for therapeutic interventions. This skill of volitionally changing brain activity presumably resembles motor skill learning which in turn is accompanied by plastic changes modulating resting state networks. Along these lines, we hypothesized that brain regulation and neurofeedback would similarly modify intrinsic networks at rest while presenting a distinct spatio-temporal pattern. High-resolution electroencephalography preceded and followed a single neurofeedback training intervention of modulating circumscribed sensorimotor low β-activity by kinesthetic motor imagery in eleven healthy participants. The participants were kept in the deliberative phase of skill acquisition with high demands for learning self-regulation through stepwise increases of task difficulty. By applying the corrected imaginary part of the coherency function, we observed increased functional connectivity of both the primary motor and the primary somatosensory cortex with their respective contralateral homologous cortices in the low β-frequency band which was self-regulated during feedback. At the same time, the primary motor cortex-but none of the surrounding cortical areas-showed connectivity to contralateral supplementary motor and dorsal premotor areas in the high β-band. Simultaneously, the neurofeedback target displayed a specific increase of functional connectivity with an ipsilateral fronto-parietal network in the α-band while presenting a de-coupling with contralateral primary and secondary sensorimotor areas in the very same frequency band. Brain self-regulation modifies resting state connections spatially selective to the neurofeedback target of the dominant hemisphere. These are anatomically distinct with regard to the cortico-cortical connectivity pattern and are functionally specific with regard to the time domain of coherent activity

  3. Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner1,2,3

    PubMed Central

    Hui, Chin Wai

    2015-01-01

    Abstract Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges, such as lipopolysaccharide (LPS) injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit. PMID:26465009

  4. Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner(1,2,3).

    PubMed

    Hui, Chin Wai; Herrup, Karl

    2015-01-01

    Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype. Nongenetic factors, including modulations of the immune status of the animal, have also recently been found to play a role in the disease phenotype. Here we report that these modulations show both cytokine and brain region specificity. The CNS changes induced by broad-spectrum immune challenges, such as lipopolysaccharide (LPS) injections are a complex mixture of neuroprotective (TNFα) and neurodegenerative (IL1β) cytokine responses that change over time. For example, LPS first induces a protective response in A-T neurons through activation of tissue repair genes through infiltration of monocytes with M2 phenotype, followed over time by a set of more degenerative responses. Additional phenotypic complexity arises because the neuronal response to an immune challenge is regionally variable; cerebellum and cortex differ in important ways in their patterns of cellular and biochemical changes. Tracking these changes reveals an important though not exclusive role for the MAP kinase pathway. Our findings suggest brain responses to cytokine challenges are temporally and regionally specific and that both features are altered by the absence of ATM. This implies that management of the immune status of A-T patients might have significant clinical benefit. PMID:26465009

  5. Dopamine Modulates Motor Control in a Specific Plane Related to Support.

    PubMed

    Herbin, Marc; Simonis, Caroline; Revéret, Lionel; Hackert, Rémi; Libourel, Paul-Antoine; Eugène, Daniel; Diaz, Jorge; de Waele, Catherine; Vidal, Pierre-Paul

    2016-01-01

    At the acute stage following unilateral labyrinthectomy (UL), rats, mice or guinea pigs exhibit a complex motor syndrome combining circling (HSCC lesion) and rolling (utricular lesion). At the chronic stage, they only display circling, because proprioceptive information related to the plane of support substitutes the missing utricular information to control posture in the frontal plane. Circling is also observed following unilateral lesion of the mesencephalic dopaminergic neurons by 6- hydroxydopamine hydrobromide (6-OHDA rats) and systemic injection of apomorphine (APO rats). The resemblance of behavior induced by unilateral vestibular and dopaminergic lesions at the chronic stage can be interpreted in two ways. One hypothesis is that the dopaminergic system exerts three-dimensional control over motricity, as the vestibular system does. If this hypothesis is correct, then a unilateral lesion of the nigro-striatal pathway should induce three-dimensional motor deficits, i.e., circling and at least some sort of barrel rolling at the acute stage of the lesion. Then, compensation could also take place very rapidly based on proprioception, which would explain the prevalence of circling. In addition, barrel rolling should reappear when the rodent is placed in water, as it occurs in UL vertebrates. Alternatively, the dopaminergic network, together with neurons processing the horizontal canal information, could control the homeostasis of posture and locomotion specifically in one and only one plane of space, i.e. the plane related to the basis of support. In that case, barrel rolling should never occur, whether at the acute or chronic stage on firm ground or in water. Moreover, circling should have the same characteristics following both types of lesions. Clearly, 6-OHDA and APO-rats never exhibited barrel rolling at the acute stage. They circled at the acute stage of the lesion and continued to do so three weeks later, including in water. In contrast, UL-rats, exhibited

  6. Dopamine Modulates Motor Control in a Specific Plane Related to Support

    PubMed Central

    Herbin, Marc; Simonis, Caroline; Revéret, Lionel; Hackert, Rémi; Libourel, Paul-Antoine; Eugène, Daniel; Diaz, Jorge; de Waele, Catherine; Vidal, Pierre-Paul

    2016-01-01

    At the acute stage following unilateral labyrinthectomy (UL), rats, mice or guinea pigs exhibit a complex motor syndrome combining circling (HSCC lesion) and rolling (utricular lesion). At the chronic stage, they only display circling, because proprioceptive information related to the plane of support substitutes the missing utricular information to control posture in the frontal plane. Circling is also observed following unilateral lesion of the mesencephalic dopaminergic neurons by 6- hydroxydopamine hydrobromide (6-OHDA rats) and systemic injection of apomorphine (APO rats). The resemblance of behavior induced by unilateral vestibular and dopaminergic lesions at the chronic stage can be interpreted in two ways. One hypothesis is that the dopaminergic system exerts three-dimensional control over motricity, as the vestibular system does. If this hypothesis is correct, then a unilateral lesion of the nigro-striatal pathway should induce three-dimensional motor deficits, i.e., circling and at least some sort of barrel rolling at the acute stage of the lesion. Then, compensation could also take place very rapidly based on proprioception, which would explain the prevalence of circling. In addition, barrel rolling should reappear when the rodent is placed in water, as it occurs in UL vertebrates. Alternatively, the dopaminergic network, together with neurons processing the horizontal canal information, could control the homeostasis of posture and locomotion specifically in one and only one plane of space, i.e. the plane related to the basis of support. In that case, barrel rolling should never occur, whether at the acute or chronic stage on firm ground or in water. Moreover, circling should have the same characteristics following both types of lesions. Clearly, 6-OHDA and APO-rats never exhibited barrel rolling at the acute stage. They circled at the acute stage of the lesion and continued to do so three weeks later, including in water. In contrast, UL-rats, exhibited

  7. Sniffing human sex-steroid derived compounds modulates mood, memory and autonomic nervous system function in specific behavioral contexts.

    PubMed

    Bensafi, M; Brown, W M; Khan, R; Levenson, B; Sobel, N

    2004-06-01

    We asked whether the effects of exposure to two human sex-steroid derived compounds were context dependent. The effects of sniffing 4,16-androstadien-3-one (AND) and 1,3,5(10),16-estratetraen-3-ol (EST) on mood, memory, and autonomic nervous system responses were explored in 72 participants. Subjects were tested with AND, EST, or a Control compound within four mood contexts: neutral, sexually aroused, sad and happy. These moods were successfully induced using selected film segments (P < 0.0001). During the neutral context, none of the compounds affected mood or autonomic nervous system function. However, compound effects were significantly increased within arousing contexts. During the sexually arousing context, both compounds increased sexual arousal (P < 0.029). During the sad context, AND maintained positive mood in women (P< 0.050) and increased negative mood in men (P < 0.031). Memory for events during the sad context was impaired by AND in women (P < 0.047) but not in men. Finally, effects of AND on physiology were observed during the sexually arousing context whereby AND increased skin temperature in both sexes (P < 0.022) but reduced abdominal respiration rate in men only (P < 0.034). These results suggest that sex-steroidal compounds modulate mood, memory and autonomic nervous system responses and increase their significance within specific behavioral contexts. These findings lend support to a specific role for these compounds in chemical communication between humans. PMID:15135965

  8. The class-specific BCR tonic signal modulates lymphomagenesis in a c-myc deregulation transgenic model

    PubMed Central

    Amin, Rada; Marfak, Abdelghafour; Pangault, Céline; Oblet, Christelle; Chanut, Aurélie; Tarte, Karin; Denizot, Yves; Cogné, Michel

    2014-01-01

    Deregulation of c-myc by translocation onto immunoglobulin (Ig) loci can promote B cell malignant proliferations with phenotypes as diverse as acute lymphoid leukemia, Burkitt lymphoma, diffuse large B cell lymphoma, myeloma… The B cell receptor (BCR) normally providing tonic signals for cell survival and mitogenic responses to antigens, can also contribute to lymphomagenesis upon sustained ligand binding or activating mutations. BCR signaling varies among cell compartments and BCR classes. For unknown reasons, some malignancies associate with expression of either IgM or class-switched Ig. We explored whether an IgA BCR, with strong tonic signaling, would affect lymphomagenesis in c-myc IgH 3′RR transgenic mice prone to lymphoproliferations. Breeding c-myc transgenics in a background where IgM expression was replaced with IgA delayed lymphomagenesis. By comparison to single c-myc transgenics, lymphomas from double mutant animals were more differentiated and less aggressive, with an altered transcriptional program. Larger tumor cells more often expressed CD43 and CD138, which culminated in a plasma cell phenotype in 10% of cases. BCR class-specific signals thus appear to modulate lymphomagenesis and may partly explain the observed association of specific Ig classes with human B cell malignancies of differential phenotype, progression and prognosis. PMID:25229630

  9. O6-alkylguanine-DNA transferase (SNAP) as capture module for site-specific covalent bioconjugation of targeting protein on nanoparticles

    NASA Astrophysics Data System (ADS)

    Mazzucchelli, Serena; Colombo, Miriam; Galbiati, Elisabetta; Corsi, Fabio; Montenegro, Josè M.; Parak, Wolfgang J.; Prosperi, Davide

    2013-02-01

    A bimodular genetic fusion comprising a delivery module (scFv) and a capture module (SNAP) is proposed as a novel strategy for the biologically mediated site-specific covalent conjugation of targeting proteins to nanoparticles. ScFv800E6, an scFv mutant selective for HER2 antigen overexpressed in breast cancer cells was chosen as targeting ligand. The fusion protein SNAP-scFv was irreversibly immobilized on magnetofluorescent nanoparticles through the recognition between SNAP module and pegylated O6-alkylguanine derivative. The targeting efficiency of the resulting nanoparticle against HER2-positive breast cancer cells was assessed by flow cytometry and immunofluorescence.

  10. Carbohydrate ingestion induces sex-specific cardiac vagal inhibition, but not vascular sympathetic modulation, in healthy older women.

    PubMed

    Cao, Lei; Graham, Stuart L; Pilowsky, Paul M

    2016-07-01

    The role of vagal function in cardiovascular risk in older women remains unclear. Autonomic modulation following carbohydrate ingestion (CI) and postural stress (PS) were investigated in 14 healthy men and 21 age-matched postmenopausal women (age: 65.0 ± 2.1 vs. 64.1 ± 1.6 years), with normal and comparable insulin sensitivity. Continuous noninvasive finger arterial pressure and ECG were recorded in the lying and the standing positions before and after ingestion of a carbohydrate-rich meal (600 kcal, carbohydrate 78%, protein 13%, and fat 8%). Low-frequency (LF, 0.04-0.15 Hz) and high-frequency (HF, 0.15-0.4 Hz) components (ms(2)) of heart rate variability (HRV), low-frequency power (mmHg(2)) of systolic blood pressure variability (SBP LF power), and the sequence method for spontaneous baroreflex sensitivity (BRS, ms/mmHg) were used to quantify autonomic modulation. In response to CI and PS, mean arterial pressure maintained stable, and heart rate increased in women and men in the lying and standing positions. Following CI (60, 90, and 120 min postprandially) in the standing position, SBP LF power increased by 40% in men (P = 0.02), with unchanged HRV parameters; in contrast, in women, HRV HF power halved (P = 0.02), with unaltered SBP LF power. During PS before and after CI, similar magnitude of SBP LF power, HRV, and BRS changes was observed in men and women. In conclusion, CI induces sex-specific vascular sympathetic activation in healthy older men, and cardiac vagal inhibition in healthy older women; this CI-mediated efferent vagal inhibition may suggest differential cardiovascular risk factors in women, irrespective of insulin resistance, and impairment of autonomic control. PMID:27147618

  11. Structural Basis and Target-specific Modulation of ADP Sensing by the Synechococcus elongatus PII Signaling Protein*

    PubMed Central

    Zeth, Kornelius; Fokina, Oleksandra; Forchhammer, Karl

    2014-01-01

    PII signaling proteins comprise one of the most versatile signaling devices in nature and have a highly conserved structure. In cyanobacteria, PipX and N-acetyl-l-glutamate kinase are receptors of PII signaling, and these interactions are modulated by ADP, ATP, and 2-oxoglutarate. These effector molecules bind interdependently to three anti-cooperative binding sites on the trimeric PII protein and thereby affect its structure. Here we used the PII protein from Synechococcus elongatus PCC 7942 to reveal the structural basis of anti-cooperative ADP binding. Furthermore, we clarified the mutual influence of PII-receptor interaction and sensing of the ATP/ADP ratio. The crystal structures of two forms of trimeric PII, one with one ADP bound and the other with all three ADP-binding sites occupied, revealed significant differences in the ADP binding mode: at one site (S1) ADP is tightly bound through side-chain and main-chain interactions, whereas at the other two sites (S2 and S3) the ADP molecules are only bound by main-chain interactions. In the presence of the PII-receptor PipX, the affinity of ADP to the first binding site S1 strongly increases, whereas the affinity for ATP decreases due to PipX favoring the S1 conformation of PII-ADP. In consequence, the PII-PipX interaction is highly sensitive to subtle fluctuations in the ATP/ADP ratio. By contrast, the PII-N-acetyl-l-glutamate kinase interaction, which is negatively affected by ADP, is insensitive to these fluctuations. Modulation of the metabolite-sensing properties of PII by its receptors allows PII to differentially perceive signals in a target-specific manner and to perform multitasking signal transduction. PMID:24519945

  12. Specific antioxidant compounds differentially modulate cytotoxic activity of doxorubicin and cisplatin: in vitro and in vivo study

    PubMed Central

    Panchuk, Rostyslav; Skorokhyd, Nadia; Chumak, Vira; Lehka, Lilya; Omelyanchik, Sofya; Gurinovich, Valery; Moiseenok, Andrey; Heffeter, Petra; Berger, Walter; Stoika, Rostyslav

    2014-01-01

    Aim To use the antioxidant compounds (sodium selenite, selenomethionine, D-pantethine) for modulation of cytotoxic effect of doxorubicin and cisplatin toward wild type and drug-resistant mutants of several human tumor cells. Similar treatments were applied in vivo toward adult male Wistar rats. Methods Human tumor cells of different lines (HCT-116, Jurkat and HL-60) with various mechanisms of drug-resistance were treated with doxorubicin or cisplatin, alone or in combination with sodium selenite, selenomethionine, or D-pantethine. Cell viability, induction of apoptosis, and production of O2- radicals were measured. Activity of redox potential modulating enzymes was measured in the liver and blood plasma of adult male Wistar rats subjected to similar treatments. Results All antioxidants used in physiologically harmless concentration inhibited cytotoxic action of doxorubicin toward tumor cells sensitive to chemotherapy treatment by 15%-30%, and slightly enhanced cytotoxic effect of this medicine toward drug-resistant malignant cells. At the same time, there was no significant effect of these antioxidants on cisplatin action. Such effects were accompanied by a complete inhibition of production of superoxide radicals induced by doxorubicin. The results of in vivo study in adult male Wistar rats were in agreement with the results of in vitro study of human tumor cells. Conclusion Protective effect of specific antioxidant agents during cytotoxic action of doxorubicin was demonstrated in vitro in drug-sensitive human tumor cells and in adult male Wistar rats, while there was no protective effect in drug-resistant sub-lines of these tumor cells during action of doxorubicin and cisplatin. PMID:24891279

  13. Androgens modulate gene expression and specific DNA methylation pattern of steroid 5α-reductases in the frog Silurana tropicalis.

    PubMed

    Bissegger, Sonja; Langlois, Valerie S

    2016-08-01

    In vertebrates, androgens are essential in many biological functions, including reproduction, immune system, metabolism, cardiovascular function, and the central nervous system. The most potent androgen 5α-dihydrotestosterone (5α-DHT), which is actively involved in sexual differentiation and development, is converted from testosterone (T) by the steroid 5α-reductases type 1, 2, and 3 (Srd5α1, Srd5α2, and Srd5α3). Alternatively, steroid 5β-reductase (Srd5β) converts T to 5β-dihydrotestosterone (5β-DHT), a metabolite believed to be involved in steroid clearance. Recent studies suggested that Srd5 isoforms are targets for endocrine disruption. Thus, understanding the regulation of Srd5 is important to expand our knowledge on how exogenous compounds can interfere with these enzymes. In this study, we exposed frog brain, liver, and gonads ex vivo to T, 5α-DHT, and 5β-DHT in order to investigate the regulation of srd5 in response to androgens as a simulation of endocrine disrupting chemicals with androgenic properties. Androgens did not modulate srd5α2, suggesting that this isoform is not regulated by T and 5α-DHT in frogs. However, the DNA methylation of srd5α2 increased following 5α-DHT treatment suggesting that androgens can modulate epigenetic mechanisms in amphibians. In contrast, the DNA methylation of srd5α1 and srd5α3 remained stable after androgen exposure, but the mRNA levels of srd5α1 and srd5α3 were modulated by T, 5α-DHT, and 5β-DHT in a sex- and tissue-specific manner. While T positively regulates srd5α1 and srd5α3 in testes, T negatively regulates srd5α3 in ovaries. Moreover, exposure to T also increased the mRNA level of srd5β in the male brain suggesting a mechanism to protect the brain from androgen action by elimination of T into 5β-DHT. Thus, exogenous compounds with androgenic properties potentially interact with srd5 transcription and DNA methylation pattern, which could adversely affect biological functions of vertebrates

  14. Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules.

    PubMed

    Nassiri, Isar; Lombardo, Rosario; Lauria, Mario; Morine, Melissa J; Moyseos, Petros; Varma, Vijayalakshmi; Nolen, Greg T; Knox, Bridgett; Sloper, Daniel; Kaput, Jim; Priami, Corrado

    2016-01-01

    The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omics-determined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules. PMID:27385551

  15. Specificity of O-glycosylation in enhancing the stability and cellulose binding affinity of Family 1 carbohydrate-binding modules

    PubMed Central

    Chen, Liqun; Drake, Matthew R.; Resch, Michael G.; Greene, Eric R.; Himmel, Michael E.; Chaffey, Patrick K.; Beckham, Gregg T.; Tan, Zhongping

    2014-01-01

    The majority of biological turnover of lignocellulosic biomass in nature is conducted by fungi, which commonly use Family 1 carbohydrate-binding modules (CBMs) for targeting enzymes to cellulose. Family 1 CBMs are glycosylated, but the effects of glycosylation on CBM function remain unknown. Here, the effects of O-mannosylation are examined on the Family 1 CBM from the Trichoderma reesei Family 7 cellobiohydrolase at three glycosylation sites. To enable this work, a procedure to synthesize glycosylated Family 1 CBMs was developed. Subsequently, a library of 20 CBMs was synthesized with mono-, di-, or trisaccharides at each site for comparison of binding affinity, proteolytic stability, and thermostability. The results show that, although CBM mannosylation does not induce major conformational changes, it can increase the thermolysin cleavage resistance up to 50-fold depending on the number of mannose units on the CBM and the attachment site. O-Mannosylation also increases the thermostability of CBM glycoforms up to 16 °C, and a mannose disaccharide at Ser3 seems to have the largest themostabilizing effect. Interestingly, the glycoforms with small glycans at each site displayed higher binding affinities for crystalline cellulose, and the glycoform with a single mannose at each of three positions conferred the highest affinity enhancement of 7.4-fold. Overall, by combining chemical glycoprotein synthesis and functional studies, we show that specific glycosylation events confer multiple beneficial properties on Family 1 CBMs. PMID:24821760

  16. Grapevine Plasticity in Response to an Altered Microclimate: Sauvignon Blanc Modulates Specific Metabolites in Response to Increased Berry Exposure.

    PubMed

    Young, Philip R; Eyeghe-Bickong, Hans A; du Plessis, Kari; Alexandersson, Erik; Jacobson, Dan A; Coetzee, Zelmari; Deloire, Alain; Vivier, Melané A

    2016-03-01

    In this study, the metabolic and physiological impacts of an altered microclimate on quality-associated primary and secondary metabolites in grape (Vitis vinifera) 'Sauvignon Blanc' berries was determined in a high-altitude vineyard. The leaf and lateral shoot removal in the bunch zones altered the microclimate by increasing the exposure of the berries. The physical parameters (berry diameter and weight), primary metabolites (sugars and organic acids), as well as bunch temperature and leaf water potential were predominantly not affected by the treatment. The increased exposure led to higher levels of specific carotenoids and volatile terpenoids in the exposed berries, with earlier berry stages reacting distinctly from the later developmental stages. Plastic/nonplastic metabolite responses could be further classified to identify metabolites that were developmentally controlled and/or responded to the treatment in a predictable fashion (assessed over two consecutive vintages). The study demonstrates that grapevine berries exhibit a degree of plasticity within their secondary metabolites and respond physiologically to the increased exposure by increasing metabolites with potential antioxidant activity. Taken together, the data provide evidence that the underlying physiological responses relate to the maintenance of stress pathways by modulating antioxidant molecules in the berries. PMID:26628747

  17. Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules

    PubMed Central

    Nassiri, Isar; Lombardo, Rosario; Lauria, Mario; Morine, Melissa J.; Moyseos, Petros; Varma, Vijayalakshmi; Nolen, Greg T.; Knox, Bridgett; Sloper, Daniel; Kaput, Jim; Priami, Corrado

    2016-01-01

    The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omics-determined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules. PMID:27385551

  18. Specificity of O-glycosylation in enhancing the stability and cellulose binding affinity of Family 1 carbohydrate-binding modules.

    PubMed

    Chen, Liqun; Drake, Matthew R; Resch, Michael G; Greene, Eric R; Himmel, Michael E; Chaffey, Patrick K; Beckham, Gregg T; Tan, Zhongping

    2014-05-27

    The majority of biological turnover of lignocellulosic biomass in nature is conducted by fungi, which commonly use Family 1 carbohydrate-binding modules (CBMs) for targeting enzymes to cellulose. Family 1 CBMs are glycosylated, but the effects of glycosylation on CBM function remain unknown. Here, the effects of O-mannosylation are examined on the Family 1 CBM from the Trichoderma reesei Family 7 cellobiohydrolase at three glycosylation sites. To enable this work, a procedure to synthesize glycosylated Family 1 CBMs was developed. Subsequently, a library of 20 CBMs was synthesized with mono-, di-, or trisaccharides at each site for comparison of binding affinity, proteolytic stability, and thermostability. The results show that, although CBM mannosylation does not induce major conformational changes, it can increase the thermolysin cleavage resistance up to 50-fold depending on the number of mannose units on the CBM and the attachment site. O-Mannosylation also increases the thermostability of CBM glycoforms up to 16 °C, and a mannose disaccharide at Ser3 seems to have the largest themostabilizing effect. Interestingly, the glycoforms with small glycans at each site displayed higher binding affinities for crystalline cellulose, and the glycoform with a single mannose at each of three positions conferred the highest affinity enhancement of 7.4-fold. Overall, by combining chemical glycoprotein synthesis and functional studies, we show that specific glycosylation events confer multiple beneficial properties on Family 1 CBMs. PMID:24821760

  19. Specific interaction with the nuclear transporter importin α2 can modulate paraspeckle protein 1 delivery to nuclear paraspeckles

    PubMed Central

    Major, Andrew T.; Hogarth, Cathryn A.; Miyamoto, Yoichi; Sarraj, Mai A.; Smith, Catherine L.; Koopman, Peter; Kurihara, Yasuyuki; Jans, David A.; Loveland, Kate L.

    2015-01-01

    Importin (IMP) superfamily members mediate regulated nucleocytoplasmic transport, which is central to key cellular processes. Although individual IMPα proteins exhibit dynamic synthesis and subcellular localization during cellular differentiation, including during spermatogenesis, little is known of how this affects cell fate. To investigate how IMPαs control cellular development, we conducted a yeast two-hybrid screen for IMPα2 cargoes in embryonic day 12.5 mouse testis, a site of peak IMPα2 expression coincident with germ-line masculization. We identified paraspeckle protein 1 (PSPC1), the original defining component of nuclear paraspeckles, as an IMPα2-binding partner. PSPC1-IMPα2 binding in testis was confirmed in immunoprecipitations and pull downs, and an enzyme-linked immunosorbent assay–based assay demonstrated direct, high-affinity PSPC1 binding to either IMPα2/IMPβ1 or IMPα6/IMPβ1. Coexpression of full-length PSPC1 and IMPα2 in HeLa cells yielded increased PSPC1 localization in nuclear paraspeckles. High-throughput image analysis of >3500 cells indicated IMPα2 levels can directly determine PSPC1-positive nuclear speckle numbers and size; a transport-deficient IMPα2 isoform or small interfering RNA knockdown of IMPα2 each reduced endogenous PSPC1 accumulation in speckles. This first validation of an IMPα2 nuclear import cargo in fetal testis provides novel evidence that PSPC1 delivery to paraspeckles, and consequently paraspeckle function, may be controlled by modulated synthesis of specific IMPs. PMID:25694451

  20. Genome-Wide Analysis of Group A Streptococci Reveals a Mutation That Modulates Global Phenotype and Disease Specificity

    PubMed Central

    2006-01-01

    Many human pathogens produce phenotypic variants as a means to circumvent the host immune system and enhance survival and, as a potential consequence, exhibit increased virulence. For example, it has been known for almost 90 y that clinical isolates of the human bacterial pathogen group A streptococci (GAS) have extensive phenotypic heterogeneity linked to variation in virulence. However, the complete underlying molecular mechanism(s) have not been defined. Expression microarray analysis of nine clinical isolates identified two fundamentally different transcriptomes, designated pharyngeal transcriptome profile (PTP) and invasive transcriptome profile (ITP). PTP and ITP GAS differed in approximately 10% of the transcriptome, including at least 23 proven or putative virulence factor genes. ITP organisms were recovered from skin lesions of mice infected subcutaneously with PTP GAS and were significantly more able to survive phagocytosis and killing by human polymorphonuclear leukocytes. Complete genome resequencing of a mouse-derived ITP GAS revealed that the organism differed from its precursor by only a 7-bp frameshift mutation in the gene (covS) encoding the sensor kinase component of a two-component signal transduction system implicated in virulence. Genetic complementation, and sequence analysis of covR/S in 42 GAS isolates confirmed the central role of covR/S in transcriptome, exoproteome, and virulence modulation. Genome-wide analysis provides a heretofore unattained understanding of phenotypic variation and disease specificity in microbial pathogens, resulting in new avenues for vaccine and therapeutics research. PMID:16446783

  1. Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules

    NASA Astrophysics Data System (ADS)

    Nassiri, Isar; Lombardo, Rosario; Lauria, Mario; Morine, Melissa J.; Moyseos, Petros; Varma, Vijayalakshmi; Nolen, Greg T.; Knox, Bridgett; Sloper, Daniel; Kaput, Jim; Priami, Corrado

    2016-07-01

    The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omics-determined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules.

  2. Cell type-specific modulation of lipid mediator's formation in murine adipose tissue by omega-3 fatty acids.

    PubMed

    Kuda, Ondrej; Rombaldova, Martina; Janovska, Petra; Flachs, Pavel; Kopecky, Jan

    2016-01-15

    Mutual interactions between adipocytes and immune cells in white adipose tissue (WAT) are involved in modulation of lipid metabolism in the tissue and also in response to omega-3 polyunsaturated fatty acids (PUFA), which counteract adverse effects of obesity. This complex interplay depends in part on in situ formed anti- as well as pro-inflammatory lipid mediators, but cell types engaged in the synthesis of the specific mediators need to be better characterized. We used tissue fractionation and metabolipidomic analysis to identify cells producing lipid mediators in epididymal WAT of mice fed for 5 weeks obesogenic high-fat diet (lipid content 35% wt/wt), which was supplemented or not by omega-3 PUFA (4.3 mg eicosapentaenoic acid and 14.7 mg docosahexaenoic acid per g of diet). Our results demonstrate selective increase in levels of anti-inflammatory lipid mediators in WAT in response to omega-3, reflecting either their association with adipocytes (endocannabinoid-related N-docosahexaenoylethanolamine) or with stromal vascular cells (pro-resolving lipid mediator protectin D1). In parallel, tissue levels of obesity-associated pro-inflammatory endocannabinoids were suppressed. Moreover, we show that adipose tissue macrophages (ATMs), which could be isolated using magnetic force from the stromal vascular fraction, are not the major producers of protectin D1 and that omega-3 PUFA lowered lipid load in ATMs while promoting their less-inflammatory phenotype. Taken together, these results further document specific roles of various cell types in WAT in control of WAT inflammation and metabolism and they suggest that also other cells but ATMs are engaged in production of pro-resolving lipid mediators in response to omega-3 PUFA. PMID:26707880

  3. Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation.

    PubMed

    Sgrò, F; Bianchi, F T; Falcone, M; Pallavicini, G; Gai, M; Chiotto, A M A; Berto, G E; Turco, E; Chang, Y J; Huttner, W B; Di Cunto, F

    2016-05-01

    Cytokinesis, the physical separation of daughter cells at the end of cell cycle, is commonly considered a highly stereotyped phenomenon. However, in some specialized cells this process may involve specific molecular events that are still largely unknown. In mammals, loss of Citron-kinase (CIT-K) leads to massive cytokinesis failure and apoptosis only in neuronal progenitors and in male germ cells, resulting in severe microcephaly and testicular hypoplasia, but the reasons for this specificity are unknown. In this report we show that CIT-K modulates the stability of midbody microtubules and that the expression of tubulin β-III (TUBB3) is crucial for this phenotype. We observed that TUBB3 is expressed in proliferating CNS progenitors, with a pattern correlating with the susceptibility to CIT-K loss. More importantly, depletion of TUBB3 in CIT-K-dependent cells makes them resistant to CIT-K loss, whereas TUBB3 overexpression increases their sensitivity to CIT-K knockdown. The loss of CIT-K leads to a strong decrease in the phosphorylation of S444 on TUBB3, a post-translational modification associated with microtubule stabilization. CIT-K may promote this event by interacting with TUBB3 and by recruiting at the midbody casein kinase-2α (CK2α) that has previously been reported to phosphorylate the S444 residue. Indeed, CK2α is lost from the midbody in CIT-K-depleted cells. Moreover, expression of the nonphosphorylatable TUBB3 mutant S444A induces cytokinesis failure, whereas expression of the phospho-mimetic mutant S444D rescues the cytokinesis failure induced by both CIT-K and CK2α loss. Altogether, our findings reveal that expression of relatively low levels of TUBB3 in mitotic cells can be detrimental for their cytokinesis and underscore the importance of CIT-K in counteracting this event. PMID:26586574

  4. Turnover Rate of NS3 Proteins Modulates Bluetongue Virus Replication Kinetics in a Host-Specific Manner

    PubMed Central

    Ftaich, Najate; Ciancia, Claire; Viarouge, Cyril; Barry, Gerald; Ratinier, Maxime; van Rijn, Piet A.; Breard, Emmanuel; Vitour, Damien; Zientara, Stephan; Palmarini, Massimo; Terzian, Christophe

    2015-01-01

    ABSTRACT Bluetongue virus (BTV) is an arbovirus transmitted to livestock by midges of the Culicoides family and is the etiological agent of a hemorrhagic disease in sheep and other ruminants. In mammalian cells, BTV particles are released primarily by virus-induced cell lysis, while in insect cells they bud from the plasma membrane and establish a persistent infection. BTV possesses a ten-segmented double-stranded RNA genome, and NS3 proteins are encoded by segment 10 (Seg-10). The viral nonstructural protein 3 (NS3) plays a key role in mediating BTV egress as well as in impeding the in vitro synthesis of type I interferon in mammalian cells. In this study, we asked whether genetically distant NS3 proteins can alter BTV-host interactions. Using a reverse genetics approach, we showed that, depending on the NS3 considered, BTV replication kinetics varied in mammals but not in insects. In particular, one of the NS3 proteins analyzed harbored a proline at position 24 that leads to its rapid intracellular decay in ovine but not in Culicoides cells and to the attenuation of BTV virulence in a mouse model of disease. Overall, our data reveal that the genetic variability of Seg-10/NS3 differentially modulates BTV replication kinetics in a host-specific manner and highlight the role of the host-specific variation in NS3 protein turnover rate. IMPORTANCE BTV is the causative agent of a severe disease transmitted between ruminants by biting midges of Culicoides species. NS3, encoded by Seg-10 of the BTV genome, fulfills key roles in BTV infection. As Seg-10 sequences from various BTV strains display genetic variability, we assessed the impact of different Seg-10 and NS3 proteins on BTV infection and host interactions. In this study, we revealed that various Seg-10/NS3 proteins alter BTV replication kinetics in mammals but not in insects. Notably, we found that NS3 protein turnover may vary in ovine but not in Culicoides cells due to a single amino acid residue that, most

  5. Specific non-coplanar PCB-mediated modulation of bottlenose dolphin and beluga whale phagocytosis upon in vitro exposure.

    PubMed

    Levin, Milton; Morsey, Brenda; Mori, Chiharu; Guise, Sylvain

    2004-10-01

    Contaminant-induced immunosuppression by organochlorines (OC), particularly polychlorinated biphenyls (PCBs), has been suspected as a cofactor in the deaths of thousands of marine mammals. One important innate defense mechanism is phagocytosis, the ability of cells to ingest extracellular macromolecules. The present study was aimed at characterizing the immunomodulatory potential of representative OCs on phagocytosis in bottlenose dolphins and beluga whales. The ability of peripheral blood leukocytes to engulf fluorescent microspheres was evaluated using flow cytometry. The immunomodulatory effects of three non-coplanar PCB congeners, 138, 153, and 180, one coplanar PCB, 169, and 2,3,7,8-TCDD and all possible mixtures (26) were tested upon in vitro exposure. In both species, all mixtures containing at least two non-coplanar PCBs significantly reduced both neutrophil and monocyte phagocytosis, with effects more marked in dolphins than in belugas. Coplanar OCs, on their own or when added to non-coplanar congeners, did not further modulate phagocytosis, suggesting an Ah receptor-independent mechanism. Concentration-response experiments with individual congeners further demonstrated a non-coplanar PCB-induced suppression of phagocytosis, while coplanar congeners produced no consistent effects. Our results suggest simple additive interactions of chemicals in a mixture. However, calculation of toxic equivalency (TEQs) failed to predict the experimentally induced immunomodulatory effects of OCs on dolphin and beluga phagocytosis, confirming the Ah receptor-independent nature of the effects on phagocytosis. Overall, our results suggest that non-AhR mechanisms may explain one facet of immunotoxicity (phagocytosis), something that is not captured using the TEQ approach. This is the first report demonstrating the immunomodulatory effects of OCs on dolphin and beluga phagocytosis, and the first overall demonstration of immunomodulatory effects on phagocytosis mediated

  6. Lactobacillus reuteri-specific immunoregulatory gene rsiR modulates histamine production and immunomodulation by Lactobacillus reuteri.

    PubMed

    Hemarajata, P; Gao, C; Pflughoeft, K J; Thomas, C M; Saulnier, D M; Spinler, J K; Versalovic, J

    2013-12-01

    Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes that were highly expressed during the stationary phase of growth, when TNF suppression is most potent. One such gene was found to be a regulator of genes involved in histidine-histamine metabolism by this probiotic species. During the course of these studies, this gene was renamed the Lactobacillus reuteri-specific immunoregulatory (rsiR) gene. The rsiR gene is essential for human TNF suppression by L. reuteri and expression of the histidine decarboxylase (hdc) gene cluster on the L. reuteri chromosome. Inactivation of rsiR resulted in diminished TNF suppression in vitro and reduced anti-inflammatory effects in vivo in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of acute colitis. A L. reuteri strain lacking an intact rsiR gene was unable to suppress colitis and resulted in greater concentrations of serum amyloid A (SAA) in the bloodstream of affected animals. The PhdcAB promoter region targeted by rsiR was defined by reporter gene experiments. These studies support the presence of a regulatory gene, rsiR, which modulates the expression of a gene cluster known to mediate immunoregulation by probiotics at the transcriptional level. These findings may point the way toward new strategies for controlling gene expression in probiotics by dietary interventions or microbiome manipulation. PMID:24123819

  7. Lactobacillus reuteri-Specific Immunoregulatory Gene rsiR Modulates Histamine Production and Immunomodulation by Lactobacillus reuteri

    PubMed Central

    Hemarajata, P.; Gao, C.; Pflughoeft, K. J.; Thomas, C. M.; Saulnier, D. M.; Spinler, J. K.

    2013-01-01

    Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes that were highly expressed during the stationary phase of growth, when TNF suppression is most potent. One such gene was found to be a regulator of genes involved in histidine-histamine metabolism by this probiotic species. During the course of these studies, this gene was renamed the Lactobacillus reuteri-specific immunoregulatory (rsiR) gene. The rsiR gene is essential for human TNF suppression by L. reuteri and expression of the histidine decarboxylase (hdc) gene cluster on the L. reuteri chromosome. Inactivation of rsiR resulted in diminished TNF suppression in vitro and reduced anti-inflammatory effects in vivo in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of acute colitis. A L. reuteri strain lacking an intact rsiR gene was unable to suppress colitis and resulted in greater concentrations of serum amyloid A (SAA) in the bloodstream of affected animals. The PhdcAB promoter region targeted by rsiR was defined by reporter gene experiments. These studies support the presence of a regulatory gene, rsiR, which modulates the expression of a gene cluster known to mediate immunoregulation by probiotics at the transcriptional level. These findings may point the way toward new strategies for controlling gene expression in probiotics by dietary interventions or microbiome manipulation. PMID:24123819

  8. The Epigenetic Reader BRD2 as a Specific Modulator of PAI-1 Expression in Lipopolysaccharide-Stimulated Mouse Primary Astrocytes.

    PubMed

    Choi, Chang Soon; Hong, Seong Hwi; Sim, Seobo; Cho, Kyu Suk; Kim, Ji-Woon; Yang, Sung Min; Jeon, Se Jin; You, Jueng Soo; Shin, Chan Young

    2015-11-01

    The post translational modification of lysine acetylation is a key mechanism that regulates chromatin structure. Epigenetic readers, such as the BET domains, are responsible for reading histone lysine acetylation which is a hallmark of open chromatin structure, further providing a scaffold that can be accessed by RNA polymerases as well as transcription factors. Recently, several reports have assessed and highlighted the roles of epigenetic readers in various cellular contexts. However, little is known about their role in the regulation of inflammatory genes, which is critical in exquisitely tuning inflammatory responses to a variety of immune stimuli. In this study, we investigated the role of epigenetic readers BRD2 and BRD4 in the lipopolysaccharide (LPS)-induced immune responses in mouse primary astrocytes. Inflammatory stimulation by LPS showed that the levels of Brd2 mRNA and protein were increased, while Brd4 mRNA levels did not change. Knocking down of Brd2 mRNA using specific small interfering RNA (siRNA) in cultured mouse primary astrocytes inhibited LPS-induced mRNA expression and secretion of plasminogen activator inhibitor-1 (PAI-1). However, no other pro-inflammatory cytokines, such as Il-6, Il-1β and Tnf-α, were affected. Indeed, treatment with bromodomain-containing protein inhibitor, JQ1, blocked Pai-1 mRNA expression through the inhibition of direct BRD2 protein-binding and active histone modification on Pai-1 promoter. Taken together, our data suggest that BRD2 is involved in the modulation of neuroinflammatory responses through PAI-1 and via the regulation of epigenetic reader BET protein, further providing a potential novel therapeutic strategy in neuroinflammatory diseases. PMID:26349765

  9. Exon-specific DNA hypomethylation of the p53 gene of rat colon induced by dimethylhydrazine. Modulation by dietary folate.

    PubMed Central

    Kim, Y. I.; Pogribny, I. P.; Salomon, R. N.; Choi, S. W.; Smith, D. E.; James, S. J.; Mason, J. B.

    1996-01-01

    Folate deficiency enhances colorectal carcinogenesis in dimethylhydrazine-treated rats. Folate is an important mediator of DNA methylation, an epigenetic modification of DNA that is known to be dysregulated in the early stages of colorectal cancer. This study investigated the effect of dimethylhydrazine on DNA methylation of the colonic p53 gene and the modulation of this effect by dietary folate. Sprague-Dawley rats were fed diets containing 0, 2, 8, or 40 mg of folate/kg of diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for fifteen weeks. Folate-depleted and folate-replete control animals did not receive dimethylhydrazine and were fed the 0- and 8-mg folate diets, respectively. The extent of p53 methylation was determined by a quantitative HpaII-polymerase chain reaction. In exons 6 and 7, significant p53 hypomethylation was observed in all dimethylhydrazine-treated rats relative to controls (P < 0.01), independent of dietary folate. In exon 8, significant p53 hypomethylation was observed only in the dimethylhydrazine-treated folate-depleted rats compared with controls (P = 0.038) and was effectively overcome by increasing levels of dietary folate (P = 0.008). In this model, dimethylhydrazine induces exon-specific p53 hypomethylation. In some exons, this occurs independent of dietary folate, and in others, increasing levels of dietary folate effectively override the induction of hypomethylation in a dose-responsive manner. This may be a mechanism by which increasing levels of dietary folate inhibit colorectal carcinogenesis. PMID:8863662

  10. Emotional learning enhances stimulus-specific top-down modulation of sensorimotor gating in socially reared rats but not isolation-reared rats.

    PubMed

    Du, Yi; Wu, Xihong; Li, Liang

    2010-01-20

    Prepulse inhibition (PPI), the suppression of the startle reflex by a preceding sensory stimulus (prepulse), can be top-down modulated in both humans and rats. This study investigated whether emotional-learning-induced enhancement of PPI in rats is prepulse specific. The results show that in socially reared rats, PPI elicited by a narrowband-noise prepulse on the broadband-noise background (masker) was enhanced after the prepulse became fear conditioned. This fear-conditioning-modulated PPI was further enhanced by introducing a perceived spatial separation between the conditioned prepulse and the broadband-noise masker. However, these PPI enhancements disappeared if the conditioned prepulse was replaced by a different narrowband-noise prepulse that was not fear conditioned. In isolation-reared rats, who had both enhanced baseline startle and reduced PPI before conditioning, neither fear conditioning of the prepulse nor perceived spatial separation between the conditioned prepulse and noise masker could enhance PPI. Thus, the emotional-learning-induced enhancement of PPI in socially reared rats is prepulse specific, indicating that auditory processing interacts with mnemonic signaling in the formation of top-down modulation of PPI. Since the deficiency of attentional modulation of PPI in schizophrenic patients is correlated with the symptom severity, the deficiency of top-down modulations of PPI in isolation-reared rats is useful for modeling schizophrenia. PMID:19761801

  11. Volumetric-Modulated Arc Therapy: Effective and Efficient End-to-End Patient-Specific Quality Assurance

    SciTech Connect

    O'Daniel, Jennifer; Das, Shiva; Wu, Q. Jackie; Yin Fangfang

    2012-04-01

    Purpose: To explore an effective and efficient end-to-end patient-specific quality-assurance (QA) protocol for volumetric modulated arc radiotherapy (VMAT) and to evaluate the suitability of a stationary radiotherapy QA device (two-dimensional [2D] ion chamber array) for VMAT QA. Methods and Materials: Three methods were used to analyze 39 VMAT treatment plans for brain, spine, and prostate: ion chamber (one-dimensional absolute, n = 39), film (2D relative, coronal/sagittal, n = 8), and 2D ion chamber array (ICA, 2D absolute, coronal/sagittal, n = 39) measurements. All measurements were compared with the treatment planning system dose calculation either via gamma analysis (3%, 3- to 4-mm distance-to-agreement criteria) or absolute point dose comparison. The film and ion chamber results were similarly compared with the ICA measurements. Results: Absolute point dose measurements agreed well with treatment planning system computed doses (ion chamber: median deviation, 1.2%, range, -0.6% to 3.3%; ICA: median deviation, 0.6%, range, -1.8% to 2.9%). The relative 2D dose measurements also showed good agreement with computed doses (>93% of pixels in all films passing gamma, >90% of pixels in all ICA measurements passing gamma). The ICA relative dose results were highly similar to those of film (>90% of pixels passing gamma). The coronal and sagittal ICA measurements were statistically indistinguishable by the paired t test with a hypothesized mean difference of 0.1%. The ion chamber and ICA absolute dose measurements showed a similar trend but had disparities of 2-3% in 18% of plans. Conclusions: After validating the new VMAT implementation with ion chamber, film, and ICA, we were able to maintain an effective yet efficient patient-specific VMAT QA protocol by reducing from five (ion chamber, film, and ICA) to two measurements (ion chamber and single ICA) per plan. The ICA (Matrixx Registered-Sign , IBA Dosimetry) was validated for VMAT QA, but ion chamber measurements are

  12. Content addressable memory project

    NASA Technical Reports Server (NTRS)

    Hall, Josh; Levy, Saul; Smith, D.; Wei, S.; Miyake, K.; Murdocca, M.

    1991-01-01

    The progress on the Rutgers CAM (Content Addressable Memory) Project is described. The overall design of the system is completed at the architectural level and described. The machine is composed of two kinds of cells: (1) the CAM cells which include both memory and processor, and support local processing within each cell; and (2) the tree cells, which have smaller instruction set, and provide global processing over the CAM cells. A parameterized design of the basic CAM cell is completed. Progress was made on the final specification of the CPS. The machine architecture was driven by the design of algorithms whose requirements are reflected in the resulted instruction set(s). A few of these algorithms are described.

  13. Awards and Addresses Summary

    PubMed Central

    2008-01-01

    Each year at the annual ASHG meeting, addresses are given in honor of the society and a number of award winners. A summary of each of these addresses is given below. On the next pages, we have printed the Presidential Address and the addresses for the William Allan Award. The other addresses, accompanied by pictures of the speakers, can be found at www.ashg.org.

  14. Magnetic content addressable memories

    NASA Astrophysics Data System (ADS)

    Jiang, Zhenye

    Content Addressable Memories are designed with comparison circuits built into every bit cell. This parallel structure can increase the speed of searching from O(n) (as with Random Access Memories) to O(1), where n is the number of entries being searched. The high cost in hardware limits the application of CAM within situations where higher searching speed is extremely desired. Spintronics technology can build non-volatile Magnetic RAM with only one device for one bit cell. There are various technologies involved, like Magnetic Tunnel Junctions, off-easy-axis programming method, Synthetic Anti-Ferromagnetic tri-layers, Domain Wall displacement, Spin Transfer Torque tri-layers and etc. With them, particularly the Tunnel Magneto-Resistance variation in MTJ due to difference in magnetization polarity of the two magnets, Magnetic CAM can be developed with reduced hardware cost. And this is demonstrated by the discussion in this dissertation. Six MCAM designs are discussed. In the first design, comparand (C), local information (S) and their complements are stored into 4 MTJs connected in XOR gate pattern. The other five designs have one or two stacks for both information storage and comparison, and full TMR ratio can be taken advantage of. Two challenges for the five are specifically programming C without changing S and selectively programming a cell out of an array. The solutions to specific programming are: by confining the programming field for C in a ring structure design; by using field programming and spin polarized current programming respectively for C and S in the SAF+DW and SAF+STT tri-layer design; by making use of the difference in thresholds between direct mode and toggle mode switching in the SAF+SAF design. The problem of selective programming is addressed by off-easy-axis method and by including SAF tri-layers. Cell with STT tri-layers for both C and S can completely avoid the problems of specific and selective programming, but subject to the limit of

  15. γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells.

    PubMed

    Kim, Sung-Eun; Hinoue, Toshinori; Kim, Michael S; Sohn, Kyoung-Jin; Cho, Robert C; Cole, Peter D; Weisenberger, Daniel J; Laird, Peter W; Kim, Young-In

    2015-01-01

    γ-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain folylpolyglutamates are associated with functionally significant DNA methylation alterations in several important biological pathways. PMID:25502219

  16. Development and first application of an Aerosol Collection Module (ACM) for quasi online compound specific aerosol measurements

    NASA Astrophysics Data System (ADS)

    Hohaus, Thorsten; Kiendler-Scharr, Astrid; Trimborn, Dagmar; Jayne, John; Wahner, Andreas; Worsnop, Doug

    2010-05-01

    Atmospheric aerosols influence climate and human health on regional and global scales (IPCC, 2007). In many environments organics are a major fraction of the aerosol influencing its properties. Due to the huge variety of organic compounds present in atmospheric aerosol current measurement techniques are far from providing a full speciation of organic aerosol (Hallquist et al., 2009). The development of new techniques for compound specific measurements with high time resolution is a timely issue in organic aerosol research. Here we present first laboratory characterisations of an aerosol collection module (ACM) which was developed to allow for the sampling and transfer of atmospheric PM1 aerosol. The system consists of an aerodynamic lens system focussing particles on a beam. This beam is directed to a 3.4 mm in diameter surface which is cooled to -30 °C with liquid nitrogen. After collection the aerosol sample can be evaporated from the surface by heating it to up to 270 °C. The sample is transferred through a 60cm long line with a carrier gas. In order to test the ACM for linearity and sensitivity we combined it with a GC-MS system. The tests were performed with octadecane aerosol. The octadecane mass as measured with the ACM-GC-MS was compared versus the mass as calculated from SMPS derived total volume. The data correlate well (R2 0.99, slope of linear fit 1.1) indicating 100 % collection efficiency. From 150 °C to 270 °C no effect of desorption temperature on transfer efficiency could be observed. The ACM-GC-MS system was proven to be linear over the mass range 2-100 ng and has a detection limit of ~ 2 ng. First experiments applying the ACM-GC-MS system were conducted at the Jülich Aerosol Chamber. Secondary organic aerosol (SOA) was formed from ozonolysis of 600 ppbv of b-pinene. The major oxidation product nopinone was detected in the aerosol and could be shown to decrease from 2 % of the total aerosol to 0.5 % of the aerosol over the 48 hours of

  17. PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1

    PubMed Central

    Giorgi, Chiara; Boro, Aleksandar; Rechfeld, Florian; Lopez-Garcia, Laura A.; Gierisch, Maria E.; Schäfer, Beat W.; Niggli, Felix K.

    2015-01-01

    Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ∼50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (−2239/+67) using various deletion constructs identified two 14bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition. PMID:26336820

  18. The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

    PubMed Central

    Rosich, Laia; Montraveta, Arnau; Roldán, Jocabed; Rodríguez, Vanina; Villamor, Neus; Aymerich, Marta; Lagisetti, Chandraiah; Webb, Thomas R.; López-Otín, Carlos; Campo, Elias; Colomer, Dolors

    2015-01-01

    Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ−/− (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients. PMID:26068951

  19. 45 CFR 170.306 - Specific certification criteria for Complete EHRs or EHR Modules designed for an inpatient setting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.306 Specific certification...

  20. 45 CFR 170.304 - Specific certification criteria for Complete EHRs or EHR Modules designed for an ambulatory setting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.304 Specific certification...

  1. 45 CFR 170.304 - Specific certification criteria for Complete EHRs or EHR Modules designed for an ambulatory setting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.304 Specific certification...

  2. 45 CFR 170.304 - Specific certification criteria for Complete EHRs or EHR Modules designed for an ambulatory setting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.304 Specific certification...

  3. 45 CFR 170.304 - Specific certification criteria for Complete EHRs or EHR Modules designed for an ambulatory setting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.304 Specific certification...

  4. 45 CFR 170.306 - Specific certification criteria for Complete EHRs or EHR Modules designed for an inpatient setting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.306 Specific certification...

  5. 45 CFR 170.306 - Specific certification criteria for Complete EHRs or EHR Modules designed for an inpatient setting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.306 Specific certification...

  6. 45 CFR 170.304 - Specific certification criteria for Complete EHRs or EHR Modules designed for an ambulatory setting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.304 Specific certification...

  7. 45 CFR 170.306 - Specific certification criteria for Complete EHRs or EHR Modules designed for an inpatient setting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.306 Specific certification...

  8. 45 CFR 170.306 - Specific certification criteria for Complete EHRs or EHR Modules designed for an inpatient setting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Certification Criteria for Health Information Technology § 170.306 Specific certification...

  9. Distinct repressing modules on the distal region of the SBP2 promoter contribute to its vascular tissue-specific expression in different vegetative organs.

    PubMed

    Freitas, Rejane L; Carvalho, Claudine M; Fietto, Luciano G; Loureiro, Marcelo E; Almeida, Andrea M; Fontes, Elizabeth P B

    2007-11-01

    The Glycine max sucrose binding protein (GmSBP2) promoter directs vascular tissue-specific expression of reporter genes in transgenic tobacco. Here we showed that an SBP2-GFP fusion protein under the control of the GmSBP2 promoter accumulates in the vascular tissues of vegetative organs, which is consistent with the proposed involvement of SBP in sucrose transport-dependent physiological processes. Through gain-of-function experiments we confirmed that the tissue-specific determinants of the SBP2 promoter reside in the distal cis-regulatory domain A, CRD-A (position -2000 to -700) that is organized into a modular configuration to suppress promoter activity in tissues other than vascular tissues. The four analyzed CRD-A sub-modules, designates Frag II (-1785/-1508), Frag III (-1507/-1237), Frag IV (-1236/-971) and Frag V (-970/-700), act independently to alter the constitutive pattern of -92pSBP2-mediated GUS expression in different organs. Frag V fused to -92pSBP2-GUS restored the tissue-specific pattern of the full-length promoter in the shoot apex, but not in other organs. Likewise, Frag IV confined GUS expression to the vascular bundle of leaves, whereas Frag II mediated vascular specific expression in roots. Strong stem expression-repressing elements were located at positions -1485 to -1212, as Frag III limited GUS expression to the inner phloem. We have also mapped a procambium silencer to the consensus sequence CAGTTnCaAccACATTcCT which is located in both distal and proximal upstream modules. Fusion of either repressing element-containing module to the constitutive -92pSBP2 promoter suppresses GUS expression in the elongation zone of roots. Together our results demonstrate the unusual aspect of distal sequences negatively controlling tissue-specificity of a plant promoter. PMID:17710554

  10. Regulatory T-cells have a prominent role in the immune modulated vaccine response by specific oligosaccharides.

    PubMed

    van't Land, Belinda; Schijf, Marcel; van Esch, Betty C A M; van Bergenhenegouwen, Jeroen; Bastiaans, Jacqueline; Schouten, Bastiaan; Boon, Louis; Garssen, Johan

    2010-08-01

    Regulatory T-cells are increasingly important in vaccine strategies. In a Flu-vaccination model the role of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) and the immune modulation by orally supplied prebiotic oligosaccharides consisting of scGOS/lcFOS/pAOS, were assessed using anti-CD25 (PC61) mediated depletion studies. As expected, in C57BL/6J mice the Flu-vaccination resulted in significantly (p<0.001) increased DTH responses when receiving scGOS/lcFOS/pAOS. In addition, increased T-bet expression of activated CD4(+) T-cells was detected compared to placebo. In vivo depletion of CD25(+) Tregs significantly (p<0.05) increased basal DTH responses, indicating the suppressive function of these CD25(+) Tregs normally present. Surprisingly, in vivo Tregs depletion diminished scGOS/lcFOS/pAOS induced immune modulation completely to control levels (p<0.05). Although no difference in number, percentage or activation of Tregs could be determined after scGOS/lcFOS/pAOS supplementation, changes in Treg function still remains to be investigated. In conclusion, CD25(+) Tregs have an important role in modulated Flu-vaccine responses induced by scGOS/lcFOS/pAOS. PMID:20600499

  11. Molecular Basis for the Selectivity and Specificity of Ligand Recognition by the Family 16 Carbohydrate-binding Modules from Thermoanaerobacterium polysaccharolyticum ManA

    SciTech Connect

    Bae, Brian; Ohene-Adjei, Samuel; Kocherginskaya, Svetlana; Mackie, Roderick I.; Spies, M. Ashley; Cann, Isaac K.O.; Nair, Satish K.

    2008-06-06

    Enzymes that hydrolyze complex polysaccharides into simple sugars are modular in architecture and consist of single or multiple catalytic domains fused to targeting modules called carbohydrate-binding modules (CBMs). CBMs bind to their ligands with high affinity and increase the efficiency of the catalytic components by targeting the enzymes to its substrate. Here we utilized a multidisciplinary approach to characterize each of the two family 16 carbohydrate-binding domain components of the highly active mannanase from the thermophile Thermoanaerobacterium polysaccharolyticum. These represent the first crystal structures of family 16 CBMs. Calorimetric analysis showed that although these CBMs demonstrate high specificity toward {beta}-1,4-linked sugars, they can engage both cello- and mannopolysaccharides. To elucidate the molecular basis for this specificity and selectivity, we have determined high resolution crystal structures of each of the two CBMs, as well as of binary complexes of CBM16-1 bound to either mannopentaose or cellopentaose. These results provide detailed molecular insights into ligand recognition and yield a framework for rational engineering experiments designed to expand the natural repertoire of these targeting modules.

  12. The perception of speech modulation cues in lexical tones is guided by early language-specific experience

    PubMed Central

    Cabrera, Laurianne; Tsao, Feng-Ming; Liu, Huei-Mei; Li, Lu-Yang; Hu, You-Hsin; Lorenzi, Christian; Bertoncini, Josiane

    2015-01-01

    A number of studies showed that infants reorganize their perception of speech sounds according to their native language categories during their first year of life. Still, information is lacking about the contribution of basic auditory mechanisms to this process. This study aimed to evaluate when native language experience starts to noticeably affect the perceptual processing of basic acoustic cues [i.e., frequency-modulation (FM) and amplitude-modulation information] known to be crucial for speech perception in adults. The discrimination of a lexical-tone contrast (rising versus low) was assessed in 6- and 10-month-old infants learning either French or Mandarin using a visual habituation paradigm. The lexical tones were presented in two conditions designed to either keep intact or to severely degrade the FM and fine spectral cues needed to accurately perceive voice-pitch trajectory. A third condition was designed to assess the discrimination of the same voice-pitch trajectories using click trains containing only the FM cues related to the fundamental-frequency (F0) in French- and Mandarin-learning 10-month-old infants. Results showed that the younger infants of both language groups and the Mandarin-learning 10-month-olds discriminated the intact lexical-tone contrast while French-learning 10-month-olds failed. However, only the French 10-month-olds discriminated degraded lexical tones when FM, and thus voice-pitch cues were reduced. Moreover, Mandarin-learning 10-month-olds were found to discriminate the pitch trajectories as presented in click trains better than French infants. Altogether, these results reveal that the perceptual reorganization occurring during the first year of life for lexical tones is coupled with changes in the auditory ability to use speech modulation cues. PMID:26379605

  13. The perception of speech modulation cues in lexical tones is guided by early language-specific experience.

    PubMed

    Cabrera, Laurianne; Tsao, Feng-Ming; Liu, Huei-Mei; Li, Lu-Yang; Hu, You-Hsin; Lorenzi, Christian; Bertoncini, Josiane

    2015-01-01

    A number of studies showed that infants reorganize their perception of speech sounds according to their native language categories during their first year of life. Still, information is lacking about the contribution of basic auditory mechanisms to this process. This study aimed to evaluate when native language experience starts to noticeably affect the perceptual processing of basic acoustic cues [i.e., frequency-modulation (FM) and amplitude-modulation information] known to be crucial for speech perception in adults. The discrimination of a lexical-tone contrast (rising versus low) was assessed in 6- and 10-month-old infants learning either French or Mandarin using a visual habituation paradigm. The lexical tones were presented in two conditions designed to either keep intact or to severely degrade the FM and fine spectral cues needed to accurately perceive voice-pitch trajectory. A third condition was designed to assess the discrimination of the same voice-pitch trajectories using click trains containing only the FM cues related to the fundamental-frequency (F0) in French- and Mandarin-learning 10-month-old infants. Results showed that the younger infants of both language groups and the Mandarin-learning 10-month-olds discriminated the intact lexical-tone contrast while French-learning 10-month-olds failed. However, only the French 10-month-olds discriminated degraded lexical tones when FM, and thus voice-pitch cues were reduced. Moreover, Mandarin-learning 10-month-olds were found to discriminate the pitch trajectories as presented in click trains better than French infants. Altogether, these results reveal that the perceptual reorganization occurring during the first year of life for lexical tones is coupled with changes in the auditory ability to use speech modulation cues. PMID:26379605

  14. Specific binding of a mutated fragment of Clostridium perfringens enterotoxin to endothelial claudin-5 and its modulation of cerebral vascular permeability.

    PubMed

    Liao, Zhuangbin; Yang, Zhenguo; Piontek, Anna; Eichner, Miriam; Krause, Gerd; Li, Longxuan; Piontek, Joerg; Zhang, Jingjing

    2016-07-01

    The vertebrate blood-brain barrier (BBB) creates an obstacle for central nervous system-related drug delivery. Claudin-5 (Cldn5), expressed in large quantities in BBB, plays a vital role in restricting BBB permeability. The C-terminal domain of Clostridium perfringens enterotoxin (cCPE) has been verified as binding to a subset of claudins (Cldns). The Cldn5-binding cCPE194-319 variant cCPEY306W/S313H was applied in this study to investigate its ability to modulate the permeability of zebrafish larval BBB. In vitro results showed that cCPEY306W/S313H is able to bind specifically to Cldn5 in murine brain vascular endothelial (bEnd.3) cells, and is transported along with Cldn5 from the cell membrane to the cytoplasm, which in turn results in a reduction in transendothelial electrical resistance (TEER). Conversely, this effect can be reversed by removal of cCPEY306W/S313H. In an in vivo experiment, this study estimates the capability of cCPEY306W/S313H to modulate Cldn5 using a rhodamine B-Dextran dye diffusion assay in zebrafish larval BBB. The results show that cCPEY306W/S313H co-localized with Cldn5 in zebrafish cerebral vascular cells and modulated BBB permeability, resulting in dye leakage. Taken together, this study suggests that cCPEY306W/S313H has the capability - both in vitro and in vivo - to modulate BBB permeability temporarily by specific binding to Cldn5. PMID:27095710

  15. HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats

    PubMed Central

    Marroquin Belaunzaran, Osiris; Kleber, Sascha; Schauer, Stefan; Hausmann, Martin; Nicholls, Flora; Van den Broek, Maries; Payeli, Sravan; Ciurea, Adrian; Milling, Simon; Stenner, Frank; Shaw, Jackie; Kollnberger, Simon; Bowness, Paul; Petrausch, Ulf; Renner, Christoph

    2015-01-01

    Objectives HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272–specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. Methods The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. Results HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. Conclusion HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders. PMID:26125554

  16. Almond brush module cutter

    SciTech Connect

    Zohns, M.A.; Jenkins, B.M.; Mehlschau, J.J.; Morrison, D.

    1983-06-01

    This paper addresses the design, construction, and evaluation of an almond brush module cutter. The module cutter is one link in a system which processes tree prunings for fuel and fiber. This system includes a modified cotton module builder, a module mover, the cutter, and a tub grinder. An economic analysis of the cutter is presented along with the problems involved in cutting brush modules.

  17. An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

    PubMed Central

    De Gassart, Aude; Bujisic, Bojan; Zaffalon, Léa; Decosterd, Laurent A.; Di Micco, Antonia; Frera, Gianluca; Tallant, Rémy; Martinon, Fabio

    2016-01-01

    Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses. PMID:26715744

  18. Addressivity in cogenerative dialogues

    NASA Astrophysics Data System (ADS)

    Hsu, Pei-Ling

    2014-03-01

    Ashraf Shady's paper provides a first-hand reflection on how a foreign teacher used cogens as culturally adaptive pedagogy to address cultural misalignments with students. In this paper, Shady drew on several cogen sessions to showcase his journey of using different forms of cogens with his students. To improve the quality of cogens, one strategy he used was to adjust the number of participants in cogens. As a result, some cogens worked and others did not. During the course of reading his paper, I was impressed by his creative and flexible use of cogens and at the same time was intrigued by the question of why some cogens work and not others. In searching for an answer, I found that Mikhail Bakhtin's dialogism, especially the concept of addressivity, provides a comprehensive framework to address this question. In this commentary, I reanalyze the cogen episodes described in Shady's paper in the light of dialogism. My analysis suggests that addressivity plays an important role in mediating the success of cogens. Cogens with high addressivity function as internally persuasive discourse that allows diverse consciousnesses to coexist and so likely affords productive dialogues. The implications of addressivity in teaching and learning are further discussed.

  19. Power Extension Package (PEP) system definition extension, orbital service module systems analysis study. Volume 4: PEP functional specification

    NASA Technical Reports Server (NTRS)

    1979-01-01

    The functional, performance, design, and test requirements for the Orbiter power extension package and its associated ground support equipment are defined. Both government and nongovernment standards and specifications are cited for the following subsystems: electrical power, structural/mechanical, avionics, and thermal control. Quality control assurance provisions and preparation for delivery are also discussed.

  20. Fat-specific protein 27 modulates nuclear factor of activated T cells 5 and the cellular response to stress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fat-specific protein 27 (FSP27), a member of the cell death-inducing DNA fragmentation factor a-like effector (Cide) family, is highly expressed in adipose tissues and is a lipid droplet (LD)-associated protein that induces the accumulation of LDs. Using a yeast two-hybrid system to examine potentia...

  1. Power Extension Package (PEP) system definition extension, orbital service module systems analysis study. Volume 5: PEP environmental specification

    NASA Technical Reports Server (NTRS)

    1979-01-01

    This specification establishes the natural and induced environments to which the power extension package may be exposed during ground operations and space operations with the shuttle system. Space induced environments are applicable at the Orbiter attach point interface location. All probable environments are systematically listed according to each ground and mission phase.

  2. Deoxyribonuclease II as a probe to sequence-specific chromatin organization: preferential cleavage in the 72 bp modulator sequence of SV40 minichromosome.

    PubMed Central

    Shakhov, A N; Nedospasov, S A; Georgiev, G P

    1982-01-01

    T prove sequence-specific chromatin structure of SV40 minichromosome, we further modified previously described hybridization mapping. Actually (i) the digestion patterns by two nucleases (micrococcal and DNAase II) were compared and (ii) the kinetics of nuclease digestion was analyzed from early time points when only a fraction of minichromosomes was cleaved once to longer digestions when oligo- and mononucleosomal bands appeared. DNAase II is shown to possess certain sequence specificity different from that of micrococcal nuclease. The major finding is that DNAase II preferentially cleaves the SV40 minichromosome at a distinct region of the genome known as 72 bp modulator element. Other hypersensitive sites are located near the replication origin and T-ag binding site II and also near BamHI site where termination of replication and "late" transcription occurs. Micrococcal nuclease splits the BglI-Hpaii region in a different manner. Images PMID:6287427

  3. DNA base-specific modulation of μA transverse edge currents through a metallic graphene nanoribbon with a nanopore

    NASA Astrophysics Data System (ADS)

    Saha, Kamal K.; Drndić, Marija; Nikolić, Branislav K.

    2012-02-01

    We study two-terminal devices for DNA sequencing which consist of a zigzag graphene nanoribbon (ZGNR) and a nanopore in its interior through which the DNA molecule is translocated. Using the nonequilibrium Green functions combined with density functional theory, we demonstrate that each of the four DNA nucleobases inserted into the nanopore, whose edge carbon atoms are passivated by either hydrogen or nitrogen, will lead to a unique change in the device conductance. Unlike other recent biosensors based on transverse electronic transport through translocated DNA, which utilize small (of the order of pA) tunneling current across a nanogap or a nanopore yielding a poor signal-to-noise ratio, our device concept relies on the fact that in ZGNRs local current density is peaked around the edges so that drilling a nanopore away from the edges will not diminish the conductance. Inserting a nucleobase into the nanopore affects the charge density in the surrounding area, thereby modulating edge conduction currents whose magnitude is of the order of μA at bias voltage ˜0.1 V. The proposed biosensors could also be realized with other nanowires supporting transverse edge currents, such as chiral GNRs or wires made of two-dimensional topological insulators.

  4. IL-23 modulated myelin-specific T cells induce EAE via an IFNγ driven, IL-17 independent pathway

    PubMed Central

    Kroenke, Mark A.; Segal, Benjamin M.

    2010-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by myelin-reactive CD4+ T cells. An unresolved issue that has important clinical implications concerns the cytokines produced by myelin-reactive T cells that determine their pathogenicity. Initially, IL-12 polarized, IFNγ producing Th1 cells were thought to be essential for the development of EAE. More recently, IL-23 polarized, IL-17 producing Th17 cells have been highlighted as critical encephalitogenic effectors. There is growing evidence that parallel autoimmune pathways can result in common clinical and histopathological endpoints. In the current study, we describe a form of EAE induced by the transfer of IL-23 modulated CD4+ T cells into IL-17 receptor (IL-17R) deficient hosts. We found that IL-23 stimulates myelin-reactive T cells to produce both IFNγ and IL-17. Surprisingly, in this model the development of EAE is IFNγ dependent. Our findings illustrate a novel mechanism by which IL-23 promotes encephalitogenicity and they further expand the spectrum of autoreactive T cells capable of mediating inflammatory demyelinating disease of the CNS. PMID:20951792

  5. Controlling the Specificity of Modularly Assembled Small Molecules for RNA via Ligand Module Spacing: Targeting the RNAs that Cause Myotonic Muscular Dystrophy

    PubMed Central

    Lee, Melissa M.; Childs-Disney, Jessica L.; Pushechnikov, Alexei; French, Jonathan M.; Sobczak, Krzysztof; Thornton, Charles A.; Disney, Matthew D.

    2009-01-01

    - × 3-fold). The trimer and tetramer also bind ∼13- and ∼63-fold more tightly to DM1 RNAs than does MBNL1. The modularly assembled compounds are cell permeable and non-toxic as determined by flow cytometry. The results establish that for these two systems: (i) a programmable modular assembly approach can provide synthetic ligands for RNA with affinities and specificities that exceed those of natural proteins; and (ii) the spacing of ligand modules can be used to tune specificity for one RNA target over another. PMID:19904940

  6. microRNAs Modulate Spatial Memory in the Hippocampus and in the Ventral Striatum in a Region-Specific Manner.

    PubMed

    Capitano, F; Camon, J; Ferretti, V; Licursi, V; De Vito, F; Rinaldi, A; Vincenti, S; Mannironi, C; Fragapane, P; Bozzoni, I; Oliverio, A; Negri, R; Presutti, C; Mele, Andrea

    2016-09-01

    MicroRNAs are endogenous, noncoding RNAs crucial for the post-transcriptional regulation of gene expression. Their role in spatial memory formation, however, is poorly explored. In this study, we analyzed learning-induced microRNA expression in the hippocampus and in the ventral striatum. Among miRNAs specifically downregulated by spatial training, we focused on the hippocampus-specific miR-324-5p and the ventral striatum-specific miR-24. In vivo overexpression of the two miRNAs demonstrated that miR-324-5p is able to impair memory if administered in the hippocampus but not in the ventral striatum, while the opposite is true for miR-24. Overall, these findings demonstrate a causal relationship between miRNA expression changes and spatial memory formation. Furthermore, they provide support for a regional dissociation in the post-transcriptional processes underlying spatial memory in the two brain structures analyzed. PMID:26307611

  7. Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome

    PubMed Central

    Tufegdzic Vidakovic, Ana; Rueda, Oscar M.; Vervoort, Stephin J.; Sati Batra, Ankita; Goldgraben, Mae Akilina; Uribe-Lewis, Santiago; Greenwood, Wendy; Coffer, Paul J.; Bruna, Alejandra; Caldas, Carlos

    2015-01-01

    Summary The transforming growth factor beta (TGF-β) signaling pathway exerts opposing effects on cancer cells, acting as either a tumor promoter or a tumor suppressor. Here, we show that these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGF-β signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-β are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC-suppressing contexts. Our data show cell-type-specific patterns of DNA and histone modifications provide a modulatory layer by determining accessibility of genes to regulation by TGF-β/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status and is crucial for TGF-β-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGF-β in cancer. PMID:26686634

  8. Estradiol and testosterone modulate the tissue-specific expression of ghrelin, ghs-r, goat and nucb2 in goldfish.

    PubMed

    Bertucci, Juan Ignacio; Blanco, Ayelén Melisa; Canosa, Luis Fabián; Unniappan, Suraj

    2016-03-01

    Ghrelin, and nesfatin-1 (encoded by nucleobindin2/nucb2) are two metabolic peptides with multiple biological effects in vertebrates. While sex steroids are known to regulate endogenous ghrelin and NUCB2 in mammals, such actions by steroids in fish remain unknown. This study aimed to determine whether estradiol (E2) and testosterone (T) affects the expression of preproghrelin, ghrelin/growth hormone secretagogue receptor (GHS-R), ghrelin O-acyl transferase (GOAT) and NUCB2 in goldfish (Carassius auratus). First, a dose-response assay was performed in which fish were intraperitoneally (ip) implanted with pellets containing 25, 50 or 100 μg/g body weight (BW) of E2 or T. It was found that sex steroids (100 μg/g BW) administered for 2.5 days achieved the highest E2 or T in circulation. In a second experiment, fish were ip implanted with pellets containing 100 μg/g BW of E2, T or without hormone (control). RT-qPCR analyses at 2.5 days post-administration show that gut preproghrelin and GOAT expression was upregulated by both E2 and T treatments, while the same effect was observed for GHS-R only in the pituitary. Both treatments also reduced hypothalamic preproghrelin mRNA expression. NUCB2 expression was increased in the forebrain of T treated group and reduced in the gut and pituitary under both treatments. These results show for the first time a modulation of preproghrelin and nucb2/nesfatin-1 by sex steroids in fish. The interaction between sex steroids and genes implicated in both metabolism and reproduction might help meeting the reproduction dependent energy demands in fish. PMID:26773340

  9. Adult Male Mice Emit Context-Specific Ultrasonic Vocalizations That Are Modulated by Prior Isolation or Group Rearing Environment

    PubMed Central

    Ey, Elodie; Bellier, Ludovic; Aubin, Thierry; Bourgeron, Thomas; Granon, Sylvie

    2012-01-01

    Social interactions in mice are frequently analysed in genetically modified strains in order to get insight of disorders affecting social interactions such as autism spectrum disorders. Different types of social interactions have been described, mostly between females and pups, and between adult males and females. However, we recently showed that social interactions between adult males could also encompass cognitive and motivational features. During social interactions, rodents emit ultrasonic vocalizations (USVs), but it remains unknown if call types are differently used depending of the context and if they are correlated with motivational state. Here, we recorded the calls of adult C57BL/6J male mice in various behavioral conditions, such as social interaction, novelty exploration and restraint stress. We introduced a modulator for the motivational state by comparing males maintained in isolation and males maintained in groups before the experiments. Male mice uttered USVs in all social and non-social situations, and even in a stressful restraint context. They nevertheless emitted the most important number of calls with the largest diversity of call types in social interactions, particularly when showing a high motivation for social contact. For mice maintained in social isolation, the number of calls recorded was positively correlated with the duration of social contacts, and most calls were uttered during contacts between the two mice. This correlation was not observed in mice maintained in groups. These results open the way for a deeper understanding and characterization of acoustic signals associated with social interactions. They can also help evaluating the role of motivational states in the emission of acoustic signals. PMID:22238608

  10. Subtype-specific Modulation of Acid-sensing Ion Channel (ASIC) Function by 2-Guanidine-4-methylquinazoline*

    PubMed Central

    Alijevic, Omar; Kellenberger, Stephan

    2012-01-01

    Acid-sensing ion channels (ASICs) are neuronal Na+-selective channels that are transiently activated by extracellular acidification. ASICs are involved in fear and anxiety, learning, neurodegeneration after ischemic stroke, and pain sensation. The small molecule 2-guanidine-4-methylquinazoline (GMQ) was recently shown to open ASIC3 at physiological pH. We have investigated the mechanisms underlying this effect and the possibility that GMQ may alter the function of other ASICs besides ASIC3. GMQ shifts the pH dependence of activation to more acidic pH in ASIC1a and ASIC1b, whereas in ASIC3 this shift goes in the opposite direction and is accompanied by a decrease in its steepness. GMQ also induces an acidic shift of the pH dependence of inactivation of ASIC1a, -1b, -2a, and -3. As a consequence, the activation and inactivation curves of ASIC3 but not other ASICs overlap in the presence of GMQ at pH 7.4, thereby creating a window current. At concentrations >1 mm, GMQ decreases maximal peak currents by reducing the unitary current amplitude. Mutation of residue Glu-79 in the palm domain of ASIC3, previously shown to be critical for channel opening by GMQ, disrupted the GMQ effects on inactivation but not activation. This suggests that this residue is involved in the consequences of GMQ binding rather than in the binding interaction itself. This study describes the mechanisms underlying the effects of a novel class of ligands that modulate the function of all ASICs as well as activate ASIC3 at physiological pH. PMID:22948146

  11. Assist Students in Developing Technical Reading Skills. Module M-2 of Category M--Assisting Students in Improving Their Basic Skills. Professional Teacher Education Module Series.

    ERIC Educational Resources Information Center

    Fardig, Glen E.; West, Gail B.

    This learning module, one of a series of 127 performance-based teacher education learning packages focusing on specific professional competencies of vocational teachers, deals with the task of assisting students in developing technical reading skills. Addressed in the individual learning experiences included in the module are the following topics:…

  12. Provide Instruction for Slower and More Capable Learners. Second Edition. Module C-14 of Category C--Instructional Execution. Professional Teacher Education Module Series.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. National Center for Research in Vocational Education.

    This module, which is one in a series of 127 performance-based teacher education learning packages focusing upon specific professional competencies of vocational teachers, deals with planning instruction for students who have differing learning rates and capacities. Addressed in the individual learning experiences included in the module are the…

  13. Target specificity among canonical nuclear poly(A) polymerases in plants modulates organ growth and pathogen response

    PubMed Central

    Vi, Son Lang; Trost, Gerda; Lange, Peggy; Czesnick, Hjördis; Rao, Nishta; Lieber, Diana; Laux, Thomas; Gray, William M.; Manley, James L.; Groth, Detlef; Kappel, Christian; Lenhard, Michael

    2013-01-01

    Polyadenylation of pre-mRNAs is critical for efficient nuclear export, stability, and translation of the mature mRNAs, and thus for gene expression. The bulk of pre-mRNAs are processed by canonical nuclear poly(A) polymerase (PAPS). Both vertebrate and higher-plant genomes encode more than one isoform of this enzyme, and these are coexpressed in different tissues. However, in neither case is it known whether the isoforms fulfill different functions or polyadenylate distinct subsets of pre-mRNAs. Here we show that the three canonical nuclear PAPS isoforms in Arabidopsis are functionally specialized owing to their evolutionarily divergent C-terminal domains. A strong loss-of-function mutation in PAPS1 causes a male gametophytic defect, whereas a weak allele leads to reduced leaf growth that results in part from a constitutive pathogen response. By contrast, plants lacking both PAPS2 and PAPS4 function are viable with wild-type leaf growth. Polyadenylation of SMALL AUXIN UP RNA (SAUR) mRNAs depends specifically on PAPS1 function. The resulting reduction in SAUR activity in paps1 mutants contributes to their reduced leaf growth, providing a causal link between polyadenylation of specific pre-mRNAs by a particular PAPS isoform and plant growth. This suggests the existence of an additional layer of regulation in plant and possibly vertebrate gene expression, whereby the relative activities of canonical nuclear PAPS isoforms control de novo synthesized poly(A) tail length and hence expression of specific subsets of mRNAs. PMID:23918356

  14. Addressing Social Issues.

    ERIC Educational Resources Information Center

    Schoebel, Susan

    1991-01-01

    Maintains that advertising can help people become more aware of social responsibilities. Describes a successful nationwide newspaper advertising competition for college students in which ads address social issues such as literacy, drugs, teen suicide, and teen pregnancy. Notes how the ads have helped grassroots programs throughout the United…

  15. Address of the President

    ERIC Educational Resources Information Center

    Ness, Frederic W.

    1976-01-01

    The president of the Association of American Colleges addresses at the 62nd annual meeting the theme of the conference: "Looking to the Future--Liberal Education in a Radically Changing Society." Contributions to be made by AAC are examined. (LBH)

  16. Addressing Sexual Harassment

    ERIC Educational Resources Information Center

    Young, Ellie L.; Ashbaker, Betty Y.

    2008-01-01

    This article discusses ways on how to address the problem of sexual harassment in schools. Sexual harassment--simply defined as any unwanted and unwelcome sexual behavior--is a sensitive topic. Merely providing students, parents, and staff members with information about the school's sexual harassment policy is insufficient; schools must take…

  17. Space sciences - Keynote address

    NASA Technical Reports Server (NTRS)

    Alexander, Joseph K.

    1990-01-01

    The present status and projected future developments of the NASA Space Science and Applications Program are addressed. Emphasis is given to biochemistry experiments that are planned for the Space Station. Projects for the late 1990s which will study the sun, the earth's magnetosphere, and the geosphere are briefly discussed.

  18. Use of substructure-specific carbohydrate binding modules to track changes in cellulose accessibility and surface morphology during the amorphogenesis step of enzymatic hydrolysis

    PubMed Central

    2012-01-01

    Background Cellulose amorphogenesis, described as the non-hydrolytic “opening up” or disruption of a cellulosic substrate, is becoming increasingly recognized as one of the key steps in the enzymatic deconstruction of cellulosic biomass when used as a feedstock for fuels and chemicals production. Although this process is thought to play a major role in facilitating hydrolysis, the lack of quantitative techniques capable of accurately describing the molecular-level changes occurring in the substrate during amorphogenesis has hindered our understanding of this process. Results In this work, techniques for measuring changes in cellulose accessibility are reviewed and a new quantitative assay method is described. Carbohydrate binding modules (CBMs) with specific affinities for crystalline (CBM2a) or amorphous (CBM44) cellulose were used to track specific changes in the surface morphology of cotton fibres during amorphogenesis. The extents of phosphoric acid-induced and Swollenin-induced changes to cellulose accessibility were successfully quantified using this technique. Conclusions The adsorption of substructure-specific CBMs can be used to accurately quantify the extent of changes to cellulose accessibility induced by non-hydrolytic disruptive proteins. The technique provided a quick, accurate and quantitative measure of the accessibility of cellulosic substrates. Expanding the range of CBMs used for adsorption studies to include those specific for such compounds as xylan or mannan should also allow for the accurate quantitative tracking of the accessibility of these and other polymers within the lignocellulosic biomass matrix. PMID:22828270

  19. A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET

    PubMed Central

    Rockne, Russell C.; Trister, Andrew D.; Jacobs, Joshua; Hawkins-Daarud, Andrea J.; Neal, Maxwell L.; Hendrickson, Kristi; Mrugala, Maciej M.; Rockhill, Jason K.; Kinahan, Paul; Krohn, Kenneth A.; Swanson, Kristin R.

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient's disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [18F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model–data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning. PMID:25540239

  20. Progress and prospects of engineered sequence-specific DNA modulating technologies for the management of liver diseases

    PubMed Central

    Nicholson, Samantha A; Moyo, Buhle; Arbuthnot, Patrick B

    2015-01-01

    Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viral hepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), homing endonucleases (HEs) and clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR associated (Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases. PMID:25937863

  1. Overcoming a species-specificity barrier in development of an inhibitory antibody targeting a modulator of tumor stroma

    PubMed Central

    Grossman, Iris; Ilani, Tal; Fleishman, Sarel Jacob; Fass, Deborah

    2016-01-01

    The secreted disulfide catalyst Quiescin sulfhydryl oxidase-1 (QSOX1) affects extracellular matrix organization and is overexpressed in various adenocarcinomas and associated stroma. Inhibition of extracellular human QSOX1 by a monoclonal antibody decreased tumor cell migration in a cell co-culture model and hence may have therapeutic potential. However, the species specificity of the QSOX1 monoclonal antibody has been a setback in assessing its utility as an anti-metastatic agent in vivo, a common problem in the antibody therapy industry. We therefore used structurally guided engineering to expand the antibody species specificity, improving its affinity toward mouse QSOX1 by at least four orders of magnitude. A crystal structure of the re-engineered variant, complexed with its mouse antigen, revealed that the antibody accomplishes dual-species targeting through altered contacts between its heavy and light chains, plus replacement of bulky aromatics by flexible side chains and versatile water-bridged polar interactions. In parallel, we produced a surrogate antibody targeting mouse QSOX1 that exhibits a new QSOX1 inhibition mode. This set of three QSOX1 inhibitory antibodies is compatible with various mouse models for pre-clinical trials and biotechnological applications. In this study we provide insights into structural blocks to cross-reactivity and set up guideposts for successful antibody design and re-engineering. PMID:26819240

  2. Some cross-linguistic evidence for modulation of implicational universals by language-specific frequency effects in phonological development

    PubMed Central

    Edwards, Jan; Beckman, Mary E.

    2009-01-01

    While broad-focus comparisons of consonant inventories across children acquiring different language can suggest that phonological development follows a universal sequence, finer-grained statistical comparisons can reveal systematic differences. This cross-linguistic study of word-initial lingual obstruents examined some effects of language-specific frequencies on consonant mastery. Repetitions of real words were elicited from 2- and 3-year-old children who were monolingual speakers of English, Cantonese, Greek, or Japanese. The repetitions were recorded and transcribed by an adult native speaker for each language. Results found support for both language-universal effects in phonological acquisition and for language-specific influences related to phoneme and phoneme sequence frequency. These results suggest that acquisition patterns that are common across languages arise in two ways. One influence is direct, via the universal constraints imposed by the physiology and physics of speech production and perception, and how these predict which contrasts will be easy and which will be difficult for the child to learn to control. The other influence is indirect, via the way universal principles of ease of perception and production tend to influence the lexicons of many languages through commonly attested sound changes. PMID:19890438

  3. Fast, simple, and informative patient-specific dose verification method for intensity modulated total marrow irradiation with helical tomotherapy

    PubMed Central

    2014-01-01

    Background Patient-specific dose verification for treatment planning in helical tomotherapy is routinely performed using a homogeneous virtual water cylindrical phantom of 30 cm diameter and 18 cm length (Cheese phantom). Because of this small length, treatment with total marrow irradiation (TMI) requires multiple deliveries of the dose verification procedures to cover a wide range of the target volumes, which significantly prolongs the dose verification process. We propose a fast, simple, and informative patient-specific dose verification method which reduce dose verification time for TMI with helical tomotherapy. Methods We constructed a two-step solid water slab phantom (length 110 cm, height 8 cm, and two-step width of 30 cm and 15 cm), termed the Whole Body Phantom (WB phantom). Three ionization chambers and three EDR-2 films can be inserted to cover extended field TMI treatment delivery. Three TMI treatment plans were conducted with a TomoTherapy HiArt Planning Station and verified using the WB phantom with ion chambers and films. Three regions simulating the head and neck, thorax, and pelvis were covered in a single treatment delivery. The results were compared to those with the cheese phantom supplied by Accuray, Inc. following three treatment deliveries to cover the body from head to pelvis. Results Use of the WB phantom provided point doses or dose distributions from head and neck to femur in a single treatment delivery of TMI. Patient-specific dose verification with the WB phantom was 62% faster than with the cheese phantom. The average pass rate in gamma analysis with the criteria of a 3-mm distance-to-agreement and 3% dose differences was 94% ± 2% for the three TMI treatment plans. The differences in pass rates between the WB and cheese phantoms at the upper thorax to abdomen regions were within 2%. The calculated dose agreed with the measured dose within 3% for all points in all five cases in both the WB and cheese phantoms. Conclusions Our

  4. Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice.

    PubMed

    Holland, Michelle L; Lowe, Robert; Caton, Paul W; Gemma, Carolina; Carbajosa, Guillermo; Danson, Amy F; Carpenter, Asha A M; Loche, Elena; Ozanne, Susan E; Rakyan, Vardhman K

    2016-07-29

    A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA). This epigenetic response remains into adulthood and is restricted to rDNA copies associated with a specific genetic variant within the promoter. Related effects are also found in models of maternal high-fat or obesogenic diets. Our work identifies environmentally induced epigenetic dynamics that are dependent on underlying genetic variation and establishes rDNA as a genomic target of nutritional insults. PMID:27386920

  5. Select membrane proteins modulate MNV-1 infection of macrophages and dendritic cells in a cell type-specific manner.

    PubMed

    Bragazzi Cunha, Juliana; Wobus, Christiane E

    2016-08-15

    Noroviruses cause gastroenteritis in humans and other animals, are shed in the feces, and spread through the fecal-oral route. Host cellular expression of attachment and entry receptors for noroviruses is thought to be a key determinant of cell tropism and the strict species-specificity. However, to date, only carbohydrates have been identified as attachment receptors for noroviruses. Thus, we investigated whether host cellular proteins play a role during the early steps of norovirus infection. We used murine norovirus (MNV) as a representative norovirus, since MNV grows well in tissue culture and is a frequently used model to study basic aspects of norovirus biology. Virus overlay protein binding assay followed by tandem mass spectrometry analysis was performed in two permissive cell lines, RAW264.7 (murine macrophages) and SRDC (murine dendritic cells) to identify four cellular membrane proteins as candidates. Loss-of-function studies revealed that CD36 and CD44 promoted MNV-1 binding to primary dendritic cells, while CD98 heavy chain (CD98) and transferrin receptor 1 (TfRc) facilitated MNV-1 binding to RAW 264.7 cells. Furthermore, the VP1 protruding domain of MNV-1 interacted directly with the extracellular domains of recombinant murine CD36, CD98 and TfRc by ELISA. Additionally, MNV-1 infection of RAW 264.7 cells was enhanced by soluble rCD98 extracellular domain. These studies demonstrate that multiple membrane proteins can promote efficient MNV-1 infection in a cell type-specific manner. Future studies are needed to determine the molecular mechanisms by which each of these proteins affect the MNV-1 infectious cycle. PMID:27264433

  6. Lead enhances CD4{sup +} T cell proliferation indirectly by targeting antigen presenting cells and modulating antigen-specific interactions

    SciTech Connect

    Farrer, David G.; Hueber, Sara M.; McCabe, Michael J. . E-mail: michael_mccabe@urmc.rochester.edu

    2005-09-01

    Although Pb is a well-known immunotoxicant, its mechanism of action is not well understood. Low levels of Pb ({approx}1 {mu}M) markedly enhance the proliferative T cell response in mixed lymphocyte culture (MLC), a process we have termed allo-enhancement. As Pb allo-enhancement occurs whether alloantigen presenting cells (APC) are derived from C57BL/6 or BALB.B10, the allo-reactive T cells involved are likely to be specific for peptide in the context of the IA{sup b} molecule as the IE molecule is null in H-2{sup b} mice. Analysis of T cell division in MLC with Pb treatment indicated that there was no significant difference between Pb and non-Pb-treated cultures until day 4 when the frequency of proliferating T cells was much greater than in non-treated cultures. Our data suggest that this increased proliferation is not coupled with increased IL-2 levels in the media as these were actually decreased with Pb treatment and that Pb-induced enhancement in the allo-proliferative response is only partially dependent upon IL-2. Pb allo-enhancement is abrogated when stimulating allo-APCs are paraformaldehyde-fixed, and T cell proliferation stimulated by concanavalin A is not enhanced with Pb treatment, suggesting that the APC is the proximate target of Pb in allo-MLC. Pb allo-enhancement does not occur when T cells respond to irradiated allo-B cells, alone; however, it is restored when syngeneic CD11c-enriched cells are added. Of the CD11c-enriched splenocytes, the fraction that is adherent after 24 h, consistent with macrophages, appears to be the cell type targeted by Pb. Using T cells from DO11.10 transgenic mice, we determined that the effect of Pb is centered around specific p:MHC interactions and that enhanced costimulation is an unlikely mechanism for Pb allo-enhancement.

  7. Role of dual-specificity protein phosphatase-5 in modulating the myogenic response in rat cerebral arteries

    PubMed Central

    Wickramasekera, Nadi T.; Gebremedhin, Debebe; Carver, Koryn A.; Vakeel, Padmanabhan; Ramchandran, Ramani; Schuett, Aaron

    2013-01-01

    The present study examined the role of the dual-specificity protein phosphatase-5 (DUSP-5) in the pressure-induced myogenic responses of organ-cultured cerebral arterial segments. In these studies, we initially compared freshly isolated and organ-cultured cerebral arterial segments with respect to responses to step increases in intravascular pressure, vasodilator and vasoconstrictor stimuli, activities of the large-conductance arterial Ca2+-activated K+ (KCa) single-channel current, and stable protein expression of DUSP-5 enzyme. The results demonstrate maintained pressure-dependent myogenic vasoconstriction, DUSP-5 protein expression, endothelium-dependent and -independent dilations, agonist-induced constriction, and unitary KCa channel conductance in organ-cultured cerebral arterial segments similar to that in freshly isolated cerebral arteries. Furthermore, using a permeabilization transfection technique in organ-cultured cerebral arterial segments, gene-specific small interfering RNA (siRNA) induced knockdown of DUSP-5 mRNA and protein, which were associated with enhanced pressure-dependent cerebral arterial myogenic constriction and increased phosphorylation of PKC-βII. In addition, siRNA knockdown of DUSP-5 reduced levels of phosphorylated ROCK and ERK1 with no change in the level of phosphorylated ERK2. Pharmacological inhibition of ERK1/2 phosphorylation significantly attenuated pressure-induced myogenic constriction in cerebral arteries. The findings within the present studies illustrate that DUSP-5, native in cerebral arterial muscle cells, appears to regulate signaling of pressure-dependent myogenic cerebral arterial constriction, which is crucial for the maintenance of constant cerebral blood flow to the brain. PMID:23172031

  8. Modulation of Heterochromatin by Male Specific Lethal Proteins and roX RNA in Drosophila melanogaster Males

    PubMed Central

    Koya, S. Kiran; Meller, Victoria H.

    2015-01-01

    The ribonucleoprotein Male Specific Lethal (MSL) complex is required for X chromosome dosage compensation in Drosophila melanogaster males. Beginning at 3 h of development the MSL complex binds transcribed X-linked genes and modifies chromatin. A subset of MSL complex proteins, including MSL1 and MSL3, is also necessary for full expression of autosomal heterochromatic genes in males, but not females. Loss of the non-coding roX RNAs, essential components of the MSL complex, lowers the expression of heterochromatic genes and suppresses position effect variegation (PEV) only in males, revealing a sex-limited disruption of heterochromatin. To explore the molecular basis of this observation we examined additional proteins that participate in compensation and found that MLE, but not Jil-1 kinase, contributes to heterochromatic gene expression. To determine if identical regions of roX RNA are required for dosage compensation and heterochromatic silencing, we tested a panel of roX1 transgenes and deletions and find that the X chromosome and heterochromatin functions are separable by some mutations. Chromatin immunoprecipitation of staged embryos revealed widespread autosomal binding of MSL3 before and after localization of the MSL complex to the X chromosome at 3 h AEL. Autosomal MSL3 binding was dependent on MSL1, supporting the idea that a subset of MSL proteins associates with chromatin throughout the genome during early development. The broad localization of these proteins early in embryogenesis supports the idea of direct action at autosomal sites. We postulate that this may contribute to the sex-specific differences in heterochromatin that we, and others, have noted. PMID:26468879

  9. Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation

    SciTech Connect

    Diermeier, Simone; Horvath, Gabor; Knuechel-Clarke, Ruth; Hofstaedter, Ferdinand; Szoellosi, Janos; Brockhoff, Gero . E-mail: Gero.Brockhoff@klinik.uni-regensburg.de

    2005-04-01

    Background: Growth factors and Herceptin specifically and differentially modulate cell proliferation of tumor cells. However, the mechanism of action on erbB-receptor level is incompletely understood. We evaluated Herceptin's capacity to modulate erbB-receptor activation and interaction on the cell surface level and thereby potentially impair cell proliferation of HER2/neu (c-erbB2) overexpressing breast cancer cells, both in the presence and absence of relevant growth factors. Methods: BT474 and SK-BR-3 breast cancer cell lines were treated with Epidermal Growth Factor (EGF), Heregulin, and with Herceptin in different combinations. Kinetics of cell proliferation were evaluated flow cytometrically based on BrdU-labeling. Fluorescence Resonance Energy Transfer, ELISAs and phosphorylation site specific Western Blotting was performed to investigate erbB-receptor interaction and activation. Results: EGF induced EGFR/EGFR and EGFR/c-erbB2 interactions correlate with stimulation of cell proliferation in BT474 cells. Both homo- and heterodimerization are considerably less pronounced in SK-BR-3 cells and heterointeraction is additionally reduced by EGF treatment, causing inhibition of cell proliferation. Heregulin stimulates cell proliferation extensively in both cell lines. Herceptin drives BT474 cells more efficiently into quiescence than it does with SK-BR-3 cells and thereby blocks cell cycle progress. In SK-BR-3 Herceptin treatment causes c-erbB2 phosphorylation of Y877 and Y1248, EGF induces Y877 and Y1112 phosphorylation. The Y1112 phosphorylation site, activated by EGF in SK-BR-3 cell, is bypassed in BT474. In addition the inhibitory capacity of Herceptin on BT474 and SK-BR-3 cell proliferation depends on the presence and absence of growth factors to a various extent. Conclusion: The growth inhibitory effect of Herceptin on c-erbB2 overexpressing breast cancer cells is considerably modulated by EGFR coexpression and consequently EGFR/c-erbB2 homo- and

  10. Excerpts from keynote address

    SciTech Connect

    Creel, G.C.

    1995-06-01

    Excerpts from the keynote principally address emissions issues in the fossil power industry as related to heat rate improvements. Stack emissions of both sulfur and nitrogen oxides are discussed, and a number of examples are given: (1) PEPCO`s Potomac River Station, and (2) Morgantown station`s NOX reduction efforts. Circulating water emissions are also briefly discussed, as are O & M costs of emission controls.

  11. Stage and tissue-specific modulation of ten conserved miRNAs and their targets during somatic embryogenesis of Valencia sweet orange.

    PubMed

    Wu, Xiao-Meng; Liu, Mei-Ya; Ge, Xiao-Xia; Xu, Qiang; Guo, Wen-Wu

    2011-03-01

    Somatic embryogenesis (SE) is a remarkable process of plant somatic cells developing into an embryo capable of forming a complete plant. MiRNAs play important roles in plant development by regulating expression of their target genes, but its function in SE has rarely been studied. Herein, ten conserved miRNAs with critical functions in plant development are detected by stem-loop qRT-PCR in the SE system of Valencia sweet orange. Sixteen unigenes from citrus are predicted to be targeted by six of the miRNAs. Cleavage sites on 15 of these target mRNAs are mapped by 5'RACE, of which ten are reported in this study. Transcript abundances of the 16 target unigenes are detected by qRT-PCR during SE process. Stage and tissue-specific expressions of miRNAs and their targets suggest their possible modulation on SE of citrus callus: miR156, 168 and 171 exert regulatory function during somatic embryo induction process; miR159, 164, 390 and 397 are related to globular-shaped embryo formation; miR166, 167 and 398 are required for cotyledon-shaped embryo morphogenesis; in addition, target genes of miR164, 166 and 397 are associated with SE disability of nonembryogenic callus. Exploration of miRNA-mediated modulation on SE is expected to provide new insights into plant cell totipotency, as well as how to maintain and enhance the embryogenic capacity of somatic cells. PMID:21103993

  12. D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

    PubMed Central

    Boccella, Serena; Vacca, Valentina; Errico, Francesco; Marinelli, Sara; Squillace, Marta; Di Maio, Anna; Vitucci, Daniela; Palazzo, Enza; De Novellis, Vito; Maione, Sabatino; Pavone, Flaminia; Usiello, Alessandro

    2015-01-01

    D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions. PMID:25629055

  13. Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth

    PubMed Central

    Lim, Key-Hwan; Suresh, Bharathi; Park, Jung-Hyun; Kim, Young-Soo; Ramakrishna, Suresh; Baek, Kwang-Hyun

    2016-01-01

    The Lethal giant larvae (Lgl) gene encodes a cortical cytoskeleton protein, Lgl, and is involved in maintaining cell polarity and epithelial integrity. Previously, we observed that Mgl-1, a mammalian homologue of the Drosophila tumor suppressor protein Lgl, is subjected to degradation via ubiquitin-proteasome pathway, and scaffolding protein RanBPM prevents the turnover of the Mgl-1 protein. Consequently, overexpression of RanBPM enhances Mgl-1-mediated cell proliferation and migration. Here, we analyzed the ability of ubiquitin-specific protease 11 (USP11) as a novel regulator of Mgl-1 and it requires RanBPM to regulate proteasomal degradation of Mgl-1. USP11 showed deubiquitinating activity and stabilized Mgl-1 protein. However, USP11-mediated Mgl-1 stabilization was inhibited in RanBPM-knockdown cells. Furthermore, in the cancer cell migration, the regulation of Mgl-1 by USP11 required RanBPM expression. In addition, an in vivo study revealed that depletion of USP11 leads to tumor formation. Taken together, the results indicated that USP11 functions as a tumor suppressor through the regulation of Mgl-1 protein degradation via RanBPM. PMID:26919101

  14. Structural Mechanism for the Specific Assembly and Activation of the Extracellular Signal Regulated Kinase 5 (ERK5) Module*

    PubMed Central

    Glatz, Gábor; Gógl, Gergő; Alexa, Anita; Reményi, Attila

    2013-01-01

    Mitogen-activated protein kinase (MAPK) activation depends on a linear binding motif found in all MAPK kinases (MKK). In addition, the PB1 (Phox and Bem1) domain of MKK5 is required for extracellular signal regulated kinase 5 (ERK5) activation. We present the crystal structure of ERK5 in complex with an MKK5 construct comprised of the PB1 domain and the linear binding motif. We show that ERK5 has distinct protein-protein interaction surfaces compared with ERK2, which is the closest ERK5 paralog. The two MAPKs have characteristically different physiological functions and their distinct protein-protein interaction surface topography enables them to bind different sets of activators and substrates. Structural and biochemical characterization revealed that the MKK5 PB1 domain cooperates with the MAPK binding linear motif to achieve substrate specific binding, and it also enables co-recruitment of the upstream activating enzyme and the downstream substrate into one signaling competent complex. Studies on present day MAPKs and MKKs hint on the way protein kinase networks may evolve. In particular, they suggest how paralogous enzymes with similar catalytic properties could acquire novel signaling roles by merely changing the way they make physical links to other proteins. PMID:23382384

  15. The splicing factor SRSF1 modulates pattern formation by inhibiting transcription of tissue specific genes during embryogenesis.

    PubMed

    Lee, Soo-Ho; Lee, Hyun-Kyung; Kim, Chowon; Kim, Yoo-Kyung; Ismail, Tayaba; Jeong, Youngeun; Park, Kyeongyeon; Park, Jeen-Woo; Kwon, Oh-Shin; Kang, Beom Sik; Lee, Dong-Seok; Park, Mae-Ja; Park, Do-Sim; Lee, Hyun-Shik

    2016-09-01

    Alternative splicing is a major mechanism regulating pattern of gene expression through the production of multiple mRNAs from a single gene transcript. Any misregulation can cause various human diseases and also have severe effects on embryogenesis. SRSF1 is one of the critical factors regulating alternative splicing at many stages of vertebrate development and any disturbance in SRSF1 leads to serious consequences. In current study, we investigated the effects of loss of the SRSF1 gene using antisense morpholino oligonucleotides (MO) in Xenopus embryogenesis. It is evident from the results of RT-PCR and whole-mount in situ hybridization that SRSF1 is a maternal gene having strong expression in head, eyes and central nervous system. Moreover, SRSF1 morphants exhibited malformed phenotypes, including miscoiled guts, heart and cartilage formation, edema in the head and heart, and small eyes. Especially, in SRSF1 morphants, bone cartilage formation was reduced in the brain and Nkx-2.5 expression was dramatically reduced in the heart of SRSF1 morphants. In addition, a dramatic reduction in functional chordin RNA in SRSF1 morphants was observed suggesting that chordin is one of the targets of SRSF1. Thus, we concluded that SRSF1 is an essential factor for pattern formation including heart, cartilage and germ layers through the regulation of specific genes. PMID:27396620

  16. 16 CFR 0.2 - Official address.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Official address. 0.2 Section 0.2 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE ORGANIZATION § 0.2... 20580, unless otherwise specifically directed. The Commission's Web site address is www.ftc.gov....

  17. 16 CFR 0.2 - Official address.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Official address. 0.2 Section 0.2 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE ORGANIZATION § 0.2... 20580, unless otherwise specifically directed. The Commission's Web site address is www.ftc.gov....

  18. Antigen-specific modulation of experimental myasthenia gravis: nasal tolerization with recombinant fragments of the human acetylcholine receptor alpha-subunit.

    PubMed

    Barchan, D; Souroujon, M C; Im, S H; Antozzi, C; Fuchs, S

    1999-07-01

    Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AcChoR) is the major autoantigen. The immune response in these diseases is heterogeneous and is directed to a wide variety of T and B cell epitopes of AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore, have a broad specificity. We used recombinant fragments of the human AcChoR, encompassing the extracellular domain of the alpha-subunit, or shorter fragments derived from it, in experiments to modulate EAMG. We have demonstrated that intranasal administration of these recombinant fragments, which represent a major portion of epitopes involved in MG, prevents the induction of EAMG in rats and immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight loss, and muscle AcChoR content. These effects on EAMG were accompanied by a marked reduction in the proliferative T-cell response and IL-2 production in response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal tolerance induced by appropriate recombinant fragments of human AcChoR is effective in suppressing EAMG and might possibly be considered as a therapeutic modality for MG. PMID:10393952

  19. Antigen-specific modulation of experimental myasthenia gravis: Nasal tolerization with recombinant fragments of the human acetylcholine receptor α-subunit

    PubMed Central

    Barchan, Dora; Souroujon, Miriam C.; Im, Sin-Hyeog; Antozzi, Carlo; Fuchs, Sara

    1999-01-01

    Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AcChoR) is the major autoantigen. The immune response in these diseases is heterogeneous and is directed to a wide variety of T and B cell epitopes of AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore, have a broad specificity. We used recombinant fragments of the human AcChoR, encompassing the extracellular domain of the α-subunit, or shorter fragments derived from it, in experiments to modulate EAMG. We have demonstrated that intranasal administration of these recombinant fragments, which represent a major portion of epitopes involved in MG, prevents the induction of EAMG in rats and immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight loss, and muscle AcChoR content. These effects on EAMG were accompanied by a marked reduction in the proliferative T-cell response and IL-2 production in response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal tolerance induced by appropriate recombinant fragments of human AcChoR is effective in suppressing EAMG and might possibly be considered as a therapeutic modality for MG. PMID:10393952

  20. Identification of cytokine-induced modulation of microRNA expression and secretion as measured by a novel microRNA specific qPCR assay.

    PubMed

    Benes, Vladimir; Collier, Paul; Kordes, Claus; Stolte, Jens; Rausch, Tobias; Muckentaler, Martina U; Häussinger, Dieter; Castoldi, Mirco

    2015-01-01

    microRNAs are an abundant class of small non-coding RNAs that control gene expression post-transcriptionally. Importantly, microRNA activity participates in the regulation of cellular processes and is a potentially valuable source of biomarkers in the diagnosis and prognosis of human diseases. Here we introduce miQPCR, an innovative method to quantify microRNAs expression by using Real-Time PCR. miQPCR exploits T4 RNA ligase activities to extend uniformly microRNAs' 3'-ends by addition of a linker-adapter. The adapter is then used as 'anchor' to prime cDNA synthesis and throughout qPCR to amplify specifically target amplicons. miQPCR is an open, adaptable and cost-effective procedure, which offers the following advantages; i) universal elongation and reverse transcription of all microRNAs; ii) Tm-adjustment of microRNA-specific primers; iii) high sensitivity and specificity in discriminating among closely related sequences and; iv) suitable for the analysis of cellular and cell-free circulating microRNAs. Analysis of cellular and cell-free circulating microRNAs secreted by rat primary hepatocytes stimulated with cytokines and growth factors identifies for the first time a widespread modulation of both microRNAs expression and secretion. Altogether, our findings suggest that the pleiotropic activity of humoral factors on microRNAs may extensively affect liver function in response to injury and regeneration. PMID:26108880

  1. Identification of cytokine-induced modulation of microRNA expression and secretion as measured by a novel microRNA specific qPCR assay

    PubMed Central

    Benes, Vladimir; Collier, Paul; Kordes, Claus; Stolte, Jens; Rausch, Tobias; Muckentaler, Martina U.; Häussinger, Dieter; Castoldi, Mirco

    2015-01-01

    microRNAs are an abundant class of small non-coding RNAs that control gene expression post-transcriptionally. Importantly, microRNA activity participates in the regulation of cellular processes and is a potentially valuable source of biomarkers in the diagnosis and prognosis of human diseases. Here we introduce miQPCR, an innovative method to quantify microRNAs expression by using Real-Time PCR. miQPCR exploits T4 RNA ligase activities to extend uniformly microRNAs’ 3′-ends by addition of a linker-adapter. The adapter is then used as ‘anchor’ to prime cDNA synthesis and throughout qPCR to amplify specifically target amplicons. miQPCR is an open, adaptable and cost-effective procedure, which offers the following advantages; i) universal elongation and reverse transcription of all microRNAs; ii) Tm-adjustment of microRNA-specific primers; iii) high sensitivity and specificity in discriminating among closely related sequences and; iv) suitable for the analysis of cellular and cell-free circulating microRNAs. Analysis of cellular and cell-free circulating microRNAs secreted by rat primary hepatocytes stimulated with cytokines and growth factors identifies for the first time a widespread modulation of both microRNAs expression and secretion. Altogether, our findings suggest that the pleiotropic activity of humoral factors on microRNAs may extensively affect liver function in response to injury and regeneration. PMID:26108880

  2. Image quality and age-specific dose estimation in head and chest CT examinations with organ-based tube-current modulation.

    PubMed

    Yamauchi-Kawaura, C; Yamauchi, M; Imai, K; Ikeda, M; Aoyama, T

    2013-12-01

    The purpose of this study was to investigate the effects of an organ-based tube-current modulation (OBTCM) system on image quality and age-specific dose in head and chest CT examinations. Image noise, contrast-to-noise ratio (CNR) and image entropy were assessed using statistical and entropy analyses. Radiation doses for newborn, 6-y-old child and adult phantoms were measured with in-phantom dosimetry systems. The quality of CT images obtained with OBTCM was not different from that obtained without OBTCM. In head CT scans, the eye lens dose decreased by 20-33 % using OBTCM. In chest CT scans, breast dose decreased by 5-32 % using OBTCM. Posterior skin dose, however, increased by 11-20 % using OBTCM in head and chest CT scans. The reduction of effective dose using OBTCM was negligibly small. Detailed image quality and dose information provided in this study can be effectively used for OBTCM application. PMID:23734058

  3. Rat Hepatocytes Weighted Gene Co-Expression Network Analysis Identifies Specific Modules and Hub Genes Related to Liver Regeneration after Partial Hepatectomy

    PubMed Central

    Zhou, Yun; Xu, Jiucheng; Liu, Yunqing; Li, Juntao; Chang, Cuifang; Xu, Cunshuan

    2014-01-01

    The recovery of liver mass is mainly mediated by proliferation of hepatocytes after 2/3 partial hepatectomy (PH) in rats. Studying the gene expression profiles of hepatocytes after 2/3 PH will be helpful to investigate the molecular mechanisms of liver regeneration (LR). We report here the first application of weighted gene co-expression network analysis (WGCNA) to analyze the biological implications of gene expression changes associated with LR. WGCNA identifies 12 specific gene modules and some hub genes from hepatocytes genome-scale microarray data in rat LR. The results suggest that upregulated MCM5 may promote hepatocytes proliferation during LR; BCL3 may play an important role by activating or inhibiting NF-kB pathway; MAPK9 may play a permissible role in DNA replication by p38 MAPK inactivation in hepatocytes proliferation stage. Thus, WGCNA can provide novel insight into understanding the molecular mechanisms of LR. PMID:24743545

  4. Nodule-specific modulation of glutamine synthetase in transgenic Medicago truncatula leads to inverse alterations in asparagine synthetase expression.

    PubMed

    Carvalho, Helena G; Lopes-Cardoso, Inês A; Lima, Ligia M; Melo, Paula M; Cullimore, Julie V

    2003-09-01

    Transgenic Medicago truncatula plants were produced harboring chimeric gene constructs of the glutamine synthetase (GS) cDNA clones (MtGS1a or MtGS1b) fused in sense or antisense orientation to the nodule-specific leghemoglobin promoter Mtlb1. A series of transgenic plants were obtained showing a 2- to 4-fold alteration in nodule GS activity when compared with control plants. Western and northern analyses revealed that the increased or decreased levels of GS activity correlate with the amount of cytosolic GS polypeptides and transcripts present in the nodule extracts. An analysis of the isoenzyme composition showed that the increased or decreased levels of GS activity were attributable to major changes in the homo-octameric isoenzyme GS1a. Nodules of plants transformed with antisense GS constructs showed an increase in the levels of both asparagine synthetase (AS) polypeptides and transcripts when compared with untransformed control plants, whereas the sense GS transformants showed decreased AS transcript levels but polypeptide levels similar to control plants. The polypeptide abundance of other nitrogen metabolic enzymes NADH-glutamic acid synthase and aspartic acid amino-transferase as well as those of major carbon metabolic enzymes phosphoenolpyruvate carboxylase, carbonic anhydrase, and sucrose synthase were not affected by the GS-gene manipulations. Increased levels of AS polypeptides and transcripts were also transiently observed in nodules by inhibiting GS activity with phosphinothricin. Taken together, the results presented here suggest that GS activity negatively regulates the level of AS in root nodules of M. truncatula. The potential role of AS in assimilating ammonium when GS becomes limiting is discussed. PMID:12970490

  5. Topoisomerase inhibitors modulate gene expression of B-cell translocation gene 2 and prostate specific antigen in prostate carcinoma cells.

    PubMed

    Chiang, Kun-Chun; Tsui, Ke-Hung; Chung, Li-Chuan; Yeh, Chun-Nan; Chang, Phei-Lang; Chen, Wen-Tsung; Juang, Horng-Heng

    2014-01-01

    Camptothecin (CPT) and doxorubicin (DOX) have been demonstrated to have potent anti-tumor activity. The B-cell translocation gene 2 (BTG2) is involved in the regulation of cell cycle progression. We evaluated the molecular mechanisms of CPT and DOX on cell proliferation and the expressions of BTG2 and prostate specific antigen (PSA) in prostate carcinoma cells. Our results indicated that CPT or DOX treatments induced Go/G1 cell cycle arrest in LNCaP cells and apoptosis at higher dosage. Immunoblot and transient gene expression assay indicated that CPT or DOX treatments induced p53 and BTG2 gene expression, with the later effect dependent on the p53 response element within BTG2 promoter area since mutation of the p53 response element from GGGAAAGTCC to GGAGTCC or from GGCAGAGCCC to GGCACC by site-directed mutagenesis abolished the stimulation of CPT or DOX on the BTG2 promoter activity, which is also supported by our results that cotreatments of pifithrin-α, an inhibitor of p53 dependent transcriptional activation, blocked the induction of CPT or DOX on BTG2 gene expression. CPT or DOX also downregulated the protein expressions of androgen receptor (AR) and PSA. Transient gene expression assays suggested that CPT or DOX's attenuation of PSA promoter activity is dependent on both the androgen and p53 response elements within of the PSA promoter. Our results indicated that CPT and DOX attenuate cell proliferation via upregulation of BTG2 gene expression through the p53-dependent pathway. The CPT and DOX block the PSA gene expression by upregulation of p53 activity and downregulation of androgen receptor activity. PMID:24586533

  6. Topoisomerase Inhibitors Modulate Gene Expression of B-Cell Translocation Gene 2 and Prostate Specific Antigen in Prostate Carcinoma Cells

    PubMed Central

    Chung, Li-Chuan; Yeh, Chun-Nan; Chang, Phei-Lang; Chen, Wen-Tsung; Juang, Horng-Heng

    2014-01-01

    Camptothecin (CPT) and doxorubicin (DOX) have been demonstrated to have potent anti-tumor activity. The B-cell translocation gene 2 (BTG2) is involved in the regulation of cell cycle progression. We evaluated the molecular mechanisms of CPT and DOX on cell proliferation and the expressions of BTG2 and prostate specific antigen (PSA) in prostate carcinoma cells. Our results indicated that CPT or DOX treatments induced Go/G1 cell cycle arrest in LNCaP cells and apoptosis at higher dosage. Immunoblot and transient gene expression assay indicated that CPT or DOX treatments induced p53 and BTG2 gene expression, with the later effect dependent on the p53 response element within BTG2 promoter area since mutation of the p53 response element from GGGAAAGTCC to GGAGTCC or from GGCAGAGCCC to GGCACC by site-directed mutagenesis abolished the stimulation of CPT or DOX on the BTG2 promoter activity, which is also supported by our results that cotreatments of pifithrin-α, an inhibitor of p53 dependent transcriptional activation, blocked the induction of CPT or DOX on BTG2 gene expression. CPT or DOX also downregulated the protein expressions of androgen receptor (AR) and PSA. Transient gene expression assays suggested that CPT or DOX’s attenuation of PSA promoter activity is dependent on both the androgen and p53 response elements within of the PSA promoter. Our results indicated that CPT and DOX attenuate cell proliferation via upregulation of BTG2 gene expression through the p53-dependent pathway. The CPT and DOX block the PSA gene expression by upregulation of p53 activity and downregulation of androgen receptor activity. PMID:24586533

  7. Nodule-Specific Modulation of Glutamine Synthetase in Transgenic Medicago truncatula Leads to Inverse Alterations in Asparagine Synthetase Expression1

    PubMed Central

    Carvalho, Helena G.; Lopes-Cardoso, Inês A.; Lima, Ligia M.; Melo, Paula M.; Cullimore, Julie V.

    2003-01-01

    Transgenic Medicago truncatula plants were produced harboring chimeric gene constructs of the glutamine synthetase (GS) cDNA clones (MtGS1a or MtGS1b) fused in sense or antisense orientation to the nodule-specific leghemoglobin promoter Mtlb1. A series of transgenic plants were obtained showing a 2- to 4-fold alteration in nodule GS activity when compared with control plants. Western and northern analyses revealed that the increased or decreased levels of GS activity correlate with the amount of cytosolic GS polypeptides and transcripts present in the nodule extracts. An analysis of the isoenzyme composition showed that the increased or decreased levels of GS activity were attributable to major changes in the homo-octameric isoenzyme GS1a. Nodules of plants transformed with antisense GS constructs showed an increase in the levels of both asparagine synthetase (AS) polypeptides and transcripts when compared with untransformed control plants, whereas the sense GS transformants showed decreased AS transcript levels but polypeptide levels similar to control plants. The polypeptide abundance of other nitrogen metabolic enzymes NADH-glutamic acid synthase and aspartic acid amino-transferase as well as those of major carbon metabolic enzymes phosphoenolpyruvate carboxylase, carbonic anhydrase, and sucrose synthase were not affected by the GS-gene manipulations. Increased levels of AS polypeptides and transcripts were also transiently observed in nodules by inhibiting GS activity with phosphinothricin. Taken together, the results presented here suggest that GS activity negatively regulates the level of AS in root nodules of M. truncatula. The potential role of AS in assimilating ammonium when GS becomes limiting is discussed. PMID:12970490

  8. Transcriptome Analysis of Tomato Flower Pedicel Tissues Reveals Abscission Zone-Specific Modulation of Key Meristem Activity Genes

    PubMed Central

    Sun, Xiuli; Zhang, Rongzhi; Wu, Liang; Liang, Yanchun; Mao, Long

    2013-01-01

    Tomato flower abscises at the anatomically distinct abscission zone that separates the pedicel into basal and apical portions. During abscission, cell separation occurs only at the abscission zone indicating distinctive molecular regulation in its cells. We conducted a transcriptome analysis of tomato pedicel tissues during ethylene promoted abscission. We found that the abscission zone was the most active site with the largest set of differentially expressed genes when compared with basal and apical portions. Gene Ontology analyses revealed enriched transcription regulation and hydrolase activities in the abscission zone. We also demonstrate coordinated responses of hormone and cell wall related genes. Besides, a number of ESTs representing homologs of key Arabidopsis shoot apical meristem activity genes were found to be preferentially expressed in the abscission zone, including WUSCHEL (WUS), KNAT6, LATERAL ORGAN BOUNDARIES DOMAIN PROTEIN 1(LBD1), and BELL-like homeodomain protein 1 (BLH1), as well as tomato axillary meristem genes BLIND (Bl) and LATERAL SUPPRESSOR (Ls). More interestingly, the homologs of WUS and the potential functional partner OVATE FAMILIY PROTEIN (OFP) were subsequently down regulated during abscission while Bl and AGL12 were continuously and specifically induced in the abscission zone. The expression patterns of meristem activity genes corroborate the idea that cells of the abscission zone confer meristem-like nature and coincide with the course of abscission and post-abscission cell differentiation. Our data therefore propose a possible regulatory scheme in tomato involving meristem genes that may be required not only for the abscission zone development, but also for abscission. PMID:23390523

  9. Transcriptome analysis of tomato flower pedicel tissues reveals abscission zone-specific modulation of key meristem activity genes.

    PubMed

    Wang, Xiang; Liu, Danmei; Li, Aili; Sun, Xiuli; Zhang, Rongzhi; Wu, Liang; Liang, Yanchun; Mao, Long

    2013-01-01

    Tomato flower abscises at the anatomically distinct abscission zone that separates the pedicel into basal and apical portions. During abscission, cell separation occurs only at the abscission zone indicating distinctive molecular regulation in its cells. We conducted a transcriptome analysis of tomato pedicel tissues during ethylene promoted abscission. We found that the abscission zone was the most active site with the largest set of differentially expressed genes when compared with basal and apical portions. Gene Ontology analyses revealed enriched transcription regulation and hydrolase activities in the abscission zone. We also demonstrate coordinated responses of hormone and cell wall related genes. Besides, a number of ESTs representing homologs of key Arabidopsis shoot apical meristem activity genes were found to be preferentially expressed in the abscission zone, including WUSCHEL (WUS), KNAT6, LATERAL ORGAN BOUNDARIES DOMAIN PROTEIN 1(LBD1), and BELL-like homeodomain protein 1 (BLH1), as well as tomato axillary meristem genes BLIND (Bl) and LATERAL SUPPRESSOR (Ls). More interestingly, the homologs of WUS and the potential functional partner OVATE FAMILIY PROTEIN (OFP) were subsequently down regulated during abscission while Bl and AGL12 were continuously and specifically induced in the abscission zone. The expression patterns of meristem activity genes corroborate the idea that cells of the abscission zone confer meristem-like nature and coincide with the course of abscission and post-abscission cell differentiation. Our data therefore propose a possible regulatory scheme in tomato involving meristem genes that may be required not only for the abscission zone development, but also for abscission. PMID:23390523

  10. Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase (POR)

    PubMed Central

    Agrawal, Vishal; Choi, Ji Ha; Giacomini, Kathleen M.; Miller, Walter L.

    2010-01-01

    Objectives CYP3A4 receives electrons from P450 oxidoreductase (POR) to metabolize about 50% of clinically used drugs. There is substantial inter-individual variation in CYP3A4 catalytic activity that is not explained by CYP3A4 genetic variants. CYP3A4 is flexible and distensible, permitting it to accommodate substrates varying in shape and size. To elucidate mechanisms of variability in CYP3A4 catalysis, we examined the effects of genetic variants of POR, and explored the possibility that substrate-induced conformational changes in CYP3A4 differentially affect the ability of POR variants to support catalysis. Methods We expressed human CYP3A4 and four POR variants (Q153R, A287P, R457H, A503V) in bacteria, reconstituted them in vitro and measured the Michaelis constant and maximum velocity with testosterone, midazolam, quinidine and erythromycin as substrates. Results POR A287P and R457H had low activity with all substrates; Q153R had 76–94% of wild type (WT) activity with midazolam and erythromycin, but 129–150% activity with testosterone and quinidine. The A503V polymorphism reduced CYP3A4 activity to 61–77% of wild type with testosterone and midazolam, but had nearly wild type activity with quinidine and erythromycin. Conclusion POR variants affect CYP3A4 activities. The impact of a POR variant on catalysis by CYP3A4 is substrate-specific, probably due to substrate-induced conformational changes in CYP3A4. PMID:20697309

  11. Imprinting in rice: the role of DNA and histone methylation in modulating parent-of-origin specific expression and determining transcript start sites.

    PubMed

    Du, Miru; Luo, Ming; Zhang, Ruofang; Finnegan, E Jean; Koltunow, Anna M G

    2014-07-01

    Over 200 imprinted genes in rice endosperm are known, but the mechanisms modulating their parental allele-specific expression are poorly understood. Here we use three imprinted genes, OsYUCCA11, yellow2-like and ubiquitin hydrolase, to show that differential DNA methylation and tri-methylation of histone H3 lysine 27 (H3K27me3 ) in the promoter and/or gene body influences allele-specific expression or the site of transcript initiation. Paternal expression of OsYUCCA11 required DNA methylation in the gene body whereas the gene body of the silenced maternal allele was hypomethylated and marked with H3K27me3 . These differential markings mirror those proposed to modulate paternal expression of two Arabidopsis genes, PHERES1 and a YUCCA homolog, indicating conservation of imprinting mechanisms. At yellow2-like, DNA hypomethylation in the upstream flanking region resulted in maternal transcripts that were longer than paternal transcripts; the maternal transcript initiation site was marked by DNA methylation in the paternal allele, and transcription initiated ~700 bp downstream. The paternal allele of an ubiquitin hydrolase gene exhibited gene body DNA methylation and produced full-length transcripts, while the maternal allele was hypomethylated in the 5' gene body and transcripts initiated from a downstream promoter. Inhibition of DNA methylation by 5-azacytidine or zebularine activated the long transcripts from yellow2-like and enhanced expression of the short transcripts from the ubiquitin hydrolase in seedlings, indicating that DNA methylation prevents transcript initiation from cryptic promoters. These observations suggest a paradigm whereby maternal genome hypomethylation is associated with the production of distinct transcripts, potentially diversifying the gene products from the two alleles. PMID:24819479

  12. SU-E-T-424: Dosimetric Verification of Modulated Electron Radiation Therapy Delivered Using An Electron Specific Multileaf Collimator for Treatment of Scalp Cases

    SciTech Connect

    Eldib, A; Jin, L; Martin, J; Li, J; Chibani, O; Galloway, T; Ma, C; Mora, G

    2014-06-01

    Purpose: Modulated electron radiotherapy (MERT) has the potential to achieve better treatment outcome for shallow tumors such as those of breast and scalp. In a separate study with scalp lesions, MERT was compared to volumetric modulated arc therapy. Our results showed a reduction in the dose reaching the brain with MERT. However dose calculation accuracy and delivery efficiency challenges remain. Thus in the current study we proceed to add more cases to demonstrate MERT beneficial outcome and its delivery accuracy using an electron specific multileaf collimator (eMLC). Methods: We have used the MCBEAM code for treatment head simulation and for generating phase space files to be used as radiation source input for our Monte Carlo based treatment planning system (MC TPS). MCPLAN code is used for calculation of patient specific dose deposition coefficient and for final MERT plan dose calculation. An in-house developed optimization code is used for the optimization process. MERT plans were generated for real patients and head and neck phantom. Film was used for dosimetric verification. The film was cut following the contour of the curved phantom surface and then sealed with black masking tape. In the measurement, the sealed film packet was sandwiched between two adjacent slabs of the head and neck phantom. The measured 2D dose distribution was then compared with calculations. Results: The eMLC allows effective treatment of scalps with multi-lesions spreading around the patient head, which was usually difficult to plan or very time consuming with conventional applicators. MERT continues to show better reduction in the brain dose. The dosimetric measurements showed slight discrepancy, which was attributed to the film setup. Conclusion: MERT can improve treatment plan quality for patients with scalp cancers. Our in-house MC TPS is capable of performing treatment planning and accurate dose calculation for MERT using the eMLC.

  13. DNA Unwinding Functions of Minute Virus of Mice NS1 Protein Are Modulated Specifically by the Lambda Isoform of Protein Kinase C

    PubMed Central

    Dettwiler, Sabine; Rommelaere, Jean; Nüesch, Jürg P. F.

    1999-01-01

    The parvovirus minute virus of mice NS1 protein is a multifunctional protein involved in a variety of processes during virus propagation, ranging from viral DNA replication to promoter regulation and cytotoxic action to the host cell. Since NS1 becomes phosphorylated during infection, it was proposed that the different tasks of this protein might be regulated in a coordinated manner by phosphorylation. Indeed, comparing biochemical functions of native NS1 with its dephosphorylated counterpart showed that site-specific nicking of the origin and the helicase and ATPase activities are remarkably reduced upon NS1 dephosphorylation while site-specific affinity of the protein to the origin became enhanced. As a consequence, the dephosphorylated polypeptide is deficient for initiation of DNA replication. By adding fractionated cell extracts to a kinase-free in vitro replication system, the combination of two protein components containing members of the protein kinase C (PKC) family was found to rescue the replication activity of the dephosphorylated NS1 protein upon addition of PKC cofactors. One of these components, termed HA-1, also stimulated NS1 helicase function in response to acidic lipids but not phorbol esters, indicating the involvement of atypical PKC isoforms in the modulation of this NS1 function (J. P. F. Nüesch, S. Dettwiler, R. Corbau, and J. Rommelaere, J. Virol. 72:9966–9977, 1998). The present study led to the identification of atypical PKCλ/ι as the active component of HA-1 responsible for the regulation of NS1 DNA unwinding and replicative functions. Moreover, a target PKCλ phosphorylation site was localized at S473 of NS1. By site-directed mutagenesis, we showed that this residue is essential for NS1 helicase activity but not promoter regulation, suggesting a possible modulation of NS1 functions by PKCλ phosphorylation at residue S473. PMID:10438831

  14. Content addressable memory project

    NASA Technical Reports Server (NTRS)

    Hall, J. Storrs; Levy, Saul; Smith, Donald E.; Miyake, Keith M.

    1992-01-01

    A parameterized version of the tree processor was designed and tested (by simulation). The leaf processor design is 90 percent complete. We expect to complete and test a combination of tree and leaf cell designs in the next period. Work is proceeding on algorithms for the computer aided manufacturing (CAM), and once the design is complete we will begin simulating algorithms for large problems. The following topics are covered: (1) the practical implementation of content addressable memory; (2) design of a LEAF cell for the Rutgers CAM architecture; (3) a circuit design tool user's manual; and (4) design and analysis of efficient hierarchical interconnection networks.

  15. Bioreactors Addressing Diabetes Mellitus

    PubMed Central

    Minteer, Danielle M.; Gerlach, Jorg C.

    2014-01-01

    The concept of bioreactors in biochemical engineering is a well-established process; however, the idea of applying bioreactor technology to biomedical and tissue engineering issues is relatively novel and has been rapidly accepted as a culture model. Tissue engineers have developed and adapted various types of bioreactors in which to culture many different cell types and therapies addressing several diseases, including diabetes mellitus types 1 and 2. With a rising world of bioreactor development and an ever increasing diagnosis rate of diabetes, this review aims to highlight bioreactor history and emerging bioreactor technologies used for diabetes-related cell culture and therapies. PMID:25160666

  16. Delegate Assembly Address

    ERIC Educational Resources Information Center

    Johnson, Jerry A.

    1976-01-01

    The report on proposed reorganization of the American Occupational Therapy Association details historical developments, demands for change, and a general rationale for reorganization, as well as specific recommendations for action. (GW)

  17. Addressing Environmental Health Inequalities.

    PubMed

    Gouveia, Nelson

    2016-01-01

    Environmental health inequalities refer to health hazards disproportionately or unfairly distributed among the most vulnerable social groups, which are generally the most discriminated, poor populations and minorities affected by environmental risks. Although it has been known for a long time that health and disease are socially determined, only recently has this idea been incorporated into the conceptual and practical framework for the formulation of policies and strategies regarding health. In this Special Issue of the International Journal of Environmental Research and Public Health (IJERPH), "Addressing Environmental Health Inequalities-Proceedings from the ISEE Conference 2015", we incorporate nine papers that were presented at the 27th Conference of the International Society for Environmental Epidemiology (ISEE), held in Sao Paulo, Brazil, in 2015. This small collection of articles provides a brief overview of the different aspects of this topic. Addressing environmental health inequalities is important for the transformation of our reality and for changing the actual development model towards more just, democratic, and sustainable societies driven by another form of relationship between nature, economy, science, and politics. PMID:27618906

  18. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

    PubMed

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    pools of neurons that may modulate specific cortical areas. PMID:27147975

  19. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

    PubMed Central

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    pools of neurons that may modulate specific cortical areas. PMID:27147975

  20. Transcriptome analysis of human primary endothelial cells (HUVEC) from umbilical cords of gestational diabetic mothers reveals candidate sites for an epigenetic modulation of specific gene expression.

    PubMed

    Ambra, R; Manca, S; Palumbo, M C; Leoni, G; Natarelli, L; De Marco, A; Consoli, A; Pandolfi, A; Virgili, F

    2014-01-01

    Within the complex pathological picture associated to diabetes, high glucose (HG) has "per se" effects on cells and tissues that involve epigenetic reprogramming of gene expression. In fetal tissues, epigenetic changes occur genome-wide and are believed to induce specific long term effects. Human umbilical vein endothelial cells (HUVEC) obtained at delivery from gestational diabetic women were used to study the transcriptomic effects of chronic hyperglycemia in fetal vascular cells using Affymetrix microarrays. In spite of the small number of samples analyzed (n=6), genes related to insulin sensing and extracellular matrix reorganization were found significantly affected by HG. Quantitative PCR analysis of gene promoters identified a significant differential DNA methylation in TGFB2. Use of Ea.hy926 endothelial cells confirms data on HUVEC. Our study corroborates recent evidences suggesting that epigenetic reprogramming of gene expression occurs with persistent HG and provides a background for future investigations addressing genomic consequences of chronic HG. PMID:24667242

  1. Bax: Addressed to kill.

    PubMed

    Renault, Thibaud T; Manon, Stéphen

    2011-09-01

    The pro-apoptototic protein Bax (Bcl-2 Associated protein X) plays a central role in the mitochondria-dependent apoptotic pathway. In healthy mammalian cells, Bax is essentially cytosolic and inactive. Following a death signal, the protein is translocated to the outer mitochondrial membrane, where it promotes a permeabilization that favors the release of different apoptogenic factors, such as cytochrome c. The regulation of Bax translocation is associated to conformational changes that are under the control of different factors. The evidences showing the involvement of different Bax domains in its mitochondrial localization are presented. The interactions between Bax and its different partners are described in relation to their ability to promote (or prevent) Bax conformational changes leading to mitochondrial addressing and to the acquisition of the capacity to permeabilize the outer mitochondrial membrane. PMID:21641962

  2. Modulational effects in accelerators

    SciTech Connect

    Satogata, T.

    1997-12-01

    We discuss effects of field modulations in accelerators, specifically those that can be used for operational beam diagnostics and beam halo control. In transverse beam dynamics, combined effects of nonlinear resonances and tune modulations influence diffusion rates with applied tune modulation has been demonstrated. In the longitudinal domain, applied RF phase and voltage modulations provide mechanisms for parasitic halo transport, useful in slow crystal extraction. Experimental experiences with transverse tune and RF modulations are also discussed.

  3. Biochemical analysis of the substrate specificity of the beta-ketoacyl-acyl carrier protein synthase domain of module 2 of the erythromycin polyketide synthase.

    PubMed

    Wu, Jiaquan; Kinoshita, Kenji; Khosla, Chaitan; Cane, David E

    2004-12-28

    The beta-ketoacyl-acyl carrier protein synthase (KS) domain of the modular 6-deoxyerythronolide B synthase (DEBS) catalyzes the fundamental chain building reaction of polyketide biosynthesis. The KS-catalyzed reaction involves two discrete steps consisting of formation of an acyl-enzyme intermediate generated from the incoming acylthioester substrate and an active site cysteine residue, and the conversion of this intermediate to the beta-ketoacyl-acyl carrier protein product by a decarboxylative condensation with a paired methylmalonyl-SACP. We have determined the rate constants for the individual biochemical steps by a combination of protein acylation and transthioesterification experiments. The first-order rate constant (k(2)) for formation of the acyl-enzyme intermediate from [1-(14)C]-(2S,3R)-2-methyl-3-hydroxypentanoyl-SNAC (2) and recombinant DEBS module 2 is 5.8 +/- 2.6 min(-)(1), with a dissociation constant (K(S)) of 3.5 +/- 2.8 mM. The acyl-enzyme adduct was formed at a near-stoichiometric ratio of approximately 0.8:1. Transthioesterification between unlabeled diketide-SNAC 2 and N-[1-(14)C-acetyl]cysteamine gave a k(exch) of 0.15 +/- 0.06 min(-)(1), with a K(m) for HSNAC of 5.7 +/- 4.9 mM and a K(m) for 2 of 5.3 +/- 0.9 mM. Under the conditions that were used, k(exch) was equal to k(-)(2), the first-order rate constant for reversal of the acyl-enzyme-forming reaction. Since the rate of the decarboxylative condensation is much greater that the rate of reversion to the starting material (k(3) > k(-)(2)), formation of the acyl-enzyme adduct is effectively irreversible, thereby establishing that the observed value of the specificity constant (k(cat)/K(m)) is solely a reflection of the intrinsic substrate specificity of the KS-catalyzed acyl-enzyme-forming reaction. These findings were also extended to a panel of diketide- and triketide-SNAC analogues, revealing that some substrate analogues that are not converted to product by DEBS module 2 form dead

  4. Addressing viral resistance through vaccines

    PubMed Central

    Laughlin, Catherine; Schleif, Amanda; Heilman, Carole A

    2015-01-01

    Antimicrobial resistance is a serious healthcare concern affecting millions of people around the world. Antiviral resistance has been viewed as a lesser threat than antibiotic resistance, but it is important to consider approaches to address this growing issue. While vaccination is a logical strategy, and has been shown to be successful many times over, next generation viral vaccines with a specific goal of curbing antiviral resistance will need to clear several hurdles including vaccine design, evaluation and implementation. This article suggests that a new model of vaccination may need to be considered: rather than focusing on public health, this model would primarily target sectors of the population who are at high risk for complications from certain infections. PMID:26604979

  5. The Ubiquitin Receptor DA1 Regulates Seed and Organ Size by Modulating the Stability of the Ubiquitin-Specific Protease UBP15/SOD2 in Arabidopsis[W

    PubMed Central

    Du, Liang; Li, Na; Chen, Liangliang; Xu, Yingxiu; Li, Yu; Zhang, Yueying; Li, Chuanyou; Li, Yunhai

    2014-01-01

    Although the control of organ size is a fundamental question in developmental biology, little is known about the genetic and molecular mechanisms that determine the final size of seeds in plants. We previously demonstrated that the ubiquitin receptor DA1 acts synergistically with the E3 ubiquitin ligases DA2 and ENHANCER1 OF DA1 (EOD1)/BIG BROTHER to restrict seed growth in Arabidopsis thaliana. Here, we describe UBIQUITIN-SPECIFIC PROTEASE15 (UBP15), encoded by SUPPRESSOR2 OF DA1 (SOD2), which acts maternally to regulate seed size by promoting cell proliferation in the integuments of ovules and developing seeds. The sod2/ubp15 mutants form small seeds, while overexpression of UBP15 increases seed size of wild-type plants. Genetic analyses indicate that UBP15 functions antagonistically in a common pathway with DA1 to influence seed size, but does so independently of DA2 and EOD1. Further results reveal that DA1 physically associates with UBP15 in vitro and in vivo and modulates the stability of UBP15. Therefore, our findings establish a genetic and molecular framework for the regulation of seed size by four ubiquitin-related proteins DA1, DA2, EOD1, and UBP15 and suggest that they are promising targets for increasing seed size in crops. PMID:24585836

  6. The amygdala's response to face and emotional information and potential category-specific modulation of temporal cortex as a function of emotion.

    PubMed

    White, Stuart F; Adalio, Christopher; Nolan, Zachary T; Yang, Jiongjiong; Martin, Alex; Blair, James R

    2014-01-01

    The amygdala has been implicated in the processing of emotion and animacy information and to be responsive to novelty. However, the way in which these functions interact is poorly understood. Subjects (N = 30) viewed threatening or neutral images that could be either animate (facial expressions) or inanimate (objects) in the context of a dot probe task. The amygdala showed responses to both emotional and animacy information, but no emotion by stimulus-type interaction; i.e., emotional face and object stimuli, when matched for arousal and valence, generate comparable amygdala activity relative to neutral face and object stimuli. Additionally, a habituation effect was not seen in amygdala; however, increased amygdala activity was observed for incongruent relative to congruent negative trials in second vs. first exposures. Furthermore, medial fusiform gyrus showed increased response to inanimate stimuli, while superior temporal sulcus showed increased response to animate stimuli. Greater functional connectivity between bilateral amygdala and medial fusiform gyrus was observed to negative vs. neutral objects, but not to fearful vs. neutral faces. The current data suggest that the amygdala is responsive to animate and emotional stimuli. Additionally, these data suggest that the interaction between the various functions of the amygdala may need to be considered simultaneously to fully understand how they interact. Moreover, they suggest category-specific modulation of medial fusiform cortex as a function of emotion. PMID:25309390

  7. Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart

    PubMed Central

    Ylä-Herttuala, Seppo; Betsholtz, Christer; Andrae, Johanna

    2016-01-01

    Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFRα and PDGFRβ) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRα agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFRα-positive fibroblasts, PDGFRβ agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirus-induced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses. PMID:27513343

  8. Filamin A-interacting protein (FILIP) is a region-specific modulator of myosin 2b and controls spine morphology and NMDA receptor accumulation

    PubMed Central

    Yagi, Hideshi; Nagano, Takashi; Xie, Min-Jue; Ikeda, Hiroshi; Kuroda, Kazuki; Komada, Munekazu; Iguchi, Tokuichi; Tariqur, Rahman M.; Morikubo, Soichi; Noguchi, Koichi; Murase, Kazuyuki; Okabe, Masaru; Sato, Makoto

    2014-01-01

    Learning and memory depend on morphological and functional changes to neural spines. Non-muscle myosin 2b regulates actin dynamics downstream of long-term potentiation induction. However, the mechanism by which myosin 2b is regulated in the spine has not been fully elucidated. Here, we show that filamin A-interacting protein (FILIP) is involved in the control of neural spine morphology and is limitedly expressed in the brain. FILIP bound near the ATPase domain of non-muscle myosin heavy chain IIb, an essential component of myosin 2b, and modified the function of myosin 2b by interfering with its actin-binding activity. In addition, FILIP altered the subcellular distribution of myosin 2b in spines. Moreover, subunits of the NMDA receptor were differently distributed in FILIP-expressing neurons, and excitation propagation was altered in FILIP-knockout mice. These results indicate that FILIP is a novel, region-specific modulator of myosin 2b. PMID:25220605

  9. Isoform-specific modulation of the chemical sensitivity of conserved TRPA1 channel in the major honeybee ectoparasitic mite, Tropilaelaps mercedesae

    PubMed Central

    Dong, Xiaofeng; Kashio, Makiko; Peng, Guangda; Wang, Xinyue; Tominaga, Makoto

    2016-01-01

    We identified and characterized the TRPA1 channel of Tropilaelaps mercedesae (TmTRPA1), one of two major species of honeybee ectoparasitic mite. Three TmTRPA1 isoforms with unique N-terminal sequences were activated by heat, and the isoform highly expressed in the mite's front legs, TmTRPA1b, was also activated by 27 plant-derived compounds including electrophiles. This suggests that the heat- and electrophile-dependent gating mechanisms as nocisensitive TRPA1 channel are well conserved between arthropod species. Intriguingly, one TmTRPA1 isoform, TmTRPA1a, was activated by only six compounds compared with two other isoforms, demonstrating that the N-terminal sequences are critical determinants for the chemical sensitivity. This is the first example of isoform-specific modulation of chemical sensitivity of TRPA1 channel in one species. α-terpineol showed repellent activity towards T. mercedesae in a laboratory assay and repressed T. mercedesae entry for reproduction into the brood cells with fifth instar larvae in hives. Thus, α-terpineol could be used as the potential compound to control two major honeybee ectoparasitic mites, T. mercedesae and Varroa destructor, in the apiculture industry. PMID:27307515

  10. Filamin A-interacting protein (FILIP) is a region-specific modulator of myosin 2b and controls spine morphology and NMDA receptor accumulation.

    PubMed

    Yagi, Hideshi; Nagano, Takashi; Xie, Min-Jue; Ikeda, Hiroshi; Kuroda, Kazuki; Komada, Munekazu; Iguchi, Tokuichi; Tariqur, Rahman M; Morikubo, Soichi; Noguchi, Koichi; Murase, Kazuyuki; Okabe, Masaru; Sato, Makoto

    2014-01-01

    Learning and memory depend on morphological and functional changes to neural spines. Non-muscle myosin 2b regulates actin dynamics downstream of long-term potentiation induction. However, the mechanism by which myosin 2b is regulated in the spine has not been fully elucidated. Here, we show that filamin A-interacting protein (FILIP) is involved in the control of neural spine morphology and is limitedly expressed in the brain. FILIP bound near the ATPase domain of non-muscle myosin heavy chain IIb, an essential component of myosin 2b, and modified the function of myosin 2b by interfering with its actin-binding activity. In addition, FILIP altered the subcellular distribution of myosin 2b in spines. Moreover, subunits of the NMDA receptor were differently distributed in FILIP-expressing neurons, and excitation propagation was altered in FILIP-knockout mice. These results indicate that FILIP is a novel, region-specific modulator of myosin 2b. PMID:25220605

  11. Isoform-specific modulation of the chemical sensitivity of conserved TRPA1 channel in the major honeybee ectoparasitic mite, Tropilaelaps mercedesae.

    PubMed

    Dong, Xiaofeng; Kashio, Makiko; Peng, Guangda; Wang, Xinyue; Tominaga, Makoto; Kadowaki, Tatsuhiko

    2016-06-01

    We identified and characterized the TRPA1 channel of Tropilaelaps mercedesae (TmTRPA1), one of two major species of honeybee ectoparasitic mite. Three TmTRPA1 isoforms with unique N-terminal sequences were activated by heat, and the isoform highly expressed in the mite's front legs, TmTRPA1b, was also activated by 27 plant-derived compounds including electrophiles. This suggests that the heat- and electrophile-dependent gating mechanisms as nocisensitive TRPA1 channel are well conserved between arthropod species. Intriguingly, one TmTRPA1 isoform, TmTRPA1a, was activated by only six compounds compared with two other isoforms, demonstrating that the N-terminal sequences are critical determinants for the chemical sensitivity. This is the first example of isoform-specific modulation of chemical sensitivity of TRPA1 channel in one species. α-terpineol showed repellent activity towards T. mercedesae in a laboratory assay and repressed T. mercedesae entry for reproduction into the brood cells with fifth instar larvae in hives. Thus, α-terpineol could be used as the potential compound to control two major honeybee ectoparasitic mites, T. mercedesae and Varroa destructor, in the apiculture industry. PMID:27307515

  12. Cell wall-associated ROOT HAIR SPECIFIC 10, a proline-rich receptor-like kinase, is a negative modulator of Arabidopsis root hair growth.

    PubMed

    Hwang, Youra; Lee, Hyodong; Lee, Young-Sook; Cho, Hyung-Taeg

    2016-03-01

    Plant cell growth is restricted by the cell wall, and cell wall dynamics act as signals for the cytoplasmic and nuclear events of cell growth. Among various receptor kinases, ROOT HAIR SPECIFIC 10 (RHS10) belongs to a poorly known receptor kinase subfamily with a proline-rich extracellular domain. Here, we report that RHS10 defines the root hair length of Arabidopsis thaliana by negatively regulating hair growth. RHS10 modulates the duration of root hair growth rather than the growth rate. As poplar and rice RHS10 orthologs also showed a root hair-inhibitory function, this receptor kinase-mediated function appears to be conserved in angiosperms. RHS10 showed a strong association with the cell wall, most probably through its extracellular proline-rich domain (ECD). Deletion analysis of the ECD demonstrated that a minimal extracellular part, which includes a few proline residues, is required for RHS10-mediated root hair inhibition. RHS10 suppressed the accumulation of reactive oxygen species (ROS) in the root, which are necessary for root hair growth. A yeast two-hybrid screening identified an RNase (RNS2) as a putative downstream target of RHS10. Accordingly, RHS10 overexpression decreased and RHS10 loss increased RNA levels in the hair-growing root region. Our results suggest that RHS10 mediates cell wall-associated signals to maintain proper root hair length, at least in part by regulating RNA catabolism and ROS accumulation. PMID:26884603

  13. Cell wall-associated ROOT HAIR SPECIFIC 10, a proline-rich receptor-like kinase, is a negative modulator of Arabidopsis root hair growth

    PubMed Central

    Hwang, Youra; Lee, Hyodong; Lee, Young-Sook; Cho, Hyung-Taeg

    2016-01-01

    Plant cell growth is restricted by the cell wall, and cell wall dynamics act as signals for the cytoplasmic and nuclear events of cell growth. Among various receptor kinases, ROOT HAIR SPECIFIC 10 (RHS10) belongs to a poorly known receptor kinase subfamily with a proline-rich extracellular domain. Here, we report that RHS10 defines the root hair length of Arabidopsis thaliana by negatively regulating hair growth. RHS10 modulates the duration of root hair growth rather than the growth rate. As poplar and rice RHS10 orthologs also showed a root hair-inhibitory function, this receptor kinase-mediated function appears to be conserved in angiosperms. RHS10 showed a strong association with the cell wall, most probably through its extracellular proline-rich domain (ECD). Deletion analysis of the ECD demonstrated that a minimal extracellular part, which includes a few proline residues, is required for RHS10-mediated root hair inhibition. RHS10 suppressed the accumulation of reactive oxygen species (ROS) in the root, which are necessary for root hair growth. A yeast two-hybrid screening identified an RNase (RNS2) as a putative downstream target of RHS10. Accordingly, RHS10 overexpression decreased and RHS10 loss increased RNA levels in the hair-growing root region. Our results suggest that RHS10 mediates cell wall-associated signals to maintain proper root hair length, at least in part by regulating RNA catabolism and ROS accumulation. PMID:26884603

  14. Spatial Light Amplifier Modulators

    NASA Technical Reports Server (NTRS)

    Eng, Sverre T.; Olsson, N. Anders

    1992-01-01

    Spatial light amplifier modulators (SLAM's) are conceptual devices that effect two-dimensional spatial modulation in optical computing and communication systems. Unlike current spatial light modulators, these provide gain. Optical processors incorporating SLAM's designed to operate in reflection or transmission mode. Each element of planar SLAM array is optical amplifier - surface-emitting diode laser. Array addressed electrically with ac modulating signals superimposed on dc bias currents supplied to lasers. SLAM device provides both desired modulation and enough optical gain to enable splitting of output signal into many optical fibers without excessive loss of power.

  15. The Dilated Cardiomyopathy-Causing Mutation ACTC E361G in Cardiac Muscle Myofibrils Specifically Abolishes Modulation of Ca2+ Regulation by Phosphorylation of Troponin I

    PubMed Central

    Vikhorev, Petr G.; Song, Weihua; Wilkinson, Ross; Copeland, O’Neal; Messer, Andrew E.; Ferenczi, Michael A.; Marston, Steven B.

    2014-01-01

    Phosphorylation of troponin I by protein kinase A (PKA) reduces Ca2+ sensitivity and increases the rate of Ca2+ release from troponin C and the rate of relaxation in cardiac muscle. In vitro experiments indicate that mutations that cause dilated cardiomyopathy (DCM) uncouple this modulation, but this has not been demonstrated in an intact contractile system. Using a Ca2+-jump protocol, we measured the effect of the DCM-causing mutation ACTC E361G on the equilibrium and kinetic parameters of Ca2+ regulation of contractility in single transgenic mouse heart myofibrils. We used propranolol treatment of mice to reduce the level of troponin I and myosin binding protein C (MyBP-C) phosphorylation in their hearts before isolating the myofibrils. In nontransgenic mouse myofibrils, the Ca2+ sensitivity of force was increased, the fast relaxation phase rate constant, kREL, was reduced, and the length of the slow linear phase, tLIN, was increased when the troponin I phosphorylation level was reduced from 1.02 to 0.3 molPi/TnI (EC50 P/unP = 1.8 ± 0.2, p < 0.001). Native myofibrils from ACTC E361G transgenic mice had a 2.4-fold higher Ca2+ sensitivity than nontransgenic mouse myofibrils. Strikingly, the Ca2+ sensitivity and relaxation parameters of ACTC E361G myofibrils did not depend on the troponin I phosphorylation level (EC50 P/unP = 0.88 ± 0.17, p = 0.39). Nevertheless, modulation of the Ca2+ sensitivity of ACTC E361G myofibrils by sarcomere length or EMD57033 was indistinguishable from that of nontransgenic myofibrils. Overall, EC50 measured in different conditions varied over a 7-fold range. The time course of relaxation, as defined by tLIN and kREL, was correlated with EC50 but varied by just 2.7- and 3.3-fold, respectively. Our results confirm that troponin I phosphorylation specifically alters the Ca2+ sensitivity of isometric tension and the time course of relaxation in cardiac muscle myofibrils. Moreover, the DCM-causing mutation ACTC E361G blunts this

  16. Tfap2a Promotes Specification and Maturation of Neurons in the Inner Ear through Modulation of Bmp, Fgf and Notch Signaling

    PubMed Central

    Kantarci, Husniye; Edlund, Renee K.; Groves, Andrew K.; Riley, Bruce B.

    2015-01-01

    Neurons of the statoacoustic ganglion (SAG) transmit auditory and vestibular information from the inner ear to the hindbrain. SAG neuroblasts originate in the floor of the otic vesicle. New neuroblasts soon delaminate and migrate towards the hindbrain while continuing to proliferate, a phase known as transit amplification. SAG cells eventually come to rest between the ear and hindbrain before terminally differentiating. Regulation of these events is only partially understood. Fgf initiates neuroblast specification within the ear. Subsequently, Fgf secreted by mature SAG neurons exceeds a maximum threshold, serving to terminate specification and delay maturation of transit-amplifying cells. Notch signaling also limits SAG development, but how it is coordinated with Fgf is unknown. Here we show that transcription factor Tfap2a coordinates multiple signaling pathways to promote neurogenesis in the zebrafish inner ear. In both zebrafish and chick, Tfap2a is expressed in a ventrolateral domain of the otic vesicle that includes neurogenic precursors. Functional studies were conducted in zebrafish. Loss of Tfap2a elevated Fgf and Notch signaling, thereby inhibiting SAG specification and slowing maturation of transit-amplifying cells. Conversely, overexpression of Tfap2a inhibited Fgf and Notch signaling, leading to excess and accelerated SAG production. However, most SAG neurons produced by Tfap2a overexpression died soon after maturation. Directly blocking either Fgf or Notch caused less dramatic acceleration of SAG development without neuronal death, whereas blocking both pathways mimicked all observed effects of Tfap2a overexpression, including apoptosis of mature neurons. Analysis of genetic mosaics showed that Tfap2a acts non-autonomously to inhibit Fgf. This led to the discovery that Tfap2a activates expression of Bmp7a, which in turn inhibits both Fgf and Notch signaling. Blocking Bmp signaling reversed the effects of overexpressing Tfap2a. Together, these data

  17. Tfap2a promotes specification and maturation of neurons in the inner ear through modulation of Bmp, Fgf and notch signaling.

    PubMed

    Kantarci, Husniye; Edlund, Renee K; Groves, Andrew K; Riley, Bruce B

    2015-03-01

    Neurons of the statoacoustic ganglion (SAG) transmit auditory and vestibular information from the inner ear to the hindbrain. SAG neuroblasts originate in the floor of the otic vesicle. New neuroblasts soon delaminate and migrate towards the hindbrain while continuing to proliferate, a phase known as transit amplification. SAG cells eventually come to rest between the ear and hindbrain before terminally differentiating. Regulation of these events is only partially understood. Fgf initiates neuroblast specification within the ear. Subsequently, Fgf secreted by mature SAG neurons exceeds a maximum threshold, serving to terminate specification and delay maturation of transit-amplifying cells. Notch signaling also limits SAG development, but how it is coordinated with Fgf is unknown. Here we show that transcription factor Tfap2a coordinates multiple signaling pathways to promote neurogenesis in the zebrafish inner ear. In both zebrafish and chick, Tfap2a is expressed in a ventrolateral domain of the otic vesicle that includes neurogenic precursors. Functional studies were conducted in zebrafish. Loss of Tfap2a elevated Fgf and Notch signaling, thereby inhibiting SAG specification and slowing maturation of transit-amplifying cells. Conversely, overexpression of Tfap2a inhibited Fgf and Notch signaling, leading to excess and accelerated SAG production. However, most SAG neurons produced by Tfap2a overexpression died soon after maturation. Directly blocking either Fgf or Notch caused less dramatic acceleration of SAG development without neuronal death, whereas blocking both pathways mimicked all observed effects of Tfap2a overexpression, including apoptosis of mature neurons. Analysis of genetic mosaics showed that Tfap2a acts non-autonomously to inhibit Fgf. This led to the discovery that Tfap2a activates expression of Bmp7a, which in turn inhibits both Fgf and Notch signaling. Blocking Bmp signaling reversed the effects of overexpressing Tfap2a. Together, these data

  18. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts.

    PubMed

    Gerber, David E; Hao, Guiyang; Watkins, Linda; Stafford, Jason H; Anderson, Jon; Holbein, Blair; Öz, Orhan K; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with (111)In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of (111)In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of (111)In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of (111)In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, (111)In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of (111)In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings. PMID:26550540

  19. Green tea epigallocatechin-3-gallate modulates differentiation of naïve CD4⁺ T cells into specific lineage effector cells.

    PubMed

    Wang, Junpeng; Pae, Munkyong; Meydani, Simin Nikbin; Wu, Dayong

    2013-04-01

    CD4(+) T helper (Th) subsets Th1, Th9, and Th17 cells are implicated in inducing autoimmunity whereas regulatory T cells (Treg) have a protective effect. We and others have previously shown that epigallocatechin-3-gallate (EGCG) attenuates experimental autoimmune encephalomyelitis (EAE) and alters CD4(+) T cell subpopulations. In this study, we investigated how EGCG impacts differentiation of naïve CD4(+) T cells into different effector lineages and report that EGCG impeded Th1, Th9, and Th17 differentiation and prevented IL-6-induced suppression of Treg development. We further showed that EGCG inhibited T-bet, PU.1, and RORγt, the specific transcription factors for Th1, Th9, and Th17 differentiation, respectively. These effects, in turn, may be mediated by EGCG-induced downregulation of transducers p-STAT1 and p-STAT4 for Th1, and p-STAT3 for Th17. EGCG-induced change in Th17/Treg balance may be mediated by its inhibition of IL-6 signaling because EGCG inhibited soluble IL-6R, membrane gp130, and IL-6-induced phosphorylation of STAT3. This notion was further supported by the in vivo results showing inhibited IL-6 and soluble IL-6R but increased soluble gp130 levels in plasma from EAE mice fed EGCG. Together, our results suggest that EGCG modulates development of CD4(+) T cell lineages through impacting their respective and interactive regulatory networks ultimately leading to an attenuated autoimmune response. PMID:23064699

  20. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

    PubMed Central

    Gerber, David E; Hao, Guiyang; Watkins, Linda; Stafford, Jason H; Anderson, Jon; Holbein, Blair; Öz, Orhan K; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with 111In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of 111In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of 111In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of 111In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, 111In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of 111In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings. PMID:26550540

  1. Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1

    PubMed Central

    Yu, Xiaoliang; Li, Yun; Chen, Qin; Su, Chenhe; Zhang, Zili; Yang, Chengkui; Hu, Zhilin; Hou, Jue; Zhou, Jinying; Gong, Ling; Jiang, Xuejun

    2015-01-01

    ABSTRACT Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells. IMPORTANCE This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV. PMID:26559832

  2. Patient-specific quality assurance for the delivery of 60Co intensity modulated radiation therapy subject to a 0.35 T lateral magnetic field

    PubMed Central

    Li, H. Harold; Rodriguez, Vivian L.; Green, Olga L.; Hu, Yanle; Kashani, Rojano; Wooten, H. Omar; Yang, Deshan; Mutic, Sasa

    2014-01-01

    Purpose This work describes a patient-specific dosimetry quality assurance (QA) program for intensity modulated radiation therapy (IMRT) using ViewRay, the first commercial magnetic resonance imaging guided radiation therapy device. Methods and materials The program consisted of the following components: 1) one-dimensional multipoint ionization chamber measurement using a customized 15 cm3 cubic phantom, 2) two-dimensional (2D) radiographic film measurement using a 30×30×20 cm3 phantom with multiple inserted ionization chambers, 3) quasi- three-dimensional (3D) diode array (ArcCHECK) measurement with a centrally inserted ionization chamber, 4) 2D fluence verification using machine delivery log files, and 5) 3D Monte-Carlo (MC) dose reconstruction with machine delivery files and phantom CT. Results The ionization chamber measurements agreed well with treatment planning system (TPS) computed doses in all phantom geometries where the mean difference (mean ± SD) was 0.0% ± 1.3% (n=102, range, −3.0 % to 2.9%). The film measurements also showed excellent agreement with the TPS computed 2D dose distributions where the mean passing rate using 3% relative/3 mm gamma criteria was 94.6% ± 3.4% (n=30, range, 87.4% to 100%). For ArcCHECK measurements, the mean passing rate using 3% relative/3 mm gamma criteria was 98.9% ± 1.1% (n=34, range, 95.8% to 100%). 2D fluence maps with a resolution of 1×1 mm2 showed 100% passing rates for all plan deliveries (n=34). The MC reconstructed doses to the phantom agreed well with planned 3D doses where the mean passing rate using 3% absolute/3 mm gamma criteria was 99.0% ± 1.0% (n=18, range, 97.0% to100%), demonstrating the feasibility of evaluating the QA results in the patient geometry. Conclusions We have developed a dosimetry program for ViewRay’s patient-specific IMRT QA. The methodology will be useful for other ViewRay users. The QA results presented here can assist the RT community to establish appropriate tolerance and

  3. Patient-Specific Quality Assurance for the Delivery of {sup 60}Co Intensity Modulated Radiation Therapy Subject to a 0.35-T Lateral Magnetic Field

    SciTech Connect

    Li, H. Harold Rodriguez, Vivian L.; Green, Olga L.; Hu, Yanle; Kashani, Rojano; Wooten, H. Omar; Yang, Deshan; Mutic, Sasa

    2015-01-01

    Purpose: This work describes a patient-specific dosimetry quality assurance (QA) program for intensity modulated radiation therapy (IMRT) using ViewRay, the first commercial magnetic resonance imaging-guided RT device. Methods and Materials: The program consisted of: (1) a 1-dimensional multipoint ionization chamber measurement using a customized 15-cm{sup 3} cube-shaped phantom; (2) 2-dimensional (2D) radiographic film measurement using a 30- × 30- × 20-cm{sup 3} phantom with multiple inserted ionization chambers; (3) quasi-3D diode array (ArcCHECK) measurement with a centrally inserted ionization chamber; (4) 2D fluence verification using machine delivery log files; and (5) 3D Monte Carlo (MC) dose reconstruction with machine delivery files and phantom CT. Results: Ionization chamber measurements agreed well with treatment planning system (TPS)-computed doses in all phantom geometries where the mean ± SD difference was 0.0% ± 1.3% (n=102; range, −3.0%-2.9%). Film measurements also showed excellent agreement with the TPS-computed 2D dose distributions where the mean passing rate using 3% relative/3 mm gamma criteria was 94.6% ± 3.4% (n=30; range, 87.4%-100%). For ArcCHECK measurements, the mean ± SD passing rate using 3% relative/3 mm gamma criteria was 98.9% ± 1.1% (n=34; range, 95.8%-100%). 2D fluence maps with a resolution of 1 × 1 mm{sup 2} showed 100% passing rates for all plan deliveries (n=34). The MC reconstructed doses to the phantom agreed well with planned 3D doses where the mean passing rate using 3% absolute/3 mm gamma criteria was 99.0% ± 1.0% (n=18; range, 97.0%-100%), demonstrating the feasibility of evaluating the QA results in the patient geometry. Conclusions: We developed a dosimetry program for ViewRay's patient-specific IMRT QA. The methodology will be useful for other ViewRay users. The QA results presented here can assist the RT community to establish appropriate tolerance and action limits for View

  4. A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms.

    PubMed

    Fantasia, Francesca; Di Capua, Emma Nora; Cenfra, Natalia; Pessina, Gloria; Mecarocci, Sergio; Rago, Angela; Cotroneo, Ettore; Busanello, Anna; Equitani, Francesco; Lo-Coco, Francesco; Nervi, Clara; Cimino, Giuseppe

    2014-04-01

    In Ph- myeloproliferative neoplasms, the quantification of the JAK2V617F transcripts may provide some advantages over the DNA allele burden determination. We developed a q-RT-PCR to assess the JAK2WT and JAK2V617F mRNA expression in 105 cases (23 donors, 13 secondary polycythemia, 22 polycythemia vera (PV), 38 essential thrombocythemia (ET), and 9 primary myelofibrosis (PMF)). Compared with the standard allele-specific oligonucleotide (ASO)-PCR technique, our assay showed a 100 % concordance rate detecting the JAK2V617F mutation in 22/22 PV (100 %), 29/38 (76.3 %) ET, and 5/9 (55.5 %) PMF cases, respectively. The sensitivity of the assay was 0.01 %. Comparing DNA and RNA samples, we found that the JAK2V617F mutational ratios were significantly higher at the RNA level both in PV (p = 0.005) and ET (p = 0.001) samples. In PV patients, JAK2WT expression levels positively correlated with the platelets (PLTs) (p = 0.003) whereas a trend to negative correlation was observed with the Hb levels (p = 0.051). JAK2V617F-positive cases showed the lowest JAK2WT and ABL1 mRNA expression levels. In all the samples, the expression pattern of beta-glucoronidase (GUSB) was more homogeneous than that of ABL1 or β2 microglobulin (B2M). Using GUSB as normalizator gene, a significant increase of the JAK2V617F mRNA levels was seen in two ET patients at time of progression to PV. In conclusion, the proposed q-RT-PCR is a sensitive and accurate method to quantify the JAK2 mutational status that can also show clinical correlations suggesting the impact of the residual amount of the JAK2WT allele on the Ph- MPN disease phenotype. Our observations also preclude the use of ABL1 as a housekeeping gene for these neoplasms. PMID:24173087

  5. 2014 ASHG Awards and Addresses

    PubMed Central

    2015-01-01

    Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of The Society and a number of award winners. A summary of each of these addresses is given below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, the Curt Stern Award, and the Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.

  6. 2013 ASHG Awards and Addresses

    PubMed Central

    2014-01-01

    Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of The Society and a number of award winners. A summary of each of these addresses is given below. On the following pages, we have printed the Presidential Address and the addresses for the William Allan Award, the Curt Stern Award, and the Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.

  7. Comparison of Gafchromic EBT2 and EBT3 for patient-specific quality assurance: Cranial stereotactic radiosurgery using volumetric modulated arc therapy with multiple noncoplanar arcs

    SciTech Connect

    Fiandra, Christian; Fusella, Marco; Filippi, Andrea Riccardo; Ricardi, Umberto; Ragona, Riccardo; Giglioli, Francesca Romana; Mantovani, Cristina

    2013-08-15

    Purpose: Patient-specific quality assurance in volumetric modulated arc therapy (VMAT) brain stereotactic radiosurgery raises specific issues on dosimetric procedures, mainly represented by the small radiation fields associated with the lack of lateral electronic equilibrium, the need of small detectors and the high dose delivered (up to 30 Gy). Gafchromic{sup TM} EBT2 and EBT3 films may be considered the dosimeter of choice, and the authors here provide some additional data about uniformity correction for this new generation of radiochromic films.Methods: A new analysis method using blue channel for marker dye correction was proposed for uniformity correction both for EBT2 and EBT3 films. Symmetry, flatness, and field-width of a reference field were analyzed to provide an evaluation in a high-spatial resolution of the film uniformity for EBT3. Absolute doses were compared with thermoluminescent dosimeters (TLD) as baseline. VMAT plans with multiple noncoplanar arcs were generated with a treatment planning system on a selected pool of eleven patients with cranial lesions and then recalculated on a water-equivalent plastic phantom by Monte Carlo algorithm for patient-specific QA. 2D quantitative dose comparison parameters were calculated, for the computed and measured dose distributions, and tested for statistically significant differences.Results: Sensitometric curves showed a different behavior above dose of 5 Gy for EBT2 and EBT3 films; with the use of inhouse marker-dye correction method, the authors obtained values of 2.5% for flatness, 1.5% of symmetry, and a field width of 4.8 cm for a 5 × 5 cm{sup 2} reference field. Compared with TLD and selecting a 5% dose tolerance, the percentage of points with ICRU index below 1 was 100% for EBT2 and 83% for EBT3. Patients analysis revealed statistically significant differences (p < 0.05) between EBT2 and EBT3 in the percentage of points with gamma values <1 (p= 0.009 and p= 0.016); the percent difference as well as

  8. Rational Rhymes for Addressing Common Childhood Issues

    ERIC Educational Resources Information Center

    Warren, Jeffrey M.

    2011-01-01

    Music-based interventions are valuable tools counselors can use when working with children. Specific types of music-based interventions, such as songs or rhymes, can be especially pertinent in addressing the thoughts, feelings, and behaviors of children. Rational-emotive behavior therapy (REBT) provides a therapeutic framework that encourages…

  9. Addressing neurological disorders with neuromodulation.

    PubMed

    Oluigbo, Chima O; Rezai, Ali R

    2011-07-01

    Neurological disorders are becoming increasingly common in developed countries as a result of the aging population. In spite of medications, these disorders can result in progressive loss of function as well as chronic physical, cognitive, and emotional disability that ultimately places enormous emotional and economic on the patient, caretakers, and the society in general. Neuromodulation is emerging as a therapeutic option in these patients. Neuromodulation is a field, which involves implantable devices that allow for the reversible adjustable application of electrical, chemical, or biological agents to the central or peripheral nervous system with the objective of altering its functioning with the objective of achieving a therapeutic or clinically beneficial effect. It is a rapidly evolving field that brings together many different specialties in the fields of medicine, materials science, computer science and technology, biomedical, and neural engineering as well as the surgical or interventional specialties. It has multiple current and emerging indications, and an enormous potential for growth. The main challenges before it are in the need for effective collaboration between engineers, basic scientists, and clinicians to develop innovations that address specific problems resulting in new devices and clinical applications. PMID:21193369

  10. 21 CFR 20.119 - Lists of names and addresses.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Lists of names and addresses. 20.119 Section 20... PUBLIC INFORMATION Availability of Specific Categories of Records § 20.119 Lists of names and addresses. Names and addresses of individuals in Food and Drug Administration records shall not be sold or...

  11. 21 CFR 20.119 - Lists of names and addresses.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Lists of names and addresses. 20.119 Section 20... PUBLIC INFORMATION Availability of Specific Categories of Records § 20.119 Lists of names and addresses. Names and addresses of individuals in Food and Drug Administration records shall not be sold or...

  12. 21 CFR 20.119 - Lists of names and addresses.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Lists of names and addresses. 20.119 Section 20... PUBLIC INFORMATION Availability of Specific Categories of Records § 20.119 Lists of names and addresses. Names and addresses of individuals in Food and Drug Administration records shall not be sold or...

  13. Addressing the Moral Agency of Culturally Specific Care Perspectives

    ERIC Educational Resources Information Center

    Johnson, Chrystal S.

    2011-01-01

    Cultural Historical Activity Theory (CHAT), as a culturally sensitive framework, realises the totality of caring in context. Few, if any, investigations into caring have articulated CHAT as a feasible mode of inquiry for inserting the cultural perspectives of both the researcher and the researched. This article elucidates CHAT as an intelligible…

  14. A Module of Human Peripheral Blood Mononuclear Cell Transcriptional Network Containing Primitive and Differentiation Markers Is Related to Specific Cardiovascular Health Variables

    PubMed Central

    Moldovan, Leni; Anghelina, Mirela; Kantor, Taylor; Jones, Desiree; Ramadan, Enass; Xiang, Yang; Huang, Kun; Kolipaka, Arunark; Malarkey, William; Ghasemzadeh, Nima; Mohler, Peter J.; Quyyumi, Arshed; Moldovan, Nicanor I.

    2014-01-01

    Peripheral blood mononuclear cells (PBMCs), including rare circulating stem and progenitor cells (CSPCs), have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their co-expressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell-associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene), defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p<0.03) with age (R2 = −0.23), vascular stiffness (R2 = −0.24), and central aortic pressure (R2 = −0.19) and positively correlated with body mass index (R2 = 0.72, in women). The co-expression of three neovascular markers was validated at the single-cell level using mRNA in situ hybridization and immunocytochemistry. The overall gene expression in this cardiovascular module was reduced by 72±22% in the patients compared with controls. However, the compactness of both modules was increased in the patients' samples, which was reflected in reduced dispersion of their nodes' degrees of connectivity, suggesting a more primitive character of the patients' CSPCs. In conclusion, our results show that the relationship between CSPCs and vascular function is encoded in modules of the PBMCs transcriptional network

  15. Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin model. Development of the SENS-IS assay.

    PubMed

    Cottrez, Françoise; Boitel, Elodie; Auriault, Claude; Aeby, Pierre; Groux, Hervé

    2015-06-01

    Analysis of genes modulated during the sensitization process either on mice (LLNA) or human (blisters) combined with data mining has allowed the definition of a comprehensive panel of sensitization biomarkers. This set of genes includes already identified markers such as the ARE family and others not yet associated with the sensitization process (the so-called SENS-IS gene subset). The expression of this set of genes has been measured on reconstituted human epidermis models (Episkin) exposed to various sensitizers and non-sensitizers. Fine analysis of their expression pattern indicates that it is the number of modulated genes rather than the intensity of up-regulation that correlates best with the sensitization potential of a chemical. Moreover, sensitizers that are weak inductors of ARE genes tend to be relevant modulators of the SENS-IS subset. By combining the expression data obtained with both gene subsets, it is now possible to identify a wide variety of sensitizers on a test system (in vitro reconstructed human epidermis) that is very similar to the in vivo situation and compatible with a large variety of test substance characteristics. PMID:25724174

  16. Electronic addressing reflective cholesteric LCD

    NASA Astrophysics Data System (ADS)

    Sorokin, Viktor M.; Sorokin, A.; Rybalochka, A.; Valyukh, S.

    2001-06-01

    Some new simple two level electronic driving circuits for the Cholesteric Reflective Displays are shown. The electronic module that consists of drivers, controller and special thermo-compensation units is described. The prototypes of ChLCD with electronic driving circuits are demonstrated.

  17. Addressing problems of employee performance.

    PubMed

    McConnell, Charles R

    2011-01-01

    Employee performance problems are essentially of 2 kinds: those that are motivational in origin and those resulting from skill deficiencies. Both kinds of problems are the province of the department manager. Performance problems differ from problems of conduct in that traditional disciplinary processes ordinarily do not apply. Rather, performance problems are addressed through educational and remedial processes. The manager has a basic responsibility in ensuring that everything reasonable is done to help each employee succeed. There are a number of steps the manager can take to address employee performance problems. PMID:21537142

  18. The Neuronal-Specific SGK1.1 (SGK1_v2) Kinase as a Transcriptional Modulator of BAG4, Brox, and PPP1CB Genes Expression

    PubMed Central

    González-Fernández, Rebeca; Ávila, Julio; Arteaga, María F.; Canessa, Cecilia M.; Martín-Vasallo, Pablo

    2015-01-01

    The Serum- and Glucocorticoid-induced Kinase 1, SGK1, exhibits a broad range of cellular functions that include regulation of the number of ion channels in plasma membrane and modulation of signaling pathways of cell survival. This diversity of functions is made possible by various regulatory processes acting upon the SGK1 gene, giving rise to various isoforms: SGK1_v1–5, each with distinct properties and distinct aminotermini that serve to target proteins to different subcellular compartments. Among cellular effects of SGK1 expression is to indirectly modulate gene transcription by phosphorylating transcriptional factors of the FOXO family. Here we examined if SGK1.1 (SGK1_v2; NM_001143676), which associates primarily to the plasma membrane, is also able to regulate gene expression. Using a differential gene expression approach we identified six genes upregulated by SGK1.1 in HeLa cells. Further analysis of transcript and protein levels validated two genes: BCL2-associated athanogene 4 (BAG-4) and Brox. The results indicate that SGK1.1 regulates gene transcription upon a different set of genes some of which participate in cell survival pathways (BAG-4) and others in intracellular vesicular traffic (Brox). PMID:25849655

  19. Module swaps between related translocator proteins pIV(f1), pIV(IKe) and PulD: identification of a specificity domain.

    PubMed

    Daefler, S; Russel, M; Model, P

    1997-03-14

    In Gram-negative bacteria, type II and type III secretion and filamentous phage assembly systems use related outer membrane proteins for substrate-specific transport across the outer membrane. We show here that the specificity domain of the phage f1 outer membrane protein pIV is contained within the 149 N-terminal amino acid residues. When the pIV(f1) specificity domain is fused to the translocator domain of the related pIV of phage IKe, the chimeric construct supports f1 but not IKe assembly. Functional coupling between the two domains in this chimeric construct is poor and is improved by a single amino acid change in the translocator domain of the pIV(IKe). In native pIV(IKe), two amino acid changes within its specificity domain are both necessary and sufficient to change the specificity from IKe to f1 assembly. Analysis of 39 chimeric constructs between pIV(f1) and the outer membrane protein PulD of the pullulanase secretion system failed to identify a comparable exchangeable specificity domain. These results indicate that the two domains may not function autonomously, and suggest that tertiary and quarternary changes of the entire translocator component rather than of an autonomous functional domain are required for specific translocation across the outer membrane. PMID:9086275

  20. Chemical Address Tags of Fluorescent Bioimaging Probes

    PubMed Central

    Shedden, Kerby; Rosania, Gus R.

    2010-01-01

    Chemical address tags can be defined as specific structural features shared by a set of bioimaging probes having a predictable influence on cell-associated visual signals obtained from these probes. Here, using a large image dataset acquired with a high content screening instrument, machine vision and cheminformatics analysis have been applied to reveal chemical address tags. With a combinatorial library of fluorescent molecules, fluorescence signal intensity, spectral, and spatial features characterizing each one of the probes' visual signals were extracted from images acquired with the three different excitation and emission channels of the imaging instrument. With multivariate regression, the additive contribution from each one of the different building blocks of the bioimaging probes towards each measured, cell-associated image-based feature was calculated. In this manner, variations in the chemical features of the molecules were associated with the resulting staining patterns, facilitating quantitative, objective analysis of chemical address tags. Hierarchical clustering and paired image-cheminformatics analysis revealed key structure-property relationships amongst many building blocks of the fluorescent molecules. The results point to different chemical modifications of the bioimaging probes that can exert similar (or different) effects on the probes' visual signals. Inspection of the clustered structures suggests intramolecular charge migration or partial charge distribution as potential mechanistic determinants of chemical address tag behavior. PMID:20104576

  1. Addressing Phonological Questions with Ultrasound

    ERIC Educational Resources Information Center

    Davidson, Lisa

    2005-01-01

    Ultrasound can be used to address unresolved questions in phonological theory. To date, some studies have shown that results from ultrasound imaging can shed light on how differences in phonological elements are implemented. Phenomena that have been investigated include transitional schwa, vowel coalescence, and transparent vowels. A study of…

  2. Communities Address Barriers to Connectivity.

    ERIC Educational Resources Information Center

    Byers, Anne

    1996-01-01

    Rural areas lag behind urban areas in access to information technologies. Public institutions play a critical role in extending the benefits of information technologies to those who would not otherwise have access. The most successful rural telecommunications plans address barriers to use, such as unawareness of the benefits, technophobia, the…

  3. Keynote Address: Rev. Mark Massa

    ERIC Educational Resources Information Center

    Massa, Mark S.

    2011-01-01

    Rev. Mark S. Massa, S.J., is the dean and professor of Church history at the School of Theology and Ministry at Boston College. He was invited to give a keynote to begin the third Catholic Higher Education Collaborative Conference (CHEC), cosponsored by Boston College and Fordham University. Fr. Massa's address posed critical questions about…

  4. State of the Lab Address

    ScienceCinema

    King, Alex

    2013-03-01

    In his third-annual State of the Lab address, Ames Laboratory Director Alex King called the past year one of "quiet but strong progress" and called for Ames Laboratory to continue to build on its strengths while responding to changing expectations for energy research.

  5. State of the Lab Address

    SciTech Connect

    King, Alex

    2010-01-01

    In his third-annual State of the Lab address, Ames Laboratory Director Alex King called the past year one of "quiet but strong progress" and called for Ames Laboratory to continue to build on its strengths while responding to changing expectations for energy research.

  6. Matching Alternative Addresses: a Semantic Web Approach

    NASA Astrophysics Data System (ADS)

    Ariannamazi, S.; Karimipour, F.; Hakimpour, F.

    2015-12-01

    Rapid development of crowd-sourcing or volunteered geographic information (VGI) provides opportunities for authoritatives that deal with geospatial information. Heterogeneity of multiple data sources and inconsistency of data types is a key characteristics of VGI datasets. The expansion of cities resulted in the growing number of POIs in the OpenStreetMap, a well-known VGI source, which causes the datasets to outdate in short periods of time. These changes made to spatial and aspatial attributes of features such as names and addresses might cause confusion or ambiguity in the processes that require feature's literal information like addressing and geocoding. VGI sources neither will conform specific vocabularies nor will remain in a specific schema for a long period of time. As a result, the integration of VGI sources is crucial and inevitable in order to avoid duplication and the waste of resources. Information integration can be used to match features and qualify different annotation alternatives for disambiguation. This study enhances the search capabilities of geospatial tools with applications able to understand user terminology to pursuit an efficient way for finding desired results. Semantic web is a capable tool for developing technologies that deal with lexical and numerical calculations and estimations. There are a vast amount of literal-spatial data representing the capability of linguistic information in knowledge modeling, but these resources need to be harmonized based on Semantic Web standards. The process of making addresses homogenous generates a helpful tool based on spatial data integration and lexical annotation matching and disambiguating.

  7. Thin-film module circuit design: Practical and reliability aspects

    NASA Technical Reports Server (NTRS)

    Daiello, R. V.; Twesme, E. N.

    1985-01-01

    This paper will address several aspects of the design and construction of submodules based on thin film amorphous silicon (a-Si) p i n solar cells. Starting from presently attainable single cell characteristics, and a realistic set of specifications, practical module designs are discussed from the viewpoints of efficient designs, the fabrication requirements, and reliability concerns. The examples center mostly on series interconnected modules of the superstrate type with detailed discussions of each portion of the structure in relation to its influence on module efficiency. Emphasis is placed on engineering topics such as: area coverage, optimal geometries, and cost and reliability. Practical constraints on achieving optimal designs, along with some examples of potential pitfalls in the manufacture and subsequent performance of a-Si modules are discussed.

  8. The Implications of Encoder/Modulator/ Phased Array Designs for Future Broadband LEO Communications

    NASA Technical Reports Server (NTRS)

    Vanderaar, Mark; Jensen, Chris A.; Terry, John D.

    1997-01-01

    In this paper we summarize the effects of modulation and channel coding on the design of wide angle scan, broadband, phased army antennas. In the paper we perform several trade studies. First, we investigate the amplifier back-off requirement as a function of variability of modulation envelope. Specifically, we contrast constant and non-constant envelope modulations, as well as single and multiple carrier schemes. Additionally, we address the issues an(f concerns of using pulse shaping filters with the above modulation types. Second, we quantify the effects of beam steering on the quality of data, recovery using selected modulation techniques. In particular, we show that the frequency response of the array introduces intersymbol interference for broadband signals and that the mode of operation for the beam steering controller may introduce additional burst or random errors. Finally, we show that the encoder/modulator design must be performed in conjunction with the phased array antenna design.

  9. Multi-port, optically addressed RAM

    NASA Technical Reports Server (NTRS)

    Johnston, Alan R. (Inventor); Nixon, Robert H. (Inventor); Bergman, Larry A. (Inventor); Esener, Sadik (Inventor)

    1989-01-01

    A random access memory addressing system utilizing optical links between memory and the read/write logic circuits comprises addressing circuits including a plurality of light signal sources, a plurality of optical gates including optical detectors associated with the memory cells, and a holographic optical element adapted to reflect and direct the light signals to the desired memory cell locations. More particularly, it is a multi-port, binary computer memory for interfacing with a plurality of computers. There are a plurality of storage cells for containing bits of binary information, the storage cells being disposed at the intersections of a plurality of row conductors and a plurality of column conductors. There is interfacing logic for receiving information from the computers directing access to ones of the storage cells. There are first light sources associated with the interfacing logic for transmitting a first light beam with the access information modulated thereon. First light detectors are associated with the storage cells for receiving the first light beam, for generating an electrical signal containing the access information, and for conducting the electrical signal to the one of the storage cells to which it is directed. There are holographic optical elements for reflecting the first light beam from the first light sources to the first light detectors.

  10. Ageing-related tissue-specific alterations in mitochondrial composition and function are modulated by dietary fat type in the rat.

    PubMed

    Quiles, José L; Martínez, Estrella; Ibáñez, Susana; Ochoa, Julio J; Martín, Yolanda; López-Frías, Magdalena; Huertas, Jesús R; Mataix, José

    2002-12-01

    This study investigated the way in which feeding rats with two fat sources (olive or sunflower oils) affected electron-transport components and function of mitotic (liver) and postmitotic (heart and skeletal muscle) tissues during ageing. Rats adapted the mitochondrial-membrane-lipid profile to dietary fat throughout the study, suggesting that the benefits to eat either of the two fats might be maintained lifelong. Liver was more resistant to dietary changes and ageing than heart and skeletal muscle, which showed higher levels of coenzyme Q, cytochrome b, and cytochrome a + a3 with ageing and lower cytochrome c oxidase and complex IV turnover. Dietary fat differentially modulated the response of tissues during ageing, with sunflower oil leading to the highest levels of coenzyme Q and cytochromes b and a + a3. Since high levels of cytochrome b have been related to increased age, it could be hypothesized that olive oil could lead to less aged mitochondria. PMID:12678443

  11. Soleus Hoffmann reflex amplitudes are specifically modulated by cutaneous inputs from the arms and opposite leg during walking but not standing.

    PubMed

    Suzuki, Shinya; Nakajima, Tsuyoshi; Futatsubashi, Genki; Mezzarane, Rinaldo A; Ohtsuka, Hiroyuki; Ohki, Yukari; Zehr, E Paul; Komiyama, Tomoyoshi

    2016-08-01

    Electrical stimulation of cutaneous nerves innervating heteronymous limbs (the arms or contralateral leg) modifies the excitability of soleus Hoffmann (H-) reflexes. The differences in the sensitivities of the H-reflex pathway to cutaneous afferents from different limbs and their modulation during the performance of motor tasks (i.e., standing and walking) are not fully understood. In the present study, we investigated changes in soleus H-reflex amplitudes induced by electrical stimulation of peripheral nerves. Selected targets for conditioning stimulation included the superficial peroneal nerve, which innervates the foot dorsum in the contralateral ankle (cSP), and the superficial radial nerve, which innervates the dorsum of the hand in the ipsilateral (iSR) or contralateral wrist (cSR). Stimulation and subsequent reflex assessment took place during the standing and early-stance phase of treadmill walking in ten healthy subjects. Cutaneous stimulation produced long-latency inhibition (conditioning-test interval of ~100 ms) of the H-reflex during the early-stance phase of walking, and the inhibition was stronger following cSP stimulation compared with iSR or cSR stimulation. In contrast, although similar conditioning stimulation significantly facilitated the H-reflex during standing, this effect remained constant irrespective of the different conditioning sites. These findings suggest that cutaneous inputs from the arms and contralateral leg had reversible effects on the H-reflex amplitudes, including inhibitions with different sensitivities during the early-stance phase of walking and facilitation during standing. Furthermore, the differential sensitivities of the H-reflex modulations were expressed only during walking when the locations of the afferent inputs were functionally relevant. PMID:27030502

  12. Modulation of Gut-Specific Mechanisms by Chronic Δ9-Tetrahydrocannabinol Administration in Male Rhesus Macaques Infected with Simian Immunodeficiency Virus: A Systems Biology Analysis

    PubMed Central

    Amedee, Angela M.; LeCapitaine, Nicole J.; Zabaleta, Jovanny; Mohan, Mahesh; Winsauer, Peter J.; Vande Stouwe, Curtis; McGoey, Robin R.; Auten, Matthew W.; LaMotte, Lynn; Chandra, Lawrance C.; Birke, Leslie L.

    2014-01-01

    Abstract Our studies have demonstrated that chronic Δ9-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4- to 6-year-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 months of chronic THC administration (0.18–0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ∼5 months postinoculation showed lower viral load, increased duodenal integrin beta 7+(β7) CD4+ and CD8+ central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified six genes that were differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified as having significant participation in (1) apoptosis, (2) cell survival, proliferation, and morphogenesis, and (3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion, and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC administration modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation. PMID:24400995

  13. Stress Modulates the Use of Spatial versus Stimulus-Response Learning Strategies in Humans

    ERIC Educational Resources Information Center

    Philippsen, Christine; Richter, Steffen; Bohringer, Andreas; Wippich, Werner; Schachinger, Hartmut; Schwabe, Lars; Oitzl, Melly S.

    2007-01-01

    Animal studies provided evidence that stress modulates multiple memory systems, favoring caudate nucleus-based "habit" memory over hippocampus-based "cognitive" memory. However, effects of stress on learning strategy and memory consolidation were not differentiated. We specifically address the effects of psychosocial stress on the applied learning…

  14. Development of training modules for magnetic particle inspection

    NASA Astrophysics Data System (ADS)

    Kosaka, Daigo; Eisenmann, David J.; Enyart, Darrel; Nakagawa, Norio; Lo, Chester; Orman, David

    2015-03-01

    Magnetic particle inspection (MPI) is a nondestructive evaluation technique used with ferromagnetic materials. Although the application of this method may appear straightforward, MPI combines the complicated nature of electromagnetics, metallurgical material effects, fluid-particle motion dynamics, and physiological human factors into a single inspection. To fully appreciate industry specifications such as ASTM E-1444, users should develop a basic understanding of the many factors that are involved in MPI. We have developed a series of MPI training modules that are aimed at addressing this requirement. The modules not only offer qualitative explanations, but also show quantitative explanations in terms of measurement and numerical simulation data in many instances. There are five modules in all. Module ♯1 shows characteristics of waveforms and magnetizing methods. This allows MPI practitioners to make optimum choice of waveform and magnetizing method. Module ♯2 explains how material properties relate to the magnetic characteristics. Module ♯3 shows the strength of the excitation field or the flux leakage from a crack and how it compares to the detectability of a crack by MPI. Module ♯4 shows how specimen status may influence defect detection. Module ♯5 shows the effects of particle properties on defect detection.

  15. Modulation of CD4+ T Cell-Dependent Specific Cytotoxic CD8+ T Cells Differentiation and Proliferation by the Timing of Increase in the Pathogen Load

    PubMed Central

    Tzelepis, Fanny; Persechini, Pedro M.; Rodrigues, Mauricio M.

    2007-01-01

    Background Following infection with viruses, bacteria or protozoan parasites, naïve antigen-specific CD8+ T cells undergo a process of differentiation and proliferation to generate effector cells. Recent evidences suggest that the timing of generation of specific effector CD8+ T cells varies widely according to different pathogens. We hypothesized that the timing of increase in the pathogen load could be a critical parameter governing this process. Methodology/Principal Findings Using increasing doses of the protozoan parasite Trypanosoma cruzi to infect C57BL/6 mice, we observed a significant acceleration in the timing of parasitemia without an increase in mouse susceptibility. In contrast, in CD8 deficient mice, we observed an inverse relationship between the parasite inoculum and the timing of death. These results suggest that in normal mice CD8+ T cells became protective earlier, following the accelerated development of parasitemia. The evaluation of specific cytotoxic responses in vivo to three distinct epitopes revealed that increasing the parasite inoculum hastened the expansion of specific CD8+ cytotoxic T cells following infection. The differentiation and expansion of T. cruzi-specific CD8+ cytotoxic T cells is in fact dependent on parasite multiplication, as radiation-attenuated parasites were unable to activate these cells. We also observed that, in contrast to most pathogens, the activation process of T. cruzi-specific CD8+ cytotoxic T cells was dependent on MHC class II restricted CD4+ T cells. Conclusions/Significance Our results are compatible with our initial hypothesis that the timing of increase in the pathogen load can be a critical parameter governing the kinetics of CD4+ T cell-dependent expansion of pathogen-specific CD8+ cytotoxic T cells. PMID:17460760

  16. Intermediate load modules for test and evaluation

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Photovoltaic modules were tested for qualification. Tests involved the following: (1) delivery of 20 solar cells for use as reference cells; (2) module documentation and inspection plans specifying the 10 Group I modules; (3) design review of module documentation from Group I modules; (4) revise module documentation to overcome any problems of deficiencies associated with the Group I modules; (5) delivery of 10 Group II modules built to revised specifications; (6) testing of Group II modules to the criteria as outlined in qualification specification. It is found that the solarvolt MSP43E40B satisfies the design criteria of qualification specification for intermediate load modules. Design changes were made in the Group I modules to overcome the deficiencies which allowed Group II modules to pass the qualification tests.

  17. International Energy Module - NEMS Documentation

    EIA Publications

    2014-01-01

    Summarizes the overall structure of the International Energy Model and its interface with other NEMS modules, mathematical specifications of behavioral relationships, and data sources and estimation methods.

  18. Is Poor Frequency Modulation Detection Linked to Literacy Problems? A Comparison of Specific Reading Disability and Mild to Moderate Sensorineural Hearing Loss

    ERIC Educational Resources Information Center

    Halliday, L. F.; Bishop, D. V. M.

    2006-01-01

    Specific reading disability (SRD) is now widely recognised as often being caused by phonological processing problems, affecting analysis of spoken as well as written language. According to one theoretical account, these phonological problems are due to low-level problems in auditory perception of dynamic acoustic cues. Evidence for this has come…

  19. Institutional patient-specific intensity-modulated radiation therapy quality assurance does not predict unacceptable plan delivery as measured by IROC Houston’s head and neck phantom

    PubMed Central

    Kry, Stephen F.; Molineu, Andrea; Kerns, James; Faught, Austin; Huang, Jessie Y.; Pulliam, Kiley; Tonigan, Jackie; Alvarez, Paola; Stingo, Francesco; Followill, David S.

    2014-01-01

    Purpose To determine whether in-house patient-specific IMRT QA results predict the Imaging and Radiation Oncology Core (IROC)-Houston phantom results. Methods and Materials IROC Houston’s IMRT head and neck phantoms have been irradiated by numerous institutions as part of clinical trial credentialing. We retrospectively compared these phantom results with those of in-house IMRT QA (following the institution’s clinical process) for 855 irradiations performed between 2003 and 2013. The sensitivity and specificity of IMRT QA to detect unacceptable or acceptable plans was determined relative to the IROC Houston phantom results. Additional analyses evaluated specific IMRT QA dosimeters and analysis methods. Results IMRT QA universally showed poor sensitivity relative to the head and neck phantom i.e., poor ability to predict a failing IROC Houston phantom result. Depending on how the IMRT QA results were interpreted, overall sensitivity ranged from 2% to 18%. For different IMRT QA methods, sensitivity ranged from 3% to 54%. Although the observed sensitivity was particularly poor at clinical thresholds (e.g., 3% dose difference or 90% of pixels passing gamma), receiver operator characteristic analysis indicated that no threshold showed good sensitivity and specificity for the devices evaluated. Conclusions IMRT QA is not a reasonable replacement for a credentialing phantom. Moreover, the particularly poor agreement between IMRT QA and the IROC Houston phantoms highlights surprising inconsistency in the QA process. PMID:25442044

  20. The (Im)possibility of the Project: Radford Address

    ERIC Educational Resources Information Center

    Green, Bill

    2010-01-01

    In this address, the author engages both with the possibility "and" the impossibility of the educational project--and suggests something of what it means to say this. His presentation is specifically addressed to the theme of the (im)possibility of the educational project. He draws from philosophy, literature, psychoanalysis and history, as well…

  1. Specific polyunsaturated fatty acids modulate lipid delivery and oocyte development in C. elegans revealed by molecular-selective label-free imaging

    PubMed Central

    Chen, Wei-Wen; Yi, Yung-Hsiang; Chien, Cheng-Hao; Hsiung, Kuei-Ching; Ma, Tian-Hsiang; Lin, Yi-Chun; Lo, Szecheng J.; Chang, Ta-Chau

    2016-01-01

    Polyunsaturated fatty acids (PUFAs) exhibit critical functions in biological systems and their importance during animal oocyte maturation has been increasingly recognized. However, the detailed mechanism of lipid transportation for oocyte development remains largely unknown. In this study, the transportation of yolk lipoprotein (lipid carrier) and the rate of lipid delivery into oocytes in live C. elegans were examined for the first time by using coherent anti-Stokes Raman scattering (CARS) microscopy. The accumulation of secreted yolk lipoprotein in the pseudocoelom of live C. elegans can be detected by CARS microscopy at both protein (~1665 cm−1) and lipid (~2845 cm−1) Raman bands. In addition, an image analysis protocol was established to quantitatively measure the levels of secreted yolk lipoprotein aberrantly accumulated in PUFA-deficient fat mutants (fat-1, fat-2, fat-3, fat-4) and PUFA-supplemented fat-2 worms (the PUFA add-back experiments). Our results revealed that the omega-6 PUFAs, not omega-3 PUFAs, play a critical role in modulating lipid/yolk level in the oocytes and regulating reproductive efficiency of C. elegans. This work demonstrates the value of using CARS microscopy as a molecular-selective label-free imaging technique for the study of PUFA regulation and oocyte development in C. elegans. PMID:27535493

  2. Xylan-specific carbohydrate-binding module belonging to family 6 enhances the catalytic performance of a GH11 endo-xylanase.

    PubMed

    Hoffmam, Zaira B; Zanphorlin, Letícia M; Cota, Junio; Diogo, José A; Almeida, Gabriela B; Damásio, André R L; Squina, Fabio; Murakami, Mario T; Ruller, Roberto

    2016-06-25

    Xylanases catalyze the hydrolysis of β-1,4-linked xylosyl moieties from xylan chains, one of the most abundant hemicellulosic polysaccharides found in plant cell walls. These enzymes can exist either as single catalytic domains or as modular proteins composed of one or more carbohydrate-binding modules (CBMs) appended to the catalytic core. However, the molecular mechanisms governing the synergistic effects between catalytic domains and their CBMs are not fully understood. Thus, the goal of this study was to evaluate the functional effects of the fusion of a CBM belonging to family 6, which exhibits high affinity to xylan, with the GH11 xylanase from Bacillus subtilis, which does not have a CBM in its wild-type form. The wild-type enzyme (BsXyl11) and the chimeric protein (BsXyl11-CBM6) were heterologously produced in Escherichia coli and purified to homogeneity for biochemical characterization. The molecular fusion did not alter the pH and temperature dependence, but kinetic data revealed an increase of 65% in the catalytic efficiency of the chimeric enzyme. Furthermore, the BsXyl11-CBM6 chimera was used to supplement the commercial cocktail Accellerase® 1500 and improved the reducing sugar release by 17% from pretreated sugarcane bagasse. These results indicate that CBM6 can be used as a molecular tool to enhance the catalytic performance of endo-xylanases (GH11) and provide a new strategy for the development of optimized biocatalysts for biotechnological applications. PMID:26923808

  3. Specific polyunsaturated fatty acids modulate lipid delivery and oocyte development in C. elegans revealed by molecular-selective label-free imaging.

    PubMed

    Chen, Wei-Wen; Yi, Yung-Hsiang; Chien, Cheng-Hao; Hsiung, Kuei-Ching; Ma, Tian-Hsiang; Lin, Yi-Chun; Lo, Szecheng J; Chang, Ta-Chau

    2016-01-01

    Polyunsaturated fatty acids (PUFAs) exhibit critical functions in biological systems and their importance during animal oocyte maturation has been increasingly recognized. However, the detailed mechanism of lipid transportation for oocyte development remains largely unknown. In this study, the transportation of yolk lipoprotein (lipid carrier) and the rate of lipid delivery into oocytes in live C. elegans were examined for the first time by using coherent anti-Stokes Raman scattering (CARS) microscopy. The accumulation of secreted yolk lipoprotein in the pseudocoelom of live C. elegans can be detected by CARS microscopy at both protein (~1665 cm(-1)) and lipid (~2845 cm(-1)) Raman bands. In addition, an image analysis protocol was established to quantitatively measure the levels of secreted yolk lipoprotein aberrantly accumulated in PUFA-deficient fat mutants (fat-1, fat-2, fat-3, fat-4) and PUFA-supplemented fat-2 worms (the PUFA add-back experiments). Our results revealed that the omega-6 PUFAs, not omega-3 PUFAs, play a critical role in modulating lipid/yolk level in the oocytes and regulating reproductive efficiency of C. elegans. This work demonstrates the value of using CARS microscopy as a molecular-selective label-free imaging technique for the study of PUFA regulation and oocyte development in C. elegans. PMID:27535493

  4. Development of a thermal storage module using modified anhydrous sodium hydroxide

    NASA Technical Reports Server (NTRS)

    Rice, R. E.; Rowny, P. E.

    1980-01-01

    The laboratory scale testing of a modified anhydrous NaOH latent heat storage concept for small solar thermal power systems such as total energy systems utilizing organic Rankine systems is discussed. A diagnostic test on the thermal energy storage module and an investigation of alternative heat transfer fluids and heat exchange concepts are specifically addressed. A previously developed computer simulation model is modified to predict the performance of the module in a solar total energy system environment. In addition, the computer model is expanded to investigate parametrically the incorporation of a second heat exchange inside the module which will vaporize and superheat the Rankine cycle power fluid.

  5. 4-Hydroxybenzoic acid derivatives as HDAC6-specific inhibitors modulating microtubular structure and HSP90α chaperone activity against prostate cancer.

    PubMed

    Seidel, Carole; Schnekenburger, Michael; Mazumder, Aloran; Teiten, Marie-Hélène; Kirsch, Gilbert; Dicato, Mario; Diederich, Marc

    2016-01-01

    Histone deacetylase (HDAC)6 is a unique isoenzyme targeting specific substrates including α-tubulin and heat shock protein (HSP)90. HDAC6 is involved in protein trafficking and degradation, cell shape and migration. Deregulation of HDAC6 activity is associated with a variety of diseases including cancer leading to a growing interest for developing HDAC6 inhibitors. Here, we identified two new structurally related 4-hydroxybenzoic acids as selective HDAC6 inhibitors reducing proliferation, colony and spheroid formation as well as viability of prostate cancer cells. Both compounds strongly enhanced α-tubulin acetylation leading to remodeling of microtubular organization. Furthermore, 4-hydroxybenzoic acids decreased HSP90α regulation of the human androgen receptor in prostate cancer cells by increasing HSP90α acetylation levels. Collectively, our data support the potential of 4-hydroxybenzoic acid derivatives as HDAC6-specific inhibitors with anti-cancer properties. PMID:26549368

  6. Structure-specific nuclease activity of RAGs is modulated by sequence, length and phase position of flanking double-stranded DNA.

    PubMed

    Kumari, Rupa; Raghavan, Sathees C

    2015-01-01

    RAGs (recombination activating genes) are responsible for the generation of antigen receptor diversity through the process of combinatorial joining of different V (variable), D (diversity) and J (joining) gene segments. In addition to its physiological property, wherein RAG functions as a sequence-specific nuclease, it can also act as a structure-specific nuclease leading to genomic instability and cancer. In the present study, we investigate the factors that regulate RAG cleavage on non-B DNA structures. We find that RAG binding and cleavage on heteroduplex DNA is dependent on the length of the double-stranded flanking region. Besides, the immediate flanking double-stranded region regulates RAG activity in a sequence-dependent manner. Interestingly, the cleavage efficiency of RAGs at the heteroduplex region is influenced by the phasing of DNA. Thus, our results suggest that sequence, length and phase positions of the DNA can affect the efficiency of RAG cleavage when it acts as a structure-specific nuclease. These findings provide novel insights on the regulation of the pathological functions of RAGs. PMID:25327637

  7. Tissue-specific expression of ghrelinergic and NUCB2/nesfatin-1 systems in goldfish (Carassius auratus) is modulated by macronutrient composition of diets.

    PubMed

    Blanco, Ayelén M; Bertucci, Juan I; Delgado, María J; Valenciano, Ana I; Unniappan, Suraj

    2016-05-01

    The macronutrient composition of diets is a very important factor in the regulation of body weight and metabolism. Several lines of research in mammals have shown that macronutrients differentially regulate metabolic hormones, including ghrelin and nesfatin-1 that have opposing effects on energy balance. This study aimed to determine whether macronutrients modulate the expression of ghrelin and the nucleobindin-2 (NUCB2) encoded nesfatin-1 in goldfish (Carassius auratus). Fish were fed once daily on control, high-carbohydrate, high-protein, high-fat and very high-fat diets for 7 (short-term) or 28 (long-term) days. The expression of preproghrelin, ghrelin O-acyl transferase (goat), growth hormone secretagogue receptor 1 (ghs-r1) and nucb2/nesfatin-1 mRNAs was quantified in the hypothalamus, pituitary, gut and liver. Short-term feeding with fat-enriched diets significantly increased nucb2 mRNA levels in hypothalamus and liver, preproghrelin, goat and ghs-r1 expression in pituitary, and ghs-r1 expression in gut. Fish fed on a high-protein diet exhibited a significant reduction in preproghrelin and ghs-r1 mRNAs in the liver. After long-term feeding, fish fed on high-carbohydrate and very high-fat diets had significantly increased preproghrelin, goat and ghs-r1 expression in pituitary. Feeding on a high-carbohydrate diet also upregulated goat and ghs-r1 transcripts in gut, while feeding on a high-fat diet elicited the same effect only for ghs-r1 in liver. Nucb2 expression increased in pituitary, while it decreased in gut after long-term feeding of a high-protein diet. Collectively, these results show for the first time in fish that macronutrients differentially regulate the expression of ghrelinergic and NUCB2/nesfatin-1 systems in central and peripheral tissues of goldfish. PMID:26805937

  8. Specific Conserved C-terminal Amino Acids of Caenorhabditis elegans HMP-1/α-Catenin Modulate F-actin Binding Independently of Vinculin*

    PubMed Central

    Maiden, Stephanie L.; Harrison, Neale; Keegan, Jack; Cain, Brian; Lynch, Allison M.; Pettitt, Jonathan; Hardin, Jeff

    2013-01-01

    Stable intercellular adhesions formed through the cadherin-catenin complex are important determinants of proper tissue architecture and help maintain tissue integrity during morphogenetic movements in developing embryos. A key regulator of this stability is α-catenin, which connects the cadherin-catenin complex to the actin cytoskeleton. Although the C-terminal F-actin-binding domain of α-catenin has been shown to be crucial for its function, a more detailed in vivo analysis of discrete regions and residues required for actin binding has not been performed. Using Caenorhabditis elegans as a model system, we have characterized mutations in hmp-1/α-catenin that identify HMP-1 residues 687–742 and 826–927, as well as amino acid 802, as critical to the localization of junctional proximal actin during epidermal morphogenesis. We also find that the S823F transition in a hypomorphic allele, hmp-1(fe4), decreases actin binding in vitro. Using hmp-1(fe4) animals in a mutagenesis screen, we were then able to identify 11 intragenic suppressors of hmp-1(fe4) that revert actin binding to wild-type levels. Using homology modeling, we show that these amino acids are positioned at key conserved sites within predicted α-helices in the C terminus. Through the use of transgenic animals, we also demonstrate that HMP-1 residues 315–494, which correspond to a putative mechanotransduction domain that binds vinculin in vertebrate αE-catenin, are not required during epidermal morphogenesis but may aid efficient recruitment of HMP-1 to the junction. Our studies are the first to identify key conserved amino acids in the C terminus of α-catenin that modulate F-actin binding in living embryos of a simple metazoan. PMID:23271732

  9. Nanoscale content-addressable memory

    NASA Technical Reports Server (NTRS)

    Davis, Bryan (Inventor); Principe, Jose C. (Inventor); Fortes, Jose (Inventor)

    2009-01-01

    A combined content addressable memory device and memory interface is provided. The combined device and interface includes one or more one molecular wire crossbar memories having spaced-apart key nanowires, spaced-apart value nanowires adjacent to the key nanowires, and configurable switches between the key nanowires and the value nanowires. The combination further includes a key microwire-nanowire grid (key MNG) electrically connected to the spaced-apart key nanowires, and a value microwire-nanowire grid (value MNG) electrically connected to the spaced-apart value nanowires. A key or value MNGs selects multiple nanowires for a given key or value.

  10. Addressing the workforce pipeline challenge

    SciTech Connect

    Leonard Bond; Kevin Kostelnik; Richard Holman

    2006-11-01

    A secure and affordable energy supply is essential for achieving U.S. national security, in continuing U.S. prosperity and in laying the foundations to enable future economic growth. To meet this goal the next generation energy workforce in the U.S., in particular those needed to support instrumentation, controls and advanced operations and maintenance, is a critical element. The workforce is aging and a new workforce pipeline, to support both current generation and new build has yet to be established. The paper reviews the challenges and some actions being taken to address this need.

  11. Identifying and Addressing Vaccine Hesitancy

    PubMed Central

    Kestenbaum, Lori A.; Feemster, Kristen A.

    2015-01-01

    In the 20th century, the introduction of multiple vaccines significantly reduced childhood morbidity, mortality, and disease outbreaks. Despite, and perhaps because of, their public health impact, an increasing number of parents and patients are choosing to delay or refuse vaccines. These individuals are described as vaccine hesitant. This phenomenon has developed due to the confluence of multiple social, cultural, political and personal factors. As immunization programs continue to expand, understanding and addressing vaccine hesitancy will be crucial to their successful implementation. This review explores the history of vaccine hesitancy, its causes, and suggested approaches for reducing hesitancy and strengthening vaccine acceptance. PMID:25875982

  12. Identifying and addressing vaccine hesitancy.

    PubMed

    Kestenbaum, Lori A; Feemster, Kristen A

    2015-04-01

    In the 20th century, the introduction of multiple vaccines significantly reduced childhood morbidity, mortality, and disease outbreaks. Despite, and perhaps because of, their public health impact, an increasing number of parents and patients are choosing to delay or refuse vaccines. These individuals are described as "vaccine hesitant." This phenomenon has developed due to the confluence of multiple social, cultural, political, and personal factors. As immunization programs continue to expand, understanding and addressing vaccine hesitancy will be crucial to their successful implementation. This review explores the history of vaccine hesitancy, its causes, and suggested approaches for reducing hesitancy and strengthening vaccine acceptance. PMID:25875982

  13. Astronaut Edgar Mitchell addresses MSC personnel and news media

    NASA Technical Reports Server (NTRS)

    1971-01-01

    Astronaut Edgar D. Mitchell, right, the Apollo 14 lunar module pilot, addresses JSC/MSC personnel and news media representatives and other visitors soon after he and his fellow crewmen were released from a 15-day confinement period in the Lunar Receiving Laboratory. Pictured with Mitchell in front of the LRL, MSC bldg 37, are Astronauts Alan B. Shepard Jr., left, commander; and Stuart A Roosa, command module pilot, Mrs Mitchell is at right and Mrs. Roosa, near left. Roosa is flanked by his four children, left to right, Christopher A., Stuart A. Roosa Jr., John D. and Rosemary D.

  14. Innovative Legal Approaches to Address Obesity

    PubMed Central

    Pomeranz, Jennifer L; Teret, Stephen P; Sugarman, Stephen D; Rutkow, Lainie; Brownell, Kelly D

    2009-01-01

    Context: The law is a powerful public health tool with considerable potential to address the obesity issue. Scientific advances, gaps in the current regulatory environment, and new ways of conceptualizing rights and responsibilities offer a foundation for legal innovation. Methods: This article connects developments in public health and nutrition with legal advances to define promising avenues for preventing obesity through the application of the law. Findings: Two sets of approaches are defined: (1) direct application of the law to factors known to contribute to obesity and (2) original and innovative legal solutions that address the weak regulatory stance of government and the ineffectiveness of existing policies used to control obesity. Specific legal strategies are discussed for limiting children's food marketing, confronting the potential addictive properties of food, compelling industry speech, increasing government speech, regulating conduct, using tort litigation, applying nuisance law as a litigation strategy, and considering performance-based regulation as an alternative to typical regulatory actions. Finally, preemption is an overriding issue and can play both a facilitative and a hindering role in obesity policy. Conclusions: Legal solutions are immediately available to the government to address obesity and should be considered at the federal, state, and local levels. New and innovative legal solutions represent opportunities to take the law in creative directions and to link legal, nutrition, and public health communities in constructive ways. PMID:19298420

  15. Global-Address Space Networking (GASNet) Library

    SciTech Connect

    Welcome, Michael L.; Bell, Christian S.

    2011-04-06

    GASNet (Global-Address Space Networking) is a language-independent, low-level networking layer that provides network-independent, high-performance communication primitives tailored for implementing parallel global address space SPMD languages such as UPC and Titanium. The interface is primarily intended as a compilation target and for use by runtime library writers (as opposed to end users), and the primary goals are high performance, interface portability, and expressiveness. GASNet is designed specifically to support high-performance, portable implementations of global address space languages on modern high-end communication networks. The interface provides the flexibility and extensibility required to express a wide variety of communication patterns without sacrificing performance by imposing large computational overheads in the interface. The design of the GASNet interface is partitioned into two layers to maximize porting ease without sacrificing performance: the lower level is a narrow but very general interface called the GASNet core API - the design is basedheavily on Active Messages, and is implemented directly on top of each individual network architecture. The upper level is a wider and more expressive interface called GASNet extended API, which provides high-level operations such as remote memory access and various collective operations. This release implements GASNet over MPI, the Quadrics "elan" API, the Myrinet "GM" API and the "LAPI" interface to the IBM SP switch. A template is provided for adding support for additional network interfaces.

  16. Global-Address Space Networking (GASNet) Library

    2011-04-06

    GASNet (Global-Address Space Networking) is a language-independent, low-level networking layer that provides network-independent, high-performance communication primitives tailored for implementing parallel global address space SPMD languages such as UPC and Titanium. The interface is primarily intended as a compilation target and for use by runtime library writers (as opposed to end users), and the primary goals are high performance, interface portability, and expressiveness. GASNet is designed specifically to support high-performance, portable implementations of global address spacemore » languages on modern high-end communication networks. The interface provides the flexibility and extensibility required to express a wide variety of communication patterns without sacrificing performance by imposing large computational overheads in the interface. The design of the GASNet interface is partitioned into two layers to maximize porting ease without sacrificing performance: the lower level is a narrow but very general interface called the GASNet core API - the design is basedheavily on Active Messages, and is implemented directly on top of each individual network architecture. The upper level is a wider and more expressive interface called GASNet extended API, which provides high-level operations such as remote memory access and various collective operations. This release implements GASNet over MPI, the Quadrics "elan" API, the Myrinet "GM" API and the "LAPI" interface to the IBM SP switch. A template is provided for adding support for additional network interfaces.« less

  17. Basic memory module

    NASA Technical Reports Server (NTRS)

    Tietze, F. C.

    1974-01-01

    Construction and electrical characterization of the 4096 x 2-bit Basic Memory Module (BMM) are reported for the Space Ultrareliable Modular Computer (SUMC) program. The module uses four 2K x 1-bit N-channel FET, random access memory chips, called array chips, and two sense amplifier chips, mounted and interconnected on a ceramic substrate. Four 5% tolerance power supplies are required. At the Module, the address, chip select, and array select lines require a 0-8.5 V MOS signal level. The data output, read-strobe, and write-enable lines operate at TTl levels. Although the module is organized as 4096 x 2 bits, it can be used in a 8196 x 1-bit application with appropriate external connections. A 4096 x 1-bit organization can be obtained by depopulating chips.

  18. Pattern Dynamics in Adaxial-Abaxial Specific Gene Expression Are Modulated by a Plastid Retrograde Signal during Arabidopsis thaliana Leaf Development

    PubMed Central

    Tameshige, Toshiaki; Fujita, Hironori; Watanabe, Keiro; Toyokura, Koichi; Kondo, Maki; Tatematsu, Kiyoshi; Matsumoto, Noritaka; Tsugeki, Ryuji; Kawaguchi, Masayoshi; Nishimura, Mikio; Okada, Kiyotaka

    2013-01-01

    The maintenance and reformation of gene expression domains are the basis for the morphogenic processes of multicellular systems. In a leaf primordium of Arabidopsis thaliana, the expression of FILAMENTOUS FLOWER (FIL) and the activity of the microRNA miR165/166 are specific to the abaxial side. This miR165/166 activity restricts the target gene expression to the adaxial side. The adaxial and abaxial specific gene expressions are crucial for the wide expansion of leaf lamina. The FIL-expression and the miR165/166-free domains are almost mutually exclusive, and they have been considered to be maintained during leaf development. However, we found here that the position of the boundary between the two domains gradually shifts from the adaxial side to the abaxial side. The cell lineage analysis revealed that this boundary shifting was associated with a sequential gene expression switch from the FIL-expressing (miR165/166 active) to the miR165/166-free (non-FIL-expressing) states. Our genetic analyses using the enlarged fil expression domain2 (enf2) mutant and chemical treatment experiments revealed that impairment in the plastid (chloroplast) gene expression machinery retards this boundary shifting and inhibits the lamina expansion. Furthermore, these developmental effects caused by the abnormal plastids were not observed in the genomes uncoupled1 (gun1) mutant background. This study characterizes the dynamic nature of the adaxial-abaxial specification process in leaf primordia and reveals that the dynamic process is affected by the GUN1-dependent retrograde signal in response to the failure of plastid gene expression. These findings advance our understanding on the molecular mechanism linking the plastid function to the leaf morphogenic processes. PMID:23935517

  19. Msa1 and Msa2 Modulate G1-Specific Transcription to Promote G1 Arrest and the Transition to Quiescence in Budding Yeast.

    PubMed

    Miles, Shawna; Croxford, Matthew W; Abeysinghe, Amali P; Breeden, Linda L

    2016-06-01

    Yeast that naturally exhaust their glucose source can enter a quiescent state that is characterized by reduced cell size, and high cell density, stress tolerance and longevity. The transition to quiescence involves highly asymmetric cell divisions, dramatic reprogramming of transcription and global changes in chromatin structure and chromosome topology. Cells enter quiescence from G1 and we find that there is a positive correlation between the length of G1 and the yield of quiescent cells. The Swi4 and Swi6 transcription factors, which form the SBF transcription complex and promote the G1 to S transition in cycling cells, are also critical for the transition to quiescence. Swi6 forms a second complex with Mbp1 (MBF), which is not required for quiescence. These are the functional analogues of the E2F complexes of higher eukaryotes. Loss of the RB analogue, Whi5, and the related protein Srl3/Whi7, delays G1 arrest, but it also delays recovery from quiescence. Two MBF- and SBF-Associated proteins have been identified that have little effect on SBF or MBF activity in cycling cells. We show that these two related proteins, Msa1 and Msa2, are specifically required for the transition to quiescence. Like the E2F complexes that are quiescence-specific, Msa1 and Msa2 are required to repress the transcription of many SBF target genes, including SWI4, the CLN2 cyclin and histones, specifically after glucose is exhausted from the media. They also activate transcription of many MBF target genes. msa1msa2 cells fail to G1 arrest and rapidly lose viability upon glucose exhaustion. msa1msa2 mutants that survive this transition are very large, but they attain the same thermo-tolerance and longevity of wild type quiescent cells. This indicates that Msa1 and Msa2 are required for successful transition to quiescence, but not for the maintenance of that state. PMID:27272642

  20. Total and Envelope Protein-Specific Antibody-Secreting Cell Response in Pediatric Dengue Is Highly Modulated by Age and Subsequent Infections

    PubMed Central

    Toro, Jessica F.; Salgado, Doris M.; Vega, Rocío; Rodríguez, Jairo A.; Rodríguez, Luz-Stella; Angel, Juana; Franco, Manuel A.; Greenberg, Harry B.; Narváez, Carlos F.

    2016-01-01

    The response of antibody-secreting cells (ASC) induced by dengue has only recently started to be characterized. We propose that young age and previous infections could be simple factors that affect this response. Here, we evaluated the primary and secondary responses of circulating ASC in infants (6–12 months old) and children (1–14 years old) infected with dengue showing different degrees of clinical severity. The ASC response was delayed and of lower magnitude in infants, compared with older children. In primary infection (PI), the total and envelope (E) protein-specific IgM ASC were dominant in infants but not in children, and a negative correlation was found between age and the number of IgM ASC (rho = −0.59, P = 0.03). However, infants with plasma dengue-specific IgG detectable in the acute phase developed an intense ASC response largely dominated by IgG and comparable to that of children with secondary infection (SI). IgM and IgG produced by ASC circulating in PI or SI were highly cross-reactive among the four serotypes. Dengue infection caused the disturbance of B cell subsets, particularly a decrease in the relative frequency of naïve B cells. Higher frequencies of total and E protein-specific IgM ASC in the infants and IgG in the children were associated with clinically severe forms of infection. Therefore, the ASC response induced by dengue is highly influenced by the age at which infection occurs and previous immune status, and its magnitude is a relevant element in the clinical outcome. These results are important in the search for correlates of protection and for determining the ideal age for vaccinating against dengue. PMID:27560782

  1. Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules.

    PubMed

    Nakamura, Yukio; de Paiva Alves, Eduardo; Veenstra, Gert Jan C; Hoppler, Stefan

    2016-06-01

    Key signalling pathways, such as canonical Wnt/β-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of β-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of β-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates β-catenin binding to Wnt target genes not only when they are transcriptionally regulated, but also in contexts in which their transcription remains unaffected. The transcriptional response to Wnt signalling depends on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which do not influence β-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/β-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of β-catenin, even to functional Wnt-response elements, can no longer be considered a proxy for identifying transcriptionally Wnt-regulated genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/β-catenin target genes subsequent to β-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated β-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts. PMID:27068107

  2. Total and Envelope Protein-Specific Antibody-Secreting Cell Response in Pediatric Dengue Is Highly Modulated by Age and Subsequent Infections.

    PubMed

    Toro, Jessica F; Salgado, Doris M; Vega, Rocío; Rodríguez, Jairo A; Rodríguez, Luz-Stella; Angel, Juana; Franco, Manuel A; Greenberg, Harry B; Narváez, Carlos F

    2016-01-01

    The response of antibody-secreting cells (ASC) induced by dengue has only recently started to be characterized. We propose that young age and previous infections could be simple factors that affect this response. Here, we evaluated the primary and secondary responses of circulating ASC in infants (6-12 months old) and children (1-14 years old) infected with dengue showing different degrees of clinical severity. The ASC response was delayed and of lower magnitude in infants, compared with older children. In primary infection (PI), the total and envelope (E) protein-specific IgM ASC were dominant in infants but not in children, and a negative correlation was found between age and the number of IgM ASC (rho = -0.59, P = 0.03). However, infants with plasma dengue-specific IgG detectable in the acute phase developed an intense ASC response largely dominated by IgG and comparable to that of children with secondary infection (SI). IgM and IgG produced by ASC circulating in PI or SI were highly cross-reactive among the four serotypes. Dengue infection caused the disturbance of B cell subsets, particularly a decrease in the relative frequency of naïve B cells. Higher frequencies of total and E protein-specific IgM ASC in the infants and IgG in the children were associated with clinically severe forms of infection. Therefore, the ASC response induced by dengue is highly influenced by the age at which infection occurs and previous immune status, and its magnitude is a relevant element in the clinical outcome. These results are important in the search for correlates of protection and for determining the ideal age for vaccinating against dengue. PMID:27560782

  3. Msa1 and Msa2 Modulate G1-Specific Transcription to Promote G1 Arrest and the Transition to Quiescence in Budding Yeast

    PubMed Central

    Miles, Shawna; Croxford, Matthew W.; Abeysinghe, Amali P.; Breeden, Linda L.

    2016-01-01

    Yeast that naturally exhaust their glucose source can enter a quiescent state that is characterized by reduced cell size, and high cell density, stress tolerance and longevity. The transition to quiescence involves highly asymmetric cell divisions, dramatic reprogramming of transcription and global changes in chromatin structure and chromosome topology. Cells enter quiescence from G1 and we find that there is a positive correlation between the length of G1 and the yield of quiescent cells. The Swi4 and Swi6 transcription factors, which form the SBF transcription complex and promote the G1 to S transition in cycling cells, are also critical for the transition to quiescence. Swi6 forms a second complex with Mbp1 (MBF), which is not required for quiescence. These are the functional analogues of the E2F complexes of higher eukaryotes. Loss of the RB analogue, Whi5, and the related protein Srl3/Whi7, delays G1 arrest, but it also delays recovery from quiescence. Two MBF- and SBF-Associated proteins have been identified that have little effect on SBF or MBF activity in cycling cells. We show that these two related proteins, Msa1 and Msa2, are specifically required for the transition to quiescence. Like the E2F complexes that are quiescence-specific, Msa1 and Msa2 are required to repress the transcription of many SBF target genes, including SWI4, the CLN2 cyclin and histones, specifically after glucose is exhausted from the media. They also activate transcription of many MBF target genes. msa1msa2 cells fail to G1 arrest and rapidly lose viability upon glucose exhaustion. msa1msa2 mutants that survive this transition are very large, but they attain the same thermo-tolerance and longevity of wild type quiescent cells. This indicates that Msa1 and Msa2 are required for successful transition to quiescence, but not for the maintenance of that state. PMID:27272642

  4. Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules

    PubMed Central

    Nakamura, Yukio; de Paiva Alves, Eduardo; Veenstra, Gert Jan C.; Hoppler, Stefan

    2016-01-01

    Key signalling pathways, such as canonical Wnt/β-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of β-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of β-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates β-catenin binding to Wnt target genes not only when they are transcriptionally regulated, but also in contexts in which their transcription remains unaffected. The transcriptional response to Wnt signalling depends on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which do not influence β-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/β-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of β-catenin, even to functional Wnt-response elements, can no longer be considered a proxy for identifying transcriptionally Wnt-regulated genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/β-catenin target genes subsequent to β-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated β-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts. PMID:27068107

  5. SU-E-T-69: Cloud-Based Monte Carlo Patient-Specific Quality Assurance (QA) Method for Volumetric Modulated Arc Therapy (VMAT)

    SciTech Connect

    Chen, X; Xing, L; Luxton, G; Bush, K; Azcona, J

    2014-06-01

    Purpose: Patient-specific QA for VMAT is incapable of providing full 3D dosimetric information and is labor intensive in the case of severe heterogeneities or small-aperture beams. A cloud-based Monte Carlo dose reconstruction method described here can perform the evaluation in entire 3D space and rapidly reveal the source of discrepancies between measured and planned dose. Methods: This QA technique consists of two integral parts: measurement using a phantom containing array of dosimeters, and a cloud-based voxel Monte Carlo algorithm (cVMC). After a VMAT plan was approved by a physician, a dose verification plan was created and delivered to the phantom using our Varian Trilogy or TrueBeam system. Actual delivery parameters (i.e., dose fraction, gantry angle, and MLC at control points) were extracted from Dynalog or trajectory files. Based on the delivery parameters, the 3D dose distribution in the phantom containing detector were recomputed using Eclipse dose calculation algorithms (AAA and AXB) and cVMC. Comparison and Gamma analysis is then conducted to evaluate the agreement between measured, recomputed, and planned dose distributions. To test the robustness of this method, we examined several representative VMAT treatments. Results: (1) The accuracy of cVMC dose calculation was validated via comparative studies. For cases that succeeded the patient specific QAs using commercial dosimetry systems such as Delta- 4, MAPCheck, and PTW Seven29 array, agreement between cVMC-recomputed, Eclipse-planned and measured doses was obtained with >90% of the points satisfying the 3%-and-3mm gamma index criteria. (2) The cVMC method incorporating Dynalog files was effective to reveal the root causes of the dosimetric discrepancies between Eclipse-planned and measured doses and provide a basis for solutions. Conclusion: The proposed method offers a highly robust and streamlined patient specific QA tool and provides a feasible solution for the rapidly increasing use of VMAT

  6. Modulation of charge transport across double-stranded DNA by the site-specific incorporation of copper bis-phenanthroline complexes.

    PubMed

    Dauphin-Ducharme, Philippe; Rosati, Fiora; Greschner, Andrea; De Bruijn, A Dowine; Salvatore, Danielle; Toader, Violeta; Lau, Kai Lin; Mauzeroll, Janine; Sleiman, Hanadi

    2015-02-10

    The site-specific incorporation of transition-metal complexes within DNA duplexes, followed by their immobilization on a gold surface, was studied by electrochemistry to characterize their ability to mediate charge. Cyclic voltammetry, square-wave voltammetry, and control experiments were carried out on fully matched and mismatched DNA strands that are mono- or bis-labeled with transition-metal complexes. These experiments are all consistent with the ability of the metal centers to act as a redox probe that is well coupled to the DNA π-stack, allowing DNA-mediated charge transport. PMID:25590949

  7. Is There an Advantage in Designing Adapted, Patient-Specific PTV Margins in Intensity Modulated Proton Beam Therapy for Prostate Cancer?

    SciTech Connect

    Góra, Joanna; Stock, Markus; Lütgendorf-Caucig, Carola

    2013-03-01

    Purpose: To investigate robust margin strategies in intensity modulated proton therapy to account for interfractional organ motion in prostate cancer. Methods and Materials: For 9 patients, one planning computed tomography (CT) scan and daily and weekly cone beam CTs (CBCTs) were acquired and coregistered. The following planning target volume (PTV) approaches were investigated: a clinical target volume (CTV) delineated on the planning CT (CTV{sub ct}) plus 10-mm margin (PTV{sub 10mm}); a reduced PTV (PTV{sub Red}): CTV{sub ct} plus 5 mm in the left-right (LR) and anterior-posterior (AP) directions and 8 mm in the inferior-superior (IS) directions; and a PTV{sub Hull} method: the sum of CTV{sub ct} and CTVs from 5 CBCTs from the first week plus 3 mm in the LR and IS directions and 5 mm in the AP direction. For each approach, separate plans were calculated using a spot-scanning technique with 2 lateral fields. Results: Each approach achieved excellent target coverage. Differences were observed in volume receiving 98% of the prescribed dose (V{sub 98%}) where PTV{sub Hull} and PTV{sub Red} results were superior to the PTV{sub 10mm} concept. The PTV{sub Hull} approach was more robust to organ motion. The V{sub 98%} for CTVs was 99.7%, whereas for PTV{sub Red} and PTV{sub 10mm} plans, V{sub 98%} was 98% and 96.1%, respectively. Doses to organs at risk were higher for PTV{sub Hull} and PTV{sub 10mm} plans than for PTV{sub Red}, but only differences between PTV{sub 10mm} and PTV{sub Red} were significant. Conclusions: In terms of organ sparing, the PTV{sub 10mm} method was inferior but not significantly different from the PTV{sub Red} and PTV{sub Hull} approaches. PTV{sub Hull} was most insensitive to target motion.

  8. Role of the Substrate Specificity-Defining Residues of Human SIRT5 in Modulating the Structural Stability and Inhibitory Features of the Enzyme.

    PubMed

    Yu, Junru; Haldar, Manas; Mallik, Sanku; Srivastava, D K

    2016-01-01

    manifested via the mutation induced modulation in the protein structure. PMID:27023330

  9. Role of the Substrate Specificity-Defining Residues of Human SIRT5 in Modulating the Structural Stability and Inhibitory Features of the Enzyme

    PubMed Central

    Yu, Junru; Haldar, Manas; Mallik, Sanku; Srivastava, D. K.

    2016-01-01

    manifested via the mutation induced modulation in the protein structure. PMID:27023330

  10. Silibinin modulates caudal-type homeobox transcription factor (CDX2), an intestine specific tumor suppressor to abrogate colon cancer in experimental rats.

    PubMed

    Sangeetha, N; Nalini, N

    2015-01-01

    To authenticate the colon cancer preventive potential of silibinin, the efficacy of silibinin needs to be tested by evaluating an organ-specific biomarker. The aim of this study was to evaluate the impact of silibinin on the colonic expression of the caudal-type homeobox transcription factor (CDX2) an intestine specific tumor suppressor gene and its downstream targets in the colon of rats challenged with 1,2 dimethyl hydrazine (DMH). Rats of groups 1 and 2 were treated as control and silibinin control. Rats under groups 3 and 4 were given DMH (20 mg/kg body weight (b.w.) subcutaneously) once a week for 15 consecutive weeks from the 4th week of the experimental period. In addition, group 4 rats alone were treated with silibinin (50 mg/kg b.w. per os) everyday throughout the study period of 32 weeks. Histological investigation and messenger RNA and protein expression studies were performed in the colonic tissues of experimental rats. Findings of the study revealed that DMH administration significantly decreased the expression of CDX2 and Guanylyl cyclase C (GCC) in the colon of experimental rats. Further the decreased levels of CDX2 protein, colonic mucin content, and increased number of mast cells in the colon of DMH alone-administered rats reflects the onset of carcinogenesis. The pathological changes caused due to CDX2 suppression were attenuated by silibinin supplementation. PMID:24740923

  11. The PAX3 paired domain and homeodomain function as a single binding module in vivo to regulate subnuclear localization and mobility by a mechanism that requires base-specific recognition.

    PubMed

    Corry, Gareth N; Raghuram, Nikhil; Missiaen, Kristal K; Hu, Ninghe; Hendzel, Michael J; Underhill, D Alan

    2010-09-10

    The transcription factor PAX3 is essential for myogenesis and neural crest development, and is one of several genes mutated in human Waardenburg syndrome. Analysis of disease-causing missense mutations in PAX3 has established the interdependence of its two DNA-binding domains, the paired domain (PD) and the homeodomain (HD), as well as defects in localization and mobility. Paradoxically, mutants that retained DNA binding activity exhibited the greatest defects in localization and mobility, regardless of the domain in which they reside. In the present study, structure-function analyses were used to determine the mechanistic basis of this effect. In the context of the isolated DNA-binding domains, HD mutants adopted an increase in mobility proportional to their loss in DNA binding, while PD mutants continued to display the inverse relationship observed in the full-length protein. At the structural level, this reflected an unexpected dependence on base-specific contacts in the PD, whereas HD mobility was more severely affected by loss of backbone contacts, as has been observed with other DNA-binding proteins. This requires that the HD switch to a base-specific mode in the full-length protein. Moreover, both domains underwent substantial reduction in mobility and altered localization when in a contiguous polypeptide with the endogenous linker segment. Notably, although the HD conferred localization to heterochromatin, this activity was masked when linked to the PD, despite the absence of determinants for subnuclear compartmentalization in the PD or linker. Last, the propensity for PAX3 heterochromatin localization was modulated by sequences at the amino and carboxy termini, supporting a model in which alternate conformations lead to unmasking of the HD. These data indicate that the PD and the HD functionally interact in vivo and behave as a single binding module whose mobility and localization are dependent on sequence-specific contacts. PMID:20643146

  12. Module 13: Bulk Packaging Shipments by Highway

    SciTech Connect

    Przybylski, J.L.

    1994-07-01

    The Hazardous Materials Modular Training Program provides participating United States Department of Energy (DOE) sites with a basic, yet comprehensive, hazardous materials transportation training program for use onsite. This program may be used to assist individual program entities to satisfy the general awareness, safety training, and function specific training requirements addressed in Code of Federal Regulation (CFR), Title 49, Part 172, Subpart H -- ``Training.`` Module 13 -- Bulk Packaging Shipments by Highway is a supplement to the Basic Hazardous Materials Workshop. Module 13 -- Bulk Packaging Shipments by Highway focuses on bulk shipments of hazardous materials by highway mode, which have additional or unique requirements beyond those addressed in the ten module core program. Attendance in this course of instruction should be limited to those individuals with work experience in transporting hazardous materials utilizing bulk packagings and who have completed the Basic Hazardous Materials Workshop or an equivalent. Participants will become familiar with the rules and regulations governing the transportation by highway of hazardous materials in bulk packagings and will demonstrate the application of these requirements through work projects and examination.

  13. Parasite-specific inserts in the bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase of Plasmodium falciparum modulate catalytic activities and domain interactions.

    PubMed Central

    Birkholtz, Lyn-Marie; Wrenger, Carsten; Joubert, Fourie; Wells, Gordon A; Walter, Rolf D; Louw, Abraham I

    2004-01-01

    Polyamine biosynthesis of the malaria parasite, Plasmodium falciparum, is regulated by a single, hinge-linked bifunctional PfAdoMetDC/ODC [ P. falciparum AdoMetDC (S-adenosylmethionine decarboxylase)/ODC (ornithine decarboxylase)] with a molecular mass of 330 kDa. The bifunctional nature of AdoMetDC/ODC is unique to Plasmodia and is shared by at least three species. The PfAdoMetDC/ODC contains four parasite-specific regions ranging in size from 39 to 274 residues. The significance of the parasite-specific inserts for activity and protein-protein interactions of the bifunctional protein was investigated by a single- and multiple-deletion strategy. Deletion of these inserts in the bifunctional protein diminished the corresponding enzyme activity and in some instances also decreased the activity of the neighbouring, non-mutated domain. Intermolecular interactions between AdoMetDC and ODC appear to be vital for optimal ODC activity. Similar results have been reported for the bifunctional P. falciparum dihydrofolate reductase-thymidylate synthase [Yuvaniyama, Chitnumsub, Kamchonwongpaisan, Vanichtanankul, Sirawaraporn, Taylor, Walkinshaw and Yuthavong (2003) Nat. Struct. Biol. 10, 357-365]. Co-incubation of the monofunctional, heterotetrameric approximately 150 kDa AdoMetDC domain with the monofunctional, homodimeric ODC domain (approximately 180 kDa) produced an active hybrid complex of 330 kDa. The hinge region is required for bifunctional complex formation and only indirectly for enzyme activities. Deletion of the smallest, most structured and conserved insert in the ODC domain had the biggest impact on the activities of both decarboxylases, homodimeric ODC arrangement and hybrid complex formation. The remaining large inserts are predicted to be non-globular regions located on the surface of these proteins. The large insert in AdoMetDC in contrast is not implicated in hybrid complex formation even though distinct interactions between this insert and the two domains

  14. Optical Electronics. Electronics Module 9. Instructor's Guide.

    ERIC Educational Resources Information Center

    Franken, Bill

    This module is the ninth of 10 modules in the competency-based electronics series. Introductory materials include a listing of competencies addressed in the module, a parts/equipment list, and a cross reference table of instructional materials. Five instructional units cover: fiber optic cable; optical coupler; lasers and masers; optical displays;…

  15. Addressing failures in exascale computing

    SciTech Connect

    Snir, Marc; Wisniewski, Robert W.; Abraham, Jacob A.; Adve, Sarita; Bagchi, Saurabh; Balaji, Pavan; Belak, Jim; Bose, Pradip; Cappello, Franck; Carlson, William; Chien, Andrew A.; Coteus, Paul; Debardeleben, Nathan A.; Diniz, Pedro; Engelmann, Christian; Erez, Mattan; Saverio, Fazzari; Geist, Al; Gupta, Rinku; Johnson, Fred; Krishnamoorthy, Sriram; Leyffer, Sven; Liberty, Dean; Mitra, Subhasish; Munson, Todd; Schreiber, Robert; Stearly, Jon; Van Hensbergen, Eric

    2014-05-01

    We present here a report produced by a workshop on “Addressing Failures in Exascale Computing” held in Park City, Utah, August 4–11, 2012. The charter of this workshop was to establish a common taxonomy about resilience across all the levels in a computing system; discuss existing knowledge on resilience across the various hardware and software layers of an exascale system; and build on those results, examining potential solutions from both a hardware and software perspective and focusing on a combined approach. The workshop brought together participants with expertise in applications, system software, and hardware; they came from industry, government, and academia; and their interests ranged from theory to implementation. The combination allowed broad and comprehensive discussions and led to this document, which summarizes and builds on those discussions.

  16. Light addressable photoelectrochemical cyanide sensor

    SciTech Connect

    Licht, S.; Myung, N.; Sun, Y.

    1996-03-15

    A sensor is demonstrated that is capable of spatial discrimination of cyanide with use of only a single stationary sensing element. Different spatial regions of the sensing element are light activated to reveal the solution cyanide concentration only at the point of illumination. In this light addressable photoelectrochemical (LAP) sensor the sensing element consists of an n-CdSe electrode immersed in solution, with the open-circuit potential determined under illumination. In alkaline ferro-ferri-cyanide solution, the open-circuit photopotential is highly responsive to cyanide, with a linear response of (120 mV) log [KCN]. LAP detection with a spatial resolution of {+-}1 mm for cyanide detection is demonstrated. The response is almost linear for 0.001-0.100 m cyanide with a resolution of 5 mV. 38 refs., 7 figs., 1 tab.

  17. Addressing Failures in Exascale Computing

    SciTech Connect

    Snir, Marc; Wisniewski, Robert; Abraham, Jacob; Adve, Sarita; Bagchi, Saurabh; Balaji, Pavan; Belak, J.; Bose, Pradip; Cappello, Franck; Carlson, Bill; Chien, Andrew; Coteus, Paul; DeBardeleben, Nathan; Diniz, Pedro; Engelmann, Christian; Erez, Mattan; Fazzari, Saverio; Geist, Al; Gupta, Rinku; Johnson, Fred; Krishnamoorthy, Sriram; Leyffer, Sven; Liberty, Dean; Mitra, Subhasish; Munson, Todd; Schreiber, Rob; Stearley, Jon; Van Hensbergen, Eric

    2014-01-01

    We present here a report produced by a workshop on Addressing failures in exascale computing' held in Park City, Utah, 4-11 August 2012. The charter of this workshop was to establish a common taxonomy about resilience across all the levels in a computing system, discuss existing knowledge on resilience across the various hardware and software layers of an exascale system, and build on those results, examining potential solutions from both a hardware and software perspective and focusing on a combined approach. The workshop brought together participants with expertise in applications, system software, and hardware; they came from industry, government, and academia, and their interests ranged from theory to implementation. The combination allowed broad and comprehensive discussions and led to this document, which summarizes and builds on those discussions.

  18. BMP signalling in human fetal ovary somatic cells is modulated in a gene-specific fashion by GREM1 and GREM2

    PubMed Central

    Bayne, Rosemary A.; Donnachie, Douglas J.; Kinnell, Hazel L.; Childs, Andrew J.; Anderson, Richard A.

    2016-01-01

    expression of BMP antagonists GREM1, GREM2 and CHRD  increases in the lead-up to primordial follicle formation in the human fetal ovary, and that the BMP pathway is active in cultured ovarian somatic cells. This leads to differential changes in the expression of a number of genes, some of which are further modulated by GREM1 and/or GREM2. The positive transcriptional regulation of LGR5 (a marker of less differentiated somatic cells) by BMP4 in vitro suggests that increasing levels of GREM1 and reduced levels of BMP4 as the ovary develops in vivo may act to reduce LGR5 levels and allow pre-granulosa cell differentiation. LIMITATIONS, REASONS FOR CAUTION While we have demonstrated that markers of different somatic cell types are expressed in the cultured ovarian somatic cells, their proportions may not represent the same cells in the intact ovary which also contains germ cells. WIDER IMPLICATIONS OF THE FINDINGS This study extends previous work identifying germ cells as targets of ovarian BMP signalling, and suggests BMPs may regulate the development of both germ and somatic cells in the developing ovary around the time of follicle formation. LARGE SCALE DATA Not applicable. STUDY FUNDING/COMPETING INTERESTS This work was supported by The UK Medical Research Council (Grant No.: G1100357 to RAA), and Medical Research Scotland (Grant No. 345FRG to AJC). The authors have no competing interests to declare. PMID:27385727

  19. Development of stably transfected human and rat hepatoma cell lines for the species-specific assessment of xenobiotic response enhancer module (XREM)-dependent induction of drug metabolism.

    PubMed

    Fery, Yvonne; Mueller, Stefan O; Schrenk, Dieter

    2010-11-01

    Based on our current knowledge, PXR holds a key position in the induction of a selective battery of enzymes and transporters of drug metabolism. In order to prevent serious adverse drug effects or unpredicted drug-drug interactions (DDI), it is compulsory to investigate the possible inducing potency of drugs under development. Furthermore, analysis of the inducing potency of environmental pollutants and new or manufactured chemicals is part of toxicological risk assessment. In non-transfected human HepG2 and rat H4IIE hepatoma cells, we examined the characteristics of expression of 45 genes involved in drug metabolism. A few gene products such as CYP2B6 or CYP3A4 mRNA were prominent in HepG2 cells while their major rat counterparts were, e.g., CYP2B3 or CYP3A1/3A3. Furthermore, a number of xenobiotic receptors including PXR were expressed in both cell lines. A number of genes were regulated in a cell type and species-specific manner after incubation with the prototypical PXR agonists rifampicin or dexamethasone, respectively. Then, we established cell-based reporter gene assays for screening for PXR-dependent induction of drug metabolism. HepG2 and H4IIE cells were stably transfected with a reporter gene containing PXR responsive elements (XREMs) which mediate the induction of PXR target genes such as CYP3A enzymes. With both stable cell lines the CYP inducers clotrimazole, dexamethasone, omeprazole, phenobarbital, rifampicin, as well as the drug candidate EMD 392949 and the brominated flame retardants hexabromocylododecane (HBCD) and a pentabromodiphenyl ether (pentaBDE) mixture were screened. In the human HepG2-XREM3 and rat H4IIE-XREM3 cells, clotrimazole and HBCD were found as common activators of the human and rat PXR whereas pentaBDE was more effective with the human cell system. Omeprazole and phenobarbital did not induce the rat PXR-dependent reporter gene expression in H4IIE-XREM3 cells, while a moderate increase was found in HepG2-XREM3 cells. EMD 392949

  20. In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract. II. Physicochemical characterization of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate pellets.

    PubMed

    Pillay, V; Fassihi, R

    1999-05-20

    Pellets of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate were produced via crosslinking in an aqueous medium for site-specific drug delivery in the gastrointestinal tract. A comparative study of their physicochemical characteristics by means of texture analysis, modulated temperature differential scanning calorimetry (MTDSC), scanning electron microscopy and swelling dynamics under different pH conditions was undertaken. It was found that the incorporation of low methoxylated pectin (i.e., degree of methoxylation approximately 35%) together with alginate appears to influence the degree of crosslinking and subsequently the physical, mechanical and resilience behavior. In general, texture analysis of various pellets indicated that both strength and resilience profiles were in the order of calcium-alginate>/=calcium-alginate-pectinate>calcium-pectinate. Calcium-alginate pellets were found to be viscoelastic, while calcium-pectinate was highly brittle. Through the application of MTDSC, depolymerization transitions, reversing and non-reversing heat flow were determined and interpreted for each formulation. Scanning electron microscopy and micro-thermal analysis revealed distinct morphological differences in each case. The influence of and nature of crosslinking, and textural properties of such pellets on drug release rate modulation is discussed. PMID:10332058

  1. MODULATION OF N-CADHERIN JUNCTIONS AND THEIR ROLE AS EPICENTERS OF DIFFERENTIATION-SPECIFIC ACTIN REGULATION IN THE DEVELOPING LENS

    PubMed Central

    Leonard, Michelle; Zhang, Liping; Zhai, Ni; Cader, Ahmad; Chan, Yim; Nowak, Roberta B.; Fowler, Velia M.; Menko, A. Sue

    2010-01-01

    Extensive elongation of lens fiber cells is a central feature of lens morphogenesis. Our study investigates the role of N-cadherin junctions in this process in vivo. We investigate both the molecular players involved in N-cadherin junctional maturation and the subsequent function of these junctions as epicenters for the assembly of an actin cytoskeleton that drives morphogenesis. We present the first evidence of nascent cadherin junctions in vivo, and show they are a prominent feature along lateral interfaces of undifferentiated lens epithelial cells. Maturation of these N-cadherin junctions, required for lens cell differentiation, preceded organization of a cortical actin cytoskeleton along the cells’ lateral borders, but was linked to recruitment of α-catenin and dephosphorylation of N-cadherin-linked β-catenin. Biochemical analysis revealed differentiation-specific recruitment of actin regulators cortactin and Arp3 to maturing N-cadherin junctions of differentiating cells, linking N-cadherin junctional maturation with actin cytoskeletal assembly during fiber cell elongation. Blocking formation of mature N-cadherin junctions led to reduced association of α-catenin with N-cadherin, prevented organization of actin along lateral borders of differentiating lens fiber cells and blocked their elongation. These studies provide a molecular link between N-cadherin junctions and the organization of an actin cytoskeleton that governs lens fiber cell morphogenesis in vivo. PMID:20969840

  2. Activation of mammalian target of rapamycin contributes to pain nociception induced in rats by BmK I, a sodium channel-specific modulator.

    PubMed

    Jiang, Feng; Hua, Li-Ming; Jiao, Yun-Lu; Ye, Pin; Fu, Jin; Cheng, Zhi-Jun; Ding, Gang; Ji, Yong-Hua

    2014-02-01

    The mammalian target of rapamycin (mTOR) pathway is essential for maintenance of the sensitivity of certain adult sensory neurons. Here, we investigated whether the mTOR cascade is involved in scorpion envenomation-induced pain hypersensitivity in rats. The results showed that intraplantar injection of a neurotoxin from Buthus martensii Karsch, BmK I (10 μg), induced the activation of mTOR, as well as its downstream molecules p70 ribosomal S6 protein kinase (p70 S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), in lumbar 5-6 dorsal root ganglia neurons on both sides in rats. The activation peaked at 2 h and recovered 1 day after injection. Compared with the control group, the ratios of p-mTOR/p-p70 S6K/p-4EBP1 in three types of neurons changed significantly. The cell typology of p-mTOR/p-p70 S6K/p-4E-BP1 immuno-reactive neurons also changed. Intrathecal administration of deforolimus, a specific inhibitor of mTOR, attenuated BmK I-induced pain responses (spontaneous flinching, paroxysmal pain-like behavior, and mechanical hypersensitivity). Together, these results imply that the mTOR signaling pathway is mobilized by and contributes to experimental scorpion sting-induced pain. PMID:24132796

  3. Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone

    PubMed Central

    Zhang, Yu-Hang; Gao, Yong-Guang; Song, Ai-Xin; van der Goot, Françoise Gisou; Hu, Hong-Yu

    2016-01-01

    Ubiquitin-specific protease 19 (USP19) is one of the deubiquitinating enzymes (DUBs) involved in regulating the ubiquitination status of substrate proteins. There are two major isoforms of USP19 with distinct C-termini; the USP19_a isoform has a transmembrane domain for anchoring to the endoplasmic reticulum, while USP19_b contains an EEVD motif. Here, we report that the cytoplasmic isoform USP19_b up-regulates the protein levels of the polyglutamine (polyQ)-containing proteins, ataxin-3 (Atx3) and huntingtin (Htt), and thus promotes aggregation of their polyQ-expanded species in cell models. Our data demonstrate that USP19_b may orchestrate the stability, aggregation and degradation of the polyQ-expanded proteins through the heat shock protein 90 (HSP90) chaperone system. USP19_b directly interacts with HSP90 through its N-terminal CS (CHORD and SGT1)/P23 domains. In conjunction with HSP90, the cytoplasmic USP19 may play a key role in triage decision for the disease-related polyQ-expanded substrates, suggesting a function of USP19 in quality control of misfolded proteins by regulating their protein levels. PMID:26808260

  4. The Copper Metabolism MURR1 Domain Protein 1 (COMMD1) Modulates the Aggregation of Misfolded Protein Species in a Client-Specific Manner

    PubMed Central

    Vonk, Willianne I. M.; Kakkar, Vaishali; Bartuzi, Paulina; Jaarsma, Dick; Berger, Ruud; Hofker, Marten H.; Klomp, Leo W. J.; Wijmenga, Cisca; Kampinga, Harm H.; van de Sluis, Bart

    2014-01-01

    The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the copper-transporters ATP7B and ATP7A, RELA and HIF-1α). Recently, we established an interaction between the Cu/Zn superoxide dismutase 1 (SOD1) and COMMD1, resulting in a decreased maturation and activation of SOD1. Mutations in SOD1, associated with the progressive neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), cause misfolding and aggregation of the mutant SOD1 (mSOD1) protein. Here, we identify COMMD1 as a novel regulator of misfolded protein aggregation as it enhances the formation of mSOD1 aggregates upon binding. Interestingly, COMMD1 co-localizes to the sites of mSOD1 inclusions and forms high molecular weight complexes in the presence of mSOD1. The effect of COMMD1 on protein aggregation is client-specific as, in contrast to mSOD1, COMMD1 decreases the abundance of mutant Parkin inclusions, associated with Parkinson’s disease. Aggregation of a polyglutamine-expanded Huntingtin, causative of Huntington’s disease, appears unaltered by COMMD1. Altogether, this study offers new research directions to expand our current knowledge on the mechanisms underlying aggregation disease pathologies. PMID:24691167

  5. The modulation of extracellular superoxide dismutase in the specifically enhanced cellular immune response against secondary challenge of Vibrio splendidus in Pacific oyster (Crassostrea gigas).

    PubMed

    Liu, Conghui; Zhang, Tao; Wang, Lingling; Wang, Mengqiang; Wang, Weilin; Jia, Zhihao; Jiang, Shuai; Song, Linsheng

    2016-10-01

    Extracellular superoxide dismutase (EcSOD) is a copper-containing glycoprotein playing an important role in antioxidant defense of living cells exposed to oxidative stress, and also participating in microorganism internalization and cell adhesion in invertebrates. EcSOD from oyster (designated CgEcSOD) had been previously reported to bind lipopolysaccharides (LPS) and act as a bridge molecule in Vibrio splendidus internalization. Its mRNA expression pattern, PAMP binding spectrum and microorganism binding capability were examined in the present study. The mRNA expression of CgEcSOD in hemocytes was significantly up-regulated at the initial phase and decreased sharply at 48 h post V. splendidus stimulation. The recombinant CgEcSOD protein (rCgEcSOD) could bind LPS, PGN and poly (I:C), as well as various microorganisms including Micrococcus luteus, Staphylococcus aureus, Escherichia coli, Vibrio anguillarum, V. splendidus, Pastoris pastoris and Yarrowia lipolytica at the presence of divalent metal ions Cu(2+). After the secondary V. splendidus stimulation, the mRNA and protein of CgEcSOD were both down-regulated significantly. The results collectively indicated that CgEcSOD could not only function in the immune recognition, but also might contribute to the immune priming of oyster by inhibiting the foreign microbe invasion through a specific down-regulation. PMID:27268574

  6. Validation of the Japanese version of the EORTC hepatocellular carcinoma-specific quality of life questionnaire module (QLQ-HCC18)

    PubMed Central

    2012-01-01

    Background This study examined the measurement properties of the Japanese version of the European Organisation for Research and Treatment of Cancer (EORTC) Hepatocellular Carcinoma-Specific Quality of Life Questionnaire (QLQ-HCC18). Methods EORTC quality of life (QOL) translation guidelines were followed to create a Japanese version of the EORTC QLQ-HCC18. This was then administered to 192 patients with hepatocellular carcinoma along with the EORTC QLQ-C30 and FACT-Hep questionnaires. Tests for reliability and validity were conducted including comparison of scores between the EORTC and FACT questionnaire and detailed assessment of the new scales and items in clinically distinct groups of patients. Results Multi-trait scaling analysis confirmed three putative scales in the QLQ-HCC18, fatigue, fever and nutrition. Cronbach’s alpha for these scales were between 0.68 and 0.78. The QLQ-HCC18 scales correlated with scales measuring similar items in the FACT-Hep and the questionnaire was stable over time with an intra-class correlation score of 0.70 for almost all scales. The questionnaire had the ability to distinguish between patients with different Karnofsky Performance Status, and Child-Pugh liver function class. Conclusions The Japanese version of EORTC QLQ-HCC18 is a reliable supplementary measure to use with EORTC QLQ-C30 to measure QOL in Japanese patients with hepatocellular carcinoma. PMID:22651810

  7. Conflict adaptation within but not across NoGo decision criteria: Event-related-potential evidence of specificity in the contextual modulation of cognitive control.

    PubMed

    Feldman, Julia L; Clark, Sheri L; Freitas, Antonio L

    2015-07-01

    From the standpoint of conflict-monitoring theory (Botvinick et al., 2001), detecting an incident of information-processing conflict should attenuate the disruptive influence of information-processing conflicts encountered subsequently, by which time cognitive-control operations will have been engaged. To examine the generality of this conflict-adaptation process across task dimensions, the present research analyzed event-related potentials in a Go/NoGo task that randomly varied the NoGo decision criterion applied across trials. Sequential analyses revealed reduced-amplitude fronto-central N2 and NoGo P3 responses on the second of two consecutive NoGo trials. Importantly, both of these conflict-adaptation effects were present only when the same NoGo decision criterion was applied across trials n and n-1. These findings support the theory that encountering information-processing conflict focuses attention on specific stimulus-response contingencies (Verguts & Notebaert, 2009) rather than engages general cognitive-control mechanisms (Freitas & Clark, 2015). Further implications for the generality of cognitive control are discussed. PMID:26003915

  8. Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions.

    PubMed

    Bonzi, Jeremy; Bornet, Olivier; Betzi, Stephane; Kasper, Brian T; Mahal, Lara K; Mancini, Stephane J; Schiff, Claudine; Sebban-Kreuzer, Corinne; Guerlesquin, Francoise; Elantak, Latifa

    2015-01-01

    Galectins are glycan-binding proteins involved in various biological processes including cell/cell interactions. During B-cell development, bone marrow stromal cells secreting galectin-1 (GAL1) constitute a specific niche for pre-BII cells. Besides binding glycans, GAL1 is also a pre-B cell receptor (pre-BCR) ligand that induces receptor clustering, the first checkpoint of B-cell differentiation. The GAL1/pre-BCR interaction is the first example of a GAL1/unglycosylated protein interaction in the extracellular compartment. Here we show that GAL1/pre-BCR interaction modifies GAL1/glycan affinity and particularly inhibits binding to LacNAc containing epitopes. GAL1/pre-BCR interaction induces local conformational changes in the GAL1 carbohydrate-binding site generating a reduction in GAL1/glycan affinity. This fine tuning of GAL1/glycan interactions may be a strategic mechanism for allowing pre-BCR clustering and pre-BII cells departure from their niche. Altogether, our data suggest a novel mechanism for a cell to modify the equilibrium of the GAL1/glycan lattice involving GAL1/unglycosylated protein interactions. PMID:25708191

  9. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function.

    PubMed Central

    Forrest, D; Hanebuth, E; Smeyne, R J; Everds, N; Stewart, C L; Wehner, J M; Curran, T

    1996-01-01

    The diverse functions of thyroid hormone (T3) are presumed to be mediated by two genes encoding the related receptors, TRalpha and TRbeta. However, the in vivo functions of TRalpha and TRbeta are undefined. Here, we report that targeted inactivation of the mouse TRbeta gene results in goitre and elevated levels of thyroid hormone. Also, thyroid-stimulating hormone (TSH), which is released by pituitary thyrotropes and which is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-) mice. These findings suggest a unique role for TRbeta that cannot be substituted by TRalpha in the T3-dependent feedback regulation of TSH transcription. Thrb-/- mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH) that exhibits a similar endocrine disorder but which is typically caused by dominant TRbeta mutants that are transcriptional inhibitors. It is unknown whether TRalpha, TRbeta or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb-/- mice suggests that antagonism of TRbeta-mediated pathways underlies the disorder of the pituitary-thyroid axis. Interestingly, in the brain, the absence of TRbeta may not mimic the defects often associated with dominant RTH, since no overt behavioural or neuroanatomical abnormalities were detected in Thrb-/- mice. These data define in vivo functions for TRbeta and indicate that specificity in T3 signalling is conferred by distinct receptor genes. Images PMID:8670802

  10. Addressing the water budget with SMOS

    NASA Astrophysics Data System (ADS)

    Kerr, Y. H.; AlBitar, A.; Tomer, S. K.; Merlin, O.; Pellarin, T.

    2012-12-01

    SMOS, a L Band radiometer using aperture synthesis to achieve a good spatial resolution, was successfully launched on November 2, 2009. It was developed and made under the leadership of the European Space Agency (ESA) as an Earth Explorer Opportunity mission. It is a joint program with the Centre National d'Etudes Spatiales (CNES) in France and the Centro para el Desarrollo Teccnologico Industrial (CDTI) in Spain. SMOS carries a single payload, an L band 2D interferometric,radiometer in the 1400-1427 MHz h protected band. This wavelength penetrates well through the vegetation and the atmosphere is almost transparent enabling to infer both soil moisture and vegetation water content. SMOS achieves an unprecedented spatial resolution of 50 km at L-band maximum (43 km on average) with multi angular-dual polarized (or fully polarized) brightness temperatures over the globe and with a revisit time smaller than 3 days. SMOS as been now acquiring data for almost 2 years. The data quality exceeds what was expected, showing very good sensitivity and stability. The data is however very much impaired by man made emission in the protected band, leading to degraded measurements in several areas including parts of Europe and of China. However, many different international teams are now addressing cal val activities in various parts of the world, with notably large field campaigns either on the long time scale or over specific targets to address the specific issues. In parallel different teams are now starting addressing data use in various fields including hydrology. It requires coupling with other models and or disaggregation to address soil moisture distribution over watersheds. Significant new results were obtained for floods and drought events, together with new potential applications in terms of precipitation monitoring This paper thus gives an overview of the science goals of the SMOS mission, a description of its main elements, and a taste of the first results including

  11. The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication.

    PubMed

    Lopez, Angelica P; Kugelman, Jeffrey R; Garcia-Rivera, Jose; Urias, Eduardo; Salinas, Sandra A; Fernandez-Zapico, Martin E; Llano, Manuel

    2016-07-17

    The lens epithelium-derived growth factor p75 (LEDGF/p75) is a chromatin-bound protein essential for efficient lentiviral integration. Genome-wide studies have located LEDGF/p75 inside actively transcribed genes where it mediates lentiviral integration. Although its role in HIV-1 integration is clearly established, the role of LEDGF/p75-associated proteins in HIV-1 infection remains unexplored. Using protein-protein interaction assays, we demonstrated that LEDGF/p75 complexes with a chromatin-remodeling complex facilitates chromatin transcription (FACT), a heterodimer of the structure-specific recognition protein 1 (SSRP1) and the human homolog of suppressor of Ty 16 (hSpt16). Detailed analysis of the interaction of LEDGF/p75 with the FACT complex indicates that LEDGF/p75 interacts with SSRP1 in an hSpt16-independent manner that requires the PWWP domain of LEDGF proteins and the HMG domain of SSRP1. Functional characterizations demonstrate a LEDGF/p75-independent role of SSRP1 in the regulation of HIV-1 replication. shRNA-mediated partial knockdown of SSRP1 reduces HIV-1 infection, but not Murine Leukemia Virus, in human CD4(+) T cells. Similarly, SSRP1 knockdown affects infection by HIV-1-derived viruses that express genes from the viral LTR but not from an internal immediate-early CMV promoter, suggesting a role of SSRP1 in LTR-driven gene expression but not in viral DNA integration. Together, our data demonstrate for the first time the association of LEDGF proteins with the FACT complex and give further support to a role of SSRP1 in HIV-1 infection. PMID:27216501

  12. Chicken-Specific Kinome Array Reveals that Salmonella enterica Serovar Enteritidis Modulates Host Immune Signaling Pathways in the Cecum to Establish a Persistence Infection

    PubMed Central

    Kogut, Michael H.; Swaggerty, Christina L.; Byrd, James Allen; Selvaraj, Ramesh; Arsenault, Ryan J.

    2016-01-01

    Non-typhoidal Salmonella enterica induces an early, short-lived pro-inflammatory response in chickens that is asymptomatic of clinical disease and results in a persistent colonization of the gastrointestinal (GI) tract that transmits infections to naïve hosts via fecal shedding of bacteria. The underlying mechanisms that control this persistent colonization of the ceca of chickens by Salmonella are only beginning to be elucidated. We hypothesize that alteration of host signaling pathways mediate the induction of a tolerance response. Using chicken-specific kinomic immune peptide arrays and quantitative RT-PCR of infected cecal tissue, we have previously evaluated the development of disease tolerance in chickens infected with Salmonella enterica serovar Enteritidis (S. Enteritidis) in a persistent infection model (4–14 days post infection). Here, we have further outlined the induction of an tolerance defense strategy in the cecum of chickens infected with S. Enteritidis beginning around four days post-primary infection. The response is characterized by alterations in the activation of T cell signaling mediated by the dephosphorylation of phospholipase c-γ1 (PLCG1) that inhibits NF-κB signaling and activates nuclear factor of activated T-cells (NFAT) signaling and blockage of interferon-γ (IFN-γ) production through the disruption of the JAK-STAT signaling pathway (dephosphorylation of JAK2, JAK3, and STAT4). Further, we measured a significant down-regulation reduction in IFN-γ mRNA expression. These studies, combined with our previous findings, describe global phenotypic changes in the avian cecum of Salmonella Enteritidis-infected chickens that decreases the host responsiveness resulting in the establishment of persistent colonization. The identified tissue protein kinases also represent potential targets for future antimicrobial compounds for decreasing Salmonella loads in the intestines of food animals before going to market. PMID:27472318

  13. Isolation of Modulators of the Liver-Specific Organic Anion-Transporting Polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae)

    PubMed Central

    Roth, Megan; Araya, Juan J.; Timmermann, Barbara N.

    2011-01-01

    Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae). Fractions of the plant extract were screened for effects on OATP1B1- and OATP1B3-mediated transport of the model substrates estradiol-17β-glucuronide and estrone-3-sulfate. We isolated three compounds, ursolic acid, oleanolic acid, and 8-trans-p-coumaroyloxy-α-terpineol, which inhibited estradiol-17β-glucuronide uptake by OATP1B1 but not OATP1B3. In addition, a rare compound, quercetin 3-O-α-l-arabinopyranosyl(1→2) α-l-rhamnopyranoside, was identified that had distinct effects on each OATP. OATP1B1 was strongly inhibited, as was OATP1B3-mediated transport of estradiol-17β-glucuronide. However, OATP1B3-mediated uptake of estrone-3-sulfate was stimulated 4- to 5-fold. Kinetic analysis of this stimulation revealed that the apparent affinity for estrone-3-sulfate was increased (decreased Km), whereas the maximal rate of transport (Vmax) was significantly reduced. These results demonstrate a mechanism through which the hepatic uptake of drug OATP substrates could be stimulated. PMID:21846839

  14. Combination of Tolfenamic acid and curcumin induces colon cancer cell growth inhibition through modulating specific transcription factors and reactive oxygen species

    PubMed Central

    Sankpal, Umesh T.; Nagaraju, Ganji Purnachandra; Gottipolu, Sriharika R.; Hurtado, Myrna; Jordan, Christopher G.; Simecka, Jerry W.; Shoji, Mamoru; El-Rayes, Bassel; Basha, Riyaz

    2016-01-01

    Curcumin (Cur) has been extensively studied in several types of malignancies including colorectal cancer (CRC); however its clinical application is greatly affected by low bioavailability. Several strategies to improve the therapeutic response of Cur are being pursued, including its combination with small molecules and drugs. We investigated the therapeutic efficacy of Cur in combination with the small molecule tolfenamic acid (TA) in CRC cell lines. TA has been shown to inhibit the growth of human cancer cells in vitro and in vivo, via targeting the transcription factor specificity protein1 (Sp1) and suppressing survivin expression. CRC cell lines HCT116 and HT29 were treated with TA and/or Cur and cell viability was measured 24–72 hours post-treatment. While both agents caused a steady reduction in cell viability, following a clear dose/time-dependent response, the combination of TA+Cur showed higher growth inhibition when compared to either single agent. Effects on apoptosis were determined using flow cytometry (JC-1 staining to measure mitochondrial membrane potential), Western blot analysis (c-PARP expression) and caspase 3/7 activity. Reactive oxygen species (ROS) levels were measured by flow cytometry and the translocation of NF-kB into the nucleus was determined using immunofluorescence. Results showed that apoptotic markers and ROS activity were significantly upregulated following combination treatment, when compared to the individual agents. This was accompanied by decreased expression of Sp1, survivin and NF-kB translocation. The combination of TA+Cur was more effective in HCT116 cells than HT29 cells. These results demonstrate that TA may enhance the anti-proliferative efficacy of Cur in CRC cells. PMID:26672603

  15. Chicken-Specific Kinome Array Reveals that Salmonella enterica Serovar Enteritidis Modulates Host Immune Signaling Pathways in the Cecum to Establish a Persistence Infection.

    PubMed

    Kogut, Michael H; Swaggerty, Christina L; Byrd, James Allen; Selvaraj, Ramesh; Arsenault, Ryan J

    2016-01-01

    Non-typhoidal Salmonella enterica induces an early, short-lived pro-inflammatory response in chickens that is asymptomatic of clinical disease and results in a persistent colonization of the gastrointestinal (GI) tract that transmits infections to naïve hosts via fecal shedding of bacteria. The underlying mechanisms that control this persistent colonization of the ceca of chickens by Salmonella are only beginning to be elucidated. We hypothesize that alteration of host signaling pathways mediate the induction of a tolerance response. Using chicken-specific kinomic immune peptide arrays and quantitative RT-PCR of infected cecal tissue, we have previously evaluated the development of disease tolerance in chickens infected with Salmonella enterica serovar Enteritidis (S. Enteritidis) in a persistent infection model (4-14 days post infection). Here, we have further outlined the induction of an tolerance defense strategy in the cecum of chickens infected with S. Enteritidis beginning around four days post-primary infection. The response is characterized by alterations in the activation of T cell signaling mediated by the dephosphorylation of phospholipase c-γ1 (PLCG1) that inhibits NF-κB signaling and activates nuclear factor of activated T-cells (NFAT) signaling and blockage of interferon-γ (IFN-γ) production through the disruption of the JAK-STAT signaling pathway (dephosphorylation of JAK2, JAK3, and STAT4). Further, we measured a significant down-regulation reduction in IFN-γ mRNA expression. These studies, combined with our previous findings, describe global phenotypic changes in the avian cecum of Salmonella Enteritidis-infected chickens that decreases the host responsiveness resulting in the establishment of persistent colonization. The identified tissue protein kinases also represent potential targets for future antimicrobial compounds for decreasing Salmonella loads in the intestines of food animals before going to market. PMID:27472318

  16. pKa Modulation of the Acid/Base Catalyst within GH32 and GH68: A Role in Substrate/Inhibitor Specificity?

    PubMed Central

    Yuan, Shuguang; Le Roy, Katrien; Venken, Tom; Lammens, Willem; Van den Ende, Wim; De Maeyer, Marc

    2012-01-01

    Glycoside hydrolases of families 32 (GH32) and 68 (GH68) belong to clan GH-J, containing hydrolytic enzymes (sucrose/fructans as donor substrates) and fructosyltransferases (sucrose/fructans as donor and acceptor substrates). In GH32 members, some of the sugar substrates can also function as inhibitors, this regulatory aspect further adding to the complexity in enzyme functionalities within this family. Although 3D structural information becomes increasingly available within this clan and huge progress has been made on structure-function relationships, it is not clear why some sugars bind as inhibitors without being catalyzed. Conserved aspartate and glutamate residues are well known to act as nucleophile and acid/bases within this clan. Based on the available 3D structures of enzymes and enzyme-ligand complexes as well as docking simulations, we calculated the pKa of the acid-base before and after substrate binding. The obtained results strongly suggest that most GH-J members show an acid-base catalyst that is not sufficiently protonated before ligand entrance, while the acid-base can be fully protonated when a substrate, but not an inhibitor, enters the catalytic pocket. This provides a new mechanistic insight aiming at understanding the complex substrate and inhibitor specificities observed within the GH-J clan. Moreover, besides the effect of substrate entrance on its own, we strongly suggest that a highly conserved arginine residue (in the RDP motif) rather than the previously proposed Tyr motif (not conserved) provides the proton to increase the pKa of the acid-base catalyst. PMID:22662155

  17. Cell-Type-Specific Characteristics Modulate the Transduction Efficiency of Adeno-Associated Virus Type 2 and Restrain Infection of Endothelial Cells

    PubMed Central

    Pajusola, Katri; Gruchala, Marcin; Joch, Hana; Lüscher, Thomas F.; Ylä-Herttuala, Seppo; Büeler, Hansruedi

    2002-01-01

    Adeno-associated viruses (AAVs) are promising vectors for various gene therapy applications due to their long-lasting transgene expression and wide spectrum of target cells. Recently, however, it has become apparent that there are considerable differences in the efficiencies of transduction of different cell types by AAVs. Here, we analyzed the efficiencies of transduction and the transport mechanisms of AAV type 2 (AAV-2) in different cell types, emphasizing endothelial cells. Expression analyses in both cultured cells and the rabbit carotid artery assay showed a remarkably low level of endothelial cell transduction in comparison to the highly permissive cell types. The study of the endosomal pathways of AAV-2 with fluorescently labeled virus showed clear targeting of the Golgi area in permissive cell lines, but this phenomenon was absent in the endothelial cell line EAhy-926. On the other hand, the response to the block of endosomal acidification by bafilomycin A1 also showed differences among the permissive cell types. We also analyzed the effect of proteasome inhibitors on endothelial cells, but their impact on the primary cells and in vivo was not significant. On the contrary, analysis of the expression pattern of heparan sulfate proteoglycans (HSPGs), the primary receptors of AAV-2, revealed massive deposits of HSPG in the extracellular matrix of endothelial cells. The matrix-associated receptors may therefore compete for virus binding and reduce transduction in endothelial cells. Accordingly, in endothelial cells detached from their matrix, AAV-2 transduction was significantly increased. Altogether, these results point to a more complex cell-type-specific mode of transduction of AAV-2 than previously appreciated. PMID:12388714

  18. Cell-type-specific characteristics modulate the transduction efficiency of adeno-associated virus type 2 and restrain infection of endothelial cells.

    PubMed

    Pajusola, Katri; Gruchala, Marcin; Joch, Hana; Lüscher, Thomas F; Ylä-Herttuala, Seppo; Büeler, Hansruedi

    2002-11-01

    Adeno-associated viruses (AAVs) are promising vectors for various gene therapy applications due to their long-lasting transgene expression and wide spectrum of target cells. Recently, however, it has become apparent that there are considerable differences in the efficiencies of transduction of different cell types by AAVs. Here, we analyzed the efficiencies of transduction and the transport mechanisms of AAV type 2 (AAV-2) in different cell types, emphasizing endothelial cells. Expression analyses in both cultured cells and the rabbit carotid artery assay showed a remarkably low level of endothelial cell transduction in comparison to the highly permissive cell types. The study of the endosomal pathways of AAV-2 with fluorescently labeled virus showed clear targeting of the Golgi area in permissive cell lines, but this phenomenon was absent in the endothelial cell line EAhy-926. On the other hand, the response to the block of endosomal acidification by bafilomycin A1 also showed differences among the permissive cell types. We also analyzed the effect of proteasome inhibitors on endothelial cells, but their impact on the primary cells and in vivo was not significant. On the contrary, analysis of the expression pattern of heparan sulfate proteoglycans (HSPGs), the primary receptors of AAV-2, revealed massive deposits of HSPG in the extracellular matrix of endothelial cells. The matrix-associated receptors may therefore compete for virus binding and reduce transduction in endothelial cells. Accordingly, in endothelial cells detached from their matrix, AAV-2 transduction was significantly increased. Altogether, these results point to a more complex cell-type-specific mode of transduction of AAV-2 than previously appreciated. PMID:12388714

  19. Maternal folic acid supplementation modulates DNA methylation and gene expression in the rat offspring in a gestation period-dependent and organ-specific manner.

    PubMed

    Ly, Anna; Ishiguro, Lisa; Kim, Denise; Im, David; Kim, Sung-Eun; Sohn, Kyoung-Jin; Croxford, Ruth; Kim, Young-In

    2016-07-01

    Maternal folic acid supplementation can alter DNA methylation and gene expression in the developing fetus, which may confer disease susceptibility later in life. We determined which gestation period and organ were most sensitive to the modifying effect of folic acid supplementation during pregnancy on DNA methylation and gene expression in the offspring. Pregnant rats were randomized to a control diet throughout pregnancy; folic acid supplementation at 2.5× the control during the 1st, 2nd or 3rd week of gestation only; or folic acid supplementation throughout pregnancy. The brain, liver, kidney and colon from newborn pups were analyzed for folate concentrations, global DNA methylation and gene expression of the Igf2, Er-α, Gr, Ppar-α and Ppar-γ genes. Folic acid supplementation during the 2nd or 3rd week gestation or throughout pregnancy significantly increased brain folate concentrations (P<.001), while only folic acid supplementation throughout pregnancy significantly increased liver folate concentrations (P=.005), in newborn pups. Brain global DNA methylation incrementally decreased from early to late gestational folic acid supplementation and was the lowest with folic acid supplementation throughout pregnancy (P=.026). Folic acid supplementation in late gestation or throughout pregnancy significantly decreased Er-α, Gr and Ppar-α gene expression in the liver (P<.05). The kidney and colon were resistant to the effect of folic acid supplementation. Maternal folic acid supplementation affects tissue folate concentrations, DNA methylation and gene expression in the offspring in a gestation-period-dependent and organ-specific manner. PMID:27152636

  20. Addressing Educational Needs of Children with HIV/AIDS.

    ERIC Educational Resources Information Center

    Naude, Hendrina; Pretorius, Etheresia

    2002-01-01

    This paper reviews medical and neuropsychological effects of HIV/AIDS in children and relates these findings specifically to educational difficulties. It then proposes an instructional delivery framework for these children that stresses the importance of addressing their educational needs and includes specific suggestions for reading instruction,…

  1. Addressing the Needs of Students with Rett Syndrome.

    ERIC Educational Resources Information Center

    Katsiyannis, Antonis; Ellenburg, Jennifer S.; Acton, Olivia M.; Torrey, Gregory

    2001-01-01

    This article discusses symptoms of students with Rett Syndrome, a disability in females characterized by the development of multiple specific deficits following a period of normal functioning after birth. Specific interventions for students with Rett syndrome are provided and address communication, stereotypic movements, self-injurious behaviors,…

  2. Gender: addressing a critical focus.

    PubMed

    Thornton, L; Wegner, M N

    1995-01-01

    The definition of gender was addressed at the Fourth World Conference on Women (Beijing, China). After extensive debate, the definition developed by the UN Population Fund in 1995 was adopted: "a set of qualities and behaviors expected from a female or male by society." The sustainability of family planning (FP) programs depends on acknowledgment of the role gender plays in contraceptive decision-making and use. For example, programs must consider the fact that women in many cultures do not make FP decisions without the consent of their spouse. AVSC is examining providers' gender-based ideas about clients and the effects of these views on the quality of reproductive health services. Questions such as how service providers can encourage joint responsibility for contraception without requiring spousal consent or how they can make men feel comfortable about using a male method in a society where FP is considered a woman's issue are being discussed. Also relevant is how service providers can discuss sexual matters openly with female clients in cultures that do not allow women to enjoy their sexuality. Another concern is the potential for physical violence to a client as a result of the provision of FP services. PMID:12294397

  3. Module two: energy utilization

    SciTech Connect

    Not Available

    1980-01-01

    This report contains a teaching module for presentation at the junior college level. A shortened version can also be presented to civic groups or high school vocational classes. Energy use in the past is contrasted with present energy use in 3 sectors: business, industry and the home. The module explains specifically the changes in energy sources and outlines energy use, the need for, and methods of conservation of energy in these 3 sections. 29 references, 7 figures. (DMC)

  4. Generation of a Mouse Model with Down-Regulated U50 snoRNA (SNORD50) Expression and Its Organ-Specific Phenotypic Modulation

    PubMed Central

    Soeno, Yuuichi; Fujita, Kazuya; Kudo, Tomoo; Asagiri, Masataka; Kakuta, Shigeru; Taya, Yuji; Shimazu, Yoshihito; Sato, Kaori; Tanaka-Fujita, Ritsuko; Kubo, Sachiko; Iwakura, Yoichiro; Nakamura, Yoshikazu; Mori, Shigeo; Aoba, Takaaki

    2013-01-01

    Box C/D-type small nucleolar RNAs (snoRNAs) are functional RNAs responsible for mediating 2′-O-ribose methylation of ribosomal RNAs (rRNAs) within the nucleolus. In the past years, evidence for the involvement of human U50 snoRNA in tumorigenesis has been accumulating. We previously identified U50HG, a non-protein-coding gene that hosted a box C/D-type U50 snoRNA, in a chromosomal breakpoint in a human B-cell lymphoma. Mouse genome analysis revealed four mouse U50 (mU50) host-genes: three mU50HG-a gene variants that were clustered in the genome and an mU50HG-b gene that we supposed to be the U50HG ortholog. In this study, to investigate the physiological importance of mU50 snoRNA and its involvement in tumorigenesis, we eliminated mU50 snoRNA sequences from the mU50HG-b gene. The established mouse line (ΔmU50(HG-b)) showed a significant reduction of mU50 snoRNA expression without alteration of the host-gene length and exon-intron structure, and the corresponding target rRNA methylation in various organs was reduced. Lifelong phenotypic monitoring showed that the ΔmU50(HG-b) mice looked almost normal without accelerated tumorigenicity; however, a notable difference was the propensity for anomalies in the lymphoid organs. Transcriptome analysis showed that dozens of genes, including heat shock proteins, were differentially expressed in ΔmU50(HG-b) mouse lymphocytes. This unique model of a single snoRNA knockdown with intact host-gene expression revealed further new insights into the discrete transcriptional regulation of multiple mU50 host-genes and the complicated dynamics involved in organ-specific processing and maintenance of snoRNAs. PMID:23991050

  5. Combined Pharmacological and Genetic Manipulations Unlock Unprecedented Temporal Elasticity and Reveal Phase-Specific Modulation of the Molecular Circadian Clock of the Mouse Suprachiasmatic Nucleus

    PubMed Central

    Patton, Andrew P.; Chesham, Johanna E.

    2016-01-01

    The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous transcriptional–translational feedback loop, whereby expression of the Period and Cryptochrome genes is negatively regulated by their protein products. This loop in turn drives circadian oscillations in gene expression that direct SCN electrical activity and thence behavior. The robustness of SCN timekeeping is further enhanced by interneuronal, circuit-level coupling. The aim of this study was to combine pharmacological and genetic manipulations to push the SCN clockwork toward its limits and, by doing so, probe cell-autonomous and emergent, circuit-level properties. Circadian oscillation of mouse SCN organotypic slice cultures was monitored as PER2::LUC bioluminescence. SCN of three genetic backgrounds—wild-type, short-period CK1εTau/Tau mutant, and long-period Fbxl3Afh/Afh mutant—all responded reversibly to pharmacological manipulation with period-altering compounds: picrotoxin, PF-670462 (4-[1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinamine dihydrochloride), and KNK437 (N-Formyl-3,4-methylenedioxy-benzylidine-gamma-butyrolactam). This revealed a remarkably wide operating range of sustained periods extending across 25 h, from ≤17 h to >42 h. Moreover, this range was maintained at network and single-cell levels. Development of a new technique for formal analysis of circadian waveform, first derivative analysis (FDA), revealed internal phase patterning to the circadian oscillation at these extreme periods and differential phase sensitivity of the SCN to genetic and pharmacological manipulations. For example, FDA of the CK1εTau/Tau mutant SCN treated with the CK1ε-specific inhibitor PF-4800567 (3-[(3-Chlorophenoxy)methyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride) revealed that period acceleration in the mutant is due to inappropriately phased

  6. Module Configuration

    DOEpatents

    Oweis, Salah; D'Ussel, Louis; Chagnon, Guy; Zuhowski, Michael; Sack, Tim; Laucournet, Gaullume; Jackson, Edward J.

    2002-06-04

    A stand alone battery module including: (a) a mechanical configuration; (b) a thermal management configuration; (c) an electrical connection configuration; and (d) an electronics configuration. Such a module is fully interchangeable in a battery pack assembly, mechanically, from the thermal management point of view, and electrically. With the same hardware, the module can accommodate different cell sizes and, therefore, can easily have different capacities. The module structure is designed to accommodate the electronics monitoring, protection, and printed wiring assembly boards (PWAs), as well as to allow airflow through the module. A plurality of modules may easily be connected together to form a battery pack. The parts of the module are designed to facilitate their manufacture and assembly.

  7. Influence of module requirements on flat plate module design evolution

    NASA Technical Reports Server (NTRS)

    Arnett, J. C.; Ross, R. G., Jr.

    1980-01-01

    Photovoltaic module design features and performance characteristics have undergone significant evolutionary changes between pre-1975 First Generation configurations and current Third Generation design technology. A major contributor to this evolution was an iterative process of continuing design guideline and specification development for major module procurements. Module manufacturers have actively responded to these evolving requirements through progressively improving designs. This iterative/feedback process is described. Interim design guidelines and preliminary design options reflecting the LSA 1982 Module Technical Readiness Specification (November 1979) are described with respect to previous design and performance requirements.

  8. An address geocoding solution for Chinese cities

    NASA Astrophysics Data System (ADS)

    Zhang, Xuehu; Ma, Haoming; Li, Qi

    2006-10-01

    We introduce the challenges of address geocoding for Chinese cities and present a potential solution along with a prototype system that deal with these challenges by combining and extending current geocoding solutions developed for United States and Japan. The proposed solution starts by separating city addresses into "standard" addresses which meet a predefined address model and non-standard ones. The standard addresses are stored in a structured relational database in their normalized forms, while a selected portion of the non-standard addresses are stored as aliases to the standard addresses. An in-memory address index is then constructed from the address database and serves as the basis for real-time address matching. Test results were obtained from two trials conducted in the city Beijing. On average 80% matching rate were achieved. Possible improvements to the current design are also discussed.

  9. Addressing Global Data Sharing Challenges.

    PubMed

    Alter, George C; Vardigan, Mary

    2015-07-01

    This issue of the Journal of Empirical Research on Human Research Ethics highlights the ethical issues that arise when researchers conducting projects in low- and middle-income countries seek to share the data they produce. Although sharing data is considered a best practice, the barriers to doing so are considerable and there is a need for guidance and examples. To that end, the authors of this article reviewed the articles in this special issue to identify challenges common to the five countries and to offer some practical advice to assist researchers in navigating this "uncharted territory," as some termed it. Concerns around informed consent, data management, data dissemination, and validation of research contributions were cited frequently as particularly challenging areas, so the authors focused on these four topics with the goal of providing specific resources to consult as well as examples of successful projects attempting to solve many of the problems raised. PMID:26297753

  10. Addressing Global Data Sharing Challenges

    PubMed Central

    Alter, George C.

    2015-01-01

    This issue of the Journal of Empirical Research on Human Research Ethics highlights the ethical issues that arise when researchers conducting projects in low- and middle-income countries seek to share the data they produce. Although sharing data is considered a best practice, the barriers to doing so are considerable and there is a need for guidance and examples. To that end, the authors of this article reviewed the articles in this special issue to identify challenges common to the five countries and to offer some practical advice to assist researchers in navigating this “uncharted territory,” as some termed it. Concerns around informed consent, data management, data dissemination, and validation of research contributions were cited frequently as particularly challenging areas, so the authors focused on these four topics with the goal of providing specific resources to consult as well as examples of successful projects attempting to solve many of the problems raised. PMID:26297753

  11. Virus-Like Particle Vaccine Containing the F Protein of Respiratory Syncytial Virus Confers Protection without Pulmonary Disease by Modulating Specific Subsets of Dendritic Cells and Effector T Cells

    PubMed Central

    Kim, Ki-Hye; Lee, Young-Tae; Hwang, Hye Suk; Kwon, Young-Man; Kim, Min-Chul; Ko, Eun-Ju; Lee, Jong Seok; Lee, Youri

    2015-01-01

    ABSTRACT There is no licensed vaccine against respiratory syncytial virus (RSV) since the failure of formalin-inactivated RSV (FI-RSV) due to its vaccine-enhanced disease. We investigated immune correlates conferring protection without causing disease after intranasal immunization with virus-like particle vaccine containing the RSV fusion protein (F VLP) in comparison to FI-RSV and live RSV. Upon RSV challenge, FI-RSV immune mice showed severe weight loss, eosinophilia, and histopathology, and RSV reinfection also caused substantial RSV disease despite their viral clearance. In contrast, F VLP immune mice showed least weight loss and no sign of histopathology and eosinophilia. High levels of interleukin-4-positive (IL-4+) and tumor necrosis factor alpha-positive (TNF-α+) CD4+ T cells were found in FI-RSV immune mice, whereas gamma interferon-positive (IFN-γ+) and TNF-α+ CD4+ T cells were predominantly detected in live RSV-infected mice. More importantly, in contrast to FI-RSV and live RSV that induced higher levels of CD11b+ dendritic cells, F VLP immunization induced CD8α+ and CD103+ dendritic cells, as well as F-specific IFN-γ+ and TNF-α+ CD8+ T cells. These results suggest that F VLP can induce protection without causing pulmonary RSV disease by inducing RSV neutralizing antibodies, as well as modulating specific subsets of dendritic cells and CD8 T cell immunity. IMPORTANCE It has been a difficult challenge to develop an effective and safe vaccine against respiratory syncytial virus (RSV), a leading cause of respiratory disease. Immune correlates conferring protection but preventing vaccine-enhanced disease remain poorly understood. RSV F virus-like particle (VLP) would be an efficient vaccine platform conferring protection. Here, we investigated the protective immune correlates without causing disease after intranasal immunization with RSV F VLP in comparison to FI-RSV and live RSV. In addition to inducing RSV neutralizing antibodies responsible for

  12. Addressable-Matrix Integrated-Circuit Test Structure

    NASA Technical Reports Server (NTRS)

    Sayah, Hoshyar R.; Buehler, Martin G.

    1991-01-01

    Method of quality control based on use of row- and column-addressable test structure speeds collection of data on widths of resistor lines and coverage of steps in integrated circuits. By use of straightforward mathematical model, line widths and step coverages deduced from measurements of electrical resistances in each of various combinations of lines, steps, and bridges addressable in test structure. Intended for use in evaluating processes and equipment used in manufacture of application-specific integrated circuits.

  13. Development of a Scale to Assess the Demand for Specific Competences in Teachers after Graduation from University

    ERIC Educational Resources Information Center

    Landmann, Mareike

    2013-01-01

    Universities in Germany show an increasing need for specific information on professional demands encountered and addressed by graduates training to become teachers. To provide information on demands and abilities in teaching graduates, a specialised teacher module was developed in the framework of the German Cooperation Project for Graduate Tracer…

  14. Quantitative velocity modulation spectroscopy.

    PubMed

    Hodges, James N; McCall, Benjamin J

    2016-05-14

    Velocity Modulation Spectroscopy (VMS) is arguably the most important development in the 20th century for spectroscopic study of molecular ions. For decades, interpretation of VMS lineshapes has presented challenges due to the intrinsic covariance of fit parameters including velocity modulation amplitude, linewidth, and intensity. This limitation has stifled the growth of this technique into the quantitative realm. In this work, we show that subtle changes in the lineshape can be used to help address this complexity. This allows for determination of the linewidth, intensity relative to other transitions, velocity modulation amplitude, and electric field strength in the positive column of a glow discharge. Additionally, we explain the large homogeneous component of the linewidth that has been previously described. Using this component, the ion mobility can be determined. PMID:27179476

  15. Quantitative velocity modulation spectroscopy

    NASA Astrophysics Data System (ADS)

    Hodges, James N.; McCall, Benjamin J.

    2016-05-01

    Velocity Modulation Spectroscopy (VMS) is arguably the most important development in the 20th century for spectroscopic study of molecular ions. For decades, interpretation of VMS lineshapes has presented challenges due to the intrinsic covariance of fit parameters including velocity modulation amplitude, linewidth, and intensity. This limitation has stifled the growth of this technique into the quantitative realm. In this work, we show that subtle changes in the lineshape can be used to help address this complexity. This allows for determination of the linewidth, intensity relative to other transitions, velocity modulation amplitude, and electric field strength in the positive column of a glow discharge. Additionally, we explain the large homogeneous component of the linewidth that has been previously described. Using this component, the ion mobility can be determined.

  16. Addressing the vaccine confidence gap.

    PubMed

    Larson, Heidi J; Cooper, Louis Z; Eskola, Juhani; Katz, Samuel L; Ratzan, Scott

    2011-08-01

    Vaccines--often lauded as one of the greatest public health interventions--are losing public confidence. Some vaccine experts have referred to this decline in confidence as a crisis. We discuss some of the characteristics of the changing global environment that are contributing to increased public questioning of vaccines, and outline some of the specific determinants of public trust. Public decision making related to vaccine acceptance is neither driven by scientific nor economic evidence alone, but is also driven by a mix of psychological, sociocultural, and political factors, all of which need to be understood and taken into account by policy and other decision makers. Public trust in vaccines is highly variable and building trust depends on understanding perceptions of vaccines and vaccine risks, historical experiences, religious or political affiliations, and socioeconomic status. Although provision of accurate, scientifically based evidence on the risk-benefit ratios of vaccines is crucial, it is not enough to redress the gap between current levels of public confidence in vaccines and levels of trust needed to ensure adequate and sustained vaccine coverage. We call for more research not just on individual determinants of public trust, but on what mix of factors are most likely to sustain public trust. The vaccine community demands rigorous evidence on vaccine efficacy and safety and technical and operational feasibility when introducing a new vaccine, but has been negligent in demanding equally rigorous research to understand the psychological, social, and political factors that affect public trust in vaccines. PMID:21664679

  17. Addressing concerns and achieving expectations

    SciTech Connect

    Miller, C.L.

    1995-12-01

    Approximately 2-1/2 years ago many of us were gathered here in Prague at a similar conference with a similar name, {open_quotes}Energy and Environment: Transitions in Eastern Europe.{close_quotes} Over 300 professionals from 26 nations attended. The objective of the conference was to: Facilitate the Solution of Long and Short Term Energy and Environmental Problems in Eastern Europe by Bringing Together People, ideas and technologies which could be applied to specific problems in a logical step-by-step manner. It was conceded at the time that the long term solution would consist of thoughtfully integrated steps and that the conference was the first step. We are here in the Czech Republic again this week to continue what was started. As before, this conference continues to: (1) Provide a forum to identify and discuss cost-effective environmentally acceptable energy and environmental technology options and their associated socioeconomic issues. (2) Stimulate the Formation of business partnerships (3) Identify key barrier issues hindering technology applications and identify implementation pathways that eliminate or avoid obstacles to progress.

  18. Computational strategies to address chromatin structure problems.

    PubMed

    Perišić, Ognjen; Schlick, Tamar

    2016-01-01

    While the genetic information is contained in double helical DNA, gene expression is a complex multilevel process that involves various functional units, from nucleosomes to fully formed chromatin fibers accompanied by a host of various chromatin binding enzymes. The chromatin fiber is a polymer composed of histone protein complexes upon which DNA wraps, like yarn upon many spools. The nature of chromatin structure has been an open question since the beginning of modern molecular biology. Many experiments have shown that the chromatin fiber is a highly dynamic entity with pronounced structural diversity that includes properties of idealized zig-zag and solenoid models, as well as other motifs. This diversity can produce a high packing ratio and thus inhibit access to a majority of the wound DNA. Despite much research, chromatin's dynamic structure has not yet been fully described. Long stretches of chromatin fibers exhibit puzzling dynamic behavior that requires interpretation in the light of gene expression patterns in various tissue and organisms. The properties of chromatin fiber can be investigated with experimental techniques, like in vitro biochemistry, in vivo imagining, and high-throughput chromosome capture technology. Those techniques provide useful insights into the fiber's structure and dynamics, but they are limited in resolution and scope, especially regarding compact fibers and chromosomes in the cellular milieu. Complementary but specialized modeling techniques are needed to handle large floppy polymers such as the chromatin fiber. In this review, we discuss current approaches in the chromatin structure field with an emphasis on modeling, such as molecular dynamics and coarse-grained computational approaches. Combinations of these computational techniques complement experiments and address many relevant biological problems, as we will illustrate with special focus on epigenetic modulation of chromatin structure. PMID:27345617

  19. Computational strategies to address chromatin structure problems

    NASA Astrophysics Data System (ADS)

    Perišić, Ognjen; Schlick, Tamar

    2016-06-01

    While the genetic information is contained in double helical DNA, gene expression is a complex multilevel process that involves various functional units, from nucleosomes to fully formed chromatin fibers accompanied by a host of various chromatin binding enzymes. The chromatin fiber is a polymer composed of histone protein complexes upon which DNA wraps, like yarn upon many spools. The nature of chromatin structure has been an open question since the beginning of modern molecular biology. Many experiments have shown that the chromatin fiber is a highly dynamic entity with pronounced structural diversity that includes properties of idealized zig-zag and solenoid models, as well as other motifs. This diversity can produce a high packing ratio and thus inhibit access to a majority of the wound DNA. Despite much research, chromatin’s dynamic structure has not yet been fully described. Long stretches of chromatin fibers exhibit puzzling dynamic behavior that requires interpretation in the light of gene expression patterns in various tissue and organisms. The properties of chromatin fiber can be investigated with experimental techniques, like in vitro biochemistry, in vivo imagining, and high-throughput chromosome capture technology. Those techniques provide useful insights into the fiber’s structure and dynamics, but they are limited in resolution and scope, especially regarding compact fibers and chromosomes in the cellular milieu. Complementary but specialized modeling techniques are needed to handle large floppy polymers such as the chromatin fiber. In this review, we discuss current approaches in the chromatin structure field with an emphasis on modeling, such as molecular dynamics and coarse-grained computational approaches. Combinations of these computational techniques complement experiments and address many relevant biological problems, as we will illustrate with special focus on epigenetic modulation of chromatin structure.

  20. Vaccine hesitancy: understanding better to address better.

    PubMed

    Kumar, Dewesh; Chandra, Rahul; Mathur, Medha; Samdariya, Saurabh; Kapoor, Neelesh

    2016-01-01

    Vaccine hesitancy is an emerging term in the socio-medical literature which describes an approach to vaccine decision making. It recognizes that there is a continuum between full acceptance and outright refusal of some or all vaccines and challenges the previous understanding of individuals or groups, as being either anti-vaccine or pro-vaccine. The behaviours responsible for vaccine hesitancy can be related to confidence, convenience and complacency. The causes of vaccine hesitancy can be described by the epidemiological triad i.e. the complex interaction of environmental- (i.e. external), agent- (i.e. vaccine) and host (or parent)- specific factors. Vaccine hesitancy is a complex and dynamic issue; future vaccination programs need to reflect and address these context-specific factors in both their design and evaluation. Many experts are of the view that it is best to counter vaccine hesitancy at the population level. They believe that it can be done by introducing more transparency into policy decision-making before immunization programs, providing up-to-date information to the public and health providers about the rigorous procedures undertaken before introduction of new vaccines, and through diversified post-marketing surveillance of vaccine-related events. PMID:26839681

  1. Modulation and anisotropy of galactic cosmic rays in the heliosphere

    NASA Technical Reports Server (NTRS)

    Kota, J.

    1986-01-01

    Modulation model are discussed with more time spent on two current ideas: episodic modulation and drift models. The various types of anisotropies are addressed. Finally, other time variations and correlation studies are reviewed.

  2. Innovative patient-centered skills training addressing challenging issues in cancer communications: Using patient's stories that teach.

    PubMed

    Bishop, Thomas W; Gorniewicz, James; Floyd, Michael; Tudiver, Fred; Odom, Amy; Zoppi, Kathy

    2016-05-01

    This workshop demonstrated the utility of a patient-centered web-based/digital Breaking Bad News communication training module designed to educate learners of various levels and disciplines. This training module is designed for independent, self-directed learning as well as group instruction. These interactive educational interventions are based upon video-recorded patient stories. Curriculum development was the result of an interdisciplinary, collaborative effort involving faculty from the East Tennessee State University (ETSU) Graduate Storytelling Program and the departments of Family and Internal Medicine at the James H. Quillen College of Medicine. The specific goals of the BBN training module are to assist learners in: (1) understanding a five-step patient-centered model that is based upon needs, preferences, and expectations of patients with cancer and (2) individualizing communication that is consistent with patient preferences in discussing emotions, informational detail, prognosis and timeline, and whether or not to discuss end-of-life issues. The pedagogical approach to the training module is to cycle through Emotional Engagement, Data, Modeled Practices, Adaptation Opportunities, and Feedback. The communication skills addressed are rooted in concepts found within the Reaching Common Ground communication training. A randomized control study investigating the effectiveness of the Breaking Bad News module found that medical students as well as resident physicians improved their communication skills as measured by an Objective Structured Clinical Examination. Four other similarly designed modules were also created: Living Through Treatment, Transitions: From Curable to Treatable/From Treatable to End-of-Life, Spirituality, and Family. PMID:27497456

  3. Addressing health literacy in patient decision aids

    PubMed Central

    2013-01-01

    in which health literacy needs were addressed. Conclusion Lower health literacy affects key decision-making outcomes, but few existing PtDAs have addressed the needs of lower health literacy users. The specific effects of PtDAs designed to mitigate the influence of low health literacy are unknown. More attention to the needs of patients with lower health literacy is indicated, to ensure that PtDAs are appropriate for lower as well as higher health literacy patients. PMID:24624970

  4. Addressing submarine geohazards through scientific drilling

    NASA Astrophysics Data System (ADS)

    Camerlenghi, A.

    2009-04-01

    eruptions, earthquakes and the associated tsunamis can lead to destruction of seafloor structures potentially capable of releasing hydrocarbon pollutants into Mediterranean waters, and damage to a dense telecommunication cables net that would cause severe economic loss. However, the most devastating effect would be that of earthquake or landslide-induced tsunamis. When compared to other basins, the Mediterranean has larger vulnerability due to its small dimensions, resulting in close proximity to tsunami sources and impact areas. Recent examples include the 1979 Nice airport submarine landslide and tsunami and the 2002 Stromboli volcano landslide and tsunami. Future international scientific drilling must include submarine geohazards among priority scientific objectives. The science advisory structure must be prepared to receive and evaluate proposal specifically addressing submarine geohazards. The implementing organizations need to be prepared for the technological needs of drilling proposals addressing geohazards. Among the most relevant: geotechnical sampling, down-hole logging at shallow depths below the seafloor, in situ geotechnical and physical measurements, capability of deployment of long-term in situ observatories. Pre-site surveys will often aim at the highest possible resolution, three dimensional imaging of the seafloor ant its sub-surface. Drilling for submarine geohazards is seen as an opportunity of multiplatform drilling, and for Mission Specific drilling in particular. Rather than turning the scientific investigation in a purely engineering exercise, proposals addressing submarine geohazards should offer an opportunity to scientists and engineers to work together to unravel the details of basic geological processes that may turn into catastrophic events.

  5. 32 CFR 516.7 - Mailing addresses.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 3 2011-07-01 2009-07-01 true Mailing addresses. 516.7 Section 516.7 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY AID OF CIVIL AUTHORITIES AND PUBLIC RELATIONS LITIGATION General § 516.7 Mailing addresses. Mailing addresses for organizations referenced...

  6. 47 CFR 97.23 - Mailing address.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Mailing address. 97.23 Section 97.23 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO... name and mailing address. The mailing address must be in an area where the amateur service is...

  7. 47 CFR 97.23 - Mailing address.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Mailing address. 97.23 Section 97.23 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO... name and mailing address. The mailing address must be in an area where the amateur service is...

  8. 47 CFR 97.23 - Mailing address.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Mailing address. 97.23 Section 97.23 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO... name and mailing address. The mailing address must be in an area where the amateur service is...

  9. 47 CFR 97.23 - Mailing address.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Mailing address. 97.23 Section 97.23 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO... name and mailing address. The mailing address must be in an area where the amateur service is...

  10. 47 CFR 97.23 - Mailing address.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Mailing address. 97.23 Section 97.23 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO... name and mailing address. The mailing address must be in an area where the amateur service is...

  11. 47 CFR 13.10 - Licensee address.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Licensee address. 13.10 Section 13.10 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL COMMERCIAL RADIO OPERATORS General § 13.10 Licensee address. In accordance with § 1.923 of this chapter all applications must specify an address where...

  12. CCCC Chair's Address: Representing Ourselves, 2008

    ERIC Educational Resources Information Center

    Glenn, Cheryl

    2008-01-01

    This article presents the text of the author's address at the fifty-ninth annual convention of the Conference on College Composition and Communication (CCCC) in March 2008. In her address, the author picks up strands of previous Chairs' addresses and weaves them through the fabric of her remarks. What she hopes will give sheen to the fabric is her…

  13. 75 FR 49813 - Change of Address

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-16

    ... COMMISSION 11 CFR Parts 9405, 9407, 9409, 9410, 9420, and 9428 Change of Address AGENCY: United States... Assistance Commission (EAC) is amending its regulations to reflect a change of address for its headquarters. This technical amendment is a nomenclature change that updates and corrects the address for...

  14. 32 CFR 516.7 - Mailing addresses.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 3 2010-07-01 2010-07-01 true Mailing addresses. 516.7 Section 516.7 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY AID OF CIVIL AUTHORITIES AND PUBLIC RELATIONS LITIGATION General § 516.7 Mailing addresses. Mailing addresses for organizations referenced...

  15. Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: Identification of target cells and a potential role for modulation of apoptosis in benzene toxicity

    SciTech Connect

    Ross, D.; Siegel, D.; Schattenberg, D.G.

    1996-12-01

    The role of cell-specific metabolism in benzene toxicity was examined in both murine and human bone marrow. Hemopoietic progenitor cells and stromal cells are important control points for regulation of hemopoiesis. We show that the selective toxicity of hydroquinone at the level of the macrophage in murine bone marrow stroma may be explained by a high peroxidase/nicotanimicle adenine dinucleotide phosphate, reduced [NAD(P)H]:quinone oxidoreductase (NQO1) ratio. Peroxidases metabolize hydroquinone to the reactive 1,4-benzoquinone, whereas NQO1 reduces the quinones formed, resulting in detoxification. Peroxidase and NQO1 activity in human stromal cultures vary as a function of time in culture, with peroxidase activity decreasing and NQO1 activity increasing with time. Peroxidase activity and, more specifically, myeloperoxidase, which had previously been considered to be expressed at the promyelocyte level, was detected in murine lineage-negative and human CD34{sup +} progenitor cells. This provides a metabolic mechanism whereby phenolic metabolites of benzene can be bioactivated in progenitor cells, which are considered initial target cells for the development of leukemias. Consequences of a high peroxidase/NQO1 ratio in HL-60 cells were shown to include hydroquinone-induced apoptosis. Hydroquinone can also inhibit proteases known to play a role in induction of apoptosis, suggesting that it may be able to inhibit apoptosis induced by other stimuli. Modulation of apoptosis may lead to aberrant hemopoiesis and neoplastic progression. This enzyme-directed approach has identified target cells of the phenolic metabolites of benzene in bone marrow and provided a metabolic basis for benzene-induced toxicity at the level of the progenitor cell in both murine and human bone marrow. 60 refs., 8 figs.

  16. An addressable cell array for a platform of biosensor chips

    NASA Astrophysics Data System (ADS)

    Yang, Seungkyoung; Choi, Soo-hee; Jung, Moon Youn; Song, Kibong; Park, Jeong Won

    2013-05-01

    In order to detect interested matters in fields, various lab-on-a-chips where chemical, physical, or biological sensors are loaded have been developed. eNOSE can be a representative example among them. Because animals can sense 300~1000 different chemicals by olfactory system - smell -, the olfactory system has been spotlighted as new materials in the field of sensing. Those investigations, however, are usually focused on how to detect signals from the olfactory neurons or receptors loaded on chips and enhance sensing efficacy of chips. Therefore, almost of those chips are designed for only one material sensing. Multi-sensing using multi-channels will be needed when the olfactory systems are adopted well on chips. For multiple sensing, we developed an addressable cell array. The chip has 38 cell-chambers arranged in a circle shape and different cell types of thirty eight can be allocated with specific addresses on the chip without any complex valve system. In order to confirm the cell addressing, we loaded EGFP-transfected and empty vector-transfected HEK293a cells into inlets of the cell array in a planned address and those cells were positioned into each chamber by brief aspiration. The arrayed cells were confirmed as a specific pattern through EGFP and nuclei staining. This cell array which can generate address of sensor materials like cells with their own specification is expected to be applied to a platform for a biosensor chip at various sensing fields.

  17. Drupal Contributed Modules

    2014-10-01

    These Drupal Modules extend the functionality of Drupal by including specific styles for dates and tabs, publishing options for scheduled and immediate publication of content modes, field visibility in content forms, keyword block filters (taxonomy based), adding content nodes to a specified queue for display in views, and status display of workflow settings.

  18. Packaging of electronic modules

    NASA Technical Reports Server (NTRS)

    Katzin, L.

    1966-01-01

    Study of design approaches that are taken toward optimizing the packaging of electronic modules with respect to size, shape, component orientation, interconnections, and structural support. The study does not present a solution to specific packaging problems, but rather the factors to be considered to achieve optimum packaging designs.

  19. Addressing Heart Failure Challenges through Illness-Informed Social Work.

    PubMed

    Hopp, Faith Pratt; Camp, Jessica K; Perry, Tam E

    2015-08-01

    This article describes the role of social workers in addressing the needs of people with heart failure. Although previous studies have explored the role of social workers in health care settings, few studies have addressed the challenges of specific chronic diseases such as heart failure. To address this gap in the literature, this study used qualitative interviews with health care social workers (n = 8) to obtain in-depth information about activities and challenges related to heart failure care. Findings suggest that health care social workers perceive heart failure as characterized by an uncertain illness trajectory, frequent hospitalizations, and difficulties accessing formal and informal care. These findings suggest the importance of what we term illness-informed social work, a practice that combines heart failure knowledge with social work competencies to address the complex psychosocial issues in heart failure care. PMID:26285359

  20. 14th Workshop on Crystalline Silicon Solar Cells& Modules: Materials and Processes; Summary of Discussion Sessions

    SciTech Connect

    Sopori, B.; Tan, T.; Sinton, R.; Swanson, D.

    2004-10-01

    The 14th Workshop discussion sessions addressed funding needs for Si research and for R&D to enhance U.S. PV manufacturing. The wrap-up session specifically addressed topics for the new university silicon program. The theme of the workshop, Crystalline Silicon Solar Cells: Leapfrogging the Barriers, was selected to reflect the astounding progress in Si PV technology during last three decades, despite a host of barriers and bottlenecks. A combination of oral, poster, and discussion sessions addressed recent advances in crystal growth technology, new cell structures and doping methods, silicon feedstock issues, hydrogen passivation and fire through metallization, and module issues/reliability. The following oral/discussion sessions were conducted: (1) Technology Update; (2) Defects and Impurities in Si/Discussion; (3) Rump Session; (4) Module Issues and Reliability/Discussion; (5) Silicon Feedstock/Discussion; (6) Novel Doping, Cells, and Hetero-Structure Designs/Discussion; (7) Metallization/Silicon Nitride Processing/Discussion; (8) Hydrogen Passivation/Discussion; (9) Characterization/Discussion; and (10) Wrap-Up. This year's workshop lasted three and a half days and, for the first time, included a session on Si modules. A rump session was held on the evening of August 8, which addressed efficiency expectations and challenges of c Si solar cells/modules. Richard King of DOE and Daren Dance of Wright Williams& Kelly (formerly of Sematech) spoke at two of the luncheon sessions. Eleven students received Graduate Student Awards from funds contributed by the PV industry.