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Sample records for cell autonomous requirement

  1. Autonomous Real Time Requirements Tracing

    Science.gov (United States)

    Plattsmier, George; Stetson, Howard

    2014-01-01

    One of the more challenging aspects of software development is the ability to verify and validate the functional software requirements dictated by the Software Requirements Specification (SRS) and the Software Detail Design (SDD). Insuring the software has achieved the intended requirements is the responsibility of the Software Quality team and the Software Test team. The utilization of Timeliner-TLX(sup TM) Auto- Procedures for relocating ground operations positions to ISS automated on-board operations has begun the transition that would be required for manned deep space missions with minimal crew requirements. This transition also moves the auto-procedures from the procedure realm into the flight software arena and as such the operational requirements and testing will be more structured and rigorous. The autoprocedures would be required to meet NASA software standards as specified in the Software Safety Standard (NASASTD- 8719), the Software Engineering Requirements (NPR 7150), the Software Assurance Standard (NASA-STD-8739) and also the Human Rating Requirements (NPR-8705). The Autonomous Fluid Transfer System (AFTS) test-bed utilizes the Timeliner-TLX(sup TM) Language for development of autonomous command and control software. The Timeliner-TLX(sup TM) system has the unique feature of providing the current line of the statement in execution during real-time execution of the software. The feature of execution line number internal reporting unlocks the capability of monitoring the execution autonomously by use of a companion Timeliner-TLX(sup TM) sequence as the line number reporting is embedded inside the Timeliner-TLX(sup TM) execution engine. This negates I/O processing of this type data as the line number status of executing sequences is built-in as a function reference. This paper will outline the design and capabilities of the AFTS Autonomous Requirements Tracker, which traces and logs SRS requirements as they are being met during real-time execution of the

  2. Requirement analysis for autonomous systems and intelligent ...

    African Journals Online (AJOL)

    First we review innovative control architectures in electric power systems such as Microgrids, Virtual power plants and Cell based systems. We evaluate application of autonomous systems and intelligent agents in each of these control architectures particularly in the context of Denmark's strategic energy plans. The second ...

  3. Tbx1 is required autonomously for cell survival and fate in the pharyngeal core mesoderm to form the muscles of mastication

    Science.gov (United States)

    Kong, Ping; Racedo, Silvia E.; Macchiarulo, Stephania; Hu, Zunju; Carpenter, Courtney; Guo, Tingwei; Wang, Tao; Zheng, Deyou; Morrow, Bernice E.

    2014-01-01

    Velo-cardio-facial/DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a congenital anomaly disorder characterized by craniofacial anomalies including velo-pharyngeal insufficiency, facial muscle hypotonia and feeding difficulties, in part due to hypoplasia of the branchiomeric muscles. Inactivation of both alleles of mouse Tbx1, encoding a T-box transcription factor, deleted on chromosome 22q11.2, results in reduction or loss of branchiomeric muscles. To identify downstream pathways, we performed gene profiling of microdissected pharyngeal arch one (PA1) from Tbx1+/+ and Tbx1−/− embryos at stages E9.5 (somites 20–25) and E10.5 (somites 30–35). Basic helix–loop–helix (bHLH) transcription factors were reduced, while secondary heart field genes were increased in expression early and were replaced by an increase in expression of cellular stress response genes later, suggesting a change in gene expression patterns or cell populations. Lineage tracing studies using Mesp1Cre and T-Cre drivers showed that core mesoderm cells within PA1 were present at E9.5 but were greatly reduced by E10.5 in Tbx1−/− embryos. Using Tbx1Cre knock-in mice, we found that cells are lost due to apoptosis, consistent with increase in expression of cellular stress response genes at E10.5. To determine whether Tbx1 is required autonomously in the core mesoderm, we used Mesp1Cre and T-Cre mesodermal drivers in combination with inactivate Tbx1 and found reduction or loss of branchiomeric muscles from PA1. These mechanistic studies inform us that Tbx1 is required upstream of key myogenic genes needed for core mesoderm cell survival and fate, between E9.5 and E10.5, resulting in formation of the branchiomeric muscles. PMID:24705356

  4. Capturing Requirements for Autonomous Spacecraft with Autonomy Requirements Engineering

    Science.gov (United States)

    Vassev, Emil; Hinchey, Mike

    2014-08-01

    The Autonomy Requirements Engineering (ARE) approach has been developed by Lero - the Irish Software Engineering Research Center within the mandate of a joint project with ESA, the European Space Agency. The approach is intended to help engineers develop missions for unmanned exploration, often with limited or no human control. Such robotics space missions rely on the most recent advances in automation and robotic technologies where autonomy and autonomic computing principles drive the design and implementation of unmanned spacecraft [1]. To tackle the integration and promotion of autonomy in software-intensive systems, ARE combines generic autonomy requirements (GAR) with goal-oriented requirements engineering (GORE). Using this approach, software engineers can determine what autonomic features to develop for a particular system (e.g., a space mission) as well as what artifacts that process might generate (e.g., goals models, requirements specification, etc.). The inputs required by this approach are the mission goals and the domain-specific GAR reflecting specifics of the mission class (e.g., interplanetary missions).

  5. cFS-based Autonomous Requirements Testing Tool, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — The S&K Team proposes design of a tool suite, Autonomy Requirements Tester (ART), to address the difficulty of stating autonomous requirements and the links to...

  6. Cheap electricity with autonomous solar cell systems

    International Nuclear Information System (INIS)

    Ouwens, C.D.

    1993-01-01

    A comparison has been made between the costs of an autonomous solar cell system and a centralized electricity supply system. In both cases investment costs are the main issue. It is shown that for households in densely populated sunny areas, the use of autonomous solar cell systems is - even with today's market prices - only as expensive or even cheaper than a grid connection, as long as efficient electric appliances are used. The modular nature of solar cell systems makes it possible to start with any number of appliances, depending on the amount of money available to be spent. (author)

  7. Requirement analysis for autonomous systems and intelligent ...

    African Journals Online (AJOL)

    user

    Danish Power System and a requirement analysis for the use of intelligent agents and ..... tries to make an optimal islanding plan at this state and tries to blackstart. ... 4 Foundation for Physical Intelligent Agents (FIPA): http://www.fipa.org ...

  8. Zebrafish model of tuberous sclerosis complex reveals cell-autonomous and non-cell-autonomous functions of mutant tuberin

    Directory of Open Access Journals (Sweden)

    Seok-Hyung Kim

    2011-03-01

    Tuberous sclerosis complex (TSC is an autosomal dominant disease caused by mutations in either the TSC1 (encodes hamartin or TSC2 (encodes tuberin genes. Patients with TSC have hamartomas in various organs throughout the whole body, most notably in the brain, skin, eye, heart, kidney and lung. To study the development of hamartomas, we generated a zebrafish model of TSC featuring a nonsense mutation (vu242 in the tsc2 gene. This tsc2vu242 allele encodes a truncated Tuberin protein lacking the GAP domain, which is required for inhibition of Rheb and of the TOR kinase within TORC1. We show that tsc2vu242 is a recessive larval-lethal mutation that causes increased cell size in the brain and liver. Greatly elevated TORC1 signaling is observed in tsc2vu242/vu242 homozygous zebrafish, and is moderately increased in tsc2vu242/+ heterozygotes. Forebrain neurons are poorly organized in tsc2vu242/vu242 homozygous mutants, which have extensive gray and white matter disorganization and ectopically positioned cells. Genetic mosaic analyses demonstrate that tsc2 limits TORC1 signaling in a cell-autonomous manner. However, in chimeric animals, tsc2vu242/vu242 mutant cells also mislocalize wild-type host cells in the forebrain in a non-cell-autonomous manner. These results demonstrate a highly conserved role of tsc2 in zebrafish and establish a new animal model for studies of TSC. The finding of a non-cell-autonomous function of mutant cells might help explain the formation of brain hamartomas and cortical malformations in human TSC.

  9. Autonomous patterning of cells on microstructured fine particles

    International Nuclear Information System (INIS)

    Takeda, Iwori; Kawanabe, Masato; Kaneko, Arata

    2015-01-01

    Regularly patterned cells can clarify cellular function and are required in some biochip applications. This study examines cell patterning along microstructures and the effect of microstructural geometry on selective cellular adhesion. Particles can be autonomously assembled on a soda-lime glass substrate that is chemically patterned by immersion in a suspension of fine particles. By adopting various sizes of fine particles, we can control the geometry of the microstructure. Cells adhere more readily to microstructured fine particles than to flat glass substrate. Silica particles hexagonally packed in 5–40 μm line and space microstructures provide an effective cell scaffold on the glass substrate. Cultured cells tend to attach and proliferate along the microstructured region while avoiding the flat region. The difference in cell adhesion is attributed to their geometries, as both of the silica particles and soda-lime glass are hydrophilic related with cell adhesiveness. After cell seeding, cells adhered to the flat region migrated toward the microstructured region. For most of the cells to assemble on the scaffold, the scaffolding microstructures must be spaced by at most 65 μm. - Highlights: • PS and SiO 2 particles provide effective scaffolds for cells. • Cells that adhere to microstructured particles successfully proliferate and differentiate. • Selective adhesion and growth along the scaffold can be achieved by patterning the fine particle microstructure. • Cells adhered to flat regions migrate toward microstructured regions. • Selective adhesion by cells depends on the microstructural geometry; specifically, on the inter-line spacing

  10. Navy Requirements for Controlling Multiple Off-Board Robots Using the Autonomous Unmanned Vehicle Workbench

    National Research Council Canada - National Science Library

    Monroe, Dennis W

    2007-01-01

    ... after a mission. This thesis examines a variety of strategic authoritative plans for autonomous vehicles to determine functional mission requirements that autonomous vehicles are expected to be performing in the near future...

  11. Autonomous Scheduling Requirements for Agile Cubesat Constellations in Earth Observation

    Science.gov (United States)

    Nag, S.; Li, A. S. X.; Kumar, S.

    2017-12-01

    Distributed Space Missions such as formation flight and constellations, are being recognized as important Earth Observation solutions to increase measurement samples over space and time. Cubesats are increasing in size (27U, 40 kg) with increasing capabilities to host imager payloads. Given the precise attitude control systems emerging commercially, Cubesats now have the ability to slew and capture images within short notice. Prior literature has demonstrated a modular framework that combines orbital mechanics, attitude control and scheduling optimization to plan the time-varying orientation of agile Cubesats in a constellation such that they maximize the number of observed images, within the constraints of hardware specs. Schedule optimization is performed on the ground autonomously, using dynamic programming with two levels of heuristics, verified and improved upon using mixed integer linear programming. Our algorithm-in-the-loop simulation applied to Landsat's use case, captured up to 161% more Landsat images than nadir-pointing sensors with the same field of view, on a 2-satellite constellation over a 12-hour simulation. In this paper, we will derive the requirements for the above algorithm to run onboard small satellites such that the constellation can make time-sensitive decisions to slew and capture images autonomously, without ground support. We will apply the above autonomous algorithm to a time critical use case - monitoring of precipitation and subsequent effects on floods, landslides and soil moisture, as quantified by the NASA Unified Weather Research and Forecasting Model. Since the latency between these event occurrences is quite low, they make a strong case for autonomous decisions among satellites in a constellation. The algorithm can be implemented in the Plan Execution Interchange Language - NASA's open source technology for automation, used to operate the International Space Station and LADEE's in flight software - enabling a controller

  12. Non-cell autonomous or secretory tumor suppression.

    Science.gov (United States)

    Chua, Christelle En Lin; Chan, Shu Ning; Tang, Bor Luen

    2014-10-01

    Many malignancies result from deletions or loss-of-function mutations in one or more tumor suppressor genes, the products of which curb unrestrained growth or induce cell death in those with dysregulated proliferative capacities. Most tumor suppressors act in a cell autonomous manner, and only very few proteins are shown to exert a non-cell autonomous tumor suppressor function on other cells. Examples of these include members of the secreted frizzled-related protein (SFRP) family and the secreted protein acidic and rich in cysteine (SPARC)-related proteins. Very recent findings have, however, considerably expanded our appreciation of non-cell autonomous tumor suppressor functions. Broadly, this may occur in two ways. Intracellular tumor suppressor proteins within cells could in principle inhibit aberrant growth of neighboring cells by conditioning an antitumor microenvironment through secreted factors. This is demonstrated by an apparent non-cell autonomous tumor suppressing property of p53. On the other hand, a tumor suppressor produced by a cell may be secreted extracellularly, and taken up by another cell with its activity intact. Intriguingly, this has been recently shown to occur for the phosphatase and tensin homolog (PTEN) by both conventional and unconventional modes of secretion. These recent findings would aid the development of therapeutic strategies that seek to reinstate tumor suppression activity in therapeutically recalcitrant tumor cells, which have lost it in the first place. © 2014 Wiley Periodicals, Inc.

  13. Autonomous Voltage Oscillations in a Direct Methanol Fuel Cell

    International Nuclear Information System (INIS)

    Nogueira, Jéssica A.; Peña Arias, Ivonne K.; Hanke-Rauschenbach, Richard; Vidakovic-Koch, Tanja; Varela, Hamilton; Sundmacher, Kai

    2016-01-01

    Proton exchange membrane fuel cells fed with H_2/CO mixtures at the anode have a considerably lower performance than fuel cells fed with pure hydrogen. However, when operated in an autonomous oscillatory regime, the overall voltage loss decreases due to a self-cleaning mechanism. Another molecule, also widely used as feed in the fuel cell and susceptible to kinetic instabilities, is methanol. To the best of our knowledge, there are no reports on autonomous voltage oscillations in the direct methanol fuel cell (DMFC). The purpose of this work was to explore if such instabilities also occur in the DMFC system. Initially, half-cell experiments with a gas diffusion electrode were performed. Then, a DMFC was operated under current control and studied by means of electrochemical impedance spectroscopy. The half-cell measurements revealed that the induction period for oscillations depends on the mass transfer conditions, where on stagnant electrode the induction time was shorter than in the case of forced convection. The DMFC showed also autonomous voltage oscillations above a certain threshold current. The results obtained by electrochemical impedance spectroscopy give evidence of a negative differential resistance in the fuel cell, hitherto not described in the literature, which can be related to the appearance of oscillations during galvanostatic methanol electro-oxidation. These results open the possibility to evaluate the performance of low-temperature fuel cells fed with carbon-containing fuels under oscillatory operating conditions.

  14. Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

    Science.gov (United States)

    Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

    2010-01-01

    The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

  15. Towards autonomous lab-on-a-chip devices for cell phone biosensing.

    Science.gov (United States)

    Comina, Germán; Suska, Anke; Filippini, Daniel

    2016-03-15

    Modern cell phones are a ubiquitous resource with a residual capacity to accommodate chemical sensing and biosensing capabilities. From the different approaches explored to capitalize on such resource, the use of autonomous disposable lab-on-a-chip (LOC) devices-conceived as only accessories to complement cell phones-underscores the possibility to entirely retain cell phones' ubiquity for distributed biosensing. The technology and principles exploited for autonomous LOC devices are here selected and reviewed focusing on their potential to serve cell phone readout configurations. Together with this requirement, the central aspects of cell phones' resources that determine their potential for analytical detection are examined. The conversion of these LOC concepts into universal architectures that are readable on unaccessorized phones is discussed within this context. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Requirement analysis for autonomous systems and intelligent agents in future Danish electric power systems

    DEFF Research Database (Denmark)

    Saleem, Arshad; Lind, Morten

    2010-01-01

    we review innovative control architectures in electric power systems such as Microgrids, Virtual power plants and Cell based systems. We evaluate application of autonomous systems and intelligent agents in each of these control architectures particularly in the context of Denmark's strategic energy...... plans. The second part formulates a flexible control architecture for electric power systems with very high penetration of distributed generation. This control architecture is based upon the requirements identified in the first part. We also present development of a software framework to test......Denmark has already achieved a record of 20% penetration of wind power and now moving towards even higher targets with an increasing part of the electricity produced by distributed generators (DGs). In this paper we report work from a sub activity "subgrid design" of the EcoGrid.dk project. First...

  17. Autonomously bioluminescent mammalian cells for continuous and real-time monitoring of cytotoxicity.

    Science.gov (United States)

    Xu, Tingting; Close, Dan M; Webb, James D; Ripp, Steven A; Sayler, Gary S

    2013-10-28

    Mammalian cell-based in vitro assays have been widely employed as alternatives to animal testing for toxicological studies but have been limited due to the high monetary and time costs of parallel sample preparation that are necessitated due to the destructive nature of firefly luciferase-based screening methods. This video describes the utilization of autonomously bioluminescent mammalian cells, which do not require the destructive addition of a luciferin substrate, as an inexpensive and facile method for monitoring the cytotoxic effects of a compound of interest. Mammalian cells stably expressing the full bacterial bioluminescence (luxCDABEfrp) gene cassette autonomously produce an optical signal that peaks at 490 nm without the addition of an expensive and possibly interfering luciferin substrate, excitation by an external energy source, or destruction of the sample that is traditionally performed during optical imaging procedures. This independence from external stimulation places the burden for maintaining the bioluminescent reaction solely on the cell, meaning that the resultant signal is only detected during active metabolism. This characteristic makes the lux-expressing cell line an excellent candidate for use as a biosentinel against cytotoxic effects because changes in bioluminescent production are indicative of adverse effects on cellular growth and metabolism. Similarly, the autonomous nature and lack of required sample destruction permits repeated imaging of the same sample in real-time throughout the period of toxicant exposure and can be performed across multiple samples using existing imaging equipment in an automated fashion.

  18. Small nuclear reactor safety design requirements for autonomous operation

    International Nuclear Information System (INIS)

    Kozier, K.S.; Kupca, S.

    1997-01-01

    Small nuclear power reactors offer compelling safety advantages in terms of the limited consequences that can arise from major accident events and the enhanced ability to use reliable, passive means to eliminate their occurrence by design. Accordingly, for some small reactor designs featuring a high degree of safety autonomy, it may be-possible to delineate a ''safety envelope'' for a given set of reactor circumstances within which safe reactor operation can be guaranteed without outside intervention for time periods of practical significance (i.e., days or weeks). The capability to operate a small reactor without the need for highly skilled technical staff permanently present, but with continuous remote monitoring, would aid the economic case for small reactors, simplify their use in remote regions and enhance safety by limiting the potential for accidents initiated by inappropriate operator action. This paper considers some of the technical design options and issues associated with the use of small power reactors in an autonomous mode for limited periods. The focus is on systems that are suitable for a variety of applications, producing steam for electricity generation, district heating, water desalination and/or marine propulsion. Near-term prospects at low power levels favour the use of pressurized, light-water-cooled reactor designs, among which those having an integral core arrangement appear to offer cost and passive-safety advantages. Small integral pressurized water reactors have been studied in many countries, including the test operation of prototype systems. (author)

  19. Computational cell model based on autonomous cell movement regulated by cell-cell signalling successfully recapitulates the "inside and outside" pattern of cell sorting

    Directory of Open Access Journals (Sweden)

    Ajioka Itsuki

    2007-09-01

    Full Text Available Abstract Background Development of multicellular organisms proceeds from a single fertilized egg as the combined effect of countless numbers of cellular interactions among highly dynamic cells. Since at least a reminiscent pattern of morphogenesis can be recapitulated in a reproducible manner in reaggregation cultures of dissociated embryonic cells, which is known as cell sorting, the cells themselves must possess some autonomous cell behaviors that assure specific and reproducible self-organization. Understanding of this self-organized dynamics of heterogeneous cell population seems to require some novel approaches so that the approaches bridge a gap between molecular events and morphogenesis in developmental and cell biology. A conceptual cell model in a computer may answer that purpose. We constructed a dynamical cell model based on autonomous cell behaviors, including cell shape, growth, division, adhesion, transformation, and motility as well as cell-cell signaling. The model gives some insights about what cellular behaviors make an appropriate global pattern of the cell population. Results We applied the model to "inside and outside" pattern of cell-sorting, in which two different embryonic cell types within a randomly mixed aggregate are sorted so that one cell type tends to gather in the central region of the aggregate and the other cell type surrounds the first cell type. Our model can modify the above cell behaviors by varying parameters related to them. We explored various parameter sets with which the "inside and outside" pattern could be achieved. The simulation results suggested that direction of cell movement responding to its neighborhood and the cell's mobility are important for this specific rearrangement. Conclusion We constructed an in silico cell model that mimics autonomous cell behaviors and applied it to cell sorting, which is a simple and appropriate phenomenon exhibiting self-organization of cell population. The model

  20. An autonomous fuel-cell system. Optimisation approach; Ein autonomes Brennstoffzellensystem. Optimierungsansaetze

    Energy Technology Data Exchange (ETDEWEB)

    Heideck, Guenter

    2006-07-20

    The reduction of the consumption of fossil energy sources and CO2 Emissions has become a worldwide issue. One promising way to accomplish this is by using hydrogen, which is predominantly produced by renewable energy sources, as energy storage. Fuel cell technology will play a key role in the field of converting chemically stored energy into electrical energy. This work contributes ways to make this conversion more effective. Because autonomous fuel cell systems have the largest application potential, this work concentrates on their optimization. To clarify the interrelationship of the parameters and the influencing physical factors as well as the potentials of optimization, models in the form of mathematical equation systems are given in the main part of this work. The focus is on the energy balance of the subsystems. The theoretical analyses showed that with improved efficiency of single subsystems, the system efficiency does not necessarily improve too, because the subsystems are not free of interactions. Instead, the system efficiency is improved through adapting single subsystems to match the needs of a given application. (orig.)

  1. Amnioserosa cell constriction but not epidermal actin cable tension autonomously drives dorsal closure.

    Science.gov (United States)

    Pasakarnis, Laurynas; Frei, Erich; Caussinus, Emmanuel; Affolter, Markus; Brunner, Damian

    2016-11-01

    Tissue morphogenesis requires coordination of multiple force-producing components. During dorsal closure in fly embryogenesis, an epidermis opening closes. A tensioned epidermal actin/MyosinII cable, which surrounds the opening, produces a force that is thought to combine with another MyosinII force mediating apical constriction of the amnioserosa cells that fill the opening. A model proposing that each force could autonomously drive dorsal closure was recently challenged by a model in which the two forces combine in a ratchet mechanism. Acute force elimination via selective MyosinII depletion in one or the other tissue shows that the amnioserosa tissue autonomously drives dorsal closure while the actin/MyosinII cable cannot. These findings exclude both previous models, although a contribution of the ratchet mechanism at dorsal closure onset remains likely. This shifts the current view of dorsal closure being a combinatorial force-component system to a single tissue-driven closure event.

  2. Organic solar cell modules for specific applications-From energy autonomous systems to large area photovoltaics

    International Nuclear Information System (INIS)

    Niggemann, M.; Zimmermann, B.; Haschke, J.; Glatthaar, M.; Gombert, A.

    2008-01-01

    We report on the development of two types of organic solar cell modules one for energy autonomous systems and one for large area energy harvesting. The first requires a specific tailoring of the solar cell geometry and cell interconnection in order to power an energy autonomous system under its specific operating conditions. We present an organic solar cell module with 22 interconnected solar cells. A power conversion efficiency of 2% under solar illumination has been reached on the active area of 46.2 cm 2 . A voltage of 4 V at the maximum power point has been obtained under indoor illumination conditions. Micro contact printing of a self assembling monolayer was employed for the patterning of the polymer anode. Large area photovoltaic modules have to meet the requirements on efficiency, lifetime and costs simultaneously. To minimize the production costs, a suitable concept for efficient reel-to-reel production of large area modules is needed. A major contribution to reduce the costs is the substitution of the commonly used indium tin oxide electrode by a cheap material. We present the state of the art of the anode wrap through concept as a reel-to-reel suited module concept and show comparative calculations of the module interconnection of the wrap through concept and the standard ITO-based cell architecture. As a result, the calculated overall module efficiency of the anode wrap through module exceeds the overall efficiency of modules based on ITO on glass (sheet resistance 15 Ω/square) and on foils (sheet resistance 60 Ω/square)

  3. hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature

    Directory of Open Access Journals (Sweden)

    Lisette M. Acevedo

    2015-06-01

    Full Text Available To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm-derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC, not the neural tube (NT. Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC-secreted nitric oxide (NO and direct contact with vascular smooth muscle cells (VSMCs via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning.

  4. TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-autonomously in Caenorhabditis elegans.

    Science.gov (United States)

    McCallum, Katie C; Liu, Bin; Fierro-González, Juan Carlos; Swoboda, Peter; Arur, Swathi; Miranda-Vizuete, Antonio; Garsin, Danielle A

    2016-05-01

    The Caenorhabditis elegans oxidative stress response transcription factor, SKN-1, is essential for the maintenance of redox homeostasis and is a functional ortholog of the Nrf family of transcription factors. The numerous levels of regulation that govern these transcription factors underscore their importance. Here, we add a thioredoxin, encoded by trx-1, to the expansive list of SKN-1 regulators. We report that loss of trx-1 promotes nuclear localization of intestinal SKN-1 in a redox-independent, cell non-autonomous fashion from the ASJ neurons. Furthermore, this regulation is not general to the thioredoxin family, as two other C. elegans thioredoxins, TRX-2 and TRX-3, do not play a role in this process. Moreover, TRX-1-dependent regulation requires signaling from the p38 MAPK-signaling pathway. However, while TRX-1 regulates SKN-1 nuclear localization, classical SKN-1 transcriptional activity associated with stress response remains largely unaffected. Interestingly, RNA-Seq analysis revealed that loss of trx-1 elicits a general, organism-wide down-regulation of several classes of genes; those encoding for collagens and lipid transport being most prevalent. Together, these results uncover a novel role for a thioredoxin in regulating intestinal SKN-1 nuclear localization in a cell non-autonomous manner, thereby contributing to the understanding of the processes involved in maintaining redox homeostasis throughout an organism. Copyright © 2016 by the Genetics Society of America.

  5. From Extended Nanofluidics to an Autonomous Solar-Light-Driven Micro Fuel-Cell Device.

    Science.gov (United States)

    Pihosh, Yuriy; Uemura, Jin; Turkevych, Ivan; Mawatari, Kazuma; Kazoe, Yutaka; Smirnova, Adelina; Kitamori, Takehiko

    2017-07-03

    Autonomous micro/nano mechanical, chemical, and biomedical sensors require persistent power sources scaled to their size. Realization of autonomous micro-power sources is a challenging task, as it requires combination of wireless energy supply, conversion, storage, and delivery to the sensor. Herein, we realized a solar-light-driven power source that consists of a micro fuel cell (μFC) and a photocatalytic micro fuel generator (μFG) integrated on a single microfluidic chip. The μFG produces hydrogen by photocatalytic water splitting under solar light. The hydrogen fuel is then consumed by the μFC to generate electricity. Importantly, the by-product water returns back to the photocatalytic μFG via recirculation loop without losses. Both devices rely on novel phenomena in extended-nano-fluidic channels that ensure ultra-fast proton transport. As a proof of concept, we demonstrate that μFG/μFC source achieves remarkable energy density of ca. 17.2 mWh cm -2 at room temperature. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Drosophila heart cell movement to the midline occurs through both cell autonomous migration and dorsal closure.

    Science.gov (United States)

    Haack, Timm; Schneider, Matthias; Schwendele, Bernd; Renault, Andrew D

    2014-12-15

    The Drosophila heart is a linear organ formed by the movement of bilaterally specified progenitor cells to the midline and adherence of contralateral heart cells. This movement occurs through the attachment of heart cells to the overlying ectoderm which is undergoing dorsal closure. Therefore heart cells are thought to move to the midline passively. Through live imaging experiments and analysis of mutants that affect the speed of dorsal closure we show that heart cells in Drosophila are autonomously migratory and part of their movement to the midline is independent of the ectoderm. This means that heart formation in flies is more similar to that in vertebrates than previously thought. We also show that defects in dorsal closure can result in failure of the amnioserosa to properly degenerate, which can physically hinder joining of contralateral heart cells leading to a broken heart phenotype. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Investigation of autonomous cell cycle oscillation in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Hansen, Morten Skov

    2007-01-01

    Autonome Oscillationer i kontinuert kultivering af Saccharomyces cerevisiae Udgangspunktet for dette Ph.d. projekt var at søge at forstå, hvad der gør det muligt at opnå multiple statiske tilstande ved kontinuert kultivering af Saccharomyces cerevisiae med glukose som begrænsende substrat...

  8. Current State of Technology of Fuel Cell Power Systems for Autonomous Underwater Vehicles

    Directory of Open Access Journals (Sweden)

    Alejandro Mendez

    2014-07-01

    Full Text Available Autonomous Underwater Vehicles (AUVs are vehicles that are primarily used to accomplish oceanographic research data collection and auxiliary offshore tasks. At the present time, they are usually powered by lithium-ion secondary batteries, which have insufficient specific energies. In order for this technology to achieve a mature state, increased endurance is required. Fuel cell power systems have been identified as an effective means to achieve this endurance but no implementation in a commercial device has yet been realized. This paper summarizes the current state of development of the technology in this field of research. First, the most adequate type of fuel cell for this application is discussed. The prototypes and design concepts of AUVs powered by fuel cells which have been developed in the last few years are described. Possible commercial and experimental fuel cell stack options are analyzed, examining solutions adopted in the analogous aerial vehicle applications, as well as the underwater ones, to see if integration in an AUV is feasible. Current solutions in oxygen and hydrogen storage systems are overviewed and energy density is objectively compared between battery power systems and fuel cell power systems for AUVs. A couple of system configuration solutions are described including the necessary lithium-ion battery hybrid system. Finally, some closing remarks on the future of this technology are given.

  9. RoBlock: a prototype autonomous manufacturing cell

    Science.gov (United States)

    Baekdal, Lars K.; Balslev, Ivar; Eriksen, Rene D.; Jensen, Soren P.; Jorgensen, Bo N.; Kirstein, Brian; Kristensen, Bent B.; Olsen, Martin M.; Perram, John W.; Petersen, Henrik G.; Petersen, Morten L.; Ruhoff, Peter T.; Skjolstrup, Carl E.; Sorensen, Anders S.; Wagenaar, Jeroen M.

    2000-10-01

    RoBlock is the first phase of an internally financed project at the Institute aimed at building a system in which two industrial robots suspended from a gantry, as shown below, cooperate to perform a task specified by an external user, in this case, assembling an unstructured collection of colored wooden blocks into a specified 3D pattern. The blocks are identified and localized using computer vision and grasped with a suction cup mechanism. Future phases of the project will involve other processes such as grasping and lifting, as well as other types of robot such as autonomous vehicles or variable geometry trusses. Innovative features of the control software system include: The use of an advanced trajectory planning system which ensures collision avoidance based on a generalization of the method of artificial potential fields, the use of a generic model-based controller which learns the values of parameters, including static and kinetic friction, of a detailed mechanical model of itself by comparing actual with planned movements, the use of fast, flexible, and robust pattern recognition and 3D-interpretation strategies, integration of trajectory planning and control with the sensor systems in a distributed Java application running on a network of PC's attached to the individual physical components. In designing this first stage, the aim was to build in the minimum complexity necessary to make the system non-trivially autonomous and to minimize the technological risks. The aims of this project, which is planned to be operational during 2000, are as follows: To provide a platform for carrying out experimental research in multi-agent systems and autonomous manufacturing systems, to test the interdisciplinary cooperation architecture of the Maersk Institute, in which researchers in the fields of applied mathematics (modeling the physical world), software engineering (modeling the system) and sensor/actuator technology (relating the virtual and real worlds) could

  10. Endogenous TasiRNAs mediate non-cell autonomous effects on gene regulation in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Rebecca Schwab

    Full Text Available BACKGROUND: Different classes of small RNAs (sRNAs refine the expression of numerous genes in higher eukaryotes by directing protein partners to complementary nucleic acids, where they mediate gene silencing. Plants encode a unique class of sRNAs, called trans-acting small interfering RNAs (tasiRNAs, which post-transcriptionally regulate protein-coding transcripts, as do microRNAs (miRNAs, and both sRNA classes control development through their targets. TasiRNA biogenesis requires multiple components of the siRNA pathway and also miRNAs. But while 21mer siRNAs originating from transgenes can mediate silencing across several cell layers, miRNA action seems spatially restricted to the producing or closely surrounding cells. PRINCIPAL FINDINGS: We have previously described the isolation of a genetrap reporter line for TAS3a, the major locus producing AUXIN RESPONS FACTOR (ARF-regulating tasiRNAs in the Arabidopsis shoot. Its activity is limited to the adaxial (upper side of leaf primordia, thus spatially isolated from ARF-activities, which are located in the abaxial (lower side. We show here by in situ hybridization and reporter fusions that the silencing activities of ARF-regulating tasiRNAs are indeed manifested non-cell autonomously to spatially control ARF activities. CONCLUSIONS/SIGNIFICANCE: Endogenous tasiRNAs are thus mediators of a mobile developmental signal and might provide effective gene silencing at a distance beyond the reach of most miRNAs.

  11. Expression of a humanized viral 2A-mediated lux operon efficiently generates autonomous bioluminescence in human cells.

    Directory of Open Access Journals (Sweden)

    Tingting Xu

    Full Text Available Expression of autonomous bioluminescence from human cells was previously reported to be impossible, suggesting that all bioluminescent-based mammalian reporter systems must therefore require application of a potentially influential chemical substrate. While this was disproven when the bacterial luciferase (lux cassette was demonstrated to function in a human cell, its expression required multiple genetic constructs, was functional in only a single cell type, and generated a significantly reduced signal compared to substrate-requiring systems. Here we investigate the use of a humanized, viral 2A-linked lux genetic architecture for the efficient introduction of an autobioluminescent phenotype across a variety of human cell lines.The lux cassette was codon optimized and assembled into a synthetic human expression operon using viral 2A elements as linker regions. Human kidney, breast cancer, and colorectal cancer cell lines were both transiently and stably transfected with the humanized operon and the resulting autobioluminescent phenotype was evaluated using common imaging instrumentation. Autobioluminescent cells were screened for cytotoxic effects resulting from lux expression and their utility as bioreporters was evaluated through the demonstration of repeated monitoring of single populations over a prolonged period using both a modified E-SCREEN assay for estrogen detection and a classical cytotoxic compound detection assay for the antibiotic Zeocin. Furthermore, the use of self-directed bioluminescent initiation in response to target detection was assessed to determine its amenability towards deployment as fully autonomous sensors. In all cases, bioluminescent measurements were supported with traditional genetic and transcriptomic evaluations.Our results demonstrate that the viral 2A-linked, humanized lux genetic architecture successfully produced autobioluminescent phenotypes in all cell lines tested without the induction of cytotoxicity

  12. Age-Dependent Differences in Systemic and Cell-Autonomous Immunity to L. monocytogenes

    Directory of Open Access Journals (Sweden)

    Ashley M. Sherrid

    2013-01-01

    Full Text Available Host defense against infection can broadly be categorized into systemic immunity and cell-autonomous immunity. Systemic immunity is crucial for all multicellular organisms, increasing in importance with increasing cellular complexity of the host. The systemic immune response to Listeria monocytogenes has been studied extensively in murine models; however, the clinical applicability of these findings to the human newborn remains incompletely understood. Furthermore, the ability to control infection at the level of an individual cell, known as “cell-autonomous immunity,” appears most relevant following infection with L. monocytogenes; as the main target, the monocyte is centrally important to innate as well as adaptive systemic immunity to listeriosis. We thus suggest that the overall increased risk to suffer and die from L. monocytogenes infection in the newborn period is a direct consequence of age-dependent differences in cell-autonomous immunity of the monocyte to L. monocytogenes. We here review what is known about age-dependent differences in systemic innate and adaptive as well as cell-autonomous immunity to infection with Listeria monocytogenes.

  13. Hatred of the System: Menacing Loners and Autonomous Cells in the Netherlands

    NARCIS (Netherlands)

    van Buuren, G.M.; de Graaf, B.A.

    2014-01-01

    In this article, the violent threat emerging from “menacing loners” and autonomous cells in The Netherlands is being historicized and contextualized by providing quantitative and qualitative insight into this threat and illuminating some of the most dramatic incidents. Although beyond the core

  14. H2-O2 fuel cell and advanced battery power systems for autonomous underwater vehicles: performance envelope comparisons

    International Nuclear Information System (INIS)

    Schubak, G.E.; Scott, D.S.

    1993-01-01

    Autonomous underwater vehicles have traditionally been powered by low energy density lead-acid batteries. Recently, advanced battery technologies and H 2 -O 2 fuel cells have become available, offering significant improvements in performance. This paper compares the solid polymer fuel cell to the lithium-thionyl chloride primary battery, sodium-sulfur battery, and lead acid battery for a variety of missions. The power system performance is simulated using computer modelling techniques. Performance envelopes are constructed, indicating domains of preference for competing power system technologies. For most mission scenarios, the solid polymer fuel cell using liquid reactant storage is the preferred system. Nevertheless, the advanced battery systems are competitive with the fuel cell systems using gaseous hydrogen storage, and they illustrate preferred performance for missions requiring high power density. 11 figs., 4 tabs., 15 refs

  15. DeltaFosB induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Sabatakos, George; Chiusaroli, Riccardo

    2004-01-01

    establishes that the skeletal phenotype is cell autonomous to the osteoblast lineage and independent of adipocyte formation. It also strongly suggests that the decreased fat phenotype of NSE-DeltaFosB mice is independent of the changes in the osteoblast lineage. In vitro, overexpression of Delta......Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing DeltaFosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis...... of DeltaFosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C/EBPbeta functions. It is concluded that the changes in osteoblast and adipocyte differentiation in DeltaFosB transgenic mice result from independent cell-autonomous mechanisms....

  16. The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

    Science.gov (United States)

    Mostowy, Serge; Shenoy, Avinash R.

    2016-01-01

    Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence. PMID:26292640

  17. Autonomous molecular cascades for evaluation of cell surfaces

    Science.gov (United States)

    Rudchenko, Maria; Taylor, Steven; Pallavi, Payal; Dechkovskaia, Alesia; Khan, Safana; Butler, Vincent P., Jr.; Rudchenko, Sergei; Stojanovic, Milan N.

    2013-08-01

    Molecular automata are mixtures of molecules that undergo precisely defined structural changes in response to sequential interactions with inputs. Previously studied nucleic acid-based automata include game-playing molecular devices (MAYA automata) and finite-state automata for the analysis of nucleic acids, with the latter inspiring circuits for the analysis of RNA species inside cells. Here, we describe automata based on strand-displacement cascades directed by antibodies that can analyse cells by using their surface markers as inputs. The final output of a molecular automaton that successfully completes its analysis is the presence of a unique molecular tag on the cell surface of a specific subpopulation of lymphocytes within human blood cells.

  18. Sliding mode control of an autonomous parallel fuel cell-super capacitor power source

    Energy Technology Data Exchange (ETDEWEB)

    More, Jeronimo J. [Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires (Argentina). Facultad de Ingenieria. Lab. de Electronica Industrial, Control e Instrumentacion], Email: jmore@ing.unlp.edu.ar; Puleston, Paul F [Consejo de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires (Argentina); Kunusch, Cristian; Colomer, Jordi Riera I [Universitat Politecnica de Catalunya, Barcelona (Spain). Inst. de Robotica i Informatica Industrial (IRII)

    2010-07-01

    Nowadays, hydrogen fuel cell (FC) based systems emerge as one promising renewable alternative to fossil fuel systems in automotive and residential applications. However, their output dynamic response is relatively slow, mostly due to water and reactant gases dynamics. To overcome this limitation, FC-super capacitors (SCs) topologies can be used. The latter is capable of managing very fast power variations, presenting in addition high power density, long life cycle and good charge/discharge efficiency. In this work, a FC-SCs-based autonomous hybrid system for residential applications is considered. The FC and SCs are connected in parallel, through two separate DC/DC converters, to a DC bus. Under steady state conditions, the FC must deliver the load power requirement, while maintaining the SCs voltage regulated to the desired value. Under sudden load variations, the FC current rate must be limited to assure a safe transition to the new point of operation. During this current rate limitation mode, the SCs must deliver or absorb the power difference. To this end, a sliding mode strategy is proposed to satisfy to control objectives. The main one is the robust regulation of the DC bus voltage, even in the presence of system uncertainties and disturbances, such as load changes and FC voltage variations. Additionally, a second control objective is attained, namely to guarantee the adequate level of charge in the SCs, once the FC reaches the new steady state operation point. In this way, the system can meet the load power demand, even under sudden changes, and it can also satisfy a power demand higher than the nominal FC power, during short periods. The proposed control strategy is evaluated exhaustively by computer simulation considering fast load variations. The results presented in this work, corresponds to the first stage of a R and D collaboration project for the design and development of a novel FC-SCs-based autonomous hybrid system. In the next phase, the proposed

  19. Sliding mode control of an autonomous parallel fuel cell-super capacitor power source

    Energy Technology Data Exchange (ETDEWEB)

    More, Jeronimo J. [Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires (Argentina). Facultad de Ingenieria. Lab. de Electronica Industrial, Control e Instrumentacion], Email: jmore@ing.unlp.edu.ar; Puleston, Paul F. [Consejo de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires (Argentina); Kunusch, Cristian; Colomer, Jordi Riera I. [Universitat Politecnica de Catalunya, Barcelona (Spain). Inst. de Robotica i Informatica Industrial (IRII)

    2010-07-01

    Nowadays, hydrogen fuel cell (FC) based systems emerge as one promising renewable alternative to fossil fuel systems in automotive and residential applications. However, their output dynamic response is relatively slow, mostly due to water and reactant gases dynamics. To overcome this limitation, FC-super capacitors (SCs) topologies can be used. The latter is capable of managing very fast power variations, presenting in addition high power density, long life cycle and good charge/discharge efficiency. In this work, a FC-SCs-based autonomous hybrid system for residential applications is considered. The FC and SCs are connected in parallel, through two separate DC/DC converters, to a DC bus. Under steady state conditions, the FC must deliver the load power requirement, while maintaining the SCs voltage regulated to the desired value. Under sudden load variations, the FC current rate must be limited to assure a safe transition to the new point of operation. During this current rate limitation mode, the SCs must deliver or absorb the power difference. To this end, a sliding mode strategy is proposed to satisfy to control objectives. The main one is the robust regulation of the DC bus voltage, even in the presence of system uncertainties and disturbances, such as load changes and FC voltage variations. Additionally, a second control objective is attained, namely to guarantee the adequate level of charge in the SCs, once the FC reaches the new steady state operation point. In this way, the system can meet the load power demand, even under sudden changes, and it can also satisfy a power demand higher than the nominal FC power, during short periods. The proposed control strategy is evaluated exhaustively by computer simulation considering fast load variations. The results presented in this work, corresponds to the first stage of a R and D collaboration project for the design and development of a novel FC-SCs-based autonomous hybrid system. In the next phase, the proposed

  20. Both cell-autonomous mechanisms and hormones contribute to sexual development in vertebrates and insects.

    Science.gov (United States)

    Bear, Ashley; Monteiro, Antónia

    2013-08-01

    The differentiation of male and female characteristics in vertebrates and insects has long been thought to proceed via different mechanisms. Traditionally, vertebrate sexual development was thought to occur in two phases: a primary and a secondary phase, the primary phase involving the differentiation of the gonads, and the secondary phase involving the differentiation of other sexual traits via the influence of sex hormones secreted by the gonads. In contrast, insect sexual development was thought to depend exclusively on cell-autonomous expression of sex-specific genes. Recently, however, new evidence indicates that both vertebrates and insects rely on sex hormones as well as cell-autonomous mechanisms to develop sexual traits. Collectively, these new data challenge the traditional vertebrate definitions of primary and secondary sexual development, call for a redefinition of these terms, and indicate the need for research aimed at explaining the relative dependence on cell-autonomous versus hormonally guided sexual development in animals. © 2013 The Authors. BioEssays published by WILEY Periodicals, Inc.

  1. Cell-autonomous defense, re-organization and trafficking of membranes in plant-microbe interactions.

    Science.gov (United States)

    Dörmann, Peter; Kim, Hyeran; Ott, Thomas; Schulze-Lefert, Paul; Trujillo, Marco; Wewer, Vera; Hückelhoven, Ralph

    2014-12-01

    Plant cells dynamically change their architecture and molecular composition following encounters with beneficial or parasitic microbes, a process referred to as host cell reprogramming. Cell-autonomous defense reactions are typically polarized to the plant cell periphery underneath microbial contact sites, including de novo cell wall biosynthesis. Alternatively, host cell reprogramming converges in the biogenesis of membrane-enveloped compartments for accommodation of beneficial bacteria or invasive infection structures of filamentous microbes. Recent advances have revealed that, in response to microbial encounters, plasma membrane symmetry is broken, membrane tethering and SNARE complexes are recruited, lipid composition changes and plasma membrane-to-cytoskeleton signaling is activated, either for pre-invasive defense or for microbial entry. We provide a critical appraisal on recent studies with a focus on how plant cells re-structure membranes and the associated cytoskeleton in interactions with microbial pathogens, nitrogen-fixing rhizobia and mycorrhiza fungi. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  2. Genome-wide mapping of autonomous promoter activity in human cells.

    Science.gov (United States)

    van Arensbergen, Joris; FitzPatrick, Vincent D; de Haas, Marcel; Pagie, Ludo; Sluimer, Jasper; Bussemaker, Harmen J; van Steensel, Bas

    2017-02-01

    Previous methods to systematically characterize sequence-intrinsic activity of promoters have been limited by relatively low throughput and the length of the sequences that could be tested. Here we present 'survey of regulatory elements' (SuRE), a method that assays more than 10 8 DNA fragments, each 0.2-2 kb in size, for their ability to drive transcription autonomously. In SuRE, a plasmid library of random genomic fragments upstream of a 20-bp barcode is constructed, and decoded by paired-end sequencing. This library is used to transfect cells, and barcodes in transcribed RNA are quantified by high-throughput sequencing. When applied to the human genome, we achieve 55-fold genome coverage, allowing us to map autonomous promoter activity genome-wide in K562 cells. By computational modeling we delineate subregions within promoters that are relevant for their activity. We show that antisense promoter transcription is generally dependent on the sense core promoter sequences, and that most enhancers and several families of repetitive elements act as autonomous transcription initiation sites.

  3. Non-Cell Autonomous Influence of the Astrocyte System xc − on Hypoglycaemic Neuronal Cell Death

    Directory of Open Access Journals (Sweden)

    Nicole A Jackman

    2012-01-01

    Full Text Available Despite longstanding evidence that hypoglycaemic neuronal injury is mediated by glutamate excitotoxicity, the cellular and molecular mechanisms involved remain incompletely defined. Here, we demonstrate that the excitotoxic neuronal death that follows GD (glucose deprivation is initiated by glutamate extruded from astrocytes via system xc −– – an amino acid transporter that imports L-cystine and exports L-glutamate. Specifically, we find that depriving mixed cortical cell cultures of glucose for up to 8 h injures neurons, but not astrocytes. Neuronal death is prevented by ionotropic glutamate receptor antagonism and is partially sensitive to tetanus toxin. Removal of amino acids during the deprivation period prevents – whereas addition of L-cystine restores – GD-induced neuronal death, implicating the cystine/glutamate antiporter, system xc−–. Indeed, drugs known to inhibit system xc −– ameliorate GD-induced neuronal death. Further, a dramatic reduction in neuronal death is observed in chimaeric cultures consisting of neurons derived from WT (wild-type mice plated on top of astrocytes derived from sut mice, which harbour a naturally occurring null mutation in the gene (Slc7a11 that encodes the substrate-specific light chain of system xc −– (xCT. Finally, enhancement of astrocytic system xc −– expression and function via IL-1β (interleukin-1β exposure potentiates hypoglycaemic neuronal death, the process of which is prevented by removal of L-cystine and/or addition of system xc −– inhibitors. Thus, under the conditions of GD, our studies demonstrate that astrocytes, via system xc −–, have a direct, non-cell autonomous effect on cortical neuron survival.

  4. Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia

    International Nuclear Information System (INIS)

    Sangkatumvong, S; Khoo, M C K; Coates, T D

    2008-01-01

    The objective of this study was to non-invasively assess cardiac autonomic control in subjects with sickle cell anemia (SCA) by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxic stimulus. Five African–American SCA patients and seven healthy control subjects were recruited to participate in this study. Each subject was exposed to a controlled hypoxic stimulus consisting of five breaths of nitrogen. Time-varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The confounding effects of changes in respiration on the HRV spectral indices were reduced by using a computational model. A significant decrease in the parameters related to parasympathetic control was detected in the post-hypoxic responses of the SCA subjects relative to normal controls. The spectral index related to sympathetic activity, on the other hand, showed a tendency to increase the following hypoxic stimulation, but the change was not significant. This study suggests that there is some degree of cardiovascular autonomic dysfunction in SCA that is revealed by the response to transient hypoxia

  5. Power optimization in body sensor networks: the case of an autonomous wireless EMG sensor powered by PV-cells.

    Science.gov (United States)

    Penders, J; Pop, V; Caballero, L; van de Molengraft, J; van Schaijk, R; Vullers, R; Van Hoof, C

    2010-01-01

    Recent advances in ultra-low-power circuits and energy harvesters are making self-powered body sensor nodes a reality. Power optimization at the system and application level is crucial in achieving ultra-low-power consumption for the entire system. This paper reviews system-level power optimization techniques, and illustrates their impact on the case of autonomous wireless EMG monitoring. The resulting prototype, an Autonomous wireless EMG sensor power by PV-cells, is presented.

  6. Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD.

    Science.gov (United States)

    Chen, Hongbo; Kankel, Mark W; Su, Susan C; Han, Steve W S; Ofengeim, Dimitry

    2018-03-01

    Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia

  7. Autonomous growth potential of leukemia blast cells is associated with poor prognosis in human acute leukemias

    Directory of Open Access Journals (Sweden)

    Jakubowski Ann A

    2009-12-01

    Full Text Available Abstract We have described a severe combined immunodeficiency (SCID mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the growth potential of leukemic blasts from 133 patients with acute leukemia, (67 acute lymphoblastic leukemia (ALL and 66 acute myeloid leukemia (AML in the animals after subcutaneous inoculation without conditioning treatment. The blasts displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 leukemias, 45 (33.8% displayed an aggressive growth pattern, 14 (10.5% displayed an indolent growth pattern and 74 (55.6% did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was nearly 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. In addition, we demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course.

  8. Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell-autonomous fashion.

    Science.gov (United States)

    Völkening, Bianca; Schönig, Kai; Kronenberg, Golo; Bartsch, Dusan; Weber, Tillmann

    2017-05-01

    Ca 2+ is a universal signal transducer which fulfills essential functions in cell development and differentiation. CACNA1C, the gene encoding the alpha-1C subunit (i.e., Ca v 1.2) of the voltage-dependent l-type calcium channel (LTCC), has been implicated as a risk gene in a variety of neuropsychiatric disorders. To parse the role of Ca v 1.2 channels located on astrocyte-like stem cells and their descendants in the development of new granule neurons, we created Tg GLAST-CreERT2 /Cacna1c fl/fl /RCE:loxP mice, a transgenic tool that allows cell-type-specific inducible deletion of Cacna1c. The EGFP reporter was used to trace the progeny of recombined type-1 cells. FACS-sorted Cacna1c-deficient neural precursor cells from the dentate gyrus showed reduced proliferative activity in neurosphere cultures. Moreover, under differentiation conditions, Cacna1c-deficient NPCs gave rise to fewer neurons and more astroglia. Similarly, under basal conditions in vivo, Cacna1c gene deletion in type-1 cells decreased type-1 cell proliferation and reduced the neuronal fate-choice decision of newly born cells, resulting in reduced net hippocampal neurogenesis. Unexpectedly, electroconvulsive seizures completely compensated for the proliferation deficit of Cacna1c deficient type-1 cells, indicating that there must be Ca v 1.2-independent mechanisms of controlling proliferation related to excitation. In the aggregate, this is the first report demonstrating the presence of functional L-type 1.2 channels on type-1 cells. Ca v 1.2 channels promote type-1 cell proliferation and push the glia-to-neuron ratio in the direction of a neuronal fate choice and subsequent neuronal differentiation. Ca v 1.2 channels expressed on NPCs and their progeny possess the ability to shape neurogenesis in a cell-autonomous fashion. © 2017 Wiley Periodicals, Inc.

  9. Autonomous Vehicles Require Socio-Political Acceptance-An Empirical and Philosophical Perspective on the Problem of Moral Decision Making.

    Science.gov (United States)

    Bergmann, Lasse T; Schlicht, Larissa; Meixner, Carmen; König, Peter; Pipa, Gordon; Boshammer, Susanne; Stephan, Achim

    2018-01-01

    Autonomous vehicles, though having enormous potential, face a number of challenges. As a computer system interacting with society on a large scale and human beings in particular, they will encounter situations, which require moral assessment. What will count as right behavior in such situations depends on which factors are considered to be both morally justified and socially acceptable. In an empirical study we investigated what factors people recognize as relevant in driving situations. The study put subjects in several "dilemma" situations, which were designed to isolate different and potentially relevant factors. Subjects showed a surprisingly high willingness to sacrifice themselves to save others, took the age of potential victims in a crash into consideration and were willing to swerve onto a sidewalk if this saved more lives. The empirical insights are intended to provide a starting point for a discussion, ultimately yielding societal agreement whereby the empirical insights should be balanced with philosophical considerations.

  10. Autonomous Vehicles Require Socio-Political Acceptance—An Empirical and Philosophical Perspective on the Problem of Moral Decision Making

    Science.gov (United States)

    Bergmann, Lasse T.; Schlicht, Larissa; Meixner, Carmen; König, Peter; Pipa, Gordon; Boshammer, Susanne; Stephan, Achim

    2018-01-01

    Autonomous vehicles, though having enormous potential, face a number of challenges. As a computer system interacting with society on a large scale and human beings in particular, they will encounter situations, which require moral assessment. What will count as right behavior in such situations depends on which factors are considered to be both morally justified and socially acceptable. In an empirical study we investigated what factors people recognize as relevant in driving situations. The study put subjects in several “dilemma” situations, which were designed to isolate different and potentially relevant factors. Subjects showed a surprisingly high willingness to sacrifice themselves to save others, took the age of potential victims in a crash into consideration and were willing to swerve onto a sidewalk if this saved more lives. The empirical insights are intended to provide a starting point for a discussion, ultimately yielding societal agreement whereby the empirical insights should be balanced with philosophical considerations. PMID:29541023

  11. Autonomous Vehicles Require Socio-Political Acceptance—An Empirical and Philosophical Perspective on the Problem of Moral Decision Making

    Directory of Open Access Journals (Sweden)

    Lasse T. Bergmann

    2018-02-01

    Full Text Available Autonomous vehicles, though having enormous potential, face a number of challenges. As a computer system interacting with society on a large scale and human beings in particular, they will encounter situations, which require moral assessment. What will count as right behavior in such situations depends on which factors are considered to be both morally justified and socially acceptable. In an empirical study we investigated what factors people recognize as relevant in driving situations. The study put subjects in several “dilemma” situations, which were designed to isolate different and potentially relevant factors. Subjects showed a surprisingly high willingness to sacrifice themselves to save others, took the age of potential victims in a crash into consideration and were willing to swerve onto a sidewalk if this saved more lives. The empirical insights are intended to provide a starting point for a discussion, ultimately yielding societal agreement whereby the empirical insights should be balanced with philosophical considerations.

  12. Advanced Modular "All in One" Battery System with Intelligent Autonomous Cell Balancing Management

    Science.gov (United States)

    Petitdidier, X.; Pasquier, E.; Defer, M.; Koch, M.; Knorr, W.

    2008-09-01

    A new generation of energy storage systems based on Li-ion technology emerged at the end of the last century.To perform the first tests in safe conditions, Saft designed a simple electronic.Today, all Li-ion batteries for autonomous applications such as drones, launchers, missiles, torpedoes and "human" applications such as cellular, laptop, hybrid vehicle and nearly sub-marines need a Battery Management System.The minimum in terms of functions is the overcharge and over-discharge protections.For a battery made of 2 cells connected in series or more, a balancing system is added to maintain the available energy during all the life of the battery. For stringent/demanding applications, the state of charge and state of health are calculated by one or more computers.It is now time to take benefit of the past 10 years of Saft's experience in the domain to re-evaluate the constraints of Li-ion batteries and provide customers with improved products by optimizing the battery management.Benefits of electronic for satellite applications:• Full control over battery.• Confidence whatever the possible change of conditions in environment.• The battery system can resist long exposure to gradient conditions with mitigated and stabilized impact on performances.• The balancing function allow to use all the energy of all the cells: optimize of installed energy (compact design, mass saving). It started out with the basic fact that electrochemists are not intended to be space rated electronic experts and vice versa, even if Saft has a good heritage in the electronic battery management system. Consequently, considering heritage and expertise in their respective core businesses, Saft and ASP teamed up.It became necessary to provide an "all in one" modular energy storage system with intelligent autonomous cell balancing management.

  13. Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Tareq Saleh

    2018-05-01

    Full Text Available In addition to promoting various forms of cell death, most conventional anti-tumor therapies also promote senescence. There is now extensive evidence that therapy-induced senescence (TIS might be transient, raising the concern that TIS could represent an undesirable outcome of therapy by providing a mechanism for tumor dormancy and eventual disease recurrence. The senescence-associated secretory phenotype (SASP is a hallmark of TIS and may contribute to aberrant effects of cancer therapy. Here, we propose that the SASP may also serve as a major driver of escape from senescence and the re-emergence of proliferating tumor cells, wherein factors secreted from the senescent cells contribute to the restoration of tumor growth in a non-cell autonomous fashion. Accordingly, anti-SASP therapies might serve to mitigate the deleterious outcomes of TIS. In addition to providing an overview of the putative actions of the SASP, we discuss recent efforts to identify and eliminate senescent tumor cells.

  14. Autonomous houses. Autonomous house

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, S. (Tokai University, Tokyo (Japan). Faculty of Engineering)

    1991-09-30

    Self-sufficiency type houses are outlined. On condition that people gain a certain amount of income in relation with the society, they self-suffice under the given environment, allowing themselves to accept a minimum of industrial products with small environmental load. Ordinary supply from outside of fossil energy and materials which depend on it is minimized. Types are classified into three: energy, energy materials and perfect self-sufficiency. A study project for environment symbiotic houses is progressing which is planned by the Ministry of Construction and Institute of Building Energy Conservation and is invested by a private company. Its target is making a house for halving an environmental load by CO{sub 2}, for the purpose of creating the environment symbiotic house which is nice to and in harmony with the global environment and human beings. As a part of the studies on energy-saving and resource conservation on houses, introduced is a plan of an autonomous house at Izu-Atagawa. The passive method and high thermal-insulation are used for air conditioning, and hot spring water for hot water supply. Electric power is generated by hydroelectric power generation using mountain streams and by solar cells. Staple food is purchased, while subsidiary food is sufficed. 17 refs., 4 figs., 1 tab.

  15. Cell Autonomous and Non-Autonomous Functions of IKKβ and NF-κB during the Pathogenesis of Gastrointestinal Tumors

    International Nuclear Information System (INIS)

    Fang, Hsin-Yu; Greten, Florian R.

    2011-01-01

    Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy

  16. Autonomous bioluminescent expression of the bacterial luciferase gene cassette (lux in a mammalian cell line.

    Directory of Open Access Journals (Sweden)

    Dan M Close

    Full Text Available The bacterial luciferase (lux gene cassette consists of five genes (luxCDABE whose protein products synergistically generate bioluminescent light signals exclusive of supplementary substrate additions or exogenous manipulations. Historically expressible only in prokaryotes, the lux operon was re-synthesized through a process of multi-bicistronic, codon-optimization to demonstrate for the first time self-directed bioluminescence emission in a mammalian HEK293 cell line in vitro and in vivo.Autonomous in vitro light production was shown to be 12-fold greater than the observable background associated with untransfected control cells. The availability of reduced riboflavin phosphate (FMNH(2 was identified as the limiting bioluminescence substrate in the mammalian cell environment even after the addition of a constitutively expressed flavin reductase gene (frp from Vibrio harveyi. FMNH(2 supplementation led to a 151-fold increase in bioluminescence in cells expressing mammalian codon-optimized luxCDE and frp genes. When injected subcutaneously into nude mice, in vivo optical imaging permitted near instantaneous light detection that persisted independently for the 60 min length of the assay with negligible background.The speed, longevity, and self-sufficiency of lux expression in the mammalian cellular environment provides a viable and powerful alternative for real-time target visualization not currently offered by existing bioluminescent and fluorescent imaging technologies.

  17. Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration.

    Science.gov (United States)

    Walsh, Gregory S; Grant, Paul K; Morgan, John A; Moens, Cecilia B

    2011-07-01

    Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons.

  18. Caenorhabditis elegans as a model system for studying non-cell-autonomous mechanisms in protein-misfolding diseases

    Directory of Open Access Journals (Sweden)

    Carmen I. Nussbaum-Krammer

    2014-01-01

    Full Text Available Caenorhabditis elegans has a number of distinct advantages that are useful for understanding the basis for cellular and organismal dysfunction underlying age-associated diseases of protein misfolding. Although protein aggregation, a key feature of human neurodegenerative diseases, has been typically explored in vivo at the single-cell level using cells in culture, there is now increasing evidence that proteotoxicity has a non-cell-autonomous component and is communicated between cells and tissues in a multicellular organism. These discoveries have opened up new avenues for the use of C. elegans as an ideal animal model system to study non-cell-autonomous proteotoxicity, prion-like propagation of aggregation-prone proteins, and the organismal regulation of stress responses and proteostasis. This Review focuses on recent evidence that C. elegans has mechanisms to transmit certain classes of toxic proteins between tissues and a complex stress response that integrates and coordinates signals from single cells and tissues across the organism. These findings emphasize the potential of C. elegans to provide insights into non-cell-autonomous proteotoxic mechanisms underlying age-related protein-misfolding diseases.

  19. Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Anthony Arlia-Ciommo

    2014-05-01

    Full Text Available A body of evidence supports the view that the signaling pathways governing cellular aging – as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae. Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific ′′master regulator′′ proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest, the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast.

  20. Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Arlia-Ciommo, Anthony; Leonov, Anna; Piano, Amanda; Svistkova, Veronika; Titorenko, Vladimir I

    2014-05-27

    A body of evidence supports the view that the signaling pathways governing cellular aging - as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae . Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific "master regulator" proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest), the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast.

  1. Continuous, real-time bioimaging of chemical bioavailability and toxicology using autonomously bioluminescent human cell lines

    Science.gov (United States)

    Xu, Tingting; Close, Dan M.; Webb, James D.; Price, Sarah L.; Ripp, Steven A.; Sayler, Gary S.

    2013-05-01

    Bioluminescent imaging is an emerging biomedical surveillance strategy that uses external cameras to detect in vivo light generated in small animal models of human physiology or in vitro light generated in tissue culture or tissue scaffold mimics of human anatomy. The most widely utilized of reporters is the firefly luciferase (luc) gene; however, it generates light only upon addition of a chemical substrate, thus only generating intermittent single time point data snapshots. To overcome this disadvantage, we have demonstrated substrate-independent bioluminescent imaging using an optimized bacterial bioluminescence (lux) system. The lux reporter produces bioluminescence autonomously using components found naturally within the cell, thereby allowing imaging to occur continuously and in real-time over the lifetime of the host. We have validated this technology in human cells with demonstrated chemical toxicological profiling against exotoxin exposures at signal strengths comparable to existing luc systems (~1.33 × 107 photons/second). As a proof-in-principle demonstration, we have engineered breast carcinoma cells to express bioluminescence for real-time screening of endocrine disrupting chemicals and validated detection of 17β-estradiol (EC50 = ~ 10 pM). These and other applications of this new reporter technology will be discussed as potential new pathways towards improved models of target chemical bioavailability, toxicology, efficacy, and human safety.

  2. Genetic programs can be compressed and autonomously decompressed in live cells

    Science.gov (United States)

    Lapique, Nicolas; Benenson, Yaakov

    2018-04-01

    Fundamental computer science concepts have inspired novel information-processing molecular systems in test tubes1-13 and genetically encoded circuits in live cells14-21. Recent research has shown that digital information storage in DNA, implemented using deep sequencing and conventional software, can approach the maximum Shannon information capacity22 of two bits per nucleotide23. In nature, DNA is used to store genetic programs, but the information content of the encoding rarely approaches this maximum24. We hypothesize that the biological function of a genetic program can be preserved while reducing the length of its DNA encoding and increasing the information content per nucleotide. Here we support this hypothesis by describing an experimental procedure for compressing a genetic program and its subsequent autonomous decompression and execution in human cells. As a test-bed we choose an RNAi cell classifier circuit25 that comprises redundant DNA sequences and is therefore amenable for compression, as are many other complex gene circuits15,18,26-28. In one example, we implement a compressed encoding of a ten-gene four-input AND gate circuit using only four genetic constructs. The compression principles applied to gene circuits can enable fitting complex genetic programs into DNA delivery vehicles with limited cargo capacity, and storing compressed and biologically inert programs in vivo for on-demand activation.

  3. Coexistent Autoimmune Autonomic Ganglionopathy and Myasthenia Gravis Associated with Non-Small Cell Lung Cancer

    Science.gov (United States)

    Peltier, Amanda C.; Black, Bonnie K.; Raj, Satish R.; Donofrio, Peter; Robertson, David; Biaggioni, Italo

    2014-01-01

    We report a case of a 55 year old man with non-small cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal two years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 supine, 66/47 mmHg standing after 10 minutes without a compensatory heart rate increase (57 to 59 bpm), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04, The plasma norepinephrine level was low (79 pg/ml supine to 330 pg/ml standing). Single fiber EMG of the right extensor digitorum communis revealed normal mean MCD (jitter) but several pairs exceeded a jitter of 100 µs. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02] and ganglionic AChR (0.34 nmol/L, normal <0.02) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mmHg standing, 66 to 79 bpm), to Valsalva (normal blood pressure overshoot, HR ratio 1.47), norepinephrine (194 pg/ml supine, 763 standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that is improved with non-supine rest. PMID:19882640

  4. Neuronal cell fate decisions:  O2 and CO2 sensing neurons require egl-13/Sox5

    DEFF Research Database (Denmark)

    Gramstrup Petersen, Jakob; Pocock, Roger David John

    2013-01-01

    We recently conducted a study that aimed to describe the differentiation mechanisms used to generate O2 and CO2 sensing neurons in C. elegans. We identified egl-13/Sox5 to be required for the differentiation of both O2 and CO2 sensing neurons. We found that egl-13 functions cell autonomously...

  5. Autonomic Neuropathy

    Science.gov (United States)

    ... risk of autonomic neuropathy. Other diseases. Amyloidosis, porphyria, hypothyroidism and cancer (usually due to side effects from treatment) may also increase the risk of autonomic neuropathy. ...

  6. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.

    Science.gov (United States)

    Ablasser, Andrea; Hemmerling, Inga; Schmid-Burgk, Jonathan L; Behrendt, Rayk; Roers, Axel; Hornung, Veit

    2014-06-15

    Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3' repair exonuclease 1 (TREX1) have been linked to the type I IFN-associated autoimmune disease Aicardi-Goutières syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP-AMP synthase for the initiation of self-DNA-induced autoimmune disorders, thus providing important implications for novel therapeutic approaches. Copyright © 2014 by The American Association of Immunologists, Inc.

  7. Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells.

    Science.gov (United States)

    Larghero, Jérôme; Gervais, Nathalie; Cassinat, Bruno; Rain, Jean-Didier; Schlageter, Marie-Hélène; Padua, Rose Ann; Chomienne, Christine; Rousselot, Philippe

    2005-05-01

    Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV.

  8. The epidermis comprises autonomous compartments maintained by distinct stem cell populations

    DEFF Research Database (Denmark)

    Page, Mahalia E; Lombard, Patrick; Ng, Felicia

    2013-01-01

    populations. In contrast, upon wounding, stem cell progeny from multiple compartments acquire lineage plasticity and make permanent contributions to regenerating tissue. We further show that oncogene activation in Lrig1(+ve) cells drives hyperplasia but requires auxiliary stimuli for tumor formation....... In summary, our data demonstrate that epidermal stem cells are lineage restricted during homeostasis and suggest that compartmentalization may constitute a conserved mechanism underlying epithelial tissue maintenance....

  9. Schwann cell myelination requires Dynein function

    Directory of Open Access Journals (Sweden)

    Langworthy Melissa M

    2012-11-01

    Full Text Available Abstract Background Interaction of Schwann cells with axons triggers signal transduction that drives expression of Pou3f1 and Egr2 transcription factors, which in turn promote myelination. Signal transduction appears to be mediated, at least in part, by cyclic adenosine monophosphate (cAMP because elevation of cAMP levels can stimulate myelination in the absence of axon contact. The mechanisms by which the myelinating signal is conveyed remain unclear. Results By analyzing mutations that disrupt myelination in zebrafish, we learned that Dynein cytoplasmic 1 heavy chain 1 (Dync1h1, which functions as a motor for intracellular molecular trafficking, is required for peripheral myelination. In dync1h1 mutants, Schwann cell progenitors migrated to peripheral nerves but then failed to express Pou3f1 and Egr2 or make myelin membrane. Genetic mosaic experiments revealed that robust Myelin Basic Protein expression required Dync1h1 function within both Schwann cells and axons. Finally, treatment of dync1h1 mutants with a drug to elevate cAMP levels stimulated myelin gene expression. Conclusion Dync1h1 is required for retrograde transport in axons and mutations of Dync1h1 have been implicated in axon disease. Our data now provide evidence that Dync1h1 is also required for efficient myelination of peripheral axons by Schwann cells, perhaps by facilitating signal transduction necessary for myelination.

  10. Nature's Autonomous Oscillators

    Science.gov (United States)

    Mayr, H. G.; Yee, J.-H.; Mayr, M.; Schnetzler, R.

    2012-01-01

    Nonlinearity is required to produce autonomous oscillations without external time dependent source, and an example is the pendulum clock. The escapement mechanism of the clock imparts an impulse for each swing direction, which keeps the pendulum oscillating at the resonance frequency. Among nature's observed autonomous oscillators, examples are the quasi-biennial oscillation and bimonthly oscillation of the Earth atmosphere, and the 22-year solar oscillation. The oscillations have been simulated in numerical models without external time dependent source, and in Section 2 we summarize the results. Specifically, we shall discuss the nonlinearities that are involved in generating the oscillations, and the processes that produce the periodicities. In biology, insects have flight muscles, which function autonomously with wing frequencies that far exceed the animals' neural capacity; Stretch-activation of muscle contraction is the mechanism that produces the high frequency oscillation of insect flight, discussed in Section 3. The same mechanism is also invoked to explain the functioning of the cardiac muscle. In Section 4, we present a tutorial review of the cardio-vascular system, heart anatomy, and muscle cell physiology, leading up to Starling's Law of the Heart, which supports our notion that the human heart is also a nonlinear oscillator. In Section 5, we offer a broad perspective of the tenuous links between the fluid dynamical oscillators and the human heart physiology.

  11. Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.

    Directory of Open Access Journals (Sweden)

    Sander Barnhoorn

    2014-10-01

    Full Text Available As part of the Nucleotide Excision Repair (NER process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS, or the infantile lethal cerebro-oculo-facio-skeletal (COFS syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.

  12. Mining in the Future: Autonomous Robotics for Safer Mines

    CSIR Research Space (South Africa)

    Shahdi, A

    2012-10-01

    Full Text Available ? Require less support infrastructure ? Advanced sensors ? CSIR 2012 Slide 4 Degree of Autonomy ? Teleoperation ? Semi-autonomous ? Autonomous ? CSIR 2012 Slide 5 Mobile Intelligent Autonomous Systems Group ? The Mobile Intelligent Autonomous...

  13. MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

    Directory of Open Access Journals (Sweden)

    Valentina Conti

    Full Text Available Rett syndrome (RTT is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions.

  14. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells.

    Science.gov (United States)

    Yu, Vionnie W C; Yusuf, Rushdia Z; Oki, Toshihiko; Wu, Juwell; Saez, Borja; Wang, Xin; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J; Lee, Eunjung; Gu, Hongcang; Meissner, Alexander; Lin, Charles P; Kharchenko, Peter V; Scadden, David T

    2016-11-17

    Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Dlx5 Is a cell autonomous regulator of chondrocyte hypertrophy in mice and functionally substitutes for Dlx6 during endochondral ossification.

    Directory of Open Access Journals (Sweden)

    Hui Zhu

    Full Text Available The axial and appendicular skeleton of vertebrates develops by endochondral ossification, in which skeletogenic tissue is initially cartilaginous and the differentiation of chondrocytes via the hypertrophic pathway precedes the differentiation of osteoblasts and the deposition of a definitive bone matrix. Results from both loss-of-function and misexpression studies have implicated the related homeobox genes Dlx5 and Dlx6 as partially redundant positive regulators of chondrocyte hypertrophy. However, experimental perturbations of Dlx expression have either not been cell type specific or have been done in the context of endogenous Dlx5 expression. Thus, it has not been possible to conclude whether the effects on chondrocyte differentiation are cell autonomous or whether they are mediated by Dlx expression in adjacent tissues, notably the perichondrium. To address this question we first engineered transgenic mice in which Dlx5 expression was specifically restricted to immature and differentiating chondrocytes and not the perichondrium. Col2a1-Dlx5 transgenic embryos and neonates displayed accelerated chondrocyte hypertrophy and mineralization throughout the endochondral skeleton. Furthermore, this transgene specifically rescued defects of chondrocyte differentiation characteristic of the Dlx5/6 null phenotype. Based on these results, we conclude that the role of Dlx5 in the hypertrophic pathway is cell autonomous. We further conclude that Dlx5 and Dlx6 are functionally equivalent in the endochondral skeleton, in that the requirement for Dlx5 and Dlx6 function during chondrocyte hypertrophy can be satisfied with Dlx5 alone.

  16. Calorie Restriction-Mediated Replicative Lifespan Extension in Yeast Is Non-Cell Autonomous

    Science.gov (United States)

    Mei, Szu-Chieh; Brenner, Charles

    2015-01-01

    In laboratory yeast strains with Sir2 and Fob1 function, wild-type NAD+ salvage is required for calorie restriction (CR) to extend replicative lifespan. CR does not significantly alter steady state levels of intracellular NAD+ metabolites. However, levels of Sir2 and Pnc1, two enzymes that sequentially convert NAD+ to nicotinic acid (NA), are up-regulated during CR. To test whether factors such as NA might be exported by glucose-restricted mother cells to survive later generations, we developed a replicative longevity paradigm in which mother cells are moved after 15 generations on defined media. The experiment reveals that CR mother cells lose the longevity benefit of CR when evacuated from their local environment to fresh CR media. Addition of NA or nicotinamide riboside (NR) allows a moved mother to maintain replicative longevity despite the move. Moreover, conditioned medium from CR-treated cells transmits the longevity benefit of CR to moved mother cells. Evidence suggests the existence of a longevity factor that is dialyzable but is neither NA nor NR, and indicates that Sir2 is not required for the longevity factor to be produced or to act. Data indicate that the benefit of glucose-restriction is transmitted from cell to cell in budding yeast, suggesting that glucose restriction may benefit neighboring cells and not only an individual cell. PMID:25633578

  17. Calorie restriction-mediated replicative lifespan extension in yeast is non-cell autonomous.

    Directory of Open Access Journals (Sweden)

    Szu-Chieh Mei

    2015-01-01

    Full Text Available In laboratory yeast strains with Sir2 and Fob1 function, wild-type NAD+ salvage is required for calorie restriction (CR to extend replicative lifespan. CR does not significantly alter steady state levels of intracellular NAD+ metabolites. However, levels of Sir2 and Pnc1, two enzymes that sequentially convert NAD+ to nicotinic acid (NA, are up-regulated during CR. To test whether factors such as NA might be exported by glucose-restricted mother cells to survive later generations, we developed a replicative longevity paradigm in which mother cells are moved after 15 generations on defined media. The experiment reveals that CR mother cells lose the longevity benefit of CR when evacuated from their local environment to fresh CR media. Addition of NA or nicotinamide riboside (NR allows a moved mother to maintain replicative longevity despite the move. Moreover, conditioned medium from CR-treated cells transmits the longevity benefit of CR to moved mother cells. Evidence suggests the existence of a longevity factor that is dialyzable but is neither NA nor NR, and indicates that Sir2 is not required for the longevity factor to be produced or to act. Data indicate that the benefit of glucose-restriction is transmitted from cell to cell in budding yeast, suggesting that glucose restriction may benefit neighboring cells and not only an individual cell.

  18. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

    Science.gov (United States)

    Pérez-Garijo, Ainhoa; Fuchs, Yaron; Steller, Hermann

    2013-01-01

    Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions. DOI: http://dx.doi.org/10.7554/eLife.01004.001 PMID:24066226

  19. Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells

    Science.gov (United States)

    Bershteyn, Marina; Hayashi, Yohei; Desachy, Guillaume; Hsiao, Edward C.; Sami, Salma; Tsang, Kathryn M.; Weiss, Lauren A.; Kriegstein, Arnold R.; Yamanaka, Shinya; Wynshaw-Boris, Anthony

    2014-03-01

    Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of `chromosome therapy' to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.

  20. Non-cell-autonomous stimulation of stem cell proliferation following ablation of Tcf3

    International Nuclear Information System (INIS)

    Yi, Fei; Merrill, Bradley J.

    2010-01-01

    A combination of cell intrinsic factors and extracellular signals determine whether mouse embryonic stem cells (ESC) divide, self-renew, and differentiate. Here, we report a new interaction between cell intrinsic aspects of the canonical Wnt/Tcf/β-catenin signaling pathway and extracellular Lif/Jak/Stat3 stimulation that combines to promote self-renewal and proliferation of ESC. Mutant ESC lacking the Tcf3 transcriptional repressor continue to self-renew in the absence of exogenous Lif and through pharmacological inhibition of Lif/Jak/Stat3 signaling; however, proliferation rates of TCF3-/- ESC were significantly decreased by inhibiting Jak/Stat3 activity. Cell mixing experiments showed that stimulation of Stat3 phosphorylation in TCF3-/- ESC was mediated through secretion of paracrine acting factors, but did not involve elevated Lif or LifR transcription. The new interaction between Wnt and Lif/Jak/Stat3 signaling pathways has potential for new insights into the growth of tumors caused by aberrant activity of Wnt/Tcf/β-catenin signaling.

  1. Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity*

    Science.gov (United States)

    Marty, Caroline; Chaligné, Ronan; Lacout, Catherine; Constantinescu, Stefan N.; Vainchenker, William; Villeval, Jean-Luc

    2009-01-01

    The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPLW515L mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPLW515L within its natural ER/Golgi maturation pathway. In contrast to cells expressing the parental MPLW515L, MPLW515L-KDEL-expressing FDC-P1 cells were unable to grow autonomously and to produce tumors in nude mice. When observed, tumor nodules resulted from in vivo selection of cells leaking the receptor at their surface. JAK2 co-immunoprecipitated with MPLW515L-KDEL but was not phosphorylated. We generated disulfide-bonded MPLW515L homodimers by the S402C substitution, both in the normal and KDEL context. Unlike MPLW515L-KDEL, MPLW515L-S402C-KDEL signaled constitutively and exhibited cell surface localization. These data establish that MPLW515L with appended JAK2 matures through the ER/Golgi system in an inactive conformation and suggest that the MPLW515L/JAK2 complex requires membrane localization for JAK2 phosphorylation, resulting in autonomous receptor signaling. PMID:19261614

  2. Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice

    Directory of Open Access Journals (Sweden)

    Sunn Nana

    2009-12-01

    Full Text Available Abstract Background Agenesis of the corpus callosum is associated with many human developmental syndromes. Key mechanisms regulating callosal formation include the guidance of axons arising from pioneering neurons in the cingulate cortex and the development of cortical midline glial populations, but their molecular regulation remains poorly characterised. Recent data have shown that mice lacking the transcription factor Nfib exhibit callosal agenesis, yet neocortical callosal neurons express only low levels of Nfib. Therefore, we investigate here how Nfib functions to regulate non-cell-autonomous mechanisms of callosal formation. Results Our investigations confirmed a reduction in glial cells at the midline in Nfib-/- mice. To determine how this occurs, we examined radial progenitors at the cortical midline and found that they were specified correctly in Nfib mutant mice, but did not differentiate into mature glia. Cellular proliferation and apoptosis occurred normally at the midline of Nfib mutant mice, indicating that the decrease in midline glia observed was due to deficits in differentiation rather than proliferation or apoptosis. Next we investigated the development of callosal pioneering axons in Nfib-/- mice. Using retrograde tracer labelling, we found that Nfib is expressed in cingulate neurons and hence may regulate their development. In Nfib-/- mice, neuropilin 1-positive axons fail to cross the midline and expression of neuropilin 1 is diminished. Tract tracing and immunohistochemistry further revealed that, in late gestation, a minor population of neocortical axons does cross the midline in Nfib mutants on a C57Bl/6J background, forming a rudimentary corpus callosum. Finally, the development of other forebrain commissures in Nfib-deficient mice is also aberrant. Conclusion The formation of the corpus callosum is severely delayed in the absence of Nfib, despite Nfib not being highly expressed in neocortical callosal neurons. Our

  3. HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.

    Science.gov (United States)

    Heilman, Patrick L; Song, SungWon; Miranda, Carlos J; Meyer, Kathrin; Srivastava, Amit K; Knapp, Amy; Wier, Christopher G; Kaspar, Brian K; Kolb, Stephen J

    2017-11-01

    Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Stability of Control Networks in Autonomous Homeostatic Regulation of Stem Cell Lineages.

    Science.gov (United States)

    Komarova, Natalia L; van den Driessche, P

    2018-05-01

    Design principles of biological networks have been studied extensively in the context of protein-protein interaction networks, metabolic networks, and regulatory (transcriptional) networks. Here we consider regulation networks that occur on larger scales, namely the cell-to-cell signaling networks that connect groups of cells in multicellular organisms. These are the feedback loops that orchestrate the complex dynamics of cell fate decisions and are necessary for the maintenance of homeostasis in stem cell lineages. We focus on "minimal" networks that are those that have the smallest possible numbers of controls. For such minimal networks, the number of controls must be equal to the number of compartments, and the reducibility/irreducibility of the network (whether or not it can be split into smaller independent sub-networks) is defined by a matrix comprised of the cell number increments induced by each of the controlled processes in each of the compartments. Using the formalism of digraphs, we show that in two-compartment lineages, reducible systems must contain two 1-cycles, and irreducible systems one 1-cycle and one 2-cycle; stability follows from the signs of the controls and does not require magnitude restrictions. In three-compartment systems, irreducible digraphs have a tree structure or have one 3-cycle and at least two more shorter cycles, at least one of which is a 1-cycle. With further work and proper biological validation, our results may serve as a first step toward an understanding of ways in which these networks become dysregulated in cancer.

  5. Fuel cell-powered microfluidic platform for lab-on-a-chip applications: Integration into an autonomous amperometric sensing device.

    Science.gov (United States)

    Esquivel, J P; Colomer-Farrarons, J; Castellarnau, M; Salleras, M; del Campo, F J; Samitier, J; Miribel-Català, P; Sabaté, N

    2012-11-07

    The present paper reports for the first time the integration of a microfluidic system, electronics modules, amperometric sensor and display, all powered by a single micro direct methanol fuel cell. In addition to activating the electronic circuitry, the integrated power source also acts as a tuneable micropump. The electronics fulfil several functions. First, they regulate the micro fuel cell output power, which off-gas controls the flow rate of different solutions toward an electrochemical sensor through microfluidic channels. Secondly, as the fuel cell powers a three-electrode electrochemical cell, the electronics compare the working electrode output signal with a set reference value. Thirdly, if the concentration measured by the sensor exceeds this threshold value, the electronics switch on an integrated organic display. This integrated approach pushes forward the development of truly autonomous point-of-care devices relying on electrochemical detection.

  6. Discerning non-autonomous dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Clemson, Philip T.; Stefanovska, Aneta, E-mail: aneta@lancaster.ac.uk

    2014-09-30

    Structure and function go hand in hand. However, while a complex structure can be relatively safely broken down into the minutest parts, and technology is now delving into nanoscales, the function of complex systems requires a completely different approach. Here the complexity clearly arises from nonlinear interactions, which prevents us from obtaining a realistic description of a system by dissecting it into its structural component parts. At best, the result of such investigations does not substantially add to our understanding or at worst it can even be misleading. Not surprisingly, the dynamics of complex systems, facilitated by increasing computational efficiency, is now readily tackled in the case of measured time series. Moreover, time series can now be collected in practically every branch of science and in any structural scale—from protein dynamics in a living cell to data collected in astrophysics or even via social networks. In searching for deterministic patterns in such data we are limited by the fact that no complex system in the real world is autonomous. Hence, as an alternative to the stochastic approach that is predominantly applied to data from inherently non-autonomous complex systems, theory and methods specifically tailored to non-autonomous systems are needed. Indeed, in the last decade we have faced a huge advance in mathematical methods, including the introduction of pullback attractors, as well as time series methods that cope with the most important characteristic of non-autonomous systems—their time-dependent behaviour. Here we review current methods for the analysis of non-autonomous dynamics including those for extracting properties of interactions and the direction of couplings. We illustrate each method by applying it to three sets of systems typical for chaotic, stochastic and non-autonomous behaviour. For the chaotic class we select the Lorenz system, for the stochastic the noise-forced Duffing system and for the non-autonomous

  7. Discerning non-autonomous dynamics

    International Nuclear Information System (INIS)

    Clemson, Philip T.; Stefanovska, Aneta

    2014-01-01

    Structure and function go hand in hand. However, while a complex structure can be relatively safely broken down into the minutest parts, and technology is now delving into nanoscales, the function of complex systems requires a completely different approach. Here the complexity clearly arises from nonlinear interactions, which prevents us from obtaining a realistic description of a system by dissecting it into its structural component parts. At best, the result of such investigations does not substantially add to our understanding or at worst it can even be misleading. Not surprisingly, the dynamics of complex systems, facilitated by increasing computational efficiency, is now readily tackled in the case of measured time series. Moreover, time series can now be collected in practically every branch of science and in any structural scale—from protein dynamics in a living cell to data collected in astrophysics or even via social networks. In searching for deterministic patterns in such data we are limited by the fact that no complex system in the real world is autonomous. Hence, as an alternative to the stochastic approach that is predominantly applied to data from inherently non-autonomous complex systems, theory and methods specifically tailored to non-autonomous systems are needed. Indeed, in the last decade we have faced a huge advance in mathematical methods, including the introduction of pullback attractors, as well as time series methods that cope with the most important characteristic of non-autonomous systems—their time-dependent behaviour. Here we review current methods for the analysis of non-autonomous dynamics including those for extracting properties of interactions and the direction of couplings. We illustrate each method by applying it to three sets of systems typical for chaotic, stochastic and non-autonomous behaviour. For the chaotic class we select the Lorenz system, for the stochastic the noise-forced Duffing system and for the non-autonomous

  8. Catecholamines and diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J

    1995-01-01

    In diabetic patients with autonomic neuropathy plasma noradrenaline concentration, used as an index of sympathetic nervous activity, is low. This decrease is, however, only found in patients with a long duration of diabetes with clinically severe autonomic neuropathy. This apparent insensitivity...... of plasma catecholamine measurements is not due to changes in the clearance of catecholamines in diabetic autonomic neuropathy. The physiological responses to infused adrenaline and to noradrenaline are enhanced, for noradrenaline mainly cardiovascular responses. Adrenoceptors (alpha and beta adrenoceptors......) are not altered in circulating blood cells in diabetic autonomic neuropathy. Thus, a generalized up-regulation of adrenoceptors does not occur in diabetic autonomic neuropathy....

  9. Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

    Science.gov (United States)

    Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

    2005-03-01

    Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure.

  10. Hsp40 gene therapy exerts therapeutic effects on polyglutamine disease mice via a non-cell autonomous mechanism.

    Directory of Open Access Journals (Sweden)

    H Akiko Popiel

    Full Text Available The polyglutamine (polyQ diseases such as Huntington's disease (HD, are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1 and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5 expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.

  11. A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways

    Science.gov (United States)

    Dong, Wenjuan; Wei, Xiuli; Zhang, Fayun; Hao, Junfeng; Huang, Feng; Zhang, Chunling; Liang, Wei

    2014-01-01

    Flavonoids are well known as a large class of polyphenolic compounds, which have a variety of physiological activities, including anti-influenza virus activity. The influenza A/WSN/33 infected A549 cells have been used to screen anti-influenza virus drugs from natural flavonoid compounds library. Unexpectedly, some flavonoid compounds significantly inhibited virus replication, while the others dramatically promoted virus replication. In this study, we attempted to understand these differences between flavonoid compounds in their antivirus mechanisms. Hesperidin and kaempferol were chosen as representatives of both sides, each of which exhibited the opposite effects on influenza virus replication. Our investigation revealed that the opposite effects produced by hesperidin and kaempferol on influenza virus were due to inducing the opposite cell-autonomous immune responses by selectively modulating MAP kinase pathways: hesperidin up-regulated P38 and JNK expression and activation, thus resulting in the enhanced cell-autonomous immunity; while kaempferol dramatically down-regulated p38 and JNK expression and activation, thereby suppressing cell-autonomous immunity. In addition, hesperidin restricted RNPs export from nucleus by down-regulating ERK activation, but kaempferol promoted RNPs export by up-regulating ERK activation. Our findings demonstrate that a new generation of anti-influenza virus drugs could be developed based on selective modulation of MAP kinase pathways to stimulate cell-autonomous immunity. PMID:25429875

  12. Autonomous control of phosphatidylinositol turnover by histamine and acetylcholine receptors in the NIE-115 neuron-like cell line

    International Nuclear Information System (INIS)

    Large, T.H.; Lambert, M.P.; Cohen, N.M.; Klein, W.L.

    1986-01-01

    Histamine was found to stimulate the turnover of phosphatidylinositol (PI) in cultures of neuron-like NE-115 cells. Turnover was measured by increased production of ( 3 H)inositol phosphates (breakdown) and by accelerated incorporation of 32 P into PI (resynthesis). Data were consistent with hydrolysis of polyphosphoinositides being the initial event in receptor-stimulated PI turnover. This response to histamine desensitized within 10 min. Receptor systems for histamine and acetylcholine were tested for possible interactions: PI turnover in response to dual stimulation was approximately equal to the sum of the individual responses while prior desensitization of the acetylcholine receptor system had no effect on subsequent stimulation of the histamine receptor system. These results are consistent with the hypothesis that components of acetylcholine and histamine receptor systems responsible for PI turnover are autonomously organised and regulated. (author)

  13. Autonomous search

    CERN Document Server

    Hamadi, Youssef; Saubion, Frédéric

    2012-01-01

    Autonomous combinatorial search (AS) represents a new field in combinatorial problem solving. Its major standpoint and originality is that it considers that problem solvers must be capable of self-improvement operations. This is the first book dedicated to AS.

  14. A multidirectional non-cell autonomous control and a genetic interaction restricting tobacco etch virus susceptibility in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Suresh Gopalan

    2007-10-01

    Full Text Available Viruses constitute a major class of pathogens that infect a variety of hosts. Understanding the intricacies of signaling during host-virus interactions should aid in designing disease prevention strategies and in understanding mechanistic aspects of host and pathogen signaling machinery.An Arabidopsis mutant, B149, impaired in susceptibility to Tobacco etch virus (TEV, a positive strand RNA virus of picoRNA family, was identified using a high-throughput genetic screen and a counterselection scheme. The defects include initiation of infection foci, rate of cell-to-cell movement and long distance movement.The defect in infectivity is conferred by a recessive locus. Molecular genetic analysis and complementation analysis with three alleles of a previously published mutant lsp1 (loss of susceptibility to potyviruses indicate a genetic interaction conferring haploinsufficiency between the B149 locus and certain alleles of lsp1 resulting in impaired host susceptibility. The pattern of restriction of TEV foci on leaves at or near the boundaries of certain cell types and leaf boundaries suggest dysregulation of a multidirectional non-cell autonomous regulatory mechanism. Understanding the nature of this multidirectional signal and the molecular genetic mechanism conferring it should potentially reveal a novel arsenal in the cellular machinery.

  15. An inducible knockout mouse to model the cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias

    Science.gov (United States)

    Mirantes, Cristina; Eritja, Núria; Dosil, Maria Alba; Santacana, Maria; Pallares, Judit; Gatius, Sónia; Bergadà, Laura; Maiques, Oscar; Matias-Guiu, Xavier; Dolcet, Xavier

    2013-01-01

    SUMMARY PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The role of PTEN in carcinogenesis has been validated by knockout mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has inhibited the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional knockout mice with transgenic mice expressing a tamoxifen-inducible Cre-ERT under the control of a chicken actin promoter, we have generated a tamoxifen-inducible mouse model that allows temporal control of PTEN deletion. Interestingly, administration of a single dose of tamoxifen resulted in PTEN deletion mainly in epithelial cells, but not in stromal, mesenchymal or hematopoietic cells. Using the mT/mG double-fluorescent Cre reporter mice, we demonstrate that epithelial-specific PTEN excision was caused by differential Cre activity among tissues and cells types. Tamoxifen-induced deletion of PTEN resulted in extremely rapid and consistent formation of endometrial in situ adenocarcinoma, prostate intraepithelial neoplasia and thyroid hyperplasia. We also analyzed the role of PTEN ablation in other epithelial cells, such as the tubular cells of the kidney, hepatocytes, colonic epithelial cells or bronchiolar epithelium, but those tissues did not exhibit neoplastic growth. Finally, to validate this model as a tool to assay the efficacy of anti-tumor drugs in PTEN deficiency, we administered the mTOR inhibitor everolimus to mice with induced PTEN deletion. Everolimus dramatically reduced the progression of endometrial proliferations and significantly reduced thyroid hyperplasia. This model could be a valuable tool to study the cell-autonomous mechanisms involved in PTEN-loss-induced carcinogenesis and provides a good platform to study the effect of anti-neoplastic drugs on PTEN-negative tumors. PMID:23471917

  16. Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Manuel E. Lopez

    2013-09-01

    Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

  17. Above-CMOS a-Si and CIGS Solar Cells for Powering Autonomous Microsystems

    NARCIS (Netherlands)

    Lu, J.; Liu, W.; van der Werf, C.H.M.; Kovalgin, A.Y.; Sun, Y.; Schropp, R.E.I.; Schmitz, J.

    2010-01-01

    Two types of solar cells are successfully grown on chips from two CMOS generations. The efficiency of amorphous-silicon (a-Si) solar cells reaches 5.2%, copperindium-gallium-selenide (CIGS) cells 7.1%. CMOS functionality is unaffected. The main integration issues: adhesion, surface topography, metal

  18. Stochastic modeling indicates that aging and somatic evolution in the hematopoetic system are driven by non-cell-autonomous processes.

    Science.gov (United States)

    Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James

    2014-12-01

    Age-dependent tissue decline and increased cancer incidence are widely accepted to be rate-limited by the accumulation of somatic mutations over time. Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate-limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and widely modulated by environment. We computationally modeled dynamic microenvironment-dependent fitness alterations in hematopoietic stem cells (HSC) within the Sprengel-Liebig system known to govern evolution at the population level. Our model for the first time integrates real data on age-dependent dynamics of HSC division rates, pool size, and accumulation of genetic changes and demonstrates that somatic evolution is not rate-limited by the occurrence of mutations, but instead results from aged microenvironment-driven alterations in the selective/fitness value of previously accumulated genetic changes. Our results are also consistent with evolutionary models of aging and thus oppose both somatic mutation-centric paradigms of carcinogenesis and tissue functional decline. In total, we demonstrate that aging directly promotes HSC fitness decline and somatic evolution via non-cell-autonomous mechanisms.

  19. Magnetic Random Access Memory based non-volatile asynchronous Muller cell for ultra-low power autonomous applications

    Science.gov (United States)

    Di Pendina, G.; Zianbetov, E.; Beigne, E.

    2015-05-01

    Micro and nano electronic integrated circuit domain is today mainly driven by the advent of the Internet of Things for which the constraints are strong, especially in terms of power consumption and autonomy, not only during the computing phases but also during the standby or idle phases. In such ultra-low power applications, the circuit has to meet new constraints mainly linked to its changing energetic environment: long idle phases, automatic wake up, data back-up when the circuit is sporadically turned off, and ultra-low voltage power supply operation. Such circuits have to be completely autonomous regarding their unstable environment, while remaining in an optimum energetic configuration. Therefore, we propose in this paper the first MRAM-based non-volatile asynchronous Muller cell. This cell has been simulated and characterized in a very advanced 28 nm CMOS fully depleted silicon-on-insulator technology, presenting good power performance results due to an extremely efficient body biasing control together with ultra-wide supply voltage range from 160 mV up to 920 mV. The leakage current can be reduced to 154 pA thanks to reverse body biasing. We also propose an efficient standard CMOS bulk version of this cell in order to be compatible with different fabrication processes.

  20. Magnetic Random Access Memory based non-volatile asynchronous Muller cell for ultra-low power autonomous applications

    Energy Technology Data Exchange (ETDEWEB)

    Di Pendina, G., E-mail: gregory.dipendina@cea.fr, E-mail: eldar.zianbetov@cea.fr, E-mail: edith.beigne@cea.fr; Zianbetov, E., E-mail: gregory.dipendina@cea.fr, E-mail: eldar.zianbetov@cea.fr, E-mail: edith.beigne@cea.fr [Univ. Grenoble Alpes, INAC-SPINTEC, F-38000 Grenoble (France); CNRS, SPINTEC, F-38000 Grenoble (France); CEA, INAC-SPINTEC, F-38000 Grenoble (France); Beigne, E., E-mail: gregory.dipendina@cea.fr, E-mail: eldar.zianbetov@cea.fr, E-mail: edith.beigne@cea.fr [Univ. Grenoble Alpes, CEA, LETI, F-38000 Grenoble (France)

    2015-05-07

    Micro and nano electronic integrated circuit domain is today mainly driven by the advent of the Internet of Things for which the constraints are strong, especially in terms of power consumption and autonomy, not only during the computing phases but also during the standby or idle phases. In such ultra-low power applications, the circuit has to meet new constraints mainly linked to its changing energetic environment: long idle phases, automatic wake up, data back-up when the circuit is sporadically turned off, and ultra-low voltage power supply operation. Such circuits have to be completely autonomous regarding their unstable environment, while remaining in an optimum energetic configuration. Therefore, we propose in this paper the first MRAM-based non-volatile asynchronous Muller cell. This cell has been simulated and characterized in a very advanced 28 nm CMOS fully depleted silicon-on-insulator technology, presenting good power performance results due to an extremely efficient body biasing control together with ultra-wide supply voltage range from 160 mV up to 920 mV. The leakage current can be reduced to 154 pA thanks to reverse body biasing. We also propose an efficient standard CMOS bulk version of this cell in order to be compatible with different fabrication processes.

  1. The double-stranded RNA binding protein RDE-4 can act cell autonomously during feeding RNAi in C. elegans.

    Science.gov (United States)

    Raman, Pravrutha; Zaghab, Soriayah M; Traver, Edward C; Jose, Antony M

    2017-08-21

    Long double-stranded RNA (dsRNA) can silence genes of matching sequence upon ingestion in many invertebrates and is therefore being developed as a pesticide. Such feeding RNA interference (RNAi) is best understood in the worm Caenorhabditis elegans, where the dsRNA-binding protein RDE-4 initiates silencing by recruiting an endonuclease to process long dsRNA into short dsRNA. These short dsRNAs are thought to move between cells because muscle-specific rescue of rde-4 using repetitive transgenes enables silencing in other tissues. Here, we extend this observation using additional promoters, report an inhibitory effect of repetitive transgenes, and discover conditions for cell-autonomous silencing in animals with tissue-specific rescue of rde-4. While expression of rde-4(+) in intestine, hypodermis, or neurons using a repetitive transgene can enable silencing also in unrescued tissues, silencing can be inhibited wihin tissues that express a repetitive transgene. Single-copy transgenes that express rde-4(+) in body-wall muscles or hypodermis, however, enable silencing selectively in the rescued tissue but not in other tissues. These results suggest that silencing by the movement of short dsRNA between cells is not an obligatory feature of feeding RNAi in C. elegans. We speculate that similar control of dsRNA movement could modulate tissue-specific silencing by feeding RNAi in other invertebrates. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  2. Magnetic Random Access Memory based non-volatile asynchronous Muller cell for ultra-low power autonomous applications

    International Nuclear Information System (INIS)

    Di Pendina, G.; Zianbetov, E.; Beigne, E.

    2015-01-01

    Micro and nano electronic integrated circuit domain is today mainly driven by the advent of the Internet of Things for which the constraints are strong, especially in terms of power consumption and autonomy, not only during the computing phases but also during the standby or idle phases. In such ultra-low power applications, the circuit has to meet new constraints mainly linked to its changing energetic environment: long idle phases, automatic wake up, data back-up when the circuit is sporadically turned off, and ultra-low voltage power supply operation. Such circuits have to be completely autonomous regarding their unstable environment, while remaining in an optimum energetic configuration. Therefore, we propose in this paper the first MRAM-based non-volatile asynchronous Muller cell. This cell has been simulated and characterized in a very advanced 28 nm CMOS fully depleted silicon-on-insulator technology, presenting good power performance results due to an extremely efficient body biasing control together with ultra-wide supply voltage range from 160 mV up to 920 mV. The leakage current can be reduced to 154 pA thanks to reverse body biasing. We also propose an efficient standard CMOS bulk version of this cell in order to be compatible with different fabrication processes

  3. Autonomic cardiac innervation

    Science.gov (United States)

    Hasan, Wohaib

    2013-01-01

    Autonomic cardiac neurons have a common origin in the neural crest but undergo distinct developmental differentiation as they mature toward their adult phenotype. Progenitor cells respond to repulsive cues during migration, followed by differentiation cues from paracrine sources that promote neurochemistry and differentiation. When autonomic axons start to innervate cardiac tissue, neurotrophic factors from vascular tissue are essential for maintenance of neurons before they reach their targets, upon which target-derived trophic factors take over final maturation, synaptic strength and postnatal survival. Although target-derived neurotrophins have a central role to play in development, alternative sources of neurotrophins may also modulate innervation. Both developing and adult sympathetic neurons express proNGF, and adult parasympathetic cardiac ganglion neurons also synthesize and release NGF. The physiological function of these “non-classical” cardiac sources of neurotrophins remains to be determined, especially in relation to autocrine/paracrine sustenance during development.   Cardiac autonomic nerves are closely spatially associated in cardiac plexuses, ganglia and pacemaker regions and so are sensitive to release of neurotransmitter, neuropeptides and trophic factors from adjacent nerves. As such, in many cardiac pathologies, it is an imbalance within the two arms of the autonomic system that is critical for disease progression. Although this crosstalk between sympathetic and parasympathetic nerves has been well established for adult nerves, it is unclear whether a degree of paracrine regulation occurs across the autonomic limbs during development. Aberrant nerve remodeling is a common occurrence in many adult cardiovascular pathologies, and the mechanisms regulating outgrowth or denervation are disparate. However, autonomic neurons display considerable plasticity in this regard with neurotrophins and inflammatory cytokines having a central regulatory

  4. Autonomous Integrated Receive System (AIRS) requirements definition. Volume 4: Functional specification for the prototype Automated Integrated Receive System (AIRS)

    Science.gov (United States)

    Chie, C. M.

    1984-01-01

    The functional requirements for the performance, design, and testing for the prototype Automated Integrated Receive System (AIRS) to be demonstrated for the TDRSS S-Band Single Access Return Link are presented.

  5. Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs.

    Science.gov (United States)

    Iser, Wendy B; Gami, Minaxi S; Wolkow, Catherine A

    2007-03-15

    In C. elegans, insulin signaling affects development, lifespan and stress resistance. Several studies have shown that insulin signaling affects lifespan in an endocrine-like manner from different cells, while the major downstream target of insulin, the FOXO transcription factor encoded by daf-16, may act preferentially in intestinal cells to prolong lifespan. This discrepancy raised the possibility that insulin may have both endocrine and cell-intrinsic outputs. Here, we further investigated the types of cells capable of producing endocrine outputs of insulin and also identified a new cell-intrinsic insulin output. We found that insulin signaling within groups of neurons promoted wildtype lifespan, showing that the endocrine outputs of insulin were not restricted to specific cells. In contrast, DAF-16 appeared to have a greater effect on lifespan when expressed in a combination of tissues. These results suggest that insulin signaling may regulate DAF-16 through cell-intrinsic and endocrine pathways. We also found that an insulin-dependent response to fasting in intestinal cells was preferentially regulated by intestinal insulin signaling and was less responsive to insulin signaling from non-intestinal cells. Together, these results show that C. elegans insulin signaling has endocrine as well as tissue-specific outputs which could influence lifespan in a combinatorial fashion.

  6. Mural cell associated VEGF is required for organotypic vessel formation.

    Directory of Open Access Journals (Sweden)

    Lasse Evensen

    Full Text Available BACKGROUND: Blood vessels comprise endothelial cells, mural cells (pericytes/vascular smooth muscle cells and basement membrane. During angiogenesis, mural cells are recruited to sprouting endothelial cells and define a stabilizing context, comprising cell-cell contacts, secreted growth factors and extracellular matrix components, that drives vessel maturation and resistance to anti-angiogenic therapeutics. METHODS AND FINDINGS: To better understand the basis for mural cell regulation of angiogenesis, we conducted high content imaging analysis on a microtiter plate format in vitro organotypic blood vessel system comprising primary human endothelial cells co-cultured with primary human mural cells. We show that endothelial cells co-cultured with mural cells undergo an extensive series of phenotypic changes reflective of several facets of blood vessel formation and maturation: Loss of cell proliferation, pathfinding-like cell migration, branching morphogenesis, basement membrane extracellular matrix protein deposition, lumen formation, anastamosis and development of a stabilized capillary-like network. This phenotypic sequence required endothelial-mural cell-cell contact, mural cell-derived VEGF and endothelial VEGFR2 signaling. Inhibiting formation of adherens junctions or basement membrane structures abrogated network formation. Notably, inhibition of mural cell VEGF expression could not be rescued by exogenous VEGF. CONCLUSIONS: These results suggest a unique role for mural cell-associated VEGF in driving vessel formation and maturation.

  7. Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

    Science.gov (United States)

    Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

    2001-07-01

    On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

  8. Experimental Autonomous Vehicle Systems

    DEFF Research Database (Denmark)

    Ravn, Ole; Andersen, Nils Axel

    1998-01-01

    The paper describes the requirements for and a prototype configuration of a software architecture for control of an experimental autonomous vehicle. The test bed nature of the system is emphasised in the choice of architecture making re-configurability, data logging and extendability simple...

  9. B Cell Receptor-Mediated Internalization of Salmonella: A Novel Pathway for Autonomous B Cell Activation and Antibody Production

    NARCIS (Netherlands)

    Souwer, Yuri; Griekspoor, Alexander; Jorritsma, Tineke; de Wit, Jelle; Janssen, Hans; Neefjes, Jacques; van Ham, S. Marieke

    2009-01-01

    The present paradigm is that primary B cells are nonphagocytosing cells. In this study, we demonstrate that human primary B cells are able to internalize bacteria when the bacteria are recognized by the BCR. BCR-mediated internalization of Salmonella typhimurium results in B cell differentiation and

  10. PCDH10 is required for the tumorigenicity of glioblastoma cells

    International Nuclear Information System (INIS)

    Echizen, Kanae; Nakada, Mitsutoshi; Hayashi, Tomoatsu; Sabit, Hemragul; Furuta, Takuya; Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui; Morishita, Yasuyuki; Hirano, Shinji; Terai, Kenta; Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito; Akiyama, Tetsu

    2014-01-01

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma

  11. Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells.

    Science.gov (United States)

    Morita, Ken; Noura, Mina; Tokushige, Chieko; Maeda, Shintaro; Kiyose, Hiroki; Kashiwazaki, Gengo; Taniguchi, Junichi; Bando, Toshikazu; Yoshida, Kenichi; Ozaki, Toshifumi; Matsuo, Hidemasa; Ogawa, Seishi; Liu, Pu Paul; Nakahata, Tatsutoshi; Sugiyama, Hiroshi; Adachi, Souichi; Kamikubo, Yasuhiko

    2017-11-30

    Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.

  12. Autonomous Precision Spraying Trials Using a Novel Cell Spray Implement Mounted on an Armadillo Tool Carrier

    DEFF Research Database (Denmark)

    Jensen, Kjeld; Laursen, Morten Stigaard; Midtiby, Henrik

    with an Armadillo robotic tool carrier consisting of two battery powered track modules mounted on each side of the implement. This paper focus on the cell sprayer implement design including camera system, sprayer module and integration with the service robot and the robot software. The FroboMind software platform...... and Armadillo robot is used and it is hypothesized that utilizing FroboMind the cell sprayer can drive smoothly through a test field with a lateral positioning accuracy better than 50 mm. A precision spraying trial in a 1 Ha maize field using different treatment methods was used for testing the hypothesis...

  13. The Thoc1 encoded ribonucleoprotein is required for myeloid progenitor cell homeostasis in the adult mouse.

    Science.gov (United States)

    Pitzonka, Laura; Ullas, Sumana; Chinnam, Meenalakshmi; Povinelli, Benjamin J; Fisher, Daniel T; Golding, Michelle; Appenheimer, Michelle M; Nemeth, Michael J; Evans, Sharon; Goodrich, David W

    2014-01-01

    Co-transcriptionally assembled ribonucleoprotein (RNP) complexes are critical for RNA processing and nuclear export. RNPs have been hypothesized to contribute to the regulation of coordinated gene expression, and defects in RNP biogenesis contribute to genome instability and disease. Despite the large number of RNPs and the importance of the molecular processes they mediate, the requirements for individual RNP complexes in mammalian development and tissue homeostasis are not well characterized. THO is an evolutionarily conserved, nuclear RNP complex that physically links nascent transcripts with the nuclear export apparatus. THO is essential for early mouse embryonic development, limiting characterization of the requirements for THO in adult tissues. To address this shortcoming, a mouse strain has been generated allowing inducible deletion of the Thoc1 gene which encodes an essential protein subunit of THO. Bone marrow reconstitution was used to generate mice in which Thoc1 deletion could be induced specifically in the hematopoietic system. We find that granulocyte macrophage progenitors have a cell autonomous requirement for Thoc1 to maintain cell growth and viability. Lymphoid lineages are not detectably affected by Thoc1 loss under the homeostatic conditions tested. Myeloid lineages may be more sensitive to Thoc1 loss due to their relatively high rate of proliferation and turnover.

  14. The Thoc1 encoded ribonucleoprotein is required for myeloid progenitor cell homeostasis in the adult mouse.

    Directory of Open Access Journals (Sweden)

    Laura Pitzonka

    Full Text Available Co-transcriptionally assembled ribonucleoprotein (RNP complexes are critical for RNA processing and nuclear export. RNPs have been hypothesized to contribute to the regulation of coordinated gene expression, and defects in RNP biogenesis contribute to genome instability and disease. Despite the large number of RNPs and the importance of the molecular processes they mediate, the requirements for individual RNP complexes in mammalian development and tissue homeostasis are not well characterized. THO is an evolutionarily conserved, nuclear RNP complex that physically links nascent transcripts with the nuclear export apparatus. THO is essential for early mouse embryonic development, limiting characterization of the requirements for THO in adult tissues. To address this shortcoming, a mouse strain has been generated allowing inducible deletion of the Thoc1 gene which encodes an essential protein subunit of THO. Bone marrow reconstitution was used to generate mice in which Thoc1 deletion could be induced specifically in the hematopoietic system. We find that granulocyte macrophage progenitors have a cell autonomous requirement for Thoc1 to maintain cell growth and viability. Lymphoid lineages are not detectably affected by Thoc1 loss under the homeostatic conditions tested. Myeloid lineages may be more sensitive to Thoc1 loss due to their relatively high rate of proliferation and turnover.

  15. Autonomous electrochemical biosensors: A new vision to direct methanol fuel cells.

    Science.gov (United States)

    Sales, M Goreti F; Brandão, Lúcia

    2017-12-15

    A new approach to biosensing devices is demonstrated aiming an easier and simpler application in routine health care systems. Our methodology considered a new concept for the biosensor transducing event that allows to obtain, simultaneously, an equipment-free, user-friendly, cheap electrical biosensor. The use of the anode triple-phase boundary (TPB) layer of a passive direct methanol fuel cell (DMFC) as biosensor transducer is herein proposed. For that, the ionomer present in the anode catalytic layer of the DMFC is partially replaced by an ionomer with molecular recognition capability working as the biorecognition element of the biosensor. In this approach, fuel cell anode catalysts are modified with a molecularly imprinted polymer (plastic antibody) capable of protein recognition (ferritin is used as model protein), inserted in a suitable membrane electrode assembly (MEA) and tested, as initial proof-of-concept, in a non-passive fuel cell operation environment. The anchoring of the ionomer-based plastic antibody on the catalyst surface follows a simple one-step grafting from approach through radical polymerization. Such modification increases fuel cell performance due to the proton conductivity and macroporosity characteristics of the polymer on the TPB. Finally, the response and selectivity of the bioreceptor inside the fuel cell showed a clear and selective signal from the biosensor. Moreover, such pioneering transducing approach allowed amplification of the electrochemical response and increased biosensor sensitivity by 2 orders of magnitude when compared to a 3-electrodes configuration system. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Regulation of Voltage and Frequency in Solid Oxide Fuel Cell-Based Autonomous Microgrids Using the Whales Optimisation Algorithm

    Directory of Open Access Journals (Sweden)

    Sajid Hussain Qazi

    2018-05-01

    Full Text Available This study explores the Whales Optimization Algorithm (WOA-based PI controller for regulating the voltage and frequency of an inverter-based autonomous microgrid (MG. The MG comprises two 50 kW DGs (solid oxide fuel cells, SOFCs interfaced using a power electronics-based voltage source inverter (VSI with a 120-kV conventional grid. Four PI controller schemes for the MG are implemented: (i stationary PI controller with fixed gain values (Kp and Ki, (ii PSO tuned PI controller, (iii GWO tuned PI controller, and (iv WOA tuned PI controller. The performance of these controllers is evaluated by monitoring the system voltage and frequency during the transition of MG operation mode and changes in the load. The MATLAB/SIMULINK tool is utilised to design the proposed model of grid-tied MG alongside the MATLAB m-file to apply an optimisation technique. The simulation results show that the WOA-based PI controller which optimises the control parameters, achieve 62.7% and 59% better results for voltage and frequency regulation, respectively. The eigenvalue analysis is also provided to check the stability of the proposed controller. Furthermore, the proposed system also satisfies the limits specified in IEEE-1547-2003 for voltage and frequency.

  17. Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

    Science.gov (United States)

    Sampathkumar, Charanya; Wu, Yuan-Ju; Vadhvani, Mayur; Trimbuch, Thorsten; Eickholt, Britta; Rosenmund, Christian

    2016-01-01

    Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. DOI: http://dx.doi.org/10.7554/eLife.19374.001 PMID:27782879

  18. Autonomous Bacterial Localization and Gene Expression Based on Nearby Cell Receptor Density

    Science.gov (United States)

    2013-01-22

    signal-peptide (lpp-ompA) sequences from the template vector, pTX101 (provided by Dr George Georgiou, University of Texas, Austin) (Francisco et al...generously providing the PCI-15B cell line, Dr George Georgiou for kindly providing the ompA surface display vector, and Dr Eiry Kobatake for providing...E, Wong WW, Suen JK, Bulter T, Lee SG, Liao JC (2005) A synthetic gene-metabolic oscillator. Nature 435: 118–122 Gardner TS, Cantor CR, Collins JJ

  19. A dendrite-autonomous mechanism for direction selectivity in retinal starburst amacrine cells.

    Science.gov (United States)

    Hausselt, Susanne E; Euler, Thomas; Detwiler, Peter B; Denk, Winfried

    2007-07-01

    Detection of image motion direction begins in the retina, with starburst amacrine cells (SACs) playing a major role. SACs generate larger dendritic Ca(2+) signals when motion is from their somata towards their dendritic tips than for motion in the opposite direction. To study the mechanisms underlying the computation of direction selectivity (DS) in SAC dendrites, electrical responses to expanding and contracting circular wave visual stimuli were measured via somatic whole-cell recordings and quantified using Fourier analysis. Fundamental and, especially, harmonic frequency components were larger for expanding stimuli. This DS persists in the presence of GABA and glycine receptor antagonists, suggesting that inhibitory network interactions are not essential. The presence of harmonics indicates nonlinearity, which, as the relationship between harmonic amplitudes and holding potential indicates, is likely due to the activation of voltage-gated channels. [Ca(2+)] changes in SAC dendrites evoked by voltage steps and monitored by two-photon microscopy suggest that the distal dendrite is tonically depolarized relative to the soma, due in part to resting currents mediated by tonic glutamatergic synaptic input, and that high-voltage-activated Ca(2+) channels are active at rest. Supported by compartmental modeling, we conclude that dendritic DS in SACs can be computed by the dendrites themselves, relying on voltage-gated channels and a dendritic voltage gradient, which provides the spatial asymmetry necessary for direction discrimination.

  20. A dendrite-autonomous mechanism for direction selectivity in retinal starburst amacrine cells.

    Directory of Open Access Journals (Sweden)

    Susanne E Hausselt

    2007-07-01

    Full Text Available Detection of image motion direction begins in the retina, with starburst amacrine cells (SACs playing a major role. SACs generate larger dendritic Ca(2+ signals when motion is from their somata towards their dendritic tips than for motion in the opposite direction. To study the mechanisms underlying the computation of direction selectivity (DS in SAC dendrites, electrical responses to expanding and contracting circular wave visual stimuli were measured via somatic whole-cell recordings and quantified using Fourier analysis. Fundamental and, especially, harmonic frequency components were larger for expanding stimuli. This DS persists in the presence of GABA and glycine receptor antagonists, suggesting that inhibitory network interactions are not essential. The presence of harmonics indicates nonlinearity, which, as the relationship between harmonic amplitudes and holding potential indicates, is likely due to the activation of voltage-gated channels. [Ca(2+] changes in SAC dendrites evoked by voltage steps and monitored by two-photon microscopy suggest that the distal dendrite is tonically depolarized relative to the soma, due in part to resting currents mediated by tonic glutamatergic synaptic input, and that high-voltage-activated Ca(2+ channels are active at rest. Supported by compartmental modeling, we conclude that dendritic DS in SACs can be computed by the dendrites themselves, relying on voltage-gated channels and a dendritic voltage gradient, which provides the spatial asymmetry necessary for direction discrimination.

  1. Retinoic acid-induced granulocytic differentiation of HL60 human promyelocytic leukemia cells is preceded by downregulation of autonomous generation of inositol lipid-derived second messengers

    International Nuclear Information System (INIS)

    Porfiri, E.; Hoffbrand, A.V.; Wickremasinghe, R.G.

    1991-01-01

    Inositol phosphates (InsPs) and diacyglycerol (DAG) are second messengers derived via the breakdown of inositol phospholipids, and which play important signalling roles in the regulation of proliferation of some cell types. The authors have studied the operation of this pathway during the early stages of retionic acid (RA)-induced granulocytic differentiation of HL60 myeloid leukemia cells. The autonomous breakdown of inositol lipids that occurred in HL60 cells labeled with [3H] inositol was completely abolished following 48 hours of RA treatment. The rate of influx of 45Ca2+ was also significantly decreased at 48 hours, consistent with the role of inositol lipid-derived second messengers in regulating Ca2+ entry into cells. The downregulation of inositol lipid metabolism clearly preceded the onset of reduced proliferation induced by RA treatment, and was therefore not a consequence of decreased cell growth. The generation of InsPs in RA-treated cells was reactivated by the fluoroaluminate ion, a direct activator of guanine nucleotide-binding protein(s) (G proteins) that regulate the inositol lipid signalling pathway. Subtle alterations to a regulatory mechanism may therefore mediate the RA-induced downregulation of this pathway. The data are consistent with the hypothesis that the autonomous generation of inositol lipid-derived second messengers may contribute to the continuous proliferation of HL60 cells, and that the RA-induced downregulation of this pathway may, in turn, play a role in signalling the cessation of proliferation that preceedes granulocytic differentiation

  2. Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity.

    Science.gov (United States)

    Wang, Yixin; Jin, Yi; Mäe, Maarja Andaloussi; Zhang, Yang; Ortsäter, Henrik; Betsholtz, Christer; Mäkinen, Taija; Jakobsson, Lars

    2017-10-01

    Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin. © 2017. Published by The Company of Biologists Ltd.

  3. Autonomous component carrier selection

    DEFF Research Database (Denmark)

    Garcia, Luis Guilherme Uzeda; Pedersen, Klaus; Mogensen, Preben

    2009-01-01

    management and efficient system operation. Due to the expected large number of user-deployed cells, centralized network planning becomes unpractical and new scalable alternatives must be sought. In this article, we propose a fully distributed and scalable solution to the interference management problem...... in local areas, basing our study case on LTE-Advanced. We present extensive network simulation results to demonstrate that a simple and robust interference management scheme, called autonomous component carrier selection allows each cell to select the most attractive frequency configuration; improving...... the experience of all users and not just the few best ones; while overall cell capacity is not compromised....

  4. Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

    Directory of Open Access Journals (Sweden)

    Shanna L. Bowman

    2015-03-01

    Full Text Available How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP, a neuropeptide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R receptor, increases the post-endocytic recycling of the mu-opioid receptor (MOR in trigeminal ganglion (TG neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeostatic interaction between the pain and analgesic systems.

  5. Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

    Science.gov (United States)

    Bowman, Shanna L.; Soohoo, Amanda L.; Shiwarski, Daniel J.; Schulz, Stefan; Pradhan, Amynah A.; Puthenveedu, Manojkumar A.

    2015-01-01

    SUMMARY How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropep-tide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post-endocytic recycling of the muopioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeo-static interaction between the pain and analgesic systems. PMID:25801029

  6. The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions.

    Science.gov (United States)

    Smits, Bart M G; Sharma, Deepak; Samuelson, David J; Woditschka, Stephan; Mau, Bob; Haag, Jill D; Gould, Michael N

    2011-08-16

    Mechanisms underlying low-penetrance, common, non-protein coding variants in breast cancer risk loci are largely undefined. We showed previously that the non-protein coding mammary carcinoma susceptibility locus Mcs5a/MCS5A modulates breast cancer risk in rats and women. The Mcs5a allele from the Wistar-Kyoto (WKy) rat strain consists of two genetically interacting elements that have to be present on the same chromosome to confer mammary carcinoma resistance. We also found that the two interacting elements of the resistant allele are required for the downregulation of transcript levels of the Fbxo10 gene specifically in T-cells. Here we describe mechanisms through which Mcs5a may reduce mammary carcinoma susceptibility. We performed mammary carcinoma multiplicity studies with three mammary carcinoma-inducing treatments, namely 7,12-dimethylbenz(a)anthracene (DMBA) and N-nitroso-N-methylurea (NMU) carcinogenesis, and mammary ductal infusion of retrovirus expressing the activated HER2/neu oncogene. We used mammary gland and bone marrow transplantation assays to assess the target tissue of Mcs5a activity. We used immunophenotyping assays on well-defined congenic rat lines carrying susceptible and resistant Mcs5a alleles to identify changes in T-cell homeostasis and function associated with resistance. We show that Mcs5a acts beyond the initial step of mammary epithelial cell transformation, during early cancer progression. We show that Mcs5a controls susceptibility in a non-mammary cell-autonomous manner through the immune system. The resistant Mcs5a allele was found to be associated with an overabundance of gd T-cell receptor (TCR)+ T-cells as well as a CD62L (L-selectin)-high population of all T-cell classes. In contrast to in mammary carcinoma, gdTCR+ T-cells are the predominant T-cell type in the mammary gland and were found to be overabundant in the mammary epithelium of Mcs5a resistant congenic rats. Most of them simultaneously expressed the CD4, CD8, and CD161

  7. Highly Skilled Autonomous Vehicles

    OpenAIRE

    Manuel Acosta Reche; Stratis Kanarachos; Mike V Blundell

    2017-01-01

    Recent research suggests that collision mitigation on low grip surfaces might require autonomous vehicles to execute maneuvers such as drift, trail braking or Scandinavian flick. In order to achieve this it is necessary to perceive the vehicle states and their interaction with the environment, and use this information to determine the chassis limits. A first look at the virtual automotive sensing problem is provided, followed by a description of Rally driving modeling approaches. Finally, a c...

  8. Verifying cell loss requirements in high-speed communication networks

    Directory of Open Access Journals (Sweden)

    Kerry W. Fendick

    1998-01-01

    Full Text Available In high-speed communication networks it is common to have requirements of very small cell loss probabilities due to buffer overflow. Losses are measured to verify that the cell loss requirements are being met, but it is not clear how to interpret such measurements. We propose methods for determining whether or not cell loss requirements are being met. A key idea is to look at the stream of losses as successive clusters of losses. Often clusters of losses, rather than individual losses, should be regarded as the important “loss events”. Thus we propose modeling the cell loss process by a batch Poisson stochastic process. Successive clusters of losses are assumed to arrive according to a Poisson process. Within each cluster, cell losses do not occur at a single time, but the distance between losses within a cluster should be negligible compared to the distance between clusters. Thus, for the purpose of estimating the cell loss probability, we ignore the spaces between successive cell losses in a cluster of losses. Asymptotic theory suggests that the counting process of losses initiating clusters often should be approximately a Poisson process even though the cell arrival process is not nearly Poisson. The batch Poisson model is relatively easy to test statistically and fit; e.g., the batch-size distribution and the batch arrival rate can readily be estimated from cell loss data. Since batch (cluster sizes may be highly variable, it may be useful to focus on the number of batches instead of the number of cells in a measurement interval. We also propose a method for approximately determining the parameters of a special batch Poisson cell loss with geometric batch-size distribution from a queueing model of the buffer content. For this step, we use a reflected Brownian motion (RBM approximation of a G/D/1/C queueing model. We also use the RBM model to estimate the input burstiness given the cell loss rate. In addition, we use the RBM model to

  9. Shielded Cells D ampersand D and Dismantlement System Requirements

    International Nuclear Information System (INIS)

    Witherspoon, R.L.

    1995-01-01

    This document describes the basis for the development of the System for Highly Radioactive Equipment Dismantlement or SHRED. It is the result of a thorough investigation into current and past dismantlement practices at shielded cell facilities around the DOE complex. This information has been used to formulate the development requirements for the SHRED

  10. Cellular growth in plants requires regulation of cell wall biochemistry.

    Science.gov (United States)

    Chebli, Youssef; Geitmann, Anja

    2017-02-01

    Cell and organ morphogenesis in plants are regulated by the chemical structure and mechanical properties of the extracellular matrix, the cell wall. The two primary load bearing components in the plant cell wall, the pectin matrix and the cellulose/xyloglucan network, are constantly remodelled to generate the morphological changes required during plant development. This remodelling is regulated by a plethora of loosening and stiffening agents such as pectin methyl-esterases, calcium ions, expansins, and glucanases. The tight spatio-temporal regulation of the activities of these agents is a sine qua non condition for proper morphogenesis at cell and tissue levels. The pectin matrix and the cellulose-xyloglucan network operate in concert and their behaviour is mutually dependent on their chemical, structural and mechanical modifications. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Cold-starting portable microenergy system. Autonomous fuel cell system using sodium borohydride as an energy source; Kaltstartfaehiges portables Mikroenergiesystem. Autarkes BZ-System mit Natriumborhydrid als Energietraeger

    Energy Technology Data Exchange (ETDEWEB)

    Groos, Ulf; Koch, Wolfgang [Fraunhofer-Institut fuer Solare Energiesysteme (ISE), Freiburg im Breisgau (Germany)

    2012-10-15

    A project consortium led by Fraunhofer-Institut fuer Solare Energiesysteme ISE developed an autonomous micro energy system (AMES) with an output of 100 W{sub el} as a charging station for applications in emergency medicine. The system is designed for a wide temperature range of -15 to +50 degC during startup, operation, and shutoff. The cold starting fuel cell system is in accordance with current standards and is suited for serial production. It can be operated with common hydrogen stores, e.g. gas flasks or metal hydrides, or else with a specially developed hydrogen generator based on sodium borohydride. (orig.)

  12. Establishment of human papillomavirus infection requires cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Dohun Pyeon

    2009-02-01

    Full Text Available Human papillomaviruses (HPVs are DNA viruses associated with major human cancers. As such there is a strong interest in developing new means, such as vaccines and microbicides, to prevent HPV infections. Developing the latter requires a better understanding of the infectious life cycle of HPVs. The HPV infectious life cycle is closely linked to the differentiation state of the stratified epithelium it infects, with progeny virus only made in the terminally differentiating suprabasal compartment. It has long been recognized that HPV must first establish its infection within the basal layer of stratified epithelium, but why this is the case has not been understood. In part this restriction might reflect specificity of expression of entry receptors. However, this hypothesis could not fully explain the differentiation restriction of HPV infection, since many cell types can be infected with HPVs in monolayer cell culture. Here, we used chemical biology approaches to reveal that cell cycle progression through mitosis is critical for HPV infection. Using infectious HPV16 particles containing the intact viral genome, G1-synchronized human keratinocytes as hosts, and early viral gene expression as a readout for infection, we learned that the recipient cell must enter M phase (mitosis for HPV infection to take place. Late M phase inhibitors had no effect on infection, whereas G1, S, G2, and early M phase cell cycle inhibitors efficiently prevented infection. We conclude that host cells need to pass through early prophase for successful onset of transcription of the HPV encapsidated genes. These findings provide one reason why HPVs initially establish infections in the basal compartment of stratified epithelia. Only this compartment of the epithelium contains cells progressing through the cell cycle, and therefore it is only in these cells that HPVs can establish their infection. By defining a major condition for cell susceptibility to HPV infection, these

  13. Chiral Orientation of Skeletal Muscle Cells Requires Rigid Substrate

    Directory of Open Access Journals (Sweden)

    Ninghao Zhu

    2017-06-01

    Full Text Available Reconstitution of tissue morphology with inherent left–right (LR asymmetry is essential for tissue/organ functions. For skeletal muscle, the largest tissue in mammalian organisms, successful myogenesis requires the regulation of the LR asymmetry to form the appropriate muscle alignment. However, the key factor for reproducing the LR asymmetry of skeletal tissues in a controllable, engineering context remains largely unknown. Recent reports indicate that cell chirality may underlie the LR development in tissue morphogenesis. Here, we report that a rigid substrate is required for the chirality of skeletal muscle cells. By using alternating micropatterned cell-adherent and cell-repellent stripes on a rigid substrate, we found that C2C12 skeletal muscle myoblasts exhibited a unidirectional tilted orientation with respect to the stripe boundary. Importantly, such chiral orientation was reduced when soft substrates were used instead. In addition, we demonstrated the key role of actin stress fibers in the formation of the chiral orientation. This study reveals that a rigid substrate is required for the chiral pattern of myoblasts, paving the way for reconstructing damaged muscle tissue with inherent LR asymmetry in the future.

  14. Activation of postnatal neural stem cells requires nuclear receptor TLX.

    Science.gov (United States)

    Niu, Wenze; Zou, Yuhua; Shen, Chengcheng; Zhang, Chun-Li

    2011-09-28

    Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.

  15. Single cell wound generates electric current circuit and cell membrane potential variations that requires calcium influx.

    Science.gov (United States)

    Luxardi, Guillaume; Reid, Brian; Maillard, Pauline; Zhao, Min

    2014-07-24

    Breaching of the cell membrane is one of the earliest and most common causes of cell injury, tissue damage, and disease. If the compromise in cell membrane is not repaired quickly, irreversible cell damage, cell death and defective organ functions will result. It is therefore fundamentally important to efficiently repair damage to the cell membrane. While the molecular aspects of single cell wound healing are starting to be deciphered, its bio-physical counterpart has been poorly investigated. Using Xenopus laevis oocytes as a model for single cell wound healing, we describe the temporal and spatial dynamics of the wound electric current circuitry and the temporal dynamics of cell membrane potential variation. In addition, we show the role of calcium influx in controlling electric current circuitry and cell membrane potential variations. (i) Upon wounding a single cell: an inward electric current appears at the wound center while an outward electric current is observed at its sides, illustrating the wound electric current circuitry; the cell membrane is depolarized; calcium flows into the cell. (ii) During cell membrane re-sealing: the wound center current density is maintained for a few minutes before decreasing; the cell membrane gradually re-polarizes; calcium flow into the cell drops. (iii) In conclusion, calcium influx is required for the formation and maintenance of the wound electric current circuitry, for cell membrane re-polarization and for wound healing.

  16. Autonomous Control of Space Reactor Systems

    International Nuclear Information System (INIS)

    Belle R. Upadhyaya; K. Zhao; S.R.P. Perillo; Xiaojia Xu; M.G. Na

    2007-01-01

    Autonomous and semi-autonomous control is a key element of space reactor design in order to meet the mission requirements of safety, reliability, survivability, and life expectancy. Interrestrial nuclear power plants, human operators are available to perform intelligent control functions that are necessary for both normal and abnormal operational conditions

  17. Autonomous Control of Space Reactor Systems

    Energy Technology Data Exchange (ETDEWEB)

    Belle R. Upadhyaya; K. Zhao; S.R.P. Perillo; Xiaojia Xu; M.G. Na

    2007-11-30

    Autonomous and semi-autonomous control is a key element of space reactor design in order to meet the mission requirements of safety, reliability, survivability, and life expectancy. Interrestrial nuclear power plants, human operators are avilable to perform intelligent control functions that are necessary for both normal and abnormal operational conditions.

  18. Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

    Science.gov (United States)

    Markwart, Robby; Condotta, Stephanie A.; Requardt, Robert P.; Borken, Farina; Schubert, Katja; Weigel, Cynthia; Bauer, Michael; Griffith, Thomas S.; Förster, Martin; Brunkhorst, Frank M.; Badovinac, Vladimir P.; Rubio, Ignacio

    2014-01-01

    Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4+/CD8+ T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells. PMID:25541945

  19. Multiple modes of proepicardial cell migration require heartbeat.

    Science.gov (United States)

    Plavicki, Jessica S; Hofsteen, Peter; Yue, Monica S; Lanham, Kevin A; Peterson, Richard E; Heideman, Warren

    2014-05-15

    injected hearts. Epicardial cells stem from a heterogeneous population of progenitors, suggesting that the progenitors in the PE have distinct identities. PE cells attach to the heart via a cellular bridge and free-floating cell clusters. Pericardiac fluid advections are not necessary for the development of the PE cluster, however heartbeat is required for epicardium formation. Epicardium formation can occur in culture without normal hydrodynamic and hemodynamic forces, but not without contraction.

  20. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3

    Science.gov (United States)

    Rimmelé, Pauline; Liang, Raymond; Bigarella, Carolina L; Kocabas, Fatih; Xie, Jingjing; Serasinghe, Madhavika N; Chipuk, Jerry; Sadek, Hesham; Zhang, Cheng Cheng; Ghaffari, Saghi

    2015-01-01

    Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3−/− HSC that are defective in their activity. We show that Foxo3−/− HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3−/− hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3−/− HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells. PMID:26209246

  1. Castration-Resistant Lgr5+ Cells Are Long-Lived Stem Cells Required for Prostatic Regeneration

    Directory of Open Access Journals (Sweden)

    Bu-er Wang

    2015-05-01

    Full Text Available The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5 is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5+ population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5+ cells and their progeny are primarily luminal. Lgr5+ castration-resistant cells are long lived and upon regeneration, both luminal Lgr5+ cells and basal Lgr5+ cells expand. Moreover, single Lgr5+ cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5+ cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5+ cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5+ cells during prostatic regeneration, and identify an Lgr5+ adult stem cell population in the prostate.

  2. Mast cell protease 6 is required for allograft tolerance.

    Science.gov (United States)

    de Vries, V C; Elgueta, R; Lee, D M; Noelle, R J

    2010-09-01

    It has been shown that mast cells (MC) are absolutely required for transplant acceptance. However, only a few of the numerous mediators produced by MC have been proposed as potential mechanisms for the observed immunosuppression. The role of proteases in acquired immune tolerance as such has not yet been addressed. In this study, we have shown the requirement for MC protease 6 (MCP6), an MC-specific tryptase, to establish tolerance toward an allogeneic skin graft. The substrate for MCP6 is interleukin (IL)-6, cytokine generally considered to indicate transplant rejection. Herein we have shown an inverse correlation between MCP6 and IL-6. High expression of MCP6 is accompanied by low levels of IL-6 when the allograft is accepted, whereas low expression of MCP6 in combination with high levels of IL-6 are observed in rejecting grafts. Moreover, tolerance toward an allogeneic graft cannot be induced in MCP6(-/-) mice. Rejection observed in these mice was comparable to that of MC-deficient hosts; it is T-cell mediated. These findings suggest that MCP6 actively depletes the local environment of IL-6 to maintain tolerance. 2010. Published by Elsevier Inc.

  3. T cell resistance to activation by dendritic cells requires long-term culture in simulated microgravity

    Science.gov (United States)

    Bradley, Jillian H.; Stein, Rachel; Randolph, Brad; Molina, Emily; Arnold, Jennifer P.; Gregg, Randal K.

    2017-11-01

    Immune impairment mediated by microgravity threatens the success of space exploration requiring long-duration spaceflight. The cells of most concern, T lymphocytes, coordinate the host response against microbial and cancerous challenges leading to elimination and long-term protection. T cells are activated upon recognition of specific microbial peptides bound on the surface of antigen presenting cells, such as dendritic cells (DC). Subsequently, this engagement results in T cell proliferation and differentiation into effector T cells driven by autocrine interleukin-2 (IL-2) and other cytokines. Finally, the effector T cells acquire the weaponry needed to destroy microbial invaders and tumors. Studies conducted on T cells during spaceflight, or using Earth-based culture systems, have shown reduced production of cytokines, proliferation and effector functions as compared to controls. This may account for the cases of viral reactivation events and opportunistic infections associated with astronauts of numerous missions. This work has largely been based upon the outcome of T cell activation by stimulatory factors that target select T cell signaling pathways rather than the complex, signaling events related to the natural process of antigen presentation by DC. This study tested the response of an ovalbumin peptide-specific T cell line, OT-II TCH, to activation by DC when the T cells were cultured 24-120 h in a simulated microgravity (SMG) environment generated by a rotary cell culture system. Following 72 h culture of T cells in SMG (SMG-T) or control static (Static-T) conditions, IL-2 production by the T cells was reduced in SMG-T cells compared to Static-T cells upon stimulation by phorbol 12-myristate 13-acetate (PMA) and ionomycin. However, when the SMG-T cells were stimulated with DC and peptide, IL-2 was significantly increased compared to Static-T cells. Such enhanced IL-2 production by SMG-T cells peaked at 72 h SMG culture time and decreased thereafter. When

  4. T cell resistance to activation by dendritic cells requires long-term culture in simulated microgravity.

    Science.gov (United States)

    Bradley, Jillian H; Stein, Rachel; Randolph, Brad; Molina, Emily; Arnold, Jennifer P; Gregg, Randal K

    2017-11-01

    Immune impairment mediated by microgravity threatens the success of space exploration requiring long-duration spaceflight. The cells of most concern, T lymphocytes, coordinate the host response against microbial and cancerous challenges leading to elimination and long-term protection. T cells are activated upon recognition of specific microbial peptides bound on the surface of antigen presenting cells, such as dendritic cells (DC). Subsequently, this engagement results in T cell proliferation and differentiation into effector T cells driven by autocrine interleukin-2 (IL-2) and other cytokines. Finally, the effector T cells acquire the weaponry needed to destroy microbial invaders and tumors. Studies conducted on T cells during spaceflight, or using Earth-based culture systems, have shown reduced production of cytokines, proliferation and effector functions as compared to controls. This may account for the cases of viral reactivation events and opportunistic infections associated with astronauts of numerous missions. This work has largely been based upon the outcome of T cell activation by stimulatory factors that target select T cell signaling pathways rather than the complex, signaling events related to the natural process of antigen presentation by DC. This study tested the response of an ovalbumin peptide-specific T cell line, OT-II TCH, to activation by DC when the T cells were cultured 24-120 h in a simulated microgravity (SMG) environment generated by a rotary cell culture system. Following 72 h culture of T cells in SMG (SMG-T) or control static (Static-T) conditions, IL-2 production by the T cells was reduced in SMG-T cells compared to Static-T cells upon stimulation by phorbol 12-myristate 13-acetate (PMA) and ionomycin. However, when the SMG-T cells were stimulated with DC and peptide, IL-2 was significantly increased compared to Static-T cells. Such enhanced IL-2 production by SMG-T cells peaked at 72 h SMG culture time and decreased thereafter

  5. Autonomic Nervous System Disorders

    Science.gov (United States)

    Your autonomic nervous system is the part of your nervous system that controls involuntary actions, such as the beating of your heart ... breathing and swallowing Erectile dysfunction in men Autonomic nervous system disorders can occur alone or as the result ...

  6. Autonomous Landing on Moving Platforms

    KAUST Repository

    Mendoza Chavez, Gilberto

    2016-08-01

    This thesis investigates autonomous landing of a micro air vehicle (MAV) on a nonstationary ground platform. Unmanned aerial vehicles (UAVs) and micro air vehicles (MAVs) are becoming every day more ubiquitous. Nonetheless, many applications still require specialized human pilots or supervisors. Current research is focusing on augmenting the scope of tasks that these vehicles are able to accomplish autonomously. Precise autonomous landing on moving platforms is essential for self-deployment and recovery of MAVs, but it remains a challenging task for both autonomous and piloted vehicles. Model Predictive Control (MPC) is a widely used and effective scheme to control constrained systems. One of its variants, output-feedback tube-based MPC, ensures robust stability for systems with bounded disturbances under system state reconstruction. This thesis proposes a MAV control strategy based on this variant of MPC to perform rapid and precise autonomous landing on moving targets whose nominal (uncommitted) trajectory and velocity are slowly varying. The proposed approach is demonstrated on an experimental setup.

  7. Cell division requirement for activation of murine leukemia virus in cell culture by irradiation

    International Nuclear Information System (INIS)

    Otten, J.A.; Quarles, J.M.; Tennant, R.W.

    1976-01-01

    Actively dividing cultures of AKR mouse cells were exposed to relatively low dose-rates of γ radiation and tested for activation of endogenous leukemia viruses. Efficient and reproducible induction of virus was obtained with actively dividing cells, but cultures deprived of serum to inhibit cell division before and during γ irradiation were not activated, even when medium with serum was added immediately after irradiation. These results show that cell division was required for virus induction but that a stable intermediate similar to the state induced by halogenated pyrimidines was not formed. In actively dividing AKR cell cultures, virus activation appeared to be proportional to the dose of γ radiation; the estimated frequency of activation was 1-8 x 10 - 5 per exposed cell and the efficiency of activation was approximately 0.012 inductions per cell per rad. Other normal primary and established mouse cell cultures tested were not activated by γ radiation. The requirement of cell division for radiation and chemical activation may reflect some common mechanism for initiation of virus expression

  8. IDC2 and IDC3, two genes involved in cell non-autonomous signaling of fruiting body development in the model fungus Podospora anserina.

    Science.gov (United States)

    Lalucque, Hervé; Malagnac, Fabienne; Green, Kimberly; Gautier, Valérie; Grognet, Pierre; Chan Ho Tong, Laetitia; Scott, Barry; Silar, Philippe

    2017-01-15

    Filamentous ascomycetes produce complex multicellular structures during sexual reproduction. Little is known about the genetic pathways enabling the construction of such structures. Here, with a combination of classical and reverse genetic methods, as well as genetic mosaic and graft analyses, we identify and provide evidence for key roles for two genes during the formation of perithecia, the sexual fruiting bodies, of the filamentous fungus Podospora anserina. Data indicate that the proteins coded by these two genes function cell-non-autonomously and that their activity depends upon conserved cysteines, making them good candidate for being involved in the transmission of a reactive oxygen species (ROS) signal generated by the PaNox1 NADPH oxidase inside the maturing fruiting body towards the PaMpk1 MAP kinase, which is located inside the underlying mycelium, in which nutrients are stored. These data provide important new insights to our understanding of how fungi build multicellular structures. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Follow-the-leader cell migration requires biased cell-cell contact and local microenvironmental signals

    Science.gov (United States)

    Wynn, Michelle L.; Rupp, Paul; Trainor, Paul A.; Schnell, Santiago; Kulesa, Paul M.

    2013-06-01

    Directed cell migration often involves at least two types of cell motility that include multicellular streaming and chain migration. However, what is unclear is how cell contact dynamics and the distinct microenvironments through which cells travel influence the selection of one migratory mode or the other. The embryonic and highly invasive neural crest (NC) are an excellent model system to study this question since NC cells have been observed in vivo to display both of these types of cell motility. Here, we present data from tissue transplantation experiments in chick and in silico modeling that test our hypothesis that cell contact dynamics with each other and the microenvironment promote and sustain either multicellular stream or chain migration. We show that when premigratory cranial NC cells (at the pre-otic level) are transplanted into a more caudal region in the head (at the post-otic level), cells alter their characteristic stream behavior and migrate in chains. Similarly, post-otic NC cells migrate in streams after transplantation into the pre-otic hindbrain, suggesting that local microenvironmental signals dictate the mode of NC cell migration. Simulations of an agent-based model (ABM) that integrates the NC cell behavioral data predict that chain migration critically depends on the interplay of biased cell-cell contact and local microenvironment signals. Together, this integrated modeling and experimental approach suggests new experiments and offers a powerful tool to examine mechanisms that underlie complex cell migration patterns.

  10. Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration.

    Science.gov (United States)

    Kawasaki, Fumiko; Koonce, Noelle L; Guo, Linda; Fatima, Shahroz; Qiu, Catherine; Moon, Mackenzie T; Zheng, Yunzhen; Ordway, Richard W

    2016-09-01

    Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule

  11. The Autonomic Nervous System Regulates the Heart Rate through cAMP-PKA Dependent and Independent Coupled-Clock Pacemaker Cell Mechanisms.

    Science.gov (United States)

    Behar, Joachim; Ganesan, Ambhighainath; Zhang, Jin; Yaniv, Yael

    2016-01-01

    Sinoatrial nodal cells (SANCs) generate spontaneous action potentials (APs) that control the cardiac rate. The brain modulates SANC automaticity, via the autonomic nervous system, by stimulating membrane receptors that activate (adrenergic) or inactivate (cholinergic) adenylyl cyclase (AC). However, these opposing afferents are not simply additive. We showed that activation of adrenergic signaling increases AC-cAMP/PKA signaling, which mediates the increase in the SANC AP firing rate (i.e., positive chronotropic modulation). However, there is a limited understanding of the underlying internal pacemaker mechanisms involved in the crosstalk between cholinergic receptors and the decrease in the SANC AP firing rate (i.e., negative chronotropic modulation). We hypothesize that changes in AC-cAMP/PKA activity are crucial for mediating either decrease or increase in the AP firing rate and that the change in rate is due to both internal and membrane mechanisms. In cultured adult rabbit pacemaker cells infected with an adenovirus expressing the FRET sensor AKAR3, PKA activity and AP firing rate were tightly linked in response to either adrenergic receptor stimulation (by isoproterenol, ISO) or cholinergic stimulation (by carbachol, CCh). To identify the main molecular targets that mediate between PKA signaling and pacemaker function, we developed a mechanistic computational model. The model includes a description of autonomic-nervous receptors, post- translation signaling cascades, membrane molecules, and internal pacemaker mechanisms. Yielding results similar to those of the experiments, the model simulations faithfully reproduce the changes in AP firing rate in response to CCh or ISO or a combination of both (i.e., accentuated antagonism). Eliminating AC-cAMP-PKA signaling abolished the core effect of autonomic receptor stimulation on the AP firing rate. Specifically, disabling the phospholamban modulation of the SERCA activity resulted in a significantly reduced effect

  12. miR126-5p down-regulation facilitates axon degeneration and NMJ disruption via a non-cell-autonomous mechanism in ALS.

    Science.gov (United States)

    Maimon, Roy; Ionescu, Ariel; Bonnie, Avichai; Sweetat, Sahar; Wald-Altman, Shane; Inbar, Shani; Gradus, Tal; Trotti, Davide; Weil, Miguel; Behar, Oded; Perlson, Eran

    2018-05-17

    Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in Amyotrophic Lateral Sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR-126-5p in pre-symptomatic ALS male mice models, and an increase in its targets: axon destabilizing type-3 Semaphorins and their co-receptor Neuropilins. Utilizing compartmentalized in vitro co-cultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 (NRP1) blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non-cell-autonomous mechanism of motor neuron degeneration in ALS. SIGNIFICANCE STATEMENT In spite of some progress, currently no effective treatment is available for ALS. We suggest a novel regulatory role for miR126-5p in ALS and demonstrate for the first time a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo. Copyright © 2018 Maimon et al.

  13. Fuel processing requirements and techniques for fuel cell propulsion power

    Science.gov (United States)

    Kumar, R.; Ahmed, S.; Yu, M.

    Fuels for fuel cells in transportation systems are likely to be methanol, natural gas, hydrogen, propane, or ethanol. Fuels other than hydrogen will need to be reformed to hydrogen on-board the vehicle. The fuel reformer must meet stringent requirements for weight and volume, product quality, and transient operation. It must be compact and lightweight, must produce low levels of CO and other byproducts, and must have rapid start-up and good dynamic response. Catalytic steam reforming, catalytic or noncatalytic partial oxidation reforming, or some combination of these processes may be used. This paper discusses salient features of the different kinds of reformers and describes the catalysts and processes being examined for the oxidation reforming of methanol and the steam reforming of ethanol. Effective catalysts and reaction conditions for the former have been identified; promising catalysts and reaction conditions for the latter are being investigated.

  14. Dose requirements of alfentanil to eliminate autonomic responses during rapid-sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

    Science.gov (United States)

    Abou-Arab, Mohammad H; Rostrup, Morten; Heier, Tom

    2016-12-01

    Opioids are integral part of anesthesia induction, but information on optimal dosing is limited. We aimed to determine doses of alfentanil needed to eliminate increases in 5 autonomic response variables (plasma concentrations of epinephrine, norepinephrine and vasopressin, arterial blood pressure [ABP], and heart rate) during rapid-sequence induction of anesthesia with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Prospective, randomized, observer-blinded, interventional clinical study. Large academic institution. Eighty-four healthy patients, aged 18 to 55 years, received 1 of 7 assessor-blinded doses of alfentanil (0, 10, 20, 30, 40, 50, and 60 μg/kg) together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg, administered in rapid succession (15 seconds). Laryngoscopy was initiated 40 seconds after rocuronium, and tracheal intubation was concluded within 15 seconds thereafter. An indwelling radial artery catheter was used for hemodynamic monitoring and blood sampling. Relationships between alfentanil dose and response variables were tested with linear regression, and the influence of covariates (sex, body weight, and age) was determined. Alfentanil dose needed to prevent increases in ABP >10% above baseline with 95% probability was estimated with logistic regression. Significant relationships were determined between alfentanil dose and response variables. Clinically interesting influence of covariates was not found. Alfentanil 55 μg/kg was needed to prevent increases in ABP postintubation >10% above baseline with 95% probability. One individual needed a bolus of vasopressor postintubation. Optimal control of autonomic responses during rapid-sequence induction was achieved with clinically relevant doses of alfentanil in healthy patients anesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. ADRES : autonomous decentralized regenerative energy systems

    Energy Technology Data Exchange (ETDEWEB)

    Brauner, G.; Einfalt, A.; Leitinger, C.; Tiefgraber, D. [Vienna Univ. of Technology (Austria)

    2007-07-01

    The autonomous decentralized regenerative energy systems (ADRES) research project demonstrates that decentralized network independent microgrids are the target power systems of the future. This paper presented a typical structure of a microgrid, demonstrating that all types of generation available can be integrated, from wind and small hydro to photovoltaic, fuel cell, biomass or biogas operated stirling motors and micro turbines. In grid connected operation the balancing energy and reactive power for voltage control will come from the public grid. If there is no interconnection to a superior grid, it will form an autonomous micro grid. In order to reduce peak power demand and base energy, autonomous microgrid technology requires highly efficient appliances. Otherwise large collector design, high storage and balancing generation capacities would be necessary, which would increase costs. End-use energy efficiency was discussed with reference to demand side management (DSM) strategies that match energy demand with actual supply in order to minimize the storage size needed. This paper also discussed network controls that comprise active and reactive power. Decentralized robust algorithms were investigated with reference to black-start ability and congestion management features. It was concluded that the trend to develop small decentralized grids in parallel to existing large systems will improve security of supply and reduce greenhouse gas emissions. Decentralized grids will also increase energy efficiency because regenerative energy will be used where it is collected in the form of electricity and heat, thus avoiding transport and the extension of transmission lines. Decentralized energy technology is now becoming more economic by efficient and economic mass production of components. Although decentralized energy technology requires energy automation, computer intelligence is becoming increasingly cost efficient. 2 refs., 4 figs.

  16. A Secure, Scalable and Elastic Autonomic Computing Systems Paradigm: Supporting Dynamic Adaptation of Self-* Services from an Autonomic Cloud

    Directory of Open Access Journals (Sweden)

    Abdul Jaleel

    2018-05-01

    Full Text Available Autonomic computing embeds self-management features in software systems using external feedback control loops, i.e., autonomic managers. In existing models of autonomic computing, adaptive behaviors are defined at the design time, autonomic managers are statically configured, and the running system has a fixed set of self-* capabilities. An autonomic computing design should accommodate autonomic capability growth by allowing the dynamic configuration of self-* services, but this causes security and integrity issues. A secure, scalable and elastic autonomic computing system (SSE-ACS paradigm is proposed to address the runtime inclusion of autonomic managers, ensuring secure communication between autonomic managers and managed resources. Applying the SSE-ACS concept, a layered approach for the dynamic adaptation of self-* services is presented with an online ‘Autonomic_Cloud’ working as the middleware between Autonomic Managers (offering the self-* services and Autonomic Computing System (requiring the self-* services. A stock trading and forecasting system is used for simulation purposes. The security impact of the SSE-ACS paradigm is verified by testing possible attack cases over the autonomic computing system with single and multiple autonomic managers running on the same and different machines. The common vulnerability scoring system (CVSS metric shows a decrease in the vulnerability severity score from high (8.8 for existing ACS to low (3.9 for SSE-ACS. Autonomic managers are introduced into the system at runtime from the Autonomic_Cloud to test the scalability and elasticity. With elastic AMs, the system optimizes the Central Processing Unit (CPU share resulting in an improved execution time for business logic. For computing systems requiring the continuous support of self-management services, the proposed system achieves a significant improvement in security, scalability, elasticity, autonomic efficiency, and issue resolving time

  17. Discovery of a Splicing Regulator Required for Cell Cycle Progression

    Energy Technology Data Exchange (ETDEWEB)

    Suvorova, Elena S.; Croken, Matthew; Kratzer, Stella; Ting, Li-Min; Conde de Felipe, Magnolia; Balu, Bharath; Markillie, Lye Meng; Weiss, Louis M.; Kim, Kami; White, Michael W.

    2013-02-01

    In the G1 phase of the cell division cycle, eukaryotic cells prepare many of the resources necessary for a new round of growth including renewal of the transcriptional and protein synthetic capacities and building the machinery for chromosome replication. The function of G1 has an early evolutionary origin and is preserved in single and multicellular organisms, although the regulatory mechanisms conducting G1 specific functions are only understood in a few model eukaryotes. Here we describe a new G1 mutant from an ancient family of apicomplexan protozoans. Toxoplasma gondii temperature-sensitive mutant 12-109C6 conditionally arrests in the G1 phase due to a single point mutation in a novel protein containing a single RNA-recognition-motif (TgRRM1). The resulting tyrosine to asparagine amino acid change in TgRRM1 causes severe temperature instability that generates an effective null phenotype for this protein when the mutant is shifted to the restrictive temperature. Orthologs of TgRRM1 are widely conserved in diverse eukaryote lineages, and the human counterpart (RBM42) can functionally replace the missing Toxoplasma factor. Transcriptome studies demonstrate that gene expression is downregulated in the mutant at the restrictive temperature due to a severe defect in splicing that affects both cell cycle and constitutively expressed mRNAs. The interaction of TgRRM1 with factors of the tri-SNP complex (U4/U6 & U5 snRNPs) indicate this factor may be required to assemble an active spliceosome. Thus, the TgRRM1 family of proteins is an unrecognized and evolutionarily conserved class of splicing regulators. This study demonstrates investigations into diverse unicellular eukaryotes, like the Apicomplexa, have the potential to yield new insights into important mechanisms conserved across modern eukaryotic kingdoms.

  18. Vectorial signalling mechanism required for cell-cell communication during sporulation in Bacillus subtilis.

    Science.gov (United States)

    Diez, Veronica; Schujman, Gustavo E; Gueiros-Filho, Frederico J; de Mendoza, Diego

    2012-01-01

    Spore formation in Bacillus subtilis takes place in a sporangium consisting of two chambers, the forespore and the mother cell, which are linked by pathways of cell-cell communication. One pathway, which couples the proteolytic activation of the mother cell transcription factor σ(E) to the action of a forespore synthesized signal molecule, SpoIIR, has remained enigmatic. Signalling by SpoIIR requires the protein to be exported to the intermembrane space between forespore and mother cell, where it will interact with and activate the integral membrane protease SpoIIGA. Here we show that SpoIIR signal activity as well as the cleavage of its N-terminal extension is strictly dependent on the prespore fatty acid biosynthetic machinery. We also report that a conserved threonine residue (T27) in SpoIIR is required for processing, suggesting that signalling of SpoIIR is dependent on fatty acid synthesis probably because of acylation of T27. In addition, SpoIIR localization in the forespore septal membrane depends on the presence of SpoIIGA. The orchestration of σ(E) activation in the intercellular space by an acylated signal protein provides a new paradigm to ensure local transmission of a weak signal across the bilayer to control cell-cell communication during development. © 2011 Blackwell Publishing Ltd.

  19. Bacterial Cell Enlargement Requires Control of Cell Wall Stiffness Mediated by Peptidoglycan Hydrolases.

    Science.gov (United States)

    Wheeler, Richard; Turner, Robert D; Bailey, Richard G; Salamaga, Bartłomiej; Mesnage, Stéphane; Mohamad, Sharifah A S; Hayhurst, Emma J; Horsburgh, Malcolm; Hobbs, Jamie K; Foster, Simon J

    2015-07-28

    Most bacterial cells are enclosed in a single macromolecule of the cell wall polymer, peptidoglycan, which is required for shape determination and maintenance of viability, while peptidoglycan biosynthesis is an important antibiotic target. It is hypothesized that cellular enlargement requires regional expansion of the cell wall through coordinated insertion and hydrolysis of peptidoglycan. Here, a group of (apparent glucosaminidase) peptidoglycan hydrolases are identified that are together required for cell enlargement and correct cellular morphology of Staphylococcus aureus, demonstrating the overall importance of this enzyme activity. These are Atl, SagA, ScaH, and SagB. The major advance here is the explanation of the observed morphological defects in terms of the mechanical and biochemical properties of peptidoglycan. It was shown that cells lacking groups of these hydrolases have increased surface stiffness and, in the absence of SagB, substantially increased glycan chain length. This indicates that, beyond their established roles (for example in cell separation), some hydrolases enable cellular enlargement by making peptidoglycan easier to stretch, providing the first direct evidence demonstrating that cellular enlargement occurs via modulation of the mechanical properties of peptidoglycan. Understanding bacterial growth and division is a fundamental problem, and knowledge in this area underlies the treatment of many infectious diseases. Almost all bacteria are surrounded by a macromolecule of peptidoglycan that encloses the cell and maintains shape, and bacterial cells must increase the size of this molecule in order to enlarge themselves. This requires not only the insertion of new peptidoglycan monomers, a process targeted by antibiotics, including penicillin, but also breakage of existing bonds, a potentially hazardous activity for the cell. Using Staphylococcus aureus, we have identified a set of enzymes that are critical for cellular enlargement. We

  20. Splenectomy reduces packed red cell transfusion requirement in children with sickle cell disease.

    Science.gov (United States)

    Haricharan, Ramanath N; Roberts, Jared M; Morgan, Traci L; Aprahamian, Charles J; Hardin, William D; Hilliard, Lee M; Georgeson, Keith E; Barnhart, Douglas C

    2008-06-01

    The purpose of the study was to measure the effect of splenectomy on packed-cell transfusion requirement in children with sickle cell disease. Thirty-seven sickle cell children who underwent splenectomies between January 2000 and May 2006 at a children's hospital were reviewed. Data were collected 6 months preoperatively to 12 months postsplenectomy. Paired t test, analysis of variance, and multivariable regression analyses were performed. Of 37 children with median age 11 years (range, 2-18 years), 34 (21 males) had data that allowed analyses. Twenty-six had Hgb-SS, 5 had Hgb-SC, and 3 had Hgb S-Thal. Laparoscopic splenectomy was attempted in 36 and completed successfully in 34 (94% success). The number of units transfused decreased by 38% for 0 to 6 months and by 45% for 6 to 12 months postsplenectomy. Postoperatively, hematocrit levels increased and reticulocytes concurrently decreased with a reduction in transfusion clinic visits. The decrease in transfusion was not influenced by spleen weight, age, or hemoglobin type. Two children had acute chest syndrome (6%), and 1 had severe pneumonia (3%). Laparoscopic splenectomy can be successfully completed in sickle cell children. Splenectomy significantly reduces the packed red cell transfusion requirement and frequency of clinic visits, in sickle cell children for at least 12 months postoperatively.

  1. LSD1 is Required for Hair Cell Regeneration in Zebrafish.

    Science.gov (United States)

    He, Yingzi; Tang, Dongmei; Cai, Chengfu; Chai, Renjie; Li, Huawei

    2016-05-01

    Lysine-specific demethylase 1 (LSD1/KDM1A) plays an important role in complex cellular processes such as differentiation, proliferation, apoptosis, and cell cycle progression. It has recently been demonstrated that during development, downregulation of LSD1 inhibits cell proliferation, modulates the expression of cell cycle regulators, and reduces hair cell formation in the zebrafish lateral line, which suggests that LSD1-mediated epigenetic regulation plays a key role in the development of hair cells. However, the role of LSD1 in hair cell regeneration after hair cell loss remains poorly understood. Here, we demonstrate the effect of LSD1 on hair cell regeneration following neomycin-induced hair cell loss. We show that the LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA) significantly decreases the regeneration of hair cells in zebrafish after neomycin damage. In addition, immunofluorescent staining demonstrates that 2-PCPA administration suppresses supporting cell proliferation and alters cell cycle progression. Finally, in situ hybridization shows that 2-PCPA significantly downregulates the expression of genes related to Wnt/β-catenin and Fgf activation. Altogether, our data suggest that downregulation of LSD1 significantly decreases hair cell regeneration after neomycin-induced hair cell loss through inactivation of the Wnt/β-catenin and Fgf signaling pathways. Thus, LSD1 plays a critical role in hair cell regeneration and might represent a novel biomarker and potential therapeutic approach for the treatment of hearing loss.

  2. Adenosinergic Immunosuppression by Human Mesenchymal Stromal Cells Requires Co-Operation with T cells.

    Science.gov (United States)

    Kerkelä, Erja; Laitinen, Anita; Räbinä, Jarkko; Valkonen, Sami; Takatalo, Maarit; Larjo, Antti; Veijola, Johanna; Lampinen, Milla; Siljander, Pia; Lehenkari, Petri; Alfthan, Kaija; Laitinen, Saara

    2016-03-01

    Mesenchymal stem/stromal cells (MSCs) have the capacity to counteract excessive inflammatory responses. MSCs possess a range of immunomodulatory mechanisms, which can be deployed in response to signals in a particular environment and in concert with other immune cells. One immunosuppressive mechanism, not so well-known in MSCs, is mediated via adenosinergic pathway by ectonucleotidases CD73 and CD39. In this study, we demonstrate that adenosine is actively produced from adenosine 5'-monophosphate (AMP) by CD73 on MSCs and MSC-derived extracellular vesicles (EVs). Our results indicate that although MSCs express CD39 at low level and it colocalizes with CD73 in bulge areas of membranes, the most efficient adenosine production from adenosine 5'-triphosphate (ATP) requires co-operation of MSCs and activated T cells. Highly CD39 expressing activated T cells produce AMP from ATP and MSCs produce adenosine from AMP via CD73 activity. Furthermore, adenosinergic signaling plays a role in suppression of T cell proliferation in vitro. In conclusion, this study shows that adenosinergic signaling is an important immunoregulatory mechanism of MSCs, especially in situations where ATP is present in the extracellular environment, like in tissue injury. An efficient production of immunosuppressive adenosine is dependent on the concerted action of CD39-positive immune cells with CD73-positive cells such as MSCs or their EVs. © 2016 AlphaMed Press.

  3. Autonomous Electrical Vehicles’ Charging Station

    OpenAIRE

    Józef Paska; Mariusz Kłos; Łukasz Rosłaniec; Rafał Bielas; Magdalena Błędzińska

    2016-01-01

    This paper presents a model of an autonomous electrical vehicles’ charging station. It consists of renewable energy sources: wind turbine system, photovoltaic cells, as well as an energy storage, load, and EV charging station. In order to optimise the operating conditions, power electronic converters were added to the system. The model was implemented in the Homer Energy programme. The first part of the paper presents the design assumptions and technological solutions. Further in the paper...

  4. The requirements for herpes simplex virus type 1 cell-cell spread via nectin-1 parallel those for virus entry.

    Science.gov (United States)

    Even, Deborah L; Henley, Allison M; Geraghty, Robert J

    2006-08-01

    Herpes simplex virus type 1 (HSV-1) spreads from an infected cell to an uninfected cell by virus entry, virus-induced cell fusion, and cell-cell spread. The three forms of virus spread require the viral proteins gB, gD, and gH-gL, as well as a cellular gD receptor. The mutual requirement for the fusion glycoproteins and gD receptor suggests that virus entry, cell fusion, and cell-cell spread occur by a similar mechanism. The goals of this study were to examine the role of the nectin-1alpha transmembrane domain and cytoplasmic tail in cell-cell spread and to obtain a better understanding of the receptor-dependent events occurring at the plasma membrane during cell-cell spread. We determined that an intact nectin-1alpha V-like domain was required for cell-cell spread, while a membrane-spanning domain and cytoplasmic tail were not. Chimeric forms of nectin-1 that were non-functional for virus entry did not mediate cell-cell spread regardless of whether they could mediate cell fusion. Also, cell-cell spread of syncytial isolates was dependent upon nectin-1alpha expression and occurred through a nectin-1-dependent mechanism. Taken together, our results indicate that nectin-1-dependent events occurring at the plasma membrane during cell-cell spread were equivalent to those for virus entry.

  5. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival.

    Directory of Open Access Journals (Sweden)

    Christian Frezza

    Full Text Available Hypoxia is one of the features of poorly vascularised areas of solid tumours but cancer cells can survive in these areas despite the low oxygen tension. The adaptation to hypoxia requires both biochemical and genetic responses that culminate in a metabolic rearrangement to counter-balance the decrease in energy supply from mitochondrial respiration. The understanding of metabolic adaptations under hypoxia could reveal novel pathways that, if targeted, would lead to specific death of hypoxic regions. In this study, we developed biochemical and metabolomic analyses to assess the effects of hypoxia on cellular metabolism of HCT116 cancer cell line. We utilized an oxygen fluorescent probe in anaerobic cuvettes to study oxygen consumption rates under hypoxic conditions without the need to re-oxygenate the cells and demonstrated that hypoxic cells can maintain active, though diminished, oxidative phosphorylation even at 1% oxygen. These results were further supported by in situ microscopy analysis of mitochondrial NADH oxidation under hypoxia. We then used metabolomic methodologies, utilizing liquid chromatography-mass spectrometry (LC-MS, to determine the metabolic profile of hypoxic cells. This approach revealed the importance of synchronized and regulated catabolism as a mechanism of adaptation to bioenergetic stress. We then confirmed the presence of autophagy under hypoxic conditions and demonstrated that the inhibition of this catabolic process dramatically reduced the ATP levels in hypoxic cells and stimulated hypoxia-induced cell death. These results suggest that under hypoxia, autophagy is required to support ATP production, in addition to glycolysis, and that the inhibition of autophagy might be used to selectively target hypoxic regions of tumours, the most notoriously resistant areas of solid tumours.

  6. Testing for autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J

    1984-01-01

    Autonomic neuropathy is a common complication in long-term diabetes, about 30% of the patients showing measurable signs of autonomic dysfunction after 10 years duration of disease. The diagnosis is often difficult to establish because clinical symptoms generally occur late in the course of the di......Autonomic neuropathy is a common complication in long-term diabetes, about 30% of the patients showing measurable signs of autonomic dysfunction after 10 years duration of disease. The diagnosis is often difficult to establish because clinical symptoms generally occur late in the course...

  7. Mobile Autonomous Reconfigurable System

    Directory of Open Access Journals (Sweden)

    Pavliuk N.A.

    2018-04-01

    Full Text Available The object of this study is a multifunctional modular robot able to assemble independently in a given configuration and responsively change it in the process of operation depending on the current task. In this work we aim at developing and examining unified modules for a modular robot, which can both perform autonomous movement and form a complex structure by connecting to other modules. The existing solutions in the field of modular robotics were reviewed and classified by power supply, the ways of interconnection, the ways of movement and the possibility of independent movement of separate modules. Basing on the analysis of the shortcomings of existing analogues, we have developed a module of mobile autonomous reconfigurable system, including a base unit, a set of magneto-mechanical connectors and two motor wheels. The basic kinematic scheme of the modular robot, the features of a single module, as well as the modular structure formed by an array of similar modules were described. Two schemes for placing sets of magneto-mechanical connectors in the basic module have been proposed. We described the principle of operation of a magneto-mechanical connector based on redirection of the magnetic flux of a permanent magnet. This solution simplifies the system for controlling a mechanism of connection with other modules, increases energy efficiency and a battery life of the module. Since the energy is required only at the moment of switching the operating modes of the connector, there is no need to power constantly the connector mechanism to maintain the coupling mode.

  8. Autonomous nutrient detection for water quality monitoring

    OpenAIRE

    Maher, Damien; Cleary, John; Cogan, Deirdre; Diamond, Dermot

    2012-01-01

    The ever increasing demand for real time environmental monitoring is currently being driven by strong legislative and societal drivers. Low cost autonomous environmental monitoring systems are required to meet this demand as current monitoring solutions are insufficient. This poster presents an autonomous nutrient analyser platform for water quality monitoring. Results from a field trial of the nutrient analyser are reported along with current work to expand the range of water quality targ...

  9. LKB1 mediates the development of conventional and innate T cells via AMP-dependent kinase autonomous pathways.

    Directory of Open Access Journals (Sweden)

    Marouan Zarrouk

    Full Text Available The present study has examined the role of the serine/threonine kinase LKB1 in the survival and differentiation of CD4/8 double positive thymocytes. LKB1-null DPs can respond to signals from the mature α/β T-cell-antigen receptor and initiate positive selection. However, in the absence of LKB1, thymocytes fail to mature to conventional single positive cells causing severe lymphopenia in the peripheral lymphoid tissues. LKB1 thus appears to be dispensable for positive selection but important for the maturation of positively selected thymocytes. LKB1 also strikingly prevented the development of invariant Vα14 NKT cells and innate TCR αβ gut lymphocytes. Previous studies with gain of function mutants have suggested that the role of LKB1 in T cell development is mediated by its substrate the AMP-activated protein kinase (AMPK. The present study now analyses the impact of AMPK deletion in DP thymocytes and shows that the role of LKB1 during the development of both conventional and innate T cells is mediated by AMPK-independent pathways.

  10. Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice.

    Directory of Open Access Journals (Sweden)

    Amanda J Beck

    Full Text Available Duchenne muscular dystrophy (DMD is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs into mdx and mdx∶utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx∶utrophin. In mdx chimeras, iPSC-dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin-positive and, at a lesser extent, utrophin-positive areas. In the mdx∶utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx∶utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx∶utrophin chimeras, despite the fact that utrophin was compromised in the mdx∶utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle.

  11. Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells.

    Science.gov (United States)

    Paglino, Justin C; Andres, Wells; van den Pol, Anthony N

    2014-05-01

    Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer

  12. Semi-Autonomous Systems Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — VisionThe Semi-Autonomous Systems Lab focuses on developing a comprehensive framework for semi-autonomous coordination of networked robotic systems. Semi-autonomous...

  13. Longitudinal Control for Mengshi Autonomous Vehicle via Gauss Cloud Model

    Directory of Open Access Journals (Sweden)

    Hongbo Gao

    2017-12-01

    Full Text Available Dynamic robustness and stability control is a requirement for self-driving of autonomous vehicle. Longitudinal control technique of autonomous vehicle is basic theory and one key complex technique which must have the reliability and precision of vehicle controller. The longitudinal control technique is one of the foundations of the safety and stability of autonomous vehicle control. In our paper, we present a longitudinal control algorithm based on cloud model for Mengshi autonomous vehicle to ensure the dynamic stability and tracking performance of Mengshi autonomous vehicle. The longitudinal control algorithm mainly uses cloud model generator to control the acceleration of the autonomous vehicle to achieve the goal that controls the speed of Mengshi autonomous vehicle. The proposed longitudinal control algorithm based on cloud model is verified by real experiments on Highway driving scene. The experiments results of the acceleration and speed show that the algorithm is validity and stability.

  14. Wnt5 is required for notochord cell intercalation in the ascidian Halocynthia roretzi.

    Science.gov (United States)

    Niwano, Tomoko; Takatori, Naohito; Kumano, Gaku; Nishida, Hiroki

    2009-08-25

    In the embryos of various animals, the body elongates after gastrulation by morphogenetic movements involving convergent extension. The Wnt/PCP (planar cell polarity) pathway plays roles in this process, particularly mediolateral polarization and intercalation of the embryonic cells. In ascidians, several factors in this pathway, including Wnt5, have been identified and found to be involved in the intercalation process of notochord cells. In the present study, the role of the Wnt5 genes, Hr-Wnt5alpha (Halocynthia roretzi Wnt5alpha) and Hr-Wnt5beta, in convergent extension was investigated in the ascidian H. roretzi by injecting antisense oligonucleotides and mRNAs into single precursor blastomeres of various tissues, including notochord, at the 64-cell stage. Hr-Wnt5alpha is expressed in developing notochord and was essential for notochord morphogenesis. Precise quantitative control of its expression level was crucial for proper cell intercalation. Overexpression of Wnt5 proteins in notochord and other tissues that surround the notochord indicated that Wnt5alpha plays a role within the notochord, and is unlikely to be the source of polarizing cues arising outside the notochord. Detailed mosaic analysis of the behaviour of individual notochord cells overexpressing Wnt5alpha indicated that a Wnt5alpha-manipulated cell does not affect the behaviour of neighbouring notochord cells, suggesting that Wnt5alpha works in a cell-autonomous manner. This is further supported by comparison of the results of Wnt5alpha and Dsh (Dishevelled) knockdown experiments. In addition, our results suggest that the Wnt/PCP pathway is also involved in mediolateral intercalation of cells of the ventral row of the nerve cord (floor plate) and the endodermal strand. The present study highlights the role of the Wnt5alpha signal in notochord convergent extension movements in ascidian embryos. Our results raise the novel possibility that Wnt5alpha functions in a cell-autonomous manner in

  15. Asymmetric cell division requires specific mechanisms for adjusting global transcription.

    Science.gov (United States)

    Mena, Adriana; Medina, Daniel A; García-Martínez, José; Begley, Victoria; Singh, Abhyudai; Chávez, Sebastián; Muñoz-Centeno, Mari C; Pérez-Ortín, José E

    2017-12-01

    Most cells divide symmetrically into two approximately identical cells. There are many examples, however, of asymmetric cell division that can generate sibling cell size differences. Whereas physical asymmetric division mechanisms and cell fate consequences have been investigated, the specific problem caused by asymmetric division at the transcription level has not yet been addressed. In symmetrically dividing cells the nascent transcription rate increases in parallel to cell volume to compensate it by keeping the actual mRNA synthesis rate constant. This cannot apply to the yeast Saccharomyces cerevisiae, where this mechanism would provoke a never-ending increasing mRNA synthesis rate in smaller daughter cells. We show here that, contrarily to other eukaryotes with symmetric division, budding yeast keeps the nascent transcription rates of its RNA polymerases constant and increases mRNA stability. This control on RNA pol II-dependent transcription rate is obtained by controlling the cellular concentration of this enzyme. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Langerhans cells are required for UVR-induced immunosuppression

    NARCIS (Netherlands)

    Schwarz, Agatha; Noordegraaf, Madelon; Maeda, Akira; Torii, Kan; Clausen, Björn E.; Schwarz, Thomas

    2010-01-01

    Painting of haptens onto UVR-exposed skin does not result in sensitization but induces regulatory T cells (Treg). This was explained by UVR-mediated depletion of Langerhans cells (LCs). Furthermore, migration of UVR-damaged but still viable LCs into lymph nodes appears to be essential to induce

  17. Genetic autonomic disorders.

    Science.gov (United States)

    Axelrod, Felicia B

    2013-03-01

    Genetic disorders affecting the autonomic nervous system can result in abnormal development of the nervous system or they can be caused by neurotransmitter imbalance, an ion-channel disturbance or by storage of deleterious material. The symptoms indicating autonomic dysfunction, however, will depend upon whether the genetic lesion has disrupted peripheral or central autonomic centers or both. Because the autonomic nervous system is pervasive and affects every organ system in the body, autonomic dysfunction will result in impaired homeostasis and symptoms will vary. The possibility of genetic confirmation by molecular testing for specific diagnosis is increasing but treatments tend to remain only supportive and directed toward particular symptoms. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Sphingosine kinase activity is not required for tumor cell viability.

    Directory of Open Access Journals (Sweden)

    Karen Rex

    Full Text Available Sphingosine kinases (SPHKs are enzymes that phosphorylate the lipid sphingosine, leading to the formation of sphingosine-1-phosphate (S1P. In addition to the well established role of extracellular S1P as a mitogen and potent chemoattractant, SPHK activity has been postulated to be an important intracellular regulator of apoptosis. According to the proposed rheostat theory, SPHK activity shifts the intracellular balance from the pro-apoptotic sphingolipids ceramide and sphingosine to the mitogenic S1P, thereby determining the susceptibility of a cell to apoptotic stress. Despite numerous publications with supporting evidence, a clear experimental confirmation of the impact of this mechanism on tumor cell viability in vitro and in vivo has been hampered by the lack of suitable tool reagents. Utilizing a structure based design approach, we developed potent and specific SPHK1/2 inhibitors. These compounds completely inhibited intracellular S1P production in human cells and attenuated vascular permeability in mice, but did not lead to reduced tumor cell growth in vitro or in vivo. In addition, siRNA experiments targeting either SPHK1 or SPHK2 in a large panel of cell lines failed to demonstrate any statistically significant effects on cell viability. These results show that the SPHK rheostat does not play a major role in tumor cell viability, and that SPHKs might not be attractive targets for pharmacological intervention in the area of oncology.

  19. Evolutionary aspects of non-cell-autonomous regulation in vascular plants: structural background and models to study

    Directory of Open Access Journals (Sweden)

    Anastasiia I. Evkaikina

    2014-02-01

    Full Text Available Plasmodesmata (PD serve for the exchange of information in form of miRNA, proteins and mRNA between adjacent cells in the course of plant development. This fundamental role of PD is well established in angiosperms but has not yet been traced back to the evolutionary ancient plant taxa where functional studies lag behind studies of PD structure and ontogenetic origin. There is convincing evidence that the ability to form secondary (post-cytokinesis PD, which can connect any adjacent cells, contrary to primary PD which form during cytokinesis and link only cells of the same lineage, appeared in the evolution of higher plants at least twice: in seed plants and in some representatives of the Lycopodiophyta. The (inability to form secondary PD is manifested in the symplastic organization of the shoot apical meristem (SAM which in most taxa of seedless vascular plants differs dramatically from that in seed plants. Lycopodiophyta appear to be suitable models to analyze the transport of developmental regulators via PD in SAMs with symplastic organization both different from, as well as analogous to, that in angiosperms, and to understand the evolutionary aspects of the role of this transport in the morphogenesis of vascular plant taxa.

  20. PEM fuel cell bipolar plate material requirements for transportation applications

    Energy Technology Data Exchange (ETDEWEB)

    Borup, R.L.; Stroh, K.R.; Vanderborgh, N.E. [Los Alamos National Lab., NM (United States)] [and others

    1996-04-01

    Cost effective bipolar plates are currently under development to help make proton exchange membrane (PEM) fuel cells commercially viable. Bipolar plates separate individual cells of the fuel cell stack, and thus must supply strength, be electrically conductive, provide for thermal control of the fuel stack, be a non-porous materials separating hydrogen and oxygen feed streams, be corrosion resistant, provide gas distribution for the feed streams and meet fuel stack cost targets. Candidate materials include conductive polymers and metal plates with corrosion resistant coatings. Possible metals include aluminium, titanium, iron/stainless steel and nickel.

  1. Alleviating Autonomic Dysreflexia after Spinal Cord Injury

    Science.gov (United States)

    2017-12-01

    tracts originating from cortex, we may eventually be able to use cell transplantation as a bridge to promote targeted, functional axon regeneration ...13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS autonomic dysreflexia, spinal cord injury, transplantation, axon regeneration 16. SECURITY...different root causes – i.e. using neural precursor cells to restore more normal innervation of sympathetic preganglionic neurons and

  2. Non-cell autonomous impairment of oligodendrocyte differentiation precedes CNS degeneration in the Zitter rat: Implications of macrophage/microglial activation in the pathogenesis

    Directory of Open Access Journals (Sweden)

    Ookawara Shigeo

    2008-04-01

    Full Text Available Abstract Background The zitter (zi/zi rat, a loss-of-function mutant of the glycosylated transmembrane protein attractin (atrn, exhibits widespread age-dependent spongiform degeneration, hypomyelination, and abnormal metabolism of reactive oxygen species (ROS in the brain. To date, the mechanisms underlying these phenotypes have remained unclear. Results Here, we show differentiation defects in zi/zi oligodendrocytes, accompanied by aberrant extension of cell-processes and hypomyelination. Axonal bundles were relatively preserved during postnatal development. With increasing in age, the injured oligodendrocytes in zi/zi rats become pathological, as evidenced by the accumulation of iron in their cell bodies. Immunohistochemical analysis revealed that atrn expression was absent from an oligodendrocyte lineage, including A2B5-positive progenitors and CNPase-positive differentiated cells. The number and distribution of Olig2-positive oligodendrocyte progenitors was unchanged in the zi/zi brain. Furthermore, an in vitro differentiation assay of cultured oligodendrocyte progenitors prepared from zi/zi brains revealed their normal competence for proliferation and differentiation into mature oligodendrocytes. Interestingly, we demonstrated the accelerated recruitment of ED1-positive macrophages/microglia to the developing zi/zi brain parenchyma prior to the onset of hypomyelination. Semiquantitative RT-PCR analysis revealed a significant up-regulation of CD26 and IL1-β in the zi/zi brain during this early postnatal stage. Conclusion We demonstrated that the onset of the impairment of oligodendrocyte differentiation occurs in a non-cell autonomous manner in zi/zi rats. Hypomyelination of oligodendrocytes was not due to a failure of the intrinsic program of oligodendrocytes, but rather, was caused by extrinsic factors that interrupt oligodendrocyte development. It is likely that macrophage/microglial activation in the zi/zi CNS leads to disturbances in

  3. Requirements for growth and IL-10 expression of highly purified human T regulatory cells

    OpenAIRE

    Bonacci, Benedetta; Edwards, Brandon; Jia, Shuang; Williams, Calvin; Hessner, Martin J.; Gauld, Stephen; Verbsky, James

    2012-01-01

    Human regulatory T cells (TR) cells have potential for the treatment of a variety of immune mediated diseases but the anergic phenotype of these cells makes them difficult to expand in vitro. We have examined the requirements for growth and cytokine expression from highly purified human TR cells, and correlated these findings with the signal transduction events of these cells. We demonstrate that these cells do not proliferate or secrete IL-10 even in the presence of high doses of IL-2. Stimu...

  4. Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells

    OpenAIRE

    Hunt, Geoffrey C.; Singh, Purva; Schwarzbauer, Jean E.

    2012-01-01

    Pluripotent cells are attached to the extracellular matrix (ECM) as they make cell fate decisions within the stem cell niche. Here we show that the ubiquitous ECM protein fibronectin is required for self-renewal decisions by cultured mouse embryonic stem (mES) cells. Undifferentiated mES cells produce fibronectin and assemble a fibrillar matrix. Increasing the level of substrate fibronectin increased cell spreading and integrin receptor signaling through focal adhesion kinase, while concomita...

  5. Genetic dissection of histone deacetylase requirement in tumor cells

    Science.gov (United States)

    Haberland, Michael; Johnson, Aaron; Mokalled, Mayssa H.; Montgomery, Rusty L.; Olson, Eric N.

    2009-01-01

    Histone deacetylase inhibitors (HDACi) represent a new group of drugs currently being tested in a wide variety of clinical applications. They are especially effective in preclinical models of cancer where they show antiproliferative action in many different types of cancer cells. Recently, the first HDACi was approved for the treatment of cutaneous T cell lymphomas. Most HDACi currently in clinical development act by unspecifically interfering with the enzymatic activity of all class I HDACs (HDAC1, 2, 3, and 8), and it is widely believed that the development of isoform-specific HDACi could lead to better therapeutic efficacy. The contribution of the individual class I HDACs to different disease states, however, has so far not been fully elucidated. Here, we use a genetic approach to dissect the involvement of the different class I HDACs in tumor cells. We show that deletion of a single HDAC is not sufficient to induce cell death, but that HDAC1 and 2 play redundant and essential roles in tumor cell survival. Their deletion leads to nuclear bridging, nuclear fragmentation, and mitotic catastrophe, mirroring the effects of HDACi on cancer cells. These findings suggest that pharmacological inhibition of HDAC1 and 2 may be sufficient for anticancer activity, providing an experimental framework for the development of isoform-specific HDAC inhibitors. PMID:19416910

  6. Cell-Intrinsic Glycogen Metabolism Supports Early Glycolytic Reprogramming Required for Dendritic Cell Immune Responses.

    Science.gov (United States)

    Thwe, Phyu M; Pelgrom, Leonard; Cooper, Rachel; Beauchamp, Saritha; Reisz, Julie A; D'Alessandro, Angelo; Everts, Bart; Amiel, Eyal

    2017-09-05

    Dendritic cell (DC) activation by Toll-like receptor (TLR) agonists causes rapid glycolytic reprogramming that is required to meet the metabolic demands of their immune activation. Recent efforts in the field have identified an important role for extracellular glucose sourcing to support DC activation. However, the contributions of intracellular glucose stores to these processes have not been well characterized. We demonstrate that DCs possess intracellular glycogen stores and that cell-intrinsic glycogen metabolism supports the early effector functions of TLR-activated DCs. Inhibition of glycogenolysis significantly attenuates TLR-mediated DC maturation and impairs their ability to initiate lymphocyte activation. We further report that DCs exhibit functional compartmentalization of glucose- and glycogen-derived carbons, where these substrates preferentially contribute to distinct metabolic pathways. This work provides novel insights into nutrient homeostasis in DCs, demonstrating that differential utilization of glycogen and glucose metabolism regulates their optimal immune function. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Folliculostellate Cells Are Required for Laminin Release from Gonadotrophs in Rat Anterior Pituitary

    International Nuclear Information System (INIS)

    Tsukada, Takehiro; Fujiwara, Ken; Horiguchi, Kotaro; Azuma, Morio; Ramadhani, Dini; Tofrizal, Alimuddin; Batchuluun, Khongorzul; Maliza, Rita; Syaidah, Rahimi; Kikuchi, Motoshi; Yashiro, Takashi

    2014-01-01

    The anterior pituitary gland is organized tissue comprising hormone-producing cells and folliculostellate (FS) cells. FS cells interconnect to form a meshwork, and their cytoplasmic processes are anchored by a basement membrane containing laminin. Recently, we developed a three-dimensional (3D) cell culture that reproduces this FS cell architecture. In this study of the novel function of FS cells, we used transgenic rats that express green fluorescent protein in FS cells for the 3D culture. Anterior pituitary cells were cultured with different proportions of FS cells (0%, 5%, 10%, and 20%). Anterior pituitary cells containing 5–20% FS cells formed round/oval cell aggregates, whereas amorphous cell aggregates were formed in the absence of FS cells. Interestingly, immunohistochemistry showed laminin-immunopositive cells instead of extracellular laminin deposition in FS cell-deficient cell aggregates. Double-immunostaining revealed that these laminin-immunopositive cells were gonadotrophs. Laminin mRNA expression did not differ in relation to the presence or absence of FS cells. When anterior pituitary cells with no FS cells were cultured with FS cell-conditioned medium, the proportion of laminin-immunopositive cells was lower than in control. These results suggest that a humoral factor from FS cells is required for laminin release from gonadotrophs

  8. Recipient dendritic cells, but not B cells, are required antigen-presenting cells for peripheral alloreactive CD8+ T-cell tolerance.

    Science.gov (United States)

    Mollov, J L; Lucas, C L; Haspot, F; Gaspar, J Kurtz C; Guzman, A; Sykes, M

    2010-03-01

    Induction of mixed allogeneic chimerism is a promising approach for achieving donor-specific tolerance, thereby obviating the need for life-long immunosuppression for solid organ allograft acceptance. In mice receiving a low dose (3Gy) of total body irradiation, allogeneic bone marrow transplantation combined with anti-CD154 tolerizes peripheral CD4 and CD8 T cells, allowing achievement of mixed chimerism with specific tolerance to donor. With this approach, peripheral CD8 T-cell tolerance requires recipient MHC class II, CD4 T cells, B cells and DCs. Recipient-type B cells from chimeras that were tolerant to donor still promoted CD8 T-cell tolerance, but their role could not be replaced by donor-type B cells. Using recipients whose B cells or DCs specifically lack MHC class I and/or class II or lack CD80 and CD86, we demonstrate that dendritic cells (DCs) must express CD80/86 and either MHC class I or class II to promote CD8 tolerance. In contrast, B cells, though required, did not need to express MHC class I or class II or CD80/86 to promote CD8 tolerance. Moreover, recipient IDO and IL-10 were not required. Thus, antigen presentation by recipient DCs and not by B cells is critical for peripheral alloreactive CD8 T cell tolerance.

  9. EDF requirements for hot cells examinations on irradiated fuel

    International Nuclear Information System (INIS)

    Segura, J.C.; Ducros, G.

    2002-01-01

    The objectives of increasing French Nuclear Power Plants (NPP) availability while lengthening the fuel irradiation cycle and reaching higher burnups lead EDF to carry out on site and hot cell examinations. The data issued from such fuel behaviour monitoring programmes will be used to ascertain that the design criteria are met. Data are also needed for modelling, development and validation. The paper deals quickly with the logistics linked to the selection and transport of fuel rods from NPP to hot cell laboratory. Hot cell PIEs remain a valuable method to obtain data in such fields as PCI (Pellet-Cladding Interaction), internal pressure, FGR (Fission Gas Release), oxide thickness, metallurgical aspects. The paper introduces burnup determination methods, inner pressure evaluation, preparation of samples for further irradiation such as power ramps for PCI and RIA (Reactivity Initiated Accident) testing. The nuclear microprobe of Perre Suee laboratory is also presented. (author)

  10. Autonomous Energy Grids: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Kroposki, Benjamin D [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Dall-Anese, Emiliano [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Bernstein, Andrey [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Zhang, Yingchen [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Hodge, Brian S [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

    2017-10-04

    With much higher levels of distributed energy resources - variable generation, energy storage, and controllable loads just to mention a few - being deployed into power systems, the data deluge from pervasive metering of energy grids, and the shaping of multi-level ancillary-service markets, current frameworks to monitoring, controlling, and optimizing large-scale energy systems are becoming increasingly inadequate. This position paper outlines the concept of 'Autonomous Energy Grids' (AEGs) - systems that are supported by a scalable, reconfigurable, and self-organizing information and control infrastructure, can be extremely secure and resilient (self-healing), and self-optimize themselves in real-time for economic and reliable performance while systematically integrating energy in all forms. AEGs rely on scalable, self-configuring cellular building blocks that ensure that each 'cell' can self-optimize when isolated from a larger grid as well as partaking in the optimal operation of a larger grid when interconnected. To realize this vision, this paper describes the concepts and key research directions in the broad domains of optimization theory, control theory, big-data analytics, and complex system modeling that will be necessary to realize the AEG vision.

  11. Human CD4+ T cells require exogenous cystine for glutathione and DNA synthesis

    DEFF Research Database (Denmark)

    Levring, Trine B; Kongsbak-Wismann, Martin; Rode, Anna Kathrine Obelitz

    2015-01-01

    . The aim of this study was to elucidate why activated human T cells require exogenous Cys2 in order to proliferate. We activated purified naïve human CD4+ T cells and found that glutathione (GSH) levels and DNA synthesis were dependent on Cys2 and increased in parallel with increasing concentrations of Cys......Adaptive immune responses require activation and expansion of antigen-specific T cells. Whereas early T cell activation is independent of exogenous cystine (Cys2), T cell proliferation is dependent of Cys2. However, the exact roles of Cys2 in T cell proliferation still need to be determined...... for the activity of ribonucleotide reductase (RNR), the enzyme responsible for generation of the deoxyribonucleotide DNA building blocks. In conclusion, we show that activated human T cells require exogenous Cys2 to proliferate and that this is partly explained by the fact that Cys2 is required for production...

  12. Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung

    Directory of Open Access Journals (Sweden)

    Henry Danahay

    2015-01-01

    Full Text Available The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.

  13. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

    Science.gov (United States)

    Scekic-Zahirovic, Jelena; Sendscheid, Oliver; El Oussini, Hajer; Jambeau, Mélanie; Sun, Ying; Mersmann, Sina; Wagner, Marina; Dieterlé, Stéphane; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Drenner, Kevin; Birling, Marie-Christine; Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong; Rouaux, Caroline; Shelkovnikova, Tatyana; Witting, Anke; Ludolph, Albert C; Kiefer, Friedemann; Storkebaum, Erik; Lagier-Tourenne, Clotilde; Dupuis, Luc

    2016-05-17

    FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  14. Distinct requirements for activation of NKT and NK cells during viral infection.

    Science.gov (United States)

    Tyznik, Aaron J; Verma, Shilpi; Wang, Qiao; Kronenberg, Mitchell; Benedict, Chris A

    2014-04-15

    NK cells are key regulators of innate defense against mouse CMV (MCMV). Like NK cells, NKT cells also produce high levels of IFN-γ rapidly after MCMV infection. However, whether similar mechanisms govern activation of these two cell types, as well as the significance of NKT cells for host resistance, remain unknown. In this article, we show that, although both NKT and NK cells are activated via cytokines, their particular cytokine requirements differ significantly in vitro and in vivo. IL-12 is required for NKT cell activation in vitro but is not sufficient, whereas NK cells have the capacity to be activated more promiscuously in response to individual cytokines from innate cells. In line with these results, GM-CSF-derived dendritic cells activated only NK cells upon MCMV infection, consistent with their virtual lack of IL-12 production, whereas Flt3 ligand-derived dendritic cells produced IL-12 and activated both NK and NKT cells. In vivo, NKT cell activation was abolished in IL-12(-/-) mice infected with MCMV, whereas NK cells were still activated. In turn, splenic NK cell activation was more IL-18 dependent. The differential requirements for IL-12 and IL-18 correlated with the levels of cytokine receptor expression by NK and NKT cells. Finally, mice lacking NKT cells showed reduced control of MCMV, and depleting NK cells further enhanced viral replication. Taken together, our results show that NKT and NK cells have differing requirements for cytokine-mediated activation, and both can contribute nonredundantly to MCMV defense, revealing that these two innate lymphocyte subsets function together to fine-tune antiviral responses.

  15. Autonomous Propellant Loading Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The AES Autonomous Propellant Loading (APL) project consists of three activities. The first is to develop software that will automatically control loading of...

  16. Autonomous Systems and Operations

    Data.gov (United States)

    National Aeronautics and Space Administration — The AES Autonomous Systems and Operations (ASO) project will develop an understanding of the impacts of increasing communication time delays on mission operations,...

  17. 1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype.

    Science.gov (United States)

    Széles, Lajos; Keresztes, Gábor; Töröcsik, Dániel; Balajthy, Zoltán; Krenács, László; Póliska, Szilárd; Steinmeyer, Andreas; Zuegel, Ulrich; Pruenster, Monika; Rot, Antal; Nagy, László

    2009-02-15

    Activation of vitamin D receptor (VDR) by 1,25-dihydroxyvitamin D(3) (1,25-vitD) reprograms dendritic cells (DC) to become tolerogenic. Previous studies suggested that 1,25-vitD could inhibit the changes brought about by differentiation and maturation of DCs. Underpinning the described phenotypic and functional alterations, there must be 1,25-vitD-coordinated transcriptional events. However, this transcriptional program has not been systematically investigated, particularly not in a developmental context. Hence, it has not been explored how 1,25-vitD-regulated genes, particularly the ones bringing about the tolerogenic phenotype, are connected to differentiation. We conducted global gene expression analysis followed by comprehensive quantitative PCR validation to clarify the interrelationship between 1,25-vitD and differentiation-driven gene expression patterns in developing human monocyte-derived and blood myeloid DCs. In this study we show that 1,25-vitD regulates a large set of genes that are not affected by differentiation. Interestingly, several genes, impacted both by the ligand and by differentiation, appear to be regulated by 1,25-vitD independently of the developmental context. We have also characterized the kinetics of generation of 1,25-vitD by using three early and robustly regulated genes, the chemokine CCL22, the inhibitory receptors CD300LF and CYP24A1. We found that monocyte-derived DCs are able to turn on 1,25-vitD sensitive genes in early phases of differentiation if the precursor is present. Our data collectively suggest that exogenous or endogenously generated 1,25-vitD regulates a large set of its targets autonomously and not via inhibition of differentiation and maturation, leading to the previously characterized tolerogenic state.

  18. Renin secretion from permeabilized juxtaglomerular cells requires a permeant cation

    DEFF Research Database (Denmark)

    Jensen, B L; Ellekvist, Peter; Skøtt, O

    1999-01-01

    The cytosolic concentration of chloride correlates directly with renin secretion from renal juxtaglomerular granular (JG) cells. In the present study, the mechanism by which chloride stimulates renin release was investigated in a preparation of permeabilized rat glomeruli with attached JG cells....... An isosmotic increase in the concentration of chloride by 129 mM stimulated renin release 16- to 20-fold. Substitution of K+ by the impermeant cation N-methyl-d-glucamine (NMDG) abolished this response, while substitution with Na+ caused marginal inhibition. Substitution with Cs+ had no effect. Addition...... of sucrose, which permeates the secretory granules poorly, also abolished the stimulation of renin secretion by KCl. The response to KCl was not affected by K+-channel antagonists or by agonists of K+ channels. Chloride channel blockers were also without effect on the secretory response to KCl. When the ATP...

  19. Autonomous Star Tracker Algorithms

    DEFF Research Database (Denmark)

    Betto, Maurizio; Jørgensen, John Leif; Kilsgaard, Søren

    1998-01-01

    Proposal, in response to an ESA R.f.P., to design algorithms for autonomous star tracker operations.The proposal also included the development of a star tracker breadboard to test the algorithms performances.......Proposal, in response to an ESA R.f.P., to design algorithms for autonomous star tracker operations.The proposal also included the development of a star tracker breadboard to test the algorithms performances....

  20. Autonomous Byte Stream Randomizer

    Science.gov (United States)

    Paloulian, George K.; Woo, Simon S.; Chow, Edward T.

    2013-01-01

    Net-centric networking environments are often faced with limited resources and must utilize bandwidth as efficiently as possible. In networking environments that span wide areas, the data transmission has to be efficient without any redundant or exuberant metadata. The Autonomous Byte Stream Randomizer software provides an extra level of security on top of existing data encryption methods. Randomizing the data s byte stream adds an extra layer to existing data protection methods, thus making it harder for an attacker to decrypt protected data. Based on a generated crypto-graphically secure random seed, a random sequence of numbers is used to intelligently and efficiently swap the organization of bytes in data using the unbiased and memory-efficient in-place Fisher-Yates shuffle method. Swapping bytes and reorganizing the crucial structure of the byte data renders the data file unreadable and leaves the data in a deconstructed state. This deconstruction adds an extra level of security requiring the byte stream to be reconstructed with the random seed in order to be readable. Once the data byte stream has been randomized, the software enables the data to be distributed to N nodes in an environment. Each piece of the data in randomized and distributed form is a separate entity unreadable on its own right, but when combined with all N pieces, is able to be reconstructed back to one. Reconstruction requires possession of the key used for randomizing the bytes, leading to the generation of the same cryptographically secure random sequence of numbers used to randomize the data. This software is a cornerstone capability possessing the ability to generate the same cryptographically secure sequence on different machines and time intervals, thus allowing this software to be used more heavily in net-centric environments where data transfer bandwidth is limited.

  1. E-cadherin is required for centrosome and spindle orientation in Drosophila male germline stem cells.

    Directory of Open Access Journals (Sweden)

    Mayu Inaba

    2010-08-01

    Full Text Available Many adult stem cells reside in a special microenvironment known as the niche, where they receive essential signals that specify stem cell identity. Cell-cell adhesion mediated by cadherin and integrin plays a crucial role in maintaining stem cells within the niche. In Drosophila melanogaster, male germline stem cells (GSCs are attached to niche component cells (i.e., the hub via adherens junctions. The GSC centrosomes and spindle are oriented toward the hub-GSC junction, where E-cadherin-based adherens junctions are highly concentrated. For this reason, adherens junctions are thought to provide a polarity cue for GSCs to enable proper orientation of centrosomes and spindles, a critical step toward asymmetric stem cell division. However, understanding the role of E-cadherin in GSC polarity has been challenging, since GSCs carrying E-cadherin mutations are not maintained in the niche. Here, we tested whether E-cadherin is required for GSC polarity by expressing a dominant-negative form of E-cadherin. We found that E-cadherin is indeed required for polarizing GSCs toward the hub cells, an effect that may be mediated by Apc2. We also demonstrated that E-cadherin is required for the GSC centrosome orientation checkpoint, which prevents mitosis when centrosomes are not correctly oriented. We propose that E-cadherin orchestrates multiple aspects of stem cell behavior, including polarization of stem cells toward the stem cell-niche interface and adhesion of stem cells to the niche supporting cells.

  2. A cell-cell signaling sensor is required for virulence and insect transmission of Xylella fastidiosa.

    Science.gov (United States)

    Chatterjee, Subhadeep; Wistrom, Christina; Lindow, Steven E

    2008-02-19

    Cell-cell signaling in Xylella fastidiosa, a xylem-colonizing plant pathogenic bacterium, mediated by a fatty acid Diffusible Signaling Factor (DSF), is required to colonize insect vectors and to suppress virulence to grape. Here, we show that a hybrid two-component regulatory protein RpfC is involved in negative regulation of DSF synthesis by RpfF in X. fastidiosa. X. fastidiosa rpfC mutants hyperexpress rpfF and overproduce DSF and are deficient in virulence and movement in the xylem vessels of grape. The expression of the genes encoding the adhesins FimA, HxfA, and HxfB is much higher in rpfC mutants, which also exhibit a hyperattachment phenotype in culture that is associated with their inability to migrate in xylem vessels and cause disease. rpfF mutants deficient in DSF production have the opposite phenotypes for all of these traits. RpfC is also involved in the regulation of other signaling components including rpfG, rpfB, a GGDEF domain protein that may be involved in intracellular signaling by modulating the levels of cyclic-di-GMP, and the virulence factors tolC and pglA required for disease. rpfC mutants are able to colonize the mouthparts of insect vectors and wild-type strains but are not transmitted as efficiently to new host plants, apparently because of their high levels of adhesiveness. Because of the conflicting contributions of adhesiveness and other traits to movement within plants and vectoring to new host plants, X. fastidiosa apparently coordinates these traits in a population-size-dependent fashion involving accumulation of DSF.

  3. Mind bomb 1 is required for pancreatic ß-cell formation

    DEFF Research Database (Denmark)

    Horn, Signe; Kobberup, Sune; Jørgensen, Mette C

    2012-01-01

    the insulin producing ß-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of ß-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and ß-cell formation. We found that endoderm...

  4. Longitudinal Control for Mengshi Autonomous Vehicle via Cloud Model

    Science.gov (United States)

    Gao, H. B.; Zhang, X. Y.; Li, D. Y.; Liu, Y. C.

    2018-03-01

    Dynamic robustness and stability control is a requirement for self-driving of autonomous vehicle. Longitudinal control method of autonomous is a key technique which has drawn the attention of industry and academe. In this paper, we present a longitudinal control algorithm based on cloud model for Mengshi autonomous vehicle to ensure the dynamic stability and tracking performance of Mengshi autonomous vehicle. An experiments is applied to test the implementation of the longitudinal control algorithm. Empirical results show that if the longitudinal control algorithm based Gauss cloud model are applied to calculate the acceleration, and the vehicles drive at different speeds, a stable longitudinal control effect is achieved.

  5. Transparent electrode requirements for thin film solar cell modules

    KAUST Repository

    Rowell, Michael W.; McGehee, Michael D.

    2011-01-01

    The transparent conductor (TC) layer in thin film solar cell modules has a significant impact on the power conversion efficiency. Reflection, absorption, resistive losses and lost active area either from the scribed interconnect region in monolithically integrated modules or from the shadow losses of a metal grid in standard modules typically reduce the efficiency by 10-25%. Here, we perform calculations to show that a competitive TC must have a transparency of at least 90% at a sheet resistance of less than 10 Ω/sq (conductivity/absorptivity ≥ 1 Ω -1) for monolithically integrated modules. For standard modules, losses are much lower and the performance of alternative lower cost TC materials may already be sufficient to replace conducting oxides in this geometry. © 2011 The Royal Society of Chemistry.

  6. Fibroblast Cluster Formation on 3D Collagen Matrices Requires Cell Contraction-Dependent Fibronectin Matrix Organization

    Science.gov (United States)

    da Rocha-Azevedo, Bruno; Ho, Chin-Han; Grinnell, Frederick

    2012-01-01

    Fibroblasts incubated on 3D collagen matrices in serum or lysophosphatidic acid (LPA)-containing medium self-organize into clusters through a mechanism that requires cell contraction. However, in platelet-derived growth factor (PDGF)-containing medium, cells migrate as individuals and do not form clusters even though they constantly encounter each other. Here, we present evidence that a required function of cell contraction in clustering is formation of fibronectin fibrillar matrix. We found that in serum or LPA but not in PDGF or basal medium, cells organized FN (both serum and cellular) into a fibrillar, detergent-insoluble matrix. Cell clusters developed concomitant with FN matrix formation. FN fibrils accumulated beneath cells and along the borders of cell clusters in regions of cell-matrix tension. Blocking Rho kinase or myosin II activity prevented FN matrix assembly and cell clustering. Using siRNA silencing and function-blocking antibodies and peptides, we found that cell clustering and FN matrix assembly required α5β1 integrins and fibronectin. Cells were still able to exert contractile force and compact the collagen matrix under the latter conditions, which showed that contraction was not sufficient for cell clustering to occur. Our findings provide new insights into how procontractile (serum/LPA) and promigratory (PDGF) growth factor environments can differentially regulate FN matrix assembly by fibroblasts interacting with collagen matrices and thereby influence mesenchymal cell morphogenetic behavior under physiologic circumstances such as wound repair, morphogenesis and malignancy. PMID:23117111

  7. Fibroblast cluster formation on 3D collagen matrices requires cell contraction dependent fibronectin matrix organization.

    Science.gov (United States)

    da Rocha-Azevedo, Bruno; Ho, Chin-Han; Grinnell, Frederick

    2013-02-15

    Fibroblasts incubated on 3D collagen matrices in serum or lysophosphatidic acid (LPA)-containing medium self-organize into clusters through a mechanism that requires cell contraction. However, in platelet-derived growth factor (PDGF)-containing medium, cells migrate as individuals and do not form clusters even though they constantly encounter each other. Here, we present evidence that a required function of cell contraction in clustering is formation of fibronectin (FN) fibrillar matrix. We found that in serum or LPA but not in PDGF or basal medium, cells organized FN (both serum and cellular) into a fibrillar, detergent-insoluble matrix. Cell clusters developed concomitant with FN matrix formation. FN fibrils accumulated beneath cells and along the borders of cell clusters in regions of cell-matrix tension. Blocking Rho kinase or myosin II activity prevented FN matrix assembly and cell clustering. Using siRNA silencing and function-blocking antibodies and peptides, we found that cell clustering and FN matrix assembly required α5β1 integrins and fibronectin. Cells were still able to exert contractile force and compact the collagen matrix under the latter conditions, which showed that contraction was not sufficient for cell clustering to occur. Our findings provide new insights into how procontractile (serum/LPA) and promigratory (PDGF) growth factor environments can differentially regulate FN matrix assembly by fibroblasts interacting with collagen matrices and thereby influence mesenchymal cell morphogenetic behavior under physiologic circumstances such as wound repair, morphogenesis and malignancy. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Germ cells are not required to establish the female pathway in mouse fetal gonads.

    Directory of Open Access Journals (Sweden)

    Danielle M Maatouk

    Full Text Available The fetal gonad is composed of a mixture of somatic cell lineages and germ cells. The fate of the gonad, male or female, is determined by a population of somatic cells that differentiate into Sertoli or granulosa cells and direct testis or ovary development. It is well established that germ cells are not required for the establishment or maintenance of Sertoli cells or testis cords in the male gonad. However, in the agametic ovary, follicles do not form suggesting that germ cells may influence granulosa cell development. Prior investigations of ovaries in which pre-meiotic germ cells were ablated during fetal life reported no histological changes during stages prior to birth. However, whether granulosa cells underwent normal molecular differentiation was not investigated. In cases where germ cell loss occurred secondary to other mutations, transdifferentiation of granulosa cells towards a Sertoli cell fate was observed, raising questions about whether germ cells play an active role in establishing or maintaining the fate of granulosa cells. We developed a group of molecular markers associated with ovarian development, and show here that the loss of pre-meiotic germ cells does not disrupt the somatic ovarian differentiation program during fetal life, or cause transdifferentiation as defined by expression of Sertoli markers. Since we do not find defects in the ovarian somatic program, the subsequent failure to form follicles at perinatal stages is likely attributable to the absence of germ cells rather than to defects in the somatic cells.

  9. Germ Cells Are Not Required to Establish the Female Pathway in Mouse Fetal Gonads

    Science.gov (United States)

    Maatouk, Danielle M.; Mork, Lindsey; Hinson, Ashley; Kobayashi, Akio; McMahon, Andrew P.; Capel, Blanche

    2012-01-01

    The fetal gonad is composed of a mixture of somatic cell lineages and germ cells. The fate of the gonad, male or female, is determined by a population of somatic cells that differentiate into Sertoli or granulosa cells and direct testis or ovary development. It is well established that germ cells are not required for the establishment or maintenance of Sertoli cells or testis cords in the male gonad. However, in the agametic ovary, follicles do not form suggesting that germ cells may influence granulosa cell development. Prior investigations of ovaries in which pre-meiotic germ cells were ablated during fetal life reported no histological changes during stages prior to birth. However, whether granulosa cells underwent normal molecular differentiation was not investigated. In cases where germ cell loss occurred secondary to other mutations, transdifferentiation of granulosa cells towards a Sertoli cell fate was observed, raising questions about whether germ cells play an active role in establishing or maintaining the fate of granulosa cells. We developed a group of molecular markers associated with ovarian development, and show here that the loss of pre-meiotic germ cells does not disrupt the somatic ovarian differentiation program during fetal life, or cause transdifferentiation as defined by expression of Sertoli markers. Since we do not find defects in the ovarian somatic program, the subsequent failure to form follicles at perinatal stages is likely attributable to the absence of germ cells rather than to defects in the somatic cells. PMID:23091613

  10. Classical dendritic cells are required for dietary antigen-mediated peripheral regulatory T cell and tolerance induction

    Science.gov (United States)

    Esterházy, Daria; Loschko, Jakob; London, Mariya; Jove, Veronica; Oliveira, Thiago Y.; Mucida, Daniel

    2016-01-01

    Oral tolerance prevents pathological inflammatory responses towards innocuous foreign antigens via peripheral regulatory T cells (pTreg cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure to instruct naïve CD4+ T cells to differentiate into pTreg cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs are dispensable, while classical dendritic cells (cDCs) are critical for pTreg cell induction and oral tolerance. CD11b− cDCs from the gut-draining lymph nodes efficiently induced pTreg cells, and conversely, loss of IRF8-dependent CD11b− cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in pTreg cell induction and their redundancy during oral tolerance development. PMID:27019226

  11. A network of (autonomic) clock outputs

    NARCIS (Netherlands)

    Kalsbeek, A.; Perreau-Lenz, S.; Buijs, R. M.

    2006-01-01

    The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each of which is dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock

  12. A network of (autonomic) clock outputs

    NARCIS (Netherlands)

    Kalsbeek, A.; Perreau-Lenz, S.; Buijs, R. M.

    2006-01-01

    The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock that

  13. The requirement for freshly isolated human colorectal cancer (CRC) cells in isolating CRC stem cells.

    Science.gov (United States)

    Fan, F; Bellister, S; Lu, J; Ye, X; Boulbes, D R; Tozzi, F; Sceusi, E; Kopetz, S; Tian, F; Xia, L; Zhou, Y; Bhattacharya, R; Ellis, L M

    2015-02-03

    Isolation of colorectal cancer (CRC) cell populations enriched for cancer stem cells (CSCs) may facilitate target identification. There is no consensus regarding the best methods for isolating CRC stem cells (CRC-SCs). We determined the suitability of various cellular models and various stem cell markers for the isolation of CRC-SCs. Established human CRC cell lines, established CRC cell lines passaged through mice, patient-derived xenograft (PDX)-derived cells, early passage/newly established cell lines, and cells directly from clinical specimens were studied. Cells were FAC-sorted for the CRC-SC markers CD44, CD133, and aldehyde dehydrogenase (ALDH). Sphere formation and in vivo tumorigenicity studies were used to validate CRC-SC enrichment. None of the markers studied in established cell lines, grown either in vitro or in vivo, consistently enriched for CRC-SCs. In the three other cellular models, CD44 and CD133 did not reliably enrich for stemness. In contrast, freshly isolated PDX-derived cells or early passage/newly established CRC cell lines with high ALDH activity formed spheres in vitro and enhanced tumorigenicity in vivo, whereas cells with low ALDH activity did not. PDX-derived cells, early passages/newly established CRC cell lines and cells from clinical specimen with high ALDH activity can be used to identify CRC-SC-enriched populations. Established CRC cell lines should not be used to isolate CSCs.

  14. Fuel cell systems for passenger cars - opportunities and requirements

    Energy Technology Data Exchange (ETDEWEB)

    Tachtler, J. [BMW, Munich (Germany); Bourne, C. [Rover Group, Coventry (United Kingdom)

    1996-12-31

    From the point of view of energy density, handling and economy, present-day motor fuels are superior to all known alternatives. The internal combustion engine powered by them satisfies the requirements of customers to an excellent degree. The search for alternatives can therefore only be justified if emissions can be avoided totally and non-fossil primary energy sources can be used or at least partially our dependence on mineral oil can be reduced. What was long suspected has been increasingly confirmed, not least by developments at BMW: electricity (stored in batteries) and hydrogen offer the best prerequisites for achieving these goals in the long term. These forms of energy can be produced in sufficient quantities and with relatively little effect on the environment. They promise to produce an absolute minimum of pollutants when used in vehicles. Natural gas, which is very similar to hydrogen, and hybrid systems, that would compensate for battery risks, could perform a valuable function in the transitional phase.

  15. Galectin-1 is required for the regulatory function of B cells.

    Science.gov (United States)

    Alhabbab, R; Blair, P; Smyth, L A; Ratnasothy, K; Peng, Q; Moreau, A; Lechler, R; Elgueta, R; Lombardi, G

    2018-02-09

    Galectin-1 (Gal-1) is required for the development of B cells in the bone marrow (BM), however very little is known about the contribution of Gal-1 to the development of B cell regulatory function. Here, we report an important role for Gal-1 in the induction of B cells regulatory function. Mice deficient of Gal-1 (Gal-1 -/- ) showed significant loss of Transitional-2 (T2) B cells, previously reported to include IL-10 + regulatory B cells. Gal-1 -/- B cells stimulated in vitro via CD40 molecules have impaired IL-10 and Tim-1 expression, the latter reported to be required for IL-10 production in regulatory B cells, and increased TNF-α expression compared to wild type (WT) B cells. Unlike their WT counterparts, T2 and T1 Gal-1 -/- B cells did not suppress TNF-α expression by CD4 + T cells activated in vitro with allogenic DCs (allo-DCs), nor were they suppressive in vivo, being unable to delay MHC-class I mismatched skin allograft rejection following adoptive transfer. Moreover, T cells stimulated with allo-DCs show an increase in their survival when co-cultured with Gal-1 -/- T2 and MZ B cells compared to WT T2 and MZ B cells. Collectively, these data suggest that Gal-1 contributes to the induction of B cells regulatory function.

  16. Human T cell colony formation in microculture: analysis of growth requirements and functional activities.

    Science.gov (United States)

    Gelfand, E W; Lee, J W; Dosch, H M; Price, G B

    1981-03-01

    A microculture method in methylcellulose has been developed for the study of human T cell colony formation. The technique is simple, reliable, does not require preincubation with lectin and requires small numbers of cells. Colony formation was dependent on the presence of phytohemagglutin-conditioned medium, a T colony precursor cell (TCPC), and a "helper" or accessory T cell. Plating efficiency was increased 10-fold in the presence of irradiated feeder cells. Progenitors of the T colony cells were identified in peripheral blood, tonsil, and spleen but not in thymus or thoracic duct. They were isolated in the E-rosetting, theophylline-resistant, Fc-IgG-negative cell populations. In peripheral blood the frequency of TCPC and accessory cells, the T colony forming unit, was estimated to be 8 X 10(-3). Colony cells proliferated in response to lectins and allogeneic cells. Forty to 80% of the cells were Ia-positive and stimulated both autologous and allogeneic mixed lymphocyte responses. They were incapable of mediating antibody-dependent cytotoxicity. In contrast, they were effective in assays of spontaneous cytotoxicity but only against certain target cells. This method for the analysis of T colony formation should prove valuable in the functional analysis of T cell subsets in immunodeficiency states or the transplant recipient.

  17. Control algorithms for autonomous robot navigation

    International Nuclear Information System (INIS)

    Jorgensen, C.C.

    1985-01-01

    This paper examines control algorithm requirements for autonomous robot navigation outside laboratory environments. Three aspects of navigation are considered: navigation control in explored terrain, environment interactions with robot sensors, and navigation control in unanticipated situations. Major navigation methods are presented and relevance of traditional human learning theory is discussed. A new navigation technique linking graph theory and incidental learning is introduced

  18. Follow-the-leader cell migration requires biased cell–cell contact and local microenvironmental signals

    International Nuclear Information System (INIS)

    Wynn, Michelle L; Rupp, Paul; Trainor, Paul A; Kulesa, Paul M; Schnell, Santiago

    2013-01-01

    Directed cell migration often involves at least two types of cell motility that include multicellular streaming and chain migration. However, what is unclear is how cell contact dynamics and the distinct microenvironments through which cells travel influence the selection of one migratory mode or the other. The embryonic and highly invasive neural crest (NC) are an excellent model system to study this question since NC cells have been observed in vivo to display both of these types of cell motility. Here, we present data from tissue transplantation experiments in chick and in silico modeling that test our hypothesis that cell contact dynamics with each other and the microenvironment promote and sustain either multicellular stream or chain migration. We show that when premigratory cranial NC cells (at the pre-otic level) are transplanted into a more caudal region in the head (at the post-otic level), cells alter their characteristic stream behavior and migrate in chains. Similarly, post-otic NC cells migrate in streams after transplantation into the pre-otic hindbrain, suggesting that local microenvironmental signals dictate the mode of NC cell migration. Simulations of an agent-based model (ABM) that integrates the NC cell behavioral data predict that chain migration critically depends on the interplay of biased cell–cell contact and local microenvironment signals. Together, this integrated modeling and experimental approach suggests new experiments and offers a powerful tool to examine mechanisms that underlie complex cell migration patterns. (paper)

  19. T-cell-independent immune responses do not require CXC ligand 13-mediated B1 cell migration.

    Science.gov (United States)

    Colombo, Matthew J; Sun, Guizhi; Alugupalli, Kishore R

    2010-09-01

    The dynamic movement of B cells increases the probability of encountering specific antigen and facilitates cell-cell interactions required for mounting a rapid antibody response. B1a and B1b cells are enriched in the coelomic cavity, contribute to T-cell-independent (TI) antibody responses, and increase in number upon antigen exposure. B1 cell movement is largely governed by Cxc ligand 13 (Cxcl13), and mice deficient in this chemokine have a severe reduction in peritoneal B1 cells. In this study, we examined the role of Cxcl13-dependent B cell migration using Borrelia hermsii infection or intraperitoneal immunization with pneumococcal polysaccharide or 4-hydroxy-3-nitrophenyl-acetyl (NP)-Ficoll, all of which induce robust antibody responses from B1b cells. Surprisingly, we found that antibody responses to B. hermsii or to FhbA, an antigenic target of B1b cells, and the resolution of bacteremia were indistinguishable between wild-type and Cxcl13-/- mice. Importantly, we did not observe an expansion of peritoneal B1b cell numbers in Cxcl13-/- mice. Nonetheless, mice that had resolved infection were resistant to reinfection, indicating that the peritoneal B1b cell reservoir is not required for controlling B. hermsii. Furthermore, despite a reduced peritoneal B1b compartment, immunization with pneumococcal polysaccharide vaccine yielded comparable antigen-specific antibody responses in wild-type and Cxcl13-/- mice and conferred protection against Streptococcus pneumoniae. Likewise, immunization with NP-Ficoll elicited similar antibody responses in wild-type and Cxcl13-/- mice. These data demonstrate that homing of B1 cells into the coelomic cavity is not a requirement for generating protective TI antibody responses, even when antigen is initially localized to this anatomical compartment.

  20. Requirements for growth and IL-10 expression of highly purified human T regulatory cells

    Science.gov (United States)

    Bonacci, Benedetta; Edwards, Brandon; Jia, Shuang; Williams, Calvin; Hessner, Martin J.; Gauld, Stephen; Verbsky, James

    2013-01-01

    Human regulatory T cells (TR) cells have potential for the treatment of a variety of immune mediated diseases but the anergic phenotype of these cells makes them difficult to expand in vitro. We have examined the requirements for growth and cytokine expression from highly purified human TR cells, and correlated these findings with the signal transduction events of these cells. We demonstrate that these cells do not proliferate or secrete IL-10 even in the presence of high doses of IL-2. Stimulation with a superagonistic anti-CD28 antibody (clone 9D4) and IL-2 partially reversed the proliferative defect, and this correlated with reversal of the defective calcium mobilization in these cells. Dendritic cells were effective at promoting TR cell proliferation, and under these conditions the proliferative capacity of TR cells was comparable to conventional CD4 lymphocytes. Blocking TGF-β activity abrogated IL-10 expression from these cells, while addition of TGF-β resulted in IL-10 production. These data demonstrate that highly purified populations of TR cells are anergic even in the presence of high doses of IL-2. Furthermore, antigen presenting cells provide proper co-stimulation to overcome the anergic phenotype of TR cells, and under these conditions they are highly sensitive to IL-2. In addition, these data demonstrate for the first time that TGF-β is critical to enable human TR cells to express IL-10. PMID:22562448

  1. Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, Celeste M.; Khauv, Davitte; Bissell, Mina J.; Radisky, Derek C.

    2008-06-26

    Cell morphology dictates response to a wide variety of stimuli, controlling cell metabolism, differentiation, proliferation, and death. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells acquire migratory characteristics, and in the process convert from a 'cuboidal' epithelial structure into an elongated mesenchymal shape. We had shown previously that matrix metalloproteinase-3 (MMP3) can stimulate EMT of cultured mouse mammary epithelial cells through a process that involves increased expression of Rac1b, a protein that stimulates alterations in cytoskeletal structure. We show here that cells treated with MMP-3 or induced to express Rac1b spread to cover a larger surface, and that this induction of cell spreading is a requirement of MMP-3/Rac1b-induced EMT. We find that limiting cell spreading, either by increasing cell density or by culturing cells on precisely defined micropatterned substrata, blocks expression of characteristic markers of EMT in cells treated with MMP-3. These effects are not caused by general disruptions in cell signaling pathways, as TGF-{beta}-induced EMT is not affected by similar limitations on cell spreading. Our data reveal a previously unanticipated cell shape-dependent mechanism that controls this key phenotypic alteration and provide insight into the distinct mechanisms activated by different EMT-inducing agents.

  2. Histone demethylases UTX and JMJD3 are required for NKT cell development in mice.

    Science.gov (United States)

    Northrup, Daniel; Yagi, Ryoji; Cui, Kairong; Proctor, William R; Wang, Chaochen; Placek, Katarzyna; Pohl, Lance R; Wang, Rongfu; Ge, Kai; Zhu, Jinfang; Zhao, Keji

    2017-01-01

    Natural killer (NK)T cells and conventional T cells share phenotypic characteristic however they differ in transcription factor requirements and functional properties. The role of histone modifying enzymes in conventional T cell development has been extensively studied, little is known about the function of enzymes regulating histone methylation in NKT cells. We show that conditional deletion of histone demethylases UTX and JMJD3 by CD4-Cre leads to near complete loss of liver NKT cells, while conventional T cells are less affected. Loss of NKT cells is cell intrinsic and not due to an insufficient selection environment. The absence of NKT cells in UTX/JMJD3-deficient mice protects mice from concanavalin A-induced liver injury, a model of NKT-mediated hepatitis. GO-analysis of RNA-seq data indicates that cell cycle genes are downregulated in UTX/JMJD3-deleted NKT progenitors, and suggest that failed expansion may account for some of the cellular deficiency. The phenotype appears to be demethylase-dependent, because UTY, a homolog of UTX that lacks catalytic function, is not sufficient to restore their development and removal of H3K27me3 by deletion of EZH2 partially rescues the defect. NKT cell development and gene expression is sensitive to proper regulation of H3K27 methylation. The H3K27me3 demethylase enzymes, in particular UTX, promote NKT cell development, and are required for effective NKT function.

  3. Autonomous calibration of single spin qubit operations

    Science.gov (United States)

    Frank, Florian; Unden, Thomas; Zoller, Jonathan; Said, Ressa S.; Calarco, Tommaso; Montangero, Simone; Naydenov, Boris; Jelezko, Fedor

    2017-12-01

    Fully autonomous precise control of qubits is crucial for quantum information processing, quantum communication, and quantum sensing applications. It requires minimal human intervention on the ability to model, to predict, and to anticipate the quantum dynamics, as well as to precisely control and calibrate single qubit operations. Here, we demonstrate single qubit autonomous calibrations via closed-loop optimisations of electron spin quantum operations in diamond. The operations are examined by quantum state and process tomographic measurements at room temperature, and their performances against systematic errors are iteratively rectified by an optimal pulse engineering algorithm. We achieve an autonomous calibrated fidelity up to 1.00 on a time scale of minutes for a spin population inversion and up to 0.98 on a time scale of hours for a single qubit π/2 -rotation within the experimental error of 2%. These results manifest a full potential for versatile quantum technologies.

  4. Development of an autonomous power system testbed

    International Nuclear Information System (INIS)

    Barton, J.R.; Adams, T.; Liffring, M.E.

    1985-01-01

    A power system testbed has been assembled to advance the development of large autonomous electrical power systems required for the space station, spacecraft, and aircraft. The power system for this effort was designed to simulate single- or dual-bus autonomous power systems, or autonomous systems that reconfigure from a single bus to a dual bus following a severe fault. The approach taken was to provide a flexible power system design with two computer systems for control and management. One computer operates as the control system and performs basic control functions, data and command processing, charge control, and provides status to the second computer. The second computer contains expert system software for mission planning, load management, fault identification and recovery, and sends load and configuration commands to the control system

  5. Overview of the Autonomic Nervous System

    Science.gov (United States)

    ... be reversible or progressive. Anatomy of the autonomic nervous system The autonomic nervous system is the part of ... organs they connect with. Function of the autonomic nervous system The autonomic nervous system controls internal body processes ...

  6. Autonomous Mower vs. Rotary Mower: Effects on Turf Quality and Weed Control in Tall Fescue Lawn

    OpenAIRE

    Michel Pirchio; Marco Fontanelli; Christian Frasconi; Luisa Martelloni; Michele Raffaelli; Andrea Peruzzi; Monica Gaetani; Simone Magni; Lisa Caturegli; Marco Volterrani; Nicola Grossi

    2018-01-01

    Autonomous mowers are battery-powered machines designed for lawn mowing that require very low human labour. Autonomous mowers can increase turf quality and reduce local noise and pollution compared with gasoline-powered rotary mowers. However, very little is known about the effects of autonomous mowing on encroaching weeds. The aim of this research was to compare the effects of an autonomous mower and an ordinary gasoline-powered mower on weed development in an artificially infested tall fesc...

  7. Musculocontractural Ehlers–Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin

    Directory of Open Access Journals (Sweden)

    Nadège Gouignard

    2016-06-01

    Full Text Available Of all live births with congenital anomalies, approximately one-third exhibit deformities of the head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC. Musculocontractural Ehlers–Danlos syndrome (MCEDS is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE. Studies in mice have extended our understanding of DS-epi1 in connective tissue maintenance; however, its role in fetal development is not understood. We demonstrate that DS-epi1 is important for the generation of isolated iduronic acid residues in chondroitin sulfate (CS/DS proteoglycans in early Xenopus embryos. The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial–mesenchymal transition (EMT and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures. Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo. Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin. Thus, our work indicates a functional link between DS and NC cell migration. We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS, which might facilitate the diagnosis and development of therapies for this distressing condition. Moreover, the presented correlations between human DS-epi1 expression and gene sets of mesenchymal character, invasion and

  8. Autonomous Forest Fire Detection

    NARCIS (Netherlands)

    Breejen, E. den; Breuers, M.; Cremer, F.; Kemp, R.A.W.; Roos, M.; Schutte, K.; Vries, J.S. de

    1998-01-01

    Forest fire detection is a very important issue in the pre-suppression process. Timely detection allows the suppression units to reach the fire in its initial stages and this will reduce the suppression costs considerably. The autonomous forest fire detection principle is based on temporal contrast

  9. Towards autonomous vehicles.

    Science.gov (United States)

    2013-11-01

    We are moving towards an age of autonomous vehicles. Cycles of innovation initiated in the public and private sectors : have led one into another since the 1990s; and out of these efforts have sprung a variety of Advanced Driver Assistance : Systems ...

  10. ADAM: ADaptive Autonomous Machine

    NARCIS (Netherlands)

    van Oosten, Daan C.; Nijenhuis, Lucas F.J.; Bakkers, André; Vervoort, Wiek

    1996-01-01

    This paper describes a part of the development of an adaptive autonomous machine that is able to move in an unknown world extract knowledge out of the perceived data, has the possibility to reason, and finally has the capability to exchange experiences and knowledge with other agents. The agent is

  11. The polycomb group protein Suz12 is required for embryonic stem cell differentiation

    DEFF Research Database (Denmark)

    Pasini, Diego; Bracken, Adrian P; Hansen, Jacob Bo Højberg

    2007-01-01

    results in early lethality of mouse embryos. Here, we demonstrate that Suz12(-/-) mouse embryonic stem (ES) cells can be established and expanded in tissue culture. The Suz12(-/-) ES cells are characterized by global loss of H3K27 trimethylation (H3K27me3) and higher expression levels of differentiation......-specific genes. Moreover, Suz12(-/-) ES cells are impaired in proper differentiation, resulting in a lack of repression of ES cell markers as well as activation of differentiation-specific genes. Finally, we demonstrate that the PcGs are actively recruited to several genes during ES cell differentiation, which...... despite an increase in H3K27me3 levels is not always sufficient to prevent transcriptional activation. In summary, we demonstrate that Suz12 is required for the establishment of specific expression programs required for ES cell differentiation. Furthermore, we provide evidence that PcGs have different...

  12. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells

    NARCIS (Netherlands)

    D. ten Berge (Derk); D. Kurek (Dorota); T. Blauwkamp (Tim); W. Koole (Wouter); A. Maas (Alex); E. Eroglu (Elif); R.K. Siu (Ronald); R. Nusse (Roel)

    2011-01-01

    textabstractPluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref.). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive

  13. Cell Based GIS as Cellular Automata for Disaster Spreading Predictions and Required Data Systems

    Directory of Open Access Journals (Sweden)

    Kohei Arai

    2013-03-01

    Full Text Available A method for prediction and simulation based on the Cell Based Geographic Information System(GIS as Cellular Automata (CA is proposed together with required data systems, in particular metasearch engine usage in an unified way. It is confirmed that the proposed cell based GIS as CA has flexible usage of the attribute information that is attached to the cell in concert with location information and does work for disaster spreading simulation and prediction.

  14. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells

    Science.gov (United States)

    Cheng, Tzuling; Sudderth, Jessica; Yang, Chendong; Mullen, Andrew R.; Jin, Eunsook S.; Matés, José M.; DeBerardinis, Ralph J.

    2011-01-01

    Tumor cells require a constant supply of macromolecular precursors, and interrupting this supply has been proposed as a therapeutic strategy in cancer. Precursors for lipids, nucleic acids, and proteins are generated in the tricarboxylic acid (TCA) cycle and removed from the mitochondria to participate in biosynthetic reactions. Refilling the pool of precursor molecules (anaplerosis) is therefore crucial to maintain cell growth. Many tumor cells use glutamine to feed anaplerosis. Here we studied how “glutamine-addicted” cells react to interruptions of glutamine metabolism. Silencing of glutaminase (GLS), which catalyzes the first step in glutamine-dependent anaplerosis, suppressed but did not eliminate the growth of glioblastoma cells in culture and in vivo. Profiling metabolic fluxes in GLS-suppressed cells revealed induction of a compensatory anaplerotic mechanism catalyzed by pyruvate carboxylase (PC), allowing the cells to use glucose-derived pyruvate rather than glutamine for anaplerosis. Although PC was dispensable when glutamine was available, forcing cells to adapt to low-glutamine conditions rendered them absolutely dependent on PC for growth. Furthermore, in other cell lines, measuring PC activity in nutrient-replete conditions predicted dependence on specific anaplerotic enzymes. Cells with high PC activity were resistant to GLS silencing and did not require glutamine for survival or growth, but displayed suppressed growth when PC was silenced. Thus, PC-mediated, glucose-dependent anaplerosis allows cells to achieve glutamine independence. Induction of PC during chronic suppression of glutamine metabolism may prove to be a mechanism of resistance to therapies targeting glutaminolysis. PMID:21555572

  15. Rapid and dynamic arginylation of the leading edge β-actin is required for cell migration.

    Science.gov (United States)

    Pavlyk, Iuliia; Leu, Nicolae A; Vedula, Pavan; Kurosaka, Satoshi; Kashina, Anna

    2018-04-01

    β-actin plays key roles in cell migration. Our previous work demonstrated that β-actin in migratory non-muscle cells is N-terminally arginylated and that this arginylation is required for normal lamellipodia extension. Here, we examined the function of β-actin arginylation in cell migration. We found that arginylated β-actin is concentrated at the leading edge of lamellipodia and that this enrichment is abolished after serum starvation as well as in contact-inhibited cells in confluent cultures, suggesting that arginylated β-actin at the cell leading edge is coupled to active migration. Arginylated actin levels exhibit dynamic changes in response to cell stimuli, lowered after serum starvation and dramatically elevating within minutes after cell stimulation by readdition of serum or lysophosphatidic acid. These dynamic changes require active translation and are not seen in confluent contact-inhibited cell cultures. Microinjection of arginylated actin antibodies into cells severely and specifically inhibits their migration rates. Together, these data strongly suggest that arginylation of β-actin is a tightly regulated dynamic process that occurs at the leading edge of locomoting cells in response to stimuli and is integral to the signaling network that regulates cell migration. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment.

    Science.gov (United States)

    Zhang, Teng; Oatley, Jon; Bardwell, Vivian J; Zarkower, David

    2016-09-01

    Male mammals produce sperm for most of postnatal life and therefore require a robust germ line stem cell system, with precise balance between self-renewal and differentiation. Prior work established doublesex- and mab-3-related transcription factor 1 (Dmrt1) as a conserved transcriptional regulator of male sexual differentiation. Here we investigate the role of Dmrt1 in mouse spermatogonial stem cell (SSC) homeostasis. We find that Dmrt1 maintains SSCs during steady state spermatogenesis, where it regulates expression of Plzf, another transcription factor required for SSC maintenance. We also find that Dmrt1 is required for recovery of spermatogenesis after germ cell depletion. Committed progenitor cells expressing Ngn3 normally do not contribute to SSCs marked by the Id4-Gfp transgene, but do so when spermatogonia are chemically depleted using busulfan. Removal of Dmrt1 from Ngn3-positive germ cells blocks the replenishment of Id4-GFP-positive SSCs and recovery of spermatogenesis after busulfan treatment. Our data therefore reveal that Dmrt1 supports SSC maintenance in two ways: allowing SSCs to remain in the stem cell pool under normal conditions; and enabling progenitor cells to help restore the stem cell pool after germ cell depletion.

  17. Apoptosis-Inducing-Factor-Dependent Mitochondrial Function Is Required for T Cell but Not B Cell Function.

    Science.gov (United States)

    Milasta, Sandra; Dillon, Christopher P; Sturm, Oliver E; Verbist, Katherine C; Brewer, Taylor L; Quarato, Giovanni; Brown, Scott A; Frase, Sharon; Janke, Laura J; Perry, S Scott; Thomas, Paul G; Green, Douglas R

    2016-01-19

    The role of apoptosis inducing factor (AIF) in promoting cell death versus survival remains controversial. We report that the loss of AIF in fibroblasts led to mitochondrial electron transport chain defects and loss of proliferation that could be restored by ectopic expression of the yeast NADH dehydrogenase Ndi1. Aif-deficiency in T cells led to decreased peripheral T cell numbers and defective homeostatic proliferation, but thymic T cell development was unaffected. In contrast, Aif-deficient B cells developed and functioned normally. The difference in the dependency of T cells versus B cells on AIF for function and survival correlated with their metabolic requirements. Ectopic Ndi1 expression rescued homeostatic proliferation of Aif-deficient T cells. Despite its reported roles in cell death, fibroblasts, thymocytes and B cells lacking AIF underwent normal death. These studies suggest that the primary role of AIF relates to complex I function, with differential effects on T and B cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Platelet-derived stromal cell-derived factor-1 is required for the transformation of circulating monocytes into multipotential cells.

    Directory of Open Access Journals (Sweden)

    Noriyuki Seta

    Full Text Available BACKGROUND: We previously described a primitive cell population derived from human circulating CD14(+ monocytes, named monocyte-derived multipotential cells (MOMCs, which are capable of differentiating into mesenchymal and endothelial lineages. To generate MOMCs in vitro, monocytes are required to bind to fibronectin and be exposed to soluble factor(s derived from circulating CD14(- cells. The present study was conducted to identify factors that induce MOMC differentiation. METHODS: We cultured CD14(+ monocytes on fibronectin in the presence or absence of platelets, CD14(- peripheral blood mononuclear cells, platelet-conditioned medium, or candidate MOMC differentiation factors. The transformation of monocytes into MOMCs was assessed by the presence of spindle-shaped adherent cells, CD34 expression, and the potential to differentiate in vitro into mesenchymal and endothelial lineages. RESULTS: The presence of platelets or platelet-conditioned medium was required to generate MOMCs from monocytes. A screening of candidate platelet-derived soluble factors identified stromal cell-derived factor (SDF-1 as a requirement for generating MOMCs. Blocking an interaction between SDF-1 and its receptor CXCR4 inhibited MOMC generation, further confirming SDF-1's critical role in this process. Finally, circulating MOMC precursors were found to reside in the CD14(+CXCR4(high cell population. CONCLUSION: The interaction of SDF-1 with CXCR4 is essential for the transformation of circulating monocytes into MOMCs.

  19. The average number of alpha-particle hits to the cell nucleus required to eradicate a tumour cell population

    International Nuclear Information System (INIS)

    Roeske, John C; Stinchcomb, Thomas G

    2006-01-01

    Alpha-particle emitters are currently being considered for the treatment of micrometastatic disease. Based on in vitro studies, it has been speculated that only a few alpha-particle hits to the cell nucleus are considered lethal. However, such estimates do not consider the stochastic variations in the number of alpha-particle hits, energy deposited, or in the cell survival process itself. Using a tumour control probability (TCP) model for alpha-particle emitters, we derive an estimate of the average number of hits to the cell nucleus required to provide a high probability of eradicating a tumour cell population. In simulation studies, our results demonstrate that the average number of hits required to achieve a 90% TCP for 10 4 clonogenic cells ranges from 18 to 108. Those cells that have large cell nuclei, high radiosensitivities and alpha-particle emissions occurring primarily in the nuclei tended to require more hits. As the clinical implementation of alpha-particle emitters is considered, this type of analysis may be useful in interpreting clinical results and in designing treatment strategies to achieve a favourable therapeutic outcome. (note)

  20. Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung.

    Science.gov (United States)

    Danahay, Henry; Pessotti, Angelica D; Coote, Julie; Montgomery, Brooke E; Xia, Donghui; Wilson, Aaron; Yang, Haidi; Wang, Zhao; Bevan, Luke; Thomas, Chris; Petit, Stephanie; London, Anne; LeMotte, Peter; Doelemeyer, Arno; Vélez-Reyes, Germán L; Bernasconi, Paula; Fryer, Christy J; Edwards, Matt; Capodieci, Paola; Chen, Amy; Hild, Marc; Jaffe, Aron B

    2015-01-13

    The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Membranes replace irradiated blast cells as growth requirement for leukemic blast progenitors in suspension culture

    International Nuclear Information System (INIS)

    Nara, N.; McCulloch, E.A.

    1985-01-01

    The blast cells of acute myeloblastic leukemia (AML) may be considered as a renewal population, maintained by blast stem cells capable of both self-renewal and the generation of progeny with reduced or absent proliferative potential. This growth requires that two conditions be met: first, the cultures must contain growth factors in media conditioned either by phytohemagglutinin (PHA)-stimulated mononuclear leukocytes (PHA-LCM), or by cells of the continuous bladder carcinoma line HTB9 (HTB9-CM). Second, the cell density must be maintained at 10(6) blasts/ml; this may be achieved by adding irradiated cells to smaller numbers of intact blasts. The authors are concerned with the mechanism of the feeding function. They present evidence that (a) cell-cell contact is required. (b) Blasts are heterogeneous in respect to their capacity to support growth. (c) Fractions containing membranes from blast cells will substitute for intact cells in promoting the generation of new blast progenitors in culture. (d) This membrane function may be specific for AML blasts, since membranes from blasts of lymphoblastic leukemia or normal marrow cells were inactive

  2. Tumour metastasis as an adaptation of tumour cells to fulfil their phosphorus requirements.

    Science.gov (United States)

    de Carvalho, Carla C C R; Caramujo, Maria José

    2012-05-01

    Inorganic phosphate (Pi) is a vital component of nucleotides, membrane phospholipids, and phosphorylated intermediates in cellular signalling. The Growth Rate Hypothesis (GRH) states that fast growing organisms should be richer in phosphorus (relatively low C:P and N:P cell content) than slow developing organisms as a result of high ribosome biogenesis. Cells that proliferate rapidly, such as cancer cells, require a high amount of ribosomes and other P-rich RNA components that are necessary to manufacture proteins. The GRH hypothesis may be applied to cancer predicting that tumour cells are richer in phosphorus than the surrounding tissue, and that they resort to metastasis in order to meet their nutrient demands. Considering that the cells most P-deprived should be located in the inner parts of the tumour we propose that changes in the membrane of these cells favour the detachment of the more peripheral cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory

    Science.gov (United States)

    Shedlock, Devon J.; Shen, Hao

    2003-04-01

    Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.

  4. ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Zhao X

    2014-02-01

    Full Text Available Xiaoting Zhao, Yinan Guo, Wentao Yue, Lina Zhang, Meng Gu, Yue Wang Department of Cellular and Molecular Biology, Beijing TB and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, People's Republic of China Background: Multidrug resistance protein 4 (MRP4, also known as ATP-cassette binding protein 4 (ABCC4, is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells. Methods: ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction. Results: ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. Conclusion: ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy. Keywords: ABCC4, cell proliferation, lung cancer, cell cycle

  5. JNK Controls the Onset of Mitosis in Planarian Stem Cells and Triggers Apoptotic Cell Death Required for Regeneration and Remodeling

    Science.gov (United States)

    Almuedo-Castillo, María; Crespo, Xenia; Seebeck, Florian; Bartscherer, Kerstin; Salò, Emili; Adell, Teresa

    2014-01-01

    Regeneration of lost tissues depends on the precise interpretation of molecular signals that control and coordinate the onset of proliferation, cellular differentiation and cell death. However, the nature of those molecular signals and the mechanisms that integrate the cellular responses remain largely unknown. The planarian flatworm is a unique model in which regeneration and tissue renewal can be comprehensively studied in vivo. The presence of a population of adult pluripotent stem cells combined with the ability to decode signaling after wounding enable planarians to regenerate a complete, correctly proportioned animal within a few days after any kind of amputation, and to adapt their size to nutritional changes without compromising functionality. Here, we demonstrate that the stress-activated c-jun–NH2–kinase (JNK) links wound-induced apoptosis to the stem cell response during planarian regeneration. We show that JNK modulates the expression of wound-related genes, triggers apoptosis and attenuates the onset of mitosis in stem cells specifically after tissue loss. Furthermore, in pre-existing body regions, JNK activity is required to establish a positive balance between cell death and stem cell proliferation to enable tissue renewal, remodeling and the maintenance of proportionality. During homeostatic degrowth, JNK RNAi blocks apoptosis, resulting in impaired organ remodeling and rescaling. Our findings indicate that JNK-dependent apoptotic cell death is crucial to coordinate tissue renewal and remodeling required to regenerate and to maintain a correctly proportioned animal. Hence, JNK might act as a hub, translating wound signals into apoptotic cell death, controlled stem cell proliferation and differentiation, all of which are required to coordinate regeneration and tissue renewal. PMID:24922054

  6. Autonomous Intersection Management

    Science.gov (United States)

    2009-12-01

    detects that the driver is not slowing sufficiently fast. Jaguar, Honda, and BMW offer similar systems. Nissan and Toyota have recently begun offering...that the driver is not braking hard enough. Both Toyota and BMW are currently selling vehicles that can parallel park completely autonomously, even...other vehicles. The system was tested both in simulation and with a robotic vehicle. This work is sponsored by Toyota , who have also currently have an

  7. Autonomía

    OpenAIRE

    Martínez Muñoz, Juan Antonio

    2007-01-01

    En este ensayo la noción de autonomía es estudiada de un modo diferente al sentido habitual; sus implicaciones y las contradicciones que encierra, específicamente como sucedáneo de la genuina libertad. El artículo describe el modelo de hombre presupuesto en su uso. Concluye con su inviabilidad para resolver problemas morales y sociales.

  8. Mobile Intelligent Autonomous Systems

    OpenAIRE

    Jitendra R. Raol; Ajith Gopal

    2010-01-01

    Mobile intelligent autonomous systems (MIAS) is a fast emerging research area. Although it can be regarded as a general R&D area, it is mainly directed towards robotics. Several important subtopics within MIAS research are:(i) perception and reasoning, (ii) mobility and navigation,(iii) haptics and teleoperation, (iv) image fusion/computervision, (v) modelling of manipulators, (vi) hardware/software architectures for planning and behaviour learning leadingto robotic architecture, (vii) ve...

  9. Autonomous Underwater Gliders

    OpenAIRE

    Wood,; Stephen,

    2009-01-01

    Autonomous Underwater Vehicles are only now being marketed as robust commercial vehicles for many industries, and of these vehicles underwater gliders are becoming the new tool for oceanographers. Satellites have provided scientists and marine specialists with measurements of the sea surface such as temperature since the late 1970s, and data via subsurface oceanographic moorings since the 1950's. As stated by David Smeed of the National Oceanography Centre, Southampton, England, that "gliders...

  10. Curiosity's Autonomous Surface Safing Behavior Design

    Science.gov (United States)

    Neilson, Tracy A.; Manning, Robert M.

    2013-01-01

    The safing routines on all robotic deep-space vehicles are designed to put the vehicle in a power and thermally safe configuration, enabling communication with the mission operators on Earth. Achieving this goal is made a little more difficult on Curiosity because the power requirements for the core avionics and the telecommunication equipment exceed the capability of the single power source, the Multi-Mission Radioisotope Thermoelectric Generator. This drove the system design to create an operational mode, called "sleep mode", where the vehicle turns off most of the loads in order to charge the two Li-ion batteries. The system must keep the vehicle safe from over-heat and under-heat conditions, battery cell failures, under-voltage conditions, and clock failures, both while the computer is running and while the system is sleeping. The other goal of a safing routine is to communicate. On most spacecraft, this simply involves turning on the receiver and transmitter continuously. For Curiosity, Earth is above the horizon only a part of the day for direct communication to the Earth, and the orbiter overpass opportunities only occur a few times a day. The design must robustly place the Rover in a communicable condition at the correct time. This paper discusses Curiosity's autonomous safing behavior and describes how the vehicle remains power and thermally safe while sleeping, as well as a description of how the Rover communicates with the orbiters and Earth at specific times.

  11. Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

    International Nuclear Information System (INIS)

    Zhan, Yu; Abi Saab, Widian F.; Modi, Nidhi; Stewart, Amanda M.; Liu, Jinsong; Chadee, Deborah N.

    2012-01-01

    Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. -- Highlights: ► Ovarian cancer cell lines have high levels of total and phosphorylated MLK3. ► MLK3 is required for MMP expression and activity in ovarian cancer cells. ► MLK3 is required for invasion of SKOV3 and HEY1B ovarian cancer cells. ► MLK3-dependent regulation of MMP-2 and MMP-9 activities requires ERK and JNK.

  12. Centriole maturation requires regulated Plk1 activity during two consecutive cell cycles.

    Science.gov (United States)

    Kong, Dong; Farmer, Veronica; Shukla, Anil; James, Jana; Gruskin, Richard; Kiriyama, Shigeo; Loncarek, Jadranka

    2014-09-29

    Newly formed centrioles in cycling cells undergo a maturation process that is almost two cell cycles long before they become competent to function as microtubule-organizing centers and basal bodies. As a result, each cell contains three generations of centrioles, only one of which is able to form cilia. It is not known how this long and complex process is regulated. We show that controlled Plk1 activity is required for gradual biochemical and structural maturation of the centrioles and timely appendage assembly. Inhibition of Plk1 impeded accumulation of appendage proteins and appendage formation. Unscheduled Plk1 activity, either in cycling or interphase-arrested cells, accelerated centriole maturation and appendage and cilia formation on the nascent centrioles, erasing the age difference between centrioles in one cell. These findings provide a new understanding of how the centriole cycle is regulated and how proper cilia and centrosome numbers are maintained in the cells.

  13. Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10

    DEFF Research Database (Denmark)

    MacDonald, Kelli P.A.; Le Texier, Laetitia; Zhang, Ping

    2014-01-01

    The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which...... the hematopoietic or nonhematopoietic compartments were wild-type, IL-10(-/-), G-CSFR(-/-), or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after G-CSF mobilization required direct signaling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio......-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4(+)CD25(+) regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast...

  14. The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Jennifer L Bandura

    Full Text Available The coordination of cell proliferation and differentiation is crucial for proper development. In particular, robust mechanisms exist to ensure that cells permanently exit the cell cycle upon terminal differentiation, and these include restraining the activities of both the E2F/DP transcription factor and Cyclin/Cdk kinases. However, the full complement of mechanisms necessary to restrain E2F/DP and Cyclin/Cdk activities in differentiating cells are not known. Here, we have performed a genetic screen in Drosophila melanogaster, designed to identify genes required for cell cycle exit. This screen utilized a PCNA-miniwhite(+ reporter that is highly E2F-responsive and results in a darker red eye color when crossed into genetic backgrounds that delay cell cycle exit. Mutation of Hsp83, the Drosophila homolog of mammalian Hsp90, results in increased E2F-dependent transcription and ectopic cell proliferation in pupal tissues at a time when neighboring wild-type cells are postmitotic. Further, these Hsp83 mutant cells have increased Cyclin/Cdk activity and accumulate proteins normally targeted for proteolysis by the anaphase-promoting complex/cyclosome (APC/C, suggesting that APC/C function is inhibited. Indeed, reducing the gene dosage of an inhibitor of Cdh1/Fzr, an activating subunit of the APC/C that is required for timely cell cycle exit, can genetically suppress the Hsp83 cell cycle exit phenotype. Based on these data, we propose that Cdh1/Fzr is a client protein of Hsp83. Our results reveal that Hsp83 plays a heretofore unappreciated role in promoting APC/C function during cell cycle exit and suggest a mechanism by which Hsp90 inhibition could promote genomic instability and carcinogenesis.

  15. The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster.

    Science.gov (United States)

    Bandura, Jennifer L; Jiang, Huaqi; Nickerson, Derek W; Edgar, Bruce A

    2013-01-01

    The coordination of cell proliferation and differentiation is crucial for proper development. In particular, robust mechanisms exist to ensure that cells permanently exit the cell cycle upon terminal differentiation, and these include restraining the activities of both the E2F/DP transcription factor and Cyclin/Cdk kinases. However, the full complement of mechanisms necessary to restrain E2F/DP and Cyclin/Cdk activities in differentiating cells are not known. Here, we have performed a genetic screen in Drosophila melanogaster, designed to identify genes required for cell cycle exit. This screen utilized a PCNA-miniwhite(+) reporter that is highly E2F-responsive and results in a darker red eye color when crossed into genetic backgrounds that delay cell cycle exit. Mutation of Hsp83, the Drosophila homolog of mammalian Hsp90, results in increased E2F-dependent transcription and ectopic cell proliferation in pupal tissues at a time when neighboring wild-type cells are postmitotic. Further, these Hsp83 mutant cells have increased Cyclin/Cdk activity and accumulate proteins normally targeted for proteolysis by the anaphase-promoting complex/cyclosome (APC/C), suggesting that APC/C function is inhibited. Indeed, reducing the gene dosage of an inhibitor of Cdh1/Fzr, an activating subunit of the APC/C that is required for timely cell cycle exit, can genetically suppress the Hsp83 cell cycle exit phenotype. Based on these data, we propose that Cdh1/Fzr is a client protein of Hsp83. Our results reveal that Hsp83 plays a heretofore unappreciated role in promoting APC/C function during cell cycle exit and suggest a mechanism by which Hsp90 inhibition could promote genomic instability and carcinogenesis.

  16. Autonomous execution of the Precision Immobilization Technique

    Science.gov (United States)

    Mascareñas, David D. L.; Stull, Christopher J.; Farrar, Charles R.

    2017-03-01

    Over the course of the last decade great advances have been made in autonomously driving cars. The technology has advanced to the point that driverless car technology is currently being tested on publicly accessed roadways. The introduction of these technologies onto publicly accessed roadways not only raises questions of safety, but also security. Autonomously driving cars are inherently cyber-physical systems and as such will have novel security vulnerabilities that couple both the cyber aspects of the vehicle including the on-board computing and any network data it makes use of, with the physical nature of the vehicle including its sensors, actuators, and the vehicle chassis. Widespread implementation of driverless car technology will require that both the cyber, as well as physical security concerns surrounding these vehicles are addressed. In this work, we specifically developed a control policy to autonomously execute the Precision Immobilization Technique, a.k.a. the PIT maneuver. The PIT maneuver was originally developed by law enforcement to end high-speed vehicular pursuits in a quasi-safe manner. However, there is still a risk of damage/roll-over to both the vehicle executing the PIT maneuver as well as to the vehicle subject to the PIT maneuver. In law enforcement applications, it would be preferable to execute the PIT maneuver using an autonomous vehicle, thus removing the danger to law-enforcement officers. Furthermore, it is entirely possible that unscrupulous individuals could inject code into an autonomously-driving car to use the PIT maneuver to immobilize other vehicles while maintaining anonymity. For these reasons it is useful to know how the PIT maneuver can be implemented on an autonomous car. In this work a simple control policy based on velocity pursuit was developed to autonomously execute the PIT maneuver using only a vision and range measurements that are both commonly collected by contemporary driverless cars. The ability of this

  17. 2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells

    Science.gov (United States)

    2017-01-01

    ABSTRACT Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein–Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8+ T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a−/− CD8+ T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a−/− CD8+ T cells responded equivalently to wild-type CD8+ T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8+ T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8+ T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8+ T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas. PMID:28344876

  18. 2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells.

    Science.gov (United States)

    Huang, Yu-Hsuan; Tsai, Kevin; Tan, Sara Y; Kang, Sohyeong; Ford, Mandy L; Harder, Kenneth W; Priatel, John J

    2017-01-01

    Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8 + T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a - / - CD8 + T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a - / - CD8 + T cells responded equivalently to wild-type CD8 + T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8 + T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8 + T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8 + T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.

  19. Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells.

    Science.gov (United States)

    Hunt, Geoffrey C; Singh, Purva; Schwarzbauer, Jean E

    2012-09-10

    Pluripotent cells are attached to the extracellular matrix (ECM) as they make cell fate decisions within the stem cell niche. Here we show that the ubiquitous ECM protein fibronectin is required for self-renewal decisions by cultured mouse embryonic stem (mES) cells. Undifferentiated mES cells produce fibronectin and assemble a fibrillar matrix. Increasing the level of substrate fibronectin increased cell spreading and integrin receptor signaling through focal adhesion kinase, while concomitantly inducing the loss of Nanog and Oct4 self-renewal markers. Conversely, reducing fibronectin production by mES cells growing on a feeder-free gelatin substrate caused loss of cell adhesion, decreased integrin signaling, and decreased expression of self-renewal markers. These effects were reversed by providing the cells with exogenous fibronectin, thereby restoring adhesion to the gelatin substrate. Interestingly, mES cells do not adhere directly to the gelatin substrate, but rather adhere indirectly through gelatin-bound fibronectin, which facilitates self-renewal via its effects on cell adhesion. These results provide new insights into the mechanism of regulation of self-renewal by growth on a gelatin-coated surface. The effects of increasing or decreasing fibronectin levels show that self-renewal depends on an intermediate level of cell-fibronectin interactions. By providing cell adhesive signals that can act with other self-renewal factors to maintain mES cell pluripotency, fibronectin is therefore a necessary component of the self-renewal signaling pathway in culture. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help.

    Directory of Open Access Journals (Sweden)

    Christopher M Collins

    2014-05-01

    Full Text Available X linked lymphoproliferative disease (XLP is an inherited immunodeficiency resulting from mutations in the gene encoding the slam associated protein (SAP. One of the defining characteristics of XLP is extreme susceptibility to infection with Epstein-Barr virus (EBV, a gammaherpesvirus belonging to the genus Lymphocryptovirus, often resulting in fatal infectious mononucleosis (FIM. However, infection of SAP deficient mice with the related Murine gammaherpesvirus 68 (MHV68, a gammaherpesvirus in the genus Rhadinovirus, does not recapitulate XLP. Here we show that MHV68 inefficiently establishes latency in B cells in SAP deficient mice due to insufficient CD4 T cell help during the germinal center response. Although MHV68 infected B cells can be found in SAP-deficient mice, significantly fewer of these cells had a germinal center phenotype compared to SAP-sufficient mice. Furthermore, we show that infected germinal center B cells in SAP-deficient mice fail to proliferate. This failure to proliferate resulted in significantly lower viral loads, and likely accounts for the inability of MHV68 to induce a FIM-like syndrome. Finally, inhibiting differentiation of T follicular helper (TFH cells in SAP-sufficient C57Bl/6 mice resulted in decreased B cell latency, and the magnitude of the TFH response directly correlated with the level of infection in B cells. This requirement for CD4 T cell help during the germinal center reaction by MHV68 is in contrast with EBV, which is thought to be capable of bypassing this requirement by expressing viral proteins that mimic signals provided by TFH cells. In conclusion, the outcome of MHV68 infection in mice in the setting of loss of SAP function is distinct from that observed in SAP-deficient patients infected with EBV, and may identify a fundamental difference between the strategies employed by the rhadinoviruses and lymphocryptoviruses to expand B cell latency during the early phase of infection.

  1. Hematopoietic stem cell development requires transient Wnt/β-catenin activity

    DEFF Research Database (Denmark)

    Ruiz-Herguido, Cristina; Guiu, Jordi; D'Altri, Teresa

    2012-01-01

    in the aorta-gonad-mesonephros (AGM) region. We show here that β-catenin is nuclear and active in few endothelial nonhematopoietic cells closely associated with the emerging hematopoietic clusters of the embryonic aorta during mouse development. Importantly, Wnt/β-catenin activity is transiently required...... of mutant cells toward the hematopoietic lineage; however, these mutant cells still contribute to the adult endothelium. Together, those findings indicate that Wnt/β-catenin activity is needed for the emergence but not the maintenance of HSCs in mouse embryos....

  2. Stomatal Function Requires Pectin De-methyl-esterification of the Guard Cell Wall.

    Science.gov (United States)

    Amsbury, Sam; Hunt, Lee; Elhaddad, Nagat; Baillie, Alice; Lundgren, Marjorie; Verhertbruggen, Yves; Scheller, Henrik V; Knox, J Paul; Fleming, Andrew J; Gray, Julie E

    2016-11-07

    Stomatal opening and closure depends on changes in turgor pressure acting within guard cells to alter cell shape [1]. The extent of these shape changes is limited by the mechanical properties of the cells, which will be largely dependent on the structure of the cell walls. Although it has long been observed that guard cells are anisotropic due to differential thickening and the orientation of cellulose microfibrils [2], our understanding of the composition of the cell wall that allows them to undergo repeated swelling and deflation remains surprisingly poor. Here, we show that the walls of guard cells are rich in un-esterified pectins. We identify a pectin methylesterase gene, PME6, which is highly expressed in guard cells and required for stomatal function. pme6-1 mutant guard cells have walls enriched in methyl-esterified pectin and show a decreased dynamic range in response to triggers of stomatal opening/closure, including elevated osmoticum, suggesting that abrogation of stomatal function reflects a mechanical change in the guard cell wall. Altered stomatal function leads to increased conductance and evaporative cooling, as well as decreased plant growth. The growth defect of the pme6-1 mutant is rescued by maintaining the plants in elevated CO 2 , substantiating gas exchange analyses, indicating that the mutant stomata can bestow an improved assimilation rate. Restoration of PME6 rescues guard cell wall pectin methyl-esterification status, stomatal function, and plant growth. Our results establish a link between gene expression in guard cells and their cell wall properties, with a corresponding effect on stomatal function and plant physiology. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Advanced Autonomous Systems for Space Operations

    Science.gov (United States)

    Gross, A. R.; Smith, B. D.; Muscettola, N.; Barrett, A.; Mjolssness, E.; Clancy, D. J.

    2002-01-01

    New missions of exploration and space operations will require unprecedented levels of autonomy to successfully accomplish their objectives. Inherently high levels of complexity, cost, and communication distances will preclude the degree of human involvement common to current and previous space flight missions. With exponentially increasing capabilities of computer hardware and software, including networks and communication systems, a new balance of work is being developed between humans and machines. This new balance holds the promise of not only meeting the greatly increased space exploration requirements, but simultaneously dramatically reducing the design, development, test, and operating costs. New information technologies, which take advantage of knowledge-based software, model-based reasoning, and high performance computer systems, will enable the development of a new generation of design and development tools, schedulers, and vehicle and system health management capabilities. Such tools will provide a degree of machine intelligence and associated autonomy that has previously been unavailable. These capabilities are critical to the future of advanced space operations, since the science and operational requirements specified by such missions, as well as the budgetary constraints will limit the current practice of monitoring and controlling missions by a standing army of ground-based controllers. System autonomy capabilities have made great strides in recent years, for both ground and space flight applications. Autonomous systems have flown on advanced spacecraft, providing new levels of spacecraft capability and mission safety. Such on-board systems operate by utilizing model-based reasoning that provides the capability to work from high-level mission goals, while deriving the detailed system commands internally, rather than having to have such commands transmitted from Earth. This enables missions of such complexity and communication` distances as are not

  4. SEC23B is required for pancreatic acinar cell function in adult mice

    Science.gov (United States)

    Khoriaty, Rami; Vogel, Nancy; Hoenerhoff, Mark J.; Sans, M. Dolors; Zhu, Guojing; Everett, Lesley; Nelson, Bradley; Durairaj, Haritha; McKnight, Brooke; Zhang, Bin; Ernst, Stephen A.; Ginsburg, David; Williams, John A.

    2017-01-01

    Mice with germline absence of SEC23B die perinatally, exhibiting massive pancreatic degeneration. We generated mice with tamoxifen-inducible, pancreatic acinar cell–specific Sec23b deletion. Inactivation of Sec23b exclusively in the pancreatic acinar cells of adult mice results in decreased overall pancreatic weights from pancreatic cell loss (decreased pancreatic DNA, RNA, and total protein content), as well as degeneration of exocrine cells, decreased zymogen granules, and alterations in the endoplasmic reticulum (ER), ranging from vesicular ER to markedly expanded cisternae with accumulation of moderate-density content or intracisternal granules. Acinar Sec23b deletion results in induction of ER stress and increased apoptosis in the pancreas, potentially explaining the loss of pancreatic cells and decreased pancreatic weight. These findings demonstrate that SEC23B is required for normal function of pancreatic acinar cells in adult mice. PMID:28539403

  5. Science, technology and the future of small autonomous drones.

    Science.gov (United States)

    Floreano, Dario; Wood, Robert J

    2015-05-28

    We are witnessing the advent of a new era of robots - drones - that can autonomously fly in natural and man-made environments. These robots, often associated with defence applications, could have a major impact on civilian tasks, including transportation, communication, agriculture, disaster mitigation and environment preservation. Autonomous flight in confined spaces presents great scientific and technical challenges owing to the energetic cost of staying airborne and to the perceptual intelligence required to negotiate complex environments. We identify scientific and technological advances that are expected to translate, within appropriate regulatory frameworks, into pervasive use of autonomous drones for civilian applications.

  6. Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation.

    Directory of Open Access Journals (Sweden)

    Christian Berrios

    2016-11-01

    Full Text Available Merkel cell polyomavirus (MCPyV is an etiological agent of Merkel cell carcinoma (MCC, a highly aggressive skin cancer. The MCPyV small tumor antigen (ST is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1. Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.

  7. FGF7 and cell density are required for final differentiation of pancreatic amylase-positive cells from human ES cells.

    Science.gov (United States)

    Takizawa-Shirasawa, Sakiko; Yoshie, Susumu; Yue, Fengming; Mogi, Akimi; Yokoyama, Tadayuki; Tomotsune, Daihachiro; Sasaki, Katsunori

    2013-12-01

    The major molecular signals of pancreatic exocrine development are largely unknown. We examine the role of fibroblast growth factor 7 (FGF7) in the final induction of pancreatic amylase-containing exocrine cells from induced-pancreatic progenitor cells derived from human embryonic stem (hES) cells. Our protocol consisted in three steps: Step I, differentiation of definitive endoderm (DE) by activin A treatment of hES cell colonies; Step II, differentiation of pancreatic progenitor cells by re-plating of the cells of Step I onto 24-well plates at high density and stimulation with all-trans retinoic acid; Step III, differentiation of pancreatic exocrine cells with a combination of FGF7, glucagon-like peptide 1 and nicotinamide. The expression levels of pancreatic endodermal markers such as Foxa2, Sox17 and gut tube endoderm marker HNF1β were up-regulated in both Step I and II. Moreover, in Step III, the induced cells expressed pancreatic markers such as amylase, carboxypeptidase A and chymotrypsinogen B, which were similar to those in normal human pancreas. From day 8 in Step III, cells immunohistochemically positive for amylase and for carboxypeptidase A, a pancreatic exocrine cell product, were induced by FGF7. Pancreatic progenitor Pdx1-positive cells were localized in proximity to the amylase-positive cells. In the absence of FGF7, few amylase-positive cells were identified. Thus, our three-step culture protocol for human ES cells effectively induces the differentiation of amylase- and carboxypeptidase-A-containing pancreatic exocrine cells.

  8. Autonomic Neuropathy in Diabetes Mellitus

    OpenAIRE

    Verrotti, Alberto; Prezioso, Giovanni; Scattoni, Raffaella; Chiarelli, Francesco

    2014-01-01

    Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent ...

  9. Pineal photoreceptor cells are required for maintaining the circadian rhythms of behavioral visual sensitivity in zebrafish.

    Directory of Open Access Journals (Sweden)

    Xinle Li

    Full Text Available In non-mammalian vertebrates, the pineal gland functions as the central pacemaker that regulates the circadian rhythms of animal behavior and physiology. We generated a transgenic zebrafish line [Tg(Gnat2:gal4-VP16/UAS:nfsB-mCherry] in which the E. coli nitroreductase is expressed in pineal photoreceptor cells. In developing embryos and young adults, the transgene is expressed in both retinal and pineal photoreceptor cells. During aging, the expression of the transgene in retinal photoreceptor cells gradually diminishes. By 8 months of age, the Gnat2 promoter-driven nitroreductase is no longer expressed in retinal photoreceptor cells, but its expression in pineal photoreceptor cells persists. This provides a tool for selective ablation of pineal photoreceptor cells, i.e., by treatments with metronidazole. In the absence of pineal photoreceptor cells, the behavioral visual sensitivity of the fish remains unchanged; however, the circadian rhythms of rod and cone sensitivity are diminished. Brief light exposures restore the circadian rhythms of behavioral visual sensitivity. Together, the data suggest that retinal photoreceptor cells respond to environmental cues and are capable of entraining the circadian rhythms of visual sensitivity; however, they are insufficient for maintaining the rhythms. Cellular signals from the pineal photoreceptor cells may be required for maintaining the circadian rhythms of visual sensitivity.

  10. Differential requirement for satellite cells during overload-induced muscle hypertrophy in growing versus mature mice.

    Science.gov (United States)

    Murach, Kevin A; White, Sarah H; Wen, Yuan; Ho, Angel; Dupont-Versteegden, Esther E; McCarthy, John J; Peterson, Charlotte A

    2017-07-10

    Pax7+ satellite cells are required for skeletal muscle fiber growth during post-natal development in mice. Satellite cell-mediated myonuclear accretion also appears to persist into early adulthood. Given the important role of satellite cells during muscle development, we hypothesized that the necessity of satellite cells for adaptation to an imposed hypertrophic stimulus depends on maturational age. Pax7 CreER -R26R DTA mice were treated for 5 days with vehicle (satellite cell-replete, SC+) or tamoxifen (satellite cell-depleted, SC-) at 2 months (young) and 4 months (mature) of age. Following a 2-week washout, mice were subjected to sham surgery or 10 day synergist ablation overload of the plantaris (n = 6-9 per group). The surgical approach minimized regeneration, de novo fiber formation, and fiber splitting while promoting muscle fiber growth. Satellite cell density (Pax7+ cells/fiber), embryonic myosin heavy chain expression (eMyHC), and muscle fiber cross sectional area (CSA) were evaluated via immunohistochemistry. Myonuclei (myonuclei/100 mm) were counted on isolated single muscle fibers. Tamoxifen treatment depleted satellite cells by ≥90% and prevented myonuclear accretion with overload in young and mature mice (p overload. Average muscle fiber CSA increased ~20% in young SC+ (p = 0.07), mature SC+ (p overload (p overload-induced hypertrophy is dependent on maturational age, and global responses to overload differ in young versus mature mice.

  11. TRPM7 is required for ovarian cancer cell growth, migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing; Liao, Qian-jin [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Yi [Department of Obstetrics and Gynaecology, Xiangya Hospital, Central South University, Changsha 410078 (China); Zhou, Hui; Luo, Chen-hui; Tang, Jie; Wang, Ying; Tang, Yan; Zhao, Min; Zhao, Xue-heng [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Qiong-yu [Department of Basic Medical Science, Yongzhou Vocational Technical College, Yong Zhou 425100 (China); Xiao, Ling, E-mail: lingxiaocsu@126.com [Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013 (China); Institute of Clinical Pharmacology, Central South University, Changsha 410018 (China)

    2014-11-28

    Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.

  12. Evaluation of accessory cell heterogeneity. I. Differential accessory cell requirement for T helper cell activation and for T-B cooperation.

    Science.gov (United States)

    Ramila, G; Studer, S; Kennedy, M; Sklenar, I; Erb, P

    1985-01-01

    Several Ia+ tumor cell lines and peritoneal exudate macrophages were tested as accessory cells (AC) for the activation of antigen-specific T cells and for T-B cooperation. The macrophages and all the Ia+ tumor lines tested induced the release of lymphokines from T cells in a major histocompatibility complex (MHC)-restricted fashion and reconstituted the antibody responses of AC-depleted spleen cells or of purified T and B cells. However, only the normal macrophages but none of the tumor lines induced carrier-specific T helper (Th) cells which help B cells for specific antihapten antibody responses by linked recognition. For T-B cooperation accessory cells were also required, but in contrast to Th cell activation any type of Ia+ AC (e.g. macrophage or tumor line) was effective. Strong MHC-restriction between the lymphocytes and the AC was seen if antigen-pulsed AC were added into the AC-depleted T-B cooperation cultures. If the AC and antigen were concomitantly added to the AC-depleted T-B cultures, MHC-restriction was less obvious. Concanavalin A supernatant reconstituted the response of AC-depleted T-B cultures provided antigen-specific Th cells and the hapten-carrier conjugate were present. If, however, tumor line-activated T cells were added instead of macrophage-induced Th cells, no cooperation with B cells took place even in the presence of Con A supernatant. The results obtained demonstrate a differential AC requirement for the induction of Th cells depending on the differentiation stage of the Th cells.

  13. Eph receptor interclass cooperation is required for the regulation of cell proliferation

    International Nuclear Information System (INIS)

    Jurek, Aleksandra; Genander, Maria; Kundu, Parag; Catchpole, Timothy; He, Xiao; Strååt, Klas; Sabelström, Hanna; Xu, Nan-Jie; Pettersson, Sven; Henkemeyer, Mark; Frisén, Jonas

    2016-01-01

    Cancer often arises by the constitutive activation of mitogenic pathways by mutations in stem cells. Eph receptors are unusual in that although they regulate the proliferation of stem/progenitor cells in many adult organs, they typically fail to transform cells. Multiple ephrins and Eph receptors are often co-expressed and are thought to be redundant, but we here describe an unexpected dichotomy with two homologous ligands, ephrin-B1 and ephrin-B2, regulating specifically migration or proliferation in the intestinal stem cell niche. We demonstrate that the combined activity of two different coexpressed Eph receptors of the A and B class assembled into common signaling clusters in response to ephrin-B2 is required for mitogenic signaling. The requirement of two different Eph receptors to convey mitogenic signals identifies a new type of cooperation within this receptor family and helps explain why constitutive activation of a single receptor fails to transform cells. - Highlights: • We demonstrate that ephrin-B1 and ephrin-B2 have largely non-overlapping functions in the intestinal stem cell niche. • Ephrin-B1 regulates cell positioning and ephrin-B2 regulates cell proliferation in the intestinal stem cell niche. • EphA4/B2 receptor cooperation in response to ephrin-B2 binding is obligatory to convey mitogenic signals in the intestine. • EphA4 facilitates EphB2 phosphorylation in response to ephrin-B2 in SW480 adenocarcinoma cells. • Ephrin-B1 and ephrin-B2 induce phosphorylation and degradation of the EphB2 receptor with different kinetics.

  14. Eph receptor interclass cooperation is required for the regulation of cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Jurek, Aleksandra; Genander, Maria [Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Kundu, Parag [Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551 (Singapore); Lee Kong Chian School of Medicine, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551 (Singapore); Catchpole, Timothy [Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas TX 75390 (United States); He, Xiao; Strååt, Klas; Sabelström, Hanna [Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Xu, Nan-Jie [Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas TX 75390 (United States); Pettersson, Sven [Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551 (Singapore); Lee Kong Chian School of Medicine, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551 (Singapore); The National Cancer Centre, Singapore General Hospital (Singapore); Henkemeyer, Mark [Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas TX 75390 (United States); Frisén, Jonas, E-mail: jonas.frisen@ki.se [Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm (Sweden)

    2016-10-15

    Cancer often arises by the constitutive activation of mitogenic pathways by mutations in stem cells. Eph receptors are unusual in that although they regulate the proliferation of stem/progenitor cells in many adult organs, they typically fail to transform cells. Multiple ephrins and Eph receptors are often co-expressed and are thought to be redundant, but we here describe an unexpected dichotomy with two homologous ligands, ephrin-B1 and ephrin-B2, regulating specifically migration or proliferation in the intestinal stem cell niche. We demonstrate that the combined activity of two different coexpressed Eph receptors of the A and B class assembled into common signaling clusters in response to ephrin-B2 is required for mitogenic signaling. The requirement of two different Eph receptors to convey mitogenic signals identifies a new type of cooperation within this receptor family and helps explain why constitutive activation of a single receptor fails to transform cells. - Highlights: • We demonstrate that ephrin-B1 and ephrin-B2 have largely non-overlapping functions in the intestinal stem cell niche. • Ephrin-B1 regulates cell positioning and ephrin-B2 regulates cell proliferation in the intestinal stem cell niche. • EphA4/B2 receptor cooperation in response to ephrin-B2 binding is obligatory to convey mitogenic signals in the intestine. • EphA4 facilitates EphB2 phosphorylation in response to ephrin-B2 in SW480 adenocarcinoma cells. • Ephrin-B1 and ephrin-B2 induce phosphorylation and degradation of the EphB2 receptor with different kinetics.

  15. ADAM13 function is required in the 3 dimensional context of the embryo during cranial neural crest cell migration in Xenopus laevis

    Science.gov (United States)

    Cousin, Hélène; Abbruzzese, Genevieve; McCusker, Catherine; Alfandari, Dominique

    2012-01-01

    The cranial neural crest (CNC) is a population of cells that arises from the lateral part of the developing brain, migrates ventrally and coordinates the entire craniofacial development of vertebrates. Many molecules are involved in CNC migration including the transmembrane metalloproteases ADAM13 and 19. We have previously shown that these ADAMs cleave a number of extracellular proteins and modify the transcription of a number of genes, and that both of these activities are important for cell migration. Here we show that the knock down of ADAM13 inhibits CNC migration in vivo but not in vitro, indicating that ADAM13 function is required in the 3-dimentional context of the embryo. We further show that the migration of CNC that do not express ADAM13 and ADAM19 can be rescued in vivo by co-grafting wild type CNC. Furthermore, the migration of CNC lacking ADAM13 can be rescued by mechanically separating the CNC from the surrounding ectoderm and mesoderm. Finally, we show that ADAM13 function is autonomous to CNC tissue, as the migration of morphant CNC can only be rescued by ADAM13 expression in the CNC and not the surrounding tissues. Together our results suggest that ADAM13 changes CNC interaction with the extracellular environment and that this change is necessary for their migration in vivo. PMID:22683825

  16. Robotics and Autonomous Systems Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — FUNCTION: Provides an environment for developing and evaluating intelligent software for both actual and simulated autonomous vehicles. Laboratory computers provide...

  17. Autonomic Fuselet Specification and Composition

    National Research Council Canada - National Science Library

    Mills, Peter H

    2006-01-01

    A framework for autonomic fuselet business logic development was developed, using semantic web services and workflow technologies to specify fuselet information needs, to define an executable workflow...

  18. Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-Ficoll. A novel cell interaction pathway requiring self-recognition of accessory cell H-2 determinants by both T cells and B cells

    International Nuclear Information System (INIS)

    Hodes, R.J.; Hathcock, K.S.; Singer, A.

    1983-01-01

    In vitro primary antibody responses to limiting concentrations of trinitrophenyl (TNP)-Ficoll were shown to be T cell dependent, requiring the cooperation of T helper (TH) cells, B cells, and accessory cells. Under these conditions, TH cells derived from long-term radiation bone marrow chimeras were major histocompatibility complex (MHC) restricted in their ability to cooperate with accessory cells expressing host-type MHC determinants. The requirement for MHC-restricted self-recognition by TNP-Ficoll-reactive B cells was assessed under these T-dependent conditions. In the presence of competent TH cells, chimeric B cells were found to be MHC restricted, cooperating only with accessory cells that expressed host-type MHC products. In contrast, the soluble products of certain monoclonal T cell lines were able to directly activate B cells in response to TNP-Ficoll, bypassing any requirement for MHC-restricted self-recognition. These findings demonstrate the existence of a novel cell interaction pathway in which B cells as well as TH cells are each required to recognize self-MHC determinants on accessory cells, but are not required to recognize each other. They further demonstrate that the requirement for self-recognition by B cells may be bypassed in certain T-dependent activation pathways

  19. Dynamic model of an autonomous solar absorption refrigerator

    International Nuclear Information System (INIS)

    Ali Fellah; Tahar Khir; Ammar Ben Brahim

    2009-01-01

    The performance analysis of a solar absorption refrigerator operating in an autonomous way is investigated. The water/LiBr machine satisfies the air-conditioning needs along the day. The refrigerator performances were simulated regarding a dynamic model. For the solar driven absorption machines, two applications could be distinguished. The sun provides the thermal part of the useful energy. In this case, it is necessary to use additional energy as the electric one to activate the pumps, the fans and the control system. On the other hand, the sun provides all the necessary energy. Here, both photovoltaic cells and thermal concentrators should be used. The simulation in dynamic regime of the cycle requires the knowledge of the geometric characteristics of every component as the exchange areas and the internal volumes. Real characteristics of a refrigerator available at the applied thermodynamic research unit (ATRU) at the engineers' national school of Gabes are notified. The development of the thermal and matter balances in every component of the cycle has permitted to simulate in dynamic regime the performances of a solar absorption refrigerator operating with the water/LiBr couple for air-conditioning needs. The developed model could be used to perform intermittent refrigeration cycle autonomously driven. (author)

  20. Toward autonomous spacecraft

    Science.gov (United States)

    Fogel, L. J.; Calabrese, P. G.; Walsh, M. J.; Owens, A. J.

    1982-01-01

    Ways in which autonomous behavior of spacecraft can be extended to treat situations wherein a closed loop control by a human may not be appropriate or even possible are explored. Predictive models that minimize mean least squared error and arbitrary cost functions are discussed. A methodology for extracting cyclic components for an arbitrary environment with respect to usual and arbitrary criteria is developed. An approach to prediction and control based on evolutionary programming is outlined. A computer program capable of predicting time series is presented. A design of a control system for a robotic dense with partially unknown physical properties is presented.

  1. Autonomous mobile robot teams

    Science.gov (United States)

    Agah, Arvin; Bekey, George A.

    1994-01-01

    This paper describes autonomous mobile robot teams performing tasks in unstructured environments. The behavior and the intelligence of the group is distributed, and the system does not include a central command base or leader. The novel concept of the Tropism-Based Cognitive Architecture is introduced, which is used by the robots in order to produce behavior transforming their sensory information to proper action. The results of a number of simulation experiments are presented. These experiments include worlds where the robot teams must locate, decompose, and gather objects, and defend themselves against hostile predators, while navigating around stationary and mobile obstacles.

  2. Wnt signaling requires retromer-dependent recycling of MIG-14/Wntless in Wnt-producing cells.

    NARCIS (Netherlands)

    Yang, P.T.; Lorenowicz, M.J.; Silhankova, M.; Coudreuse, D.Y.M.; Betist, M.C.; Korswagen, H.C.

    2008-01-01

    Wnt proteins are secreted signaling molecules that play a central role in development and adult tissue homeostasis. We have previously shown that Wnt signaling requires retromer function in Wnt-producing cells. The retromer is a multiprotein complex that mediates endosome-to-Golgi transport of

  3. Differential Requirements for T Cells in Viruslike Particle- and Rotavirus-Induced Protective Immunity▿

    Science.gov (United States)

    Blutt, Sarah E.; Warfield, Kelly L.; Estes, Mary K.; Conner, Margaret E.

    2008-01-01

    Correlates of protection from rotavirus infection are controversial. We compared the roles of B and T lymphocytes in protective immunity induced either by intranasally administered nonreplicating viruslike particles or inactivated virus or by orally administered murine rotavirus. We found that protection induced by nonreplicating vaccines requires CD4+ T cells and CD40/CD40L. In contrast, T cells were not required for short-term protective immunity induced by infection, but both T-cell-dependent and -independent mechanisms contributed to long-term maintenance of protection. Our findings indicate that more than one marker of protective immunity exists and that these markers depend on the vaccine that is administered. PMID:18184712

  4. Three domains of SLP-76 are required for its optimal function in a T cell line.

    Science.gov (United States)

    Musci, M A; Motto, D G; Ross, S E; Fang, N; Koretzky, G A

    1997-08-15

    We and others have shown that overexpression of SLP-76 augments TCR-stimulated IL-2 promoter activity in the Jurkat T cell line. In this report we investigate the signaling mechanisms through which SLP-76 mediates its effect on T cell activation. We show that overexpressed SLP-76 acts downstream of TCR-stimulated protein tyrosine kinases, but does not affect calcium signaling. Overexpression of SLP-76 does, however, augment TCR stimulation of both ERK (extracellular signal-regulated kinase) activity and a reporter construct driven by activating protein-1 binding sites. Structure/function analysis reveals that three distinct regions of SLP-76, each important for protein associations, are required for augmentation of TCR-induced nuclear factor-AT activity. These data suggest that SLP-76 functions as an adapter molecule that requires three unique domains to link proximal TCR signals in T cells.

  5. In vitro preparation of radionuclides labeled blood cells: Status and requirements

    International Nuclear Information System (INIS)

    Couret, I.; Desruet, M.D.; Bolot, C.; Chassel, M.L.; Pellegrin, M.

    2010-01-01

    Labelled blood cells permit nuclear medicine imaging using their physiological behaviours. The radiolabeling must be performed in vitro because of the lack of specific markers and requires several highly technical stages of preparation. Labelled blood cells have not the medication drug status, so that the nuclear physician conducting the nuclear test is fully liable. In most cases, the physician delegates the technical responsibility to radio-pharmacists. Although the status of radiolabelled autologous cells is not legally defined and in the absence of a specific repository, it is essential that their preparation is subject to the requirements of the rules of French Good Manufacturing Practice published by Agence francaise de securite sanitaire des produits de sante (Afssaps). It would be desirable to harmonize the practices of radiolabeling cellular blood components by editing a repository. (authors)

  6. Requirement for Dlgh-1 in planar cell polarity and skeletogenesis during vertebrate development.

    Directory of Open Access Journals (Sweden)

    Charlene Rivera

    Full Text Available The development of specialized organs is tightly linked to the regulation of cell growth, orientation, migration and adhesion during embryogenesis. In addition, the directed movements of cells and their orientation within the plane of a tissue, termed planar cell polarity (PCP, appear to be crucial for the proper formation of the body plan. In Drosophila embryogenesis, Discs large (dlg plays a critical role in apical-basal cell polarity, cell adhesion and cell proliferation. Craniofacial defects in mice carrying an insertional mutation in Dlgh-1 suggest that Dlgh-1 is required for vertebrate development. To determine what roles Dlgh-1 plays in vertebrate development, we generated mice carrying a null mutation in Dlgh-1. We found that deletion of Dlgh-1 caused open eyelids, open neural tube, and misorientation of cochlear hair cell stereociliary bundles, indicative of defects in planar cell polarity (PCP. Deletion of Dlgh-1 also caused skeletal defects throughout the embryo. These findings identify novel roles for Dlgh-1 in vertebrates that differ from its well-characterized roles in invertebrates and suggest that the Dlgh-1 null mouse may be a useful animal model to study certain human congenital birth defects.

  7. c-Src activity is differentially required by cancer cell motility modes.

    Science.gov (United States)

    Logue, Jeremy S; Cartagena-Rivera, Alexander X; Chadwick, Richard S

    2018-04-01

    Cancer cell migration requires that cells respond and adapt to their surroundings. In the absence of extracellular matrix cues, cancer cells will undergo a mesenchymal to ameboid transition, whereas a highly confining space will trigger a switch to "leader bleb-based" migration. To identify oncogenic signaling pathways mediating these transitions, we undertook a targeted screen using clinically useful inhibitors. Elevated Src activity was found to change actin and focal adhesion dynamics, whereas inhibiting Src triggered focal adhesion disassembly and blebbing. On non-adherent substrates and in collagen matrices, amoeboid-like, blebbing cells having high Src activity formed protrusions of the plasma membrane. To evaluate the role of Src in confined cells, we use a novel approach that places cells under a slab of polydimethylsiloxane (PDMS), which is held at a defined height. Using this method, we find that leader bleb-based migration is resistant to Src inhibition. High Src activity was found to markedly change the architecture of cortical actomyosin, reduce cell mechanical properties, and the percentage of cells that undergo leader bleb-based migration. Thus, Src is a signal transducer that can potently influence transitions between migration modes with implications for the rational development of metastasis inhibitors.

  8. Glutathione requirement for the rejoining of radiation-induced DNA breaks in misonidazole-treated cells

    International Nuclear Information System (INIS)

    Edgren, M.; Revesz, L.

    1985-01-01

    The role of glutathione (GSH) in the rejoining of radiation-induced single-strand DNA breaks (ssb) was studied in human fibroblast cultures sensitized to radiation by a 30 min treatment with 1 mM misonidazole (MISO). Hypoxically irradiated cells, deficient in GSH, either inherently, or due to a 16 h incubation with 1 mM buthionine sulphoximine (BSO), rejoined the breaks after MISO treatment at a lower rate and to a lesser extent than did GSH-proficient cells. Without MISO treatment, the hypoxically induced ssb were rejoined in the GSH-deficient cells as effectively as in the proficient cells. It is concluded that a large proportion of the breaks which arise after hypoxic irradiation in the presence of MISO are of a different type to those which arise in the absence of the drug, and require a particular GSH-dependent, enzymatic repair system. This requirement for rejoining in hypoxically irradiated, MISO-treated cells is similar to that seen earlier in MISO-untreated, oxically irradiated cells, and suggests that the ssb induced by radiation in the presence of MISO or oxygen are of a similar nature. (author)

  9. A mex3 homolog is required for differentiation during planarian stem cell lineage development

    Science.gov (United States)

    Zhu, Shu Jun; Hallows, Stephanie E; Currie, Ko W; Xu, ChangJiang; Pearson, Bret J

    2015-01-01

    Neoblasts are adult stem cells (ASCs) in planarians that sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving postmitotic fates remain poorly defined. In this study, we used transcriptional profiling of irradiation-sensitive and irradiation-insensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers distinguishing two main epithelial progenitor populations and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3-1 was required for generating differentiated cells of multiple lineages, while restricting the size of the stem cell compartment. We also demonstrated the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results identified mex3-1 as a cell fate regulator, broadly required for differentiation, and suggest that mex3-1 helps to mediate the balance between ASC self-renewal and commitment. DOI: http://dx.doi.org/10.7554/eLife.07025.001 PMID:26114597

  10. Notch signal reception is required in vascular smooth muscle cells for ductus arteriosus closure

    Science.gov (United States)

    Krebs, Luke T.; Norton, Christine R.; Gridley, Thomas

    2017-01-01

    Summary The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus, and is one of the most common congenital heart defects. Our previous work demonstrated that vascular smooth muscle cell expression of the Jag1 gene, which encodes a ligand for Notch family receptors, is essential for postnatal closure of the ductus arteriosus in mice. However, it was not known what cell population was responsible for receiving the Jag1-mediated signal. Here we show, using smooth muscle cell-specific deletion of the Rbpj gene, which encodes a transcription factor that mediates all canonical Notch signaling, that Notch signal reception in the vascular smooth muscle cell compartment is required for ductus arteriosus closure. These data indicate that homotypic vascular smooth muscle cell interactions are required for proper contractile smooth muscle cell differentiation and postnatal closure of the ductus arteriosus in mice. PMID:26742650

  11. Growth in rice cells requires de novo purine biosynthesis by the blast fungus Magnaporthe oryzae

    Science.gov (United States)

    Fernandez, Jessie; Yang, Kuan Ting; Cornwell, Kathryn M.; Wright, Janet D.; Wilson, Richard A.

    2013-01-01

    Increasing incidences of human disease, crop destruction and ecosystem perturbations are attributable to fungi and threaten socioeconomic progress and food security on a global scale. The blast fungus Magnaporthe oryzae is the most devastating pathogen of cultivated rice, but its metabolic requirements in the host are unclear. Here we report that a purine-requiring mutant of M. oryzae could develop functional appressoria, penetrate host cells and undergo the morphogenetic transition to elaborate bulbous invasive hyphae from primary hyphae, but further in planta growth was aborted. Invasive hyphal growth following rice cell ingress is thus dependent on de novo purine biosynthesis by the pathogen and, moreover, plant sources of purines are neither available to the mutant nor required by the wild type during the early biotrophic phase of infection. This work provides new knowledge about the metabolic interface between fungus and host that might be applicable to other important intracellular fungal pathogens. PMID:23928947

  12. Autonomic headache with autonomic seizures: a case report.

    Science.gov (United States)

    Ozge, Aynur; Kaleagasi, Hakan; Yalçin Tasmertek, Fazilet

    2006-10-01

    The aim of the report is to present a case of an autonomic headache associated with autonomic seizures. A 19-year-old male who had had complex partial seizures for 15 years was admitted with autonomic complaints and left hemicranial headache, independent from seizures, that he had had for 2 years and were provoked by watching television. Brain magnetic resonance imaging showed right hippocampal sclerosis and electroencephalography revealed epileptic activity in right hemispheric areas. Treatment with valproic acid decreased the complaints. The headache did not fulfil the criteria for the diagnosis of trigeminal autonomic cephalalgias, and was different from epileptic headache, which was defined as a pressing type pain felt over the forehead for several minutes to a few hours. Although epileptic headache responds to anti-epileptics and the complaints of the present case decreased with antiepileptics, it has been suggested that the headache could be a non-trigeminal autonomic headache instead of an epileptic headache.

  13. Learning for Autonomous Navigation

    Science.gov (United States)

    Angelova, Anelia; Howard, Andrew; Matthies, Larry; Tang, Benyang; Turmon, Michael; Mjolsness, Eric

    2005-01-01

    Robotic ground vehicles for outdoor applications have achieved some remarkable successes, notably in autonomous highway following (Dickmanns, 1987), planetary exploration (1), and off-road navigation on Earth (1). Nevertheless, major challenges remain to enable reliable, high-speed, autonomous navigation in a wide variety of complex, off-road terrain. 3-D perception of terrain geometry with imaging range sensors is the mainstay of off-road driving systems. However, the stopping distance at high speed exceeds the effective lookahead distance of existing range sensors. Prospects for extending the range of 3-D sensors is strongly limited by sensor physics, eye safety of lasers, and related issues. Range sensor limitations also allow vehicles to enter large cul-de-sacs even at low speed, leading to long detours. Moreover, sensing only terrain geometry fails to reveal mechanical properties of terrain that are critical to assessing its traversability, such as potential for slippage, sinkage, and the degree of compliance of potential obstacles. Rovers in the Mars Exploration Rover (MER) mission have got stuck in sand dunes and experienced significant downhill slippage in the vicinity of large rock hazards. Earth-based off-road robots today have very limited ability to discriminate traversable vegetation from non-traversable vegetation or rough ground. It is impossible today to preprogram a system with knowledge of these properties for all types of terrain and weather conditions that might be encountered.

  14. Towards autonomous vehicular clouds

    Directory of Open Access Journals (Sweden)

    Stephan Olariu

    2011-09-01

    Full Text Available The dawn of the 21st century has seen a growing interest in vehicular networking and its myriad potential applications. The initial view of practitioners and researchers was that radio-equipped vehicles could keep the drivers informed about potential safety risks and increase their awareness of road conditions. The view then expanded to include access to the Internet and associated services. This position paper proposes and promotes a novel and more comprehensive vision namely, that advances in vehicular networks, embedded devices and cloud computing will enable the formation of autonomous clouds of vehicular computing, communication, sensing, power and physical resources. Hence, we coin the term, autonomous vehicular clouds (AVCs. A key feature distinguishing AVCs from conventional cloud computing is that mobile AVC resources can be pooled dynamically to serve authorized users and to enable autonomy in real-time service sharing and management on terrestrial, aerial, or aquatic pathways or theaters of operations. In addition to general-purpose AVCs, we also envision the emergence of specialized AVCs such as mobile analytics laboratories. Furthermore, we envision that the integration of AVCs with ubiquitous smart infrastructures including intelligent transportation systems, smart cities and smart electric power grids will have an enormous societal impact enabling ubiquitous utility cyber-physical services at the right place, right time and with right-sized resources.

  15. Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells

    Science.gov (United States)

    Wang, Jennifer T; Kong, Dong; Hoerner, Christian R; Loncarek, Jadranka

    2017-01-01

    Centrioles are composed of long-lived microtubules arranged in nine triplets. However, the contribution of triplet microtubules to mammalian centriole formation and stability is unknown. Little is known of the mechanism of triplet microtubule formation, but experiments in unicellular eukaryotes indicate that delta-tubulin and epsilon-tubulin, two less-studied tubulin family members, are required. Here, we report that centrioles in delta-tubulin and epsilon-tubulin null mutant human cells lack triplet microtubules and fail to undergo centriole maturation. These aberrant centrioles are formed de novo each cell cycle, but are unstable and do not persist to the next cell cycle, leading to a futile cycle of centriole formation and disintegration. Disintegration can be suppressed by paclitaxel treatment. Delta-tubulin and epsilon-tubulin physically interact, indicating that these tubulins act together to maintain triplet microtubules and that these are necessary for inheritance of centrioles from one cell cycle to the next. PMID:28906251

  16. Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells.

    Science.gov (United States)

    Wang, Jennifer T; Kong, Dong; Hoerner, Christian R; Loncarek, Jadranka; Stearns, Tim

    2017-09-14

    Centrioles are composed of long-lived microtubules arranged in nine triplets. However, the contribution of triplet microtubules to mammalian centriole formation and stability is unknown. Little is known of the mechanism of triplet microtubule formation, but experiments in unicellular eukaryotes indicate that delta-tubulin and epsilon-tubulin, two less-studied tubulin family members, are required. Here, we report that centrioles in delta-tubulin and epsilon-tubulin null mutant human cells lack triplet microtubules and fail to undergo centriole maturation. These aberrant centrioles are formed de novo each cell cycle, but are unstable and do not persist to the next cell cycle, leading to a futile cycle of centriole formation and disintegration. Disintegration can be suppressed by paclitaxel treatment. Delta-tubulin and epsilon-tubulin physically interact, indicating that these tubulins act together to maintain triplet microtubules and that these are necessary for inheritance of centrioles from one cell cycle to the next.

  17. Behavioural domain knowledge transfer for autonomous agents

    CSIR Research Space (South Africa)

    Rosman, Benjamin S

    2014-11-01

    Full Text Available , and Behavior Transfer in Autonomous Robots, AAAI 2014 Fall Symposium Series, 13-15 November 2014 Behavioural Domain Knowledge Transfer for Autonomous Agents Benjamin Rosman Mobile Intelligent Autonomous Systems Modelling and Digital Science Council...

  18. Induction of functional Fc receptors in P388 leukemia cells. Requirement for multiple differentiation signals.

    Science.gov (United States)

    Cohen, D A; Stotelmyer, N L; Kaplan, A M

    1985-04-01

    The development of functional Fc receptors (FcR) during induced differentiation with the tumor promoter, phorbol myristate acetate (PMA), was studied in the murine tumor cell line, P388. PMA induced the appearance of FcR on the membranes of P388 cells as indicated by the binding of IgG-coated sheep red blood cells (IgG-SRBC). Concentrations of PMA as low as 1 ng/ml were sufficient to induce the expression of FcR as well as to inhibit cellular division and to induce adherence in the P388 tumor cell line; however, optimal FcR induction occurred at PMA concentrations of 10-100 ng/ml. Immunofluorescent analysis with heat-aggregated myeloma proteins indicated that PMA induced FcR which were capable of binding IgG2a and IgG2b immunoglobulins, but not IgG1. Adherence to a substratum was determined to be a second required signal for expression of FcR, since PMA induction of P388 tumor cells in teflon dishes failed to fully develop FcR and adherence of P388 cells to poly-L-lysine-coated culture dishes in the absence of PMA was insufficient for FcR expression. FcR which appeared after PMA induction were non-functional in the sense that membrane-bound IgG-SRBC were not ingested to any significant extent by the tumor cells. However, if FcR induction occurred in the presence conA-induced rat spleen cell culture supernatants, phagocytosis of membrane-bound erythrocytes occurred. These findings suggest that for the expression of FcR which are capable of particle internalization, at least three identifiable membrane-transmitted signals are required during differentiation.

  19. Autonomous Spacecraft Communication Interface for Load Planning

    Science.gov (United States)

    Dever, Timothy P.; May, Ryan D.; Morris, Paul H.

    2014-01-01

    Ground-based controllers can remain in continuous communication with spacecraft in low Earth orbit (LEO) with near-instantaneous communication speeds. This permits near real-time control of all of the core spacecraft systems by ground personnel. However, as NASA missions move beyond LEO, light-time communication delay issues, such as time lag and low bandwidth, will prohibit this type of operation. As missions become more distant, autonomous control of manned spacecraft will be required. The focus of this paper is the power subsystem. For present missions, controllers on the ground develop a complete schedule of power usage for all spacecraft components. This paper presents work currently underway at NASA to develop an architecture for an autonomous spacecraft, and focuses on the development of communication between the Mission Manager and the Autonomous Power Controller. These two systems must work together in order to plan future load use and respond to unanticipated plan deviations. Using a nominal spacecraft architecture and prototype versions of these two key components, a number of simulations are run under a variety of operational conditions, enabling development of content and format of the messages necessary to achieve the desired goals. The goals include negotiation of a load schedule that meets the global requirements (contained in the Mission Manager) and local power system requirements (contained in the Autonomous Power Controller), and communication of off-plan disturbances that arise while executing a negotiated plan. The message content is developed in two steps: first, a set of rapid-prototyping "paper" simulations are preformed; then the resultant optimized messages are codified for computer communication for use in automated testing.

  20. Autonomous Optofluidic Chemical Analyzers for Marine Applications: Insights from the Submersible Autonomous Moored Instruments (SAMI for pH and pCO2

    Directory of Open Access Journals (Sweden)

    Chun-Ze Lai

    2018-01-01

    Full Text Available The commercial availability of inexpensive fiber optics and small volume pumps in the early 1990's provided the components necessary for the successful development of low power, low reagent consumption, autonomous optofluidic analyzers for marine applications. It was evident that to achieve calibration-free performance, reagent-based sensors would require frequent renewal of the reagent by pumping the reagent from an impermeable, inert reservoir to the sensing interface. Pumping also enabled measurement of a spectral blank further enhancing accuracy and stability. The first instrument that was developed based on this strategy, the Submersible Autonomous Moored Instrument for CO2 (SAMI-CO2, uses a pH indicator for measurement of the partial pressure of CO2 (pCO2. Because the pH indicator gives an optical response, the instrument requires an optofluidic design where the indicator is pumped into a gas permeable membrane and then to an optical cell for analysis. The pH indicator is periodically flushed from the optical cell by using a valve to switch from the pH indicator to a blank solution. Because of the small volume and low power light source, over 8,500 measurements can be obtained with a ~500 mL reagent bag and 8 alkaline D-cell battery pack. The primary drawback is that the design is more complex compared to the single-ended electrode or optode that is envisioned as the ideal sensor. The SAMI technology has subsequently been used for the successful development of autonomous pH and total alkalinity analyzers. In this manuscript, we will discuss the pros and cons of the SAMI pCO2 and pH optofluidic technology and highlight some past data sets and applications for studying the carbon cycle in aquatic ecosystems.

  1. QFD-based conceptual design of an autonomous underwater robot

    Directory of Open Access Journals (Sweden)

    Thip Pasawang

    2015-12-01

    Full Text Available Autonomous underwater robots in the past few years have been designed according to the individual concepts and experiences of the researchers. To design a robot, which meets all the requirements of potential users, is an advanced work. Hence, a systematic design method that could include users’ preferences and requirements is needed. This paper presents the quality function deployment (QFD technique to design an autonomous underwater robot focusing on the Thai Navy military mission. Important user requirements extracted from the QFD method are the ability to record videos, operating at depth up to 10 meters, the ability to operate remotely with cable and safety concerns related to water leakages. Less important user requirements include beauty, using renewable energy, operating remotely with radio and ability to work during night time. The important design parameters derived from the user requirements are a low cost-controller, an autonomous control algorithm, a compass sensor and vertical gyroscope, and a depth sensor. Of low-importance ranked design parameters include the module design, use clean energy, a low noise electric motor, remote surveillance design, a pressure hull, and a beautiful hull form design. The study results show the feasibility of using QFD techniques to systematically design the autonomous underwater robot to meet user requirements. Mapping between the design and expected parameters and a conceptual drafting design of an autonomous underwater robot are also presented.

  2. From cooperative to autonomous vehicles

    NARCIS (Netherlands)

    van der Sande, T.P.J.; Nijmeijer, H.; Fossen, T.I.; Pettersen, K.Y.; Nijmeijer, H.

    2017-01-01

    What defines an autonomous vehicle? In this chapter the authors will try to answer this question and formulate the limitations of driver assistance systems as well as for—conditionally—autonomous vehicles . First a short summary of the levels of automation as provided by the society of automotive

  3. Autonomous Learner Model Resource Book

    Science.gov (United States)

    Betts, George T.; Carey, Robin J.; Kapushion, Blanche M.

    2016-01-01

    "Autonomous Learner Model Resource Book" includes activities and strategies to support the development of autonomous learners. More than 40 activities are included, all geared to the emotional, social, cognitive, and physical development of students. Teachers may use these activities and strategies with the entire class, small groups, or…

  4. Oct1 and OCA-B are selectively required for CD4 memory T cell function.

    Science.gov (United States)

    Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean

    2015-11-16

    Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. © 2015 Shakya et al.

  5. Cell mediated lympholysis: CML. A microplate technique requiring few target cells and employing a new method of supernatant collection

    International Nuclear Information System (INIS)

    Hirschberg, A.; Thorsby, E.

    1977-01-01

    A micromethod for the 51 Cr release assay is described. Allogeneically induced cytotoxic lymphocytes are generated in mixed lymphocyte microcultures in the wells of microplates. Their cytotoxic capacity is assayed by adding 51 Cr-labelled PHA derived lymphoblasts directly into the microcultures with no pooling or transfer of the cytotoxic effector cells being required. The 51 Cr isotope released into the cell supernatants is collected by inserting a cellulose acetate absorption cartridge into each well. A glass fiber filter attached to the cartridge effectively separates the supernatant from the cellular elemets. This system allows the simultaneous collection of the supernatant from 96 wells, and can be used with either adherent or non-adherent target cells

  6. Localized cyclic AMP-dependent protein kinase activity is required for myogenic cell fusion

    International Nuclear Information System (INIS)

    Mukai, Atsushi; Hashimoto, Naohiro

    2008-01-01

    Multinucleated myotubes are formed by fusion of mononucleated myogenic progenitor cells (myoblasts) during terminal skeletal muscle differentiation. In addition, myoblasts fuse with myotubes, but terminally differentiated myotubes have not been shown to fuse with each other. We show here that an adenylate cyclase activator, forskolin, and other reagents that elevate intracellular cyclic AMP (cAMP) levels induced cell fusion between small bipolar myotubes in vitro. Then an extra-large myotube, designated a 'myosheet,' was produced by both primary and established mouse myogenic cells. Myotube-to-myotube fusion always occurred between the leading edge of lamellipodia at the polar end of one myotube and the lateral plasma membrane of the other. Forskolin enhanced the formation of lamellipodia where cAMP-dependent protein kinase (PKA) was accumulated. Blocking enzymatic activity or anchoring of PKA suppressed forskolin-enhanced lamellipodium formation and prevented fusion of multinucleated myotubes. Localized PKA activity was also required for fusion of mononucleated myoblasts. The present results suggest that localized PKA plays a pivotal role in the early steps of myogenic cell fusion, such as cell-to-cell contact/recognition through lamellipodium formation. Furthermore, the localized cAMP-PKA pathway might be involved in the specification of the fusion-competent areas of the plasma membrane in lamellipodia of myogenic cells

  7. Fuel cells for transport: can the promise be fulfilled? Technical requirements and demands from customers

    Science.gov (United States)

    Klaiber, Thomas

    The paper discusses the technical requirements and the customer demands for vehicles that have an on-board methanol reformer and fuel cells. The research concentrates on the technical developmental risks which include minimizing volume, reducing weight and, at the same time, improving efficiency and system dynamics. Fuel cell powered vehicles with methanol reformers are not only suitable for a niche market but also these vehicles will compete with conventional vehicles. The greatest hindrance will be the price of the fuel cell. A possible progressive development of the number of fuel cell powered vehicles in conjunction with a reduction in costs will be discussed in the paper. When fuel cell vehicles come to the market it is necessary that an infrastructure for the fuel methanol or hydrogen is installed. Therefore, it will only be possible to introduce fuel cell vehicles into special markets, e.g. California. Such a process will need to be subsidized by additional incentives like tax concessions. Today there are many technical risks and unsolved problems relating to production technologies, infrastructure, and costs. Nevertheless, among the alternative power units, the fuel cell seems to be the only one that might be competitive to the conventional power unit, especially relating to emissions.

  8. Nuclear thioredoxin-1 is required to suppress cisplatin-mediated apoptosis of MCF-7 cells

    International Nuclear Information System (INIS)

    Chen, Xiao-Ping; Liu, Shou; Tang, Wen-Xin; Chen, Zheng-Wang

    2007-01-01

    Different cell line with increased thioredoxin-1 (Trx-1) showed a decreased or increased sensitivity to cell killing by cisplatin. Recently, several studies found that the subcellular localization of Trx-1 is closely associated with its functions. In this study, we explored the association of the nuclear Trx-1 with the cisplatin-mediated apoptosis of breast cancer cells MCF-7. Firstly, we found that higher total Trx-1 accompanied by no change of nuclear Trx-1 can not influence apoptosis induced by cisplatin in MCF-7 cells transferred with Trx-1 cDNA. Secondly, higher nuclear Trx-1 accompanied by no change of total Trx-1 can protect cells from apoptosis induced by cisplatin. Thirdly, high nuclear Trx-1 involves in the cisplatin-resistance in cisplatin-resistive cells. Meanwhile, we found that the mRNA level of p53 is closely correlated with the level of nuclear Trx-1. In summary, we concluded that the nuclear Trx-1 is required to resist apoptosis of MCF-7 cells induced by cisplatin, probably through up-regulating the anti-apoptotic gene, p53

  9. Serum-free media formulations are cell line-specific and require optimization for microcarrier culture.

    Science.gov (United States)

    Tan, Kah Yong; Teo, Kim Leng; Lim, Jessica F Y; Chen, Allen K L; Choolani, Mahesh; Reuveny, Shaul; Chan, Jerry; Oh, Steve Kw

    2015-08-01

    Mesenchymal stromal cells (MSCs) are being investigated as potential cell therapies for many different indications. Current methods of production rely on traditional monolayer culture on tissue-culture plastic, usually with the use of serum-supplemented growth media. However, the monolayer culturing system has scale-up limitations and may not meet the projected hundreds of billions to trillions batches of cells needed for therapy. Furthermore, serum-free medium offers several advantages over serum-supplemented medium, which may have supply and contaminant issues, leading to many serum-free medium formulations being developed. We cultured seven MSC lines in six different serum-free media and compared their growth between monolayer and microcarrier culture. We show that (i) expansion levels of MSCs in serum-free monolayer cultures may not correlate with expansion in serum-containing media; (ii) optimal culture conditions (serum-free media for monolayer or microcarrier culture) differ for each cell line; (iii) growth in static microcarrier culture does not correlate with growth in stirred spinner culture; (iv) and that early cell attachment and spreading onto microcarriers does not necessarily predict efficiency of cell expansion in agitated microcarrier culture. Current serum-free media developed for monolayer cultures of MSCs may not support MSC proliferation in microcarrier cultures. Further optimization in medium composition will be required for microcarrier suspension culture for each cell line. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  10. Use of fuel cells to meet military requirements for mobile power

    International Nuclear Information System (INIS)

    Andrukaitis, E.

    2004-01-01

    'Full text:' The use of fuel cell technology in military applications will depend on safe, high energy density systems being developed. An important part of using this technology is also the development of alternative hydrogen producing fuels with high energy densities and are easy to transport. Fuel cells are now a very large R and D effort for several military applications around the world. The major reason is because of the high power demands needed requires electrical energy sources that far exceed the capabilities of batteries currently being fielded for portable applications. Fuel cells are regarded as highly efficient, tactical energy converters that can be adapted for wide range of power requirements. They are potentially the lowest weight power source when coupled with batteries or capacitors to form hybrid systems. Generally electrical power is needed to support a number of applications from ultra-high power for electrical pulses (radios, sensors) to reliable, conditioned power for command and control systems. In the future, sustained power for electric drive systems, will also be required. Some of the promising applications in the military and the R and D challenges that remain to reach performance and reliability targets suitable for military requirements will be discussed. (author)

  11. Glycosylphosphatidylinositol-anchored proteins are required for cell wall synthesis and morphogenesis in Arabidopsis.

    Science.gov (United States)

    Gillmor, C Stewart; Lukowitz, Wolfgang; Brininstool, Ginger; Sedbrook, John C; Hamann, Thorsten; Poindexter, Patricia; Somerville, Chris

    2005-04-01

    Mutations at five loci named PEANUT1-5 (PNT) were identified in a genetic screen for radially swollen embryo mutants. pnt1 cell walls showed decreased crystalline cellulose, increased pectins, and irregular and ectopic deposition of pectins, xyloglucans, and callose. Furthermore, pnt1 pollen is less viable than the wild type, and pnt1 embryos were delayed in morphogenesis and showed defects in shoot and root meristems. The PNT1 gene encodes the Arabidopsis thaliana homolog of mammalian PIG-M, an endoplasmic reticulum-localized mannosyltransferase that is required for synthesis of the glycosylphosphatidylinositol (GPI) anchor. All five pnt mutants showed strongly reduced accumulation of GPI-anchored proteins, suggesting that they all have defects in GPI anchor synthesis. Although the mutants are seedling lethal, pnt1 cells are able to proliferate for a limited time as undifferentiated callus and do not show the massive deposition of ectopic cell wall material seen in pnt1 embryos. The different phenotype of pnt1 cells in embryos and callus suggest a differential requirement for GPI-anchored proteins in cell wall synthesis in these two tissues and points to the importance of GPI anchoring in coordinated multicellular growth.

  12. Defective quorum sensing of acute lymphoblastic leukemic cells: evidence of collective behavior of leukemic populations as semi-autonomous aberrant ecosystems

    Science.gov (United States)

    Patel, Sapan J; Dao, Su; Darie, Costel C; Clarkson, Bayard D

    2016-01-01

    Quorum sensing (QS) is a generic term used to describe cell-cell communication and collective decision making by bacterial and social insects to regulate the expression of specific genes in controlling cell density and other properties of the populations in response to nutrient supply or changes in the environment. QS mechanisms also have a role in higher organisms in maintaining homeostasis, regulation of the immune system and collective behavior of cancer cell populations. In the present study, we used a p190BCR-ABL driven pre-B acute lymphoblastic leukemia (ALL3) cell line derived from the pleural fluid of a terminally ill patient with ALL to test the QS hypothesis in leukemia. ALL3 cells don’t grow at low density (LD) in liquid media but grow progressively faster at increasingly high cell densities (HD) in contrast to other established leukemic cell lines that grow well at very low starting cell densities. The ALL3 cells at LD are poised to grow but shortly die without additional stimulation. Supernates of ALL3 cells (HDSN) and some other primary cells grown at HD stimulate the growth of the LD ALL3 cells without which they won’t survive. To get further insight into the activation processes we performed microarray analysis of the LD ALL3 cells after stimulation with ALL3 HDSN at days 1, 3, and 6. This screen identified several candidate genes, and we linked them to signaling networks and their functions. We observed that genes involved in lipid, cholesterol, fatty acid metabolism, and B cell activation are most up- or down-regulated upon stimulation of the LD ALL3 cells using HDSN. We also discuss other pathways that are differentially expressed upon stimulation of the LD ALL3 cells. Our findings suggest that the Ph+ ALL population achieves dominance by functioning as a collective aberrant ecosystem subject to defective quorum-sensing regulatory mechanisms. PMID:27429840

  13. Evolution of New cis-Regulatory Motifs Required for Cell-Specific Gene Expression in Caenorhabditis.

    Directory of Open Access Journals (Sweden)

    Michalis Barkoulas

    2016-09-01

    Full Text Available Patterning of C. elegans vulval cell fates relies on inductive signaling. In this induction event, a single cell, the gonadal anchor cell, secretes LIN-3/EGF and induces three out of six competent precursor cells to acquire a vulval fate. We previously showed that this developmental system is robust to a four-fold variation in lin-3/EGF genetic dose. Here using single-molecule FISH, we find that the mean level of expression of lin-3 in the anchor cell is remarkably conserved. No change in lin-3 expression level could be detected among C. elegans wild isolates and only a low level of change-less than 30%-in the Caenorhabditis genus and in Oscheius tipulae. In C. elegans, lin-3 expression in the anchor cell is known to require three transcription factor binding sites, specifically two E-boxes and a nuclear-hormone-receptor (NHR binding site. Mutation of any of these three elements in C. elegans results in a dramatic decrease in lin-3 expression. Yet only a single E-box is found in the Drosophilae supergroup of Caenorhabditis species, including C. angaria, while the NHR-binding site likely only evolved at the base of the Elegans group. We find that a transgene from C. angaria bearing a single E-box is sufficient for normal expression in C. elegans. Even a short 58 bp cis-regulatory fragment from C. angaria with this single E-box is able to replace the three transcription factor binding sites at the endogenous C. elegans lin-3 locus, resulting in the wild-type expression level. Thus, regulatory evolution occurring in cis within a 58 bp lin-3 fragment, results in a strict requirement for the NHR binding site and a second E-box in C. elegans. This single-cell, single-molecule, quantitative and functional evo-devo study demonstrates that conserved expression levels can hide extensive change in cis-regulatory site requirements and highlights the evolution of new cis-regulatory elements required for cell-specific gene expression.

  14. Research Institute for Autonomous Precision Guided Systems

    National Research Council Canada - National Science Library

    Rogacki, John R

    2007-01-01

    ... vehicles, cooperative flight of autonomous aerial vehicles using GPS and vision information, cooperative and sharing of information in search missions involving multiple autonomous agents, multi-scale...

  15. Dll1- and Dll4-mediated Notch signaling is required for homeostasis of intestinal stem cells

    Science.gov (United States)

    Pellegrinet, Luca; Rodilla, Veronica; Liu, Zhenyi; Chen, Shuang; Koch, Ute; Espinosa, Lluis; Kaestner, Klaus H.; Kopan, Raphael; Lewis, Julian; Radtke, Freddy

    2011-01-01

    Background & Aims Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors, due to their conversion into post-mitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SC), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiological ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Methods Trasgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ERT2). Results Notch1 signaling was found to be activated in intestinal SC. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into post-mitotic goblet cells, concomitant with loss of SC (Olfm4+, Lgr5+ and Ascl2+). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Conclusions Notch signaling in SC and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SC. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. PMID:21238454

  16. Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.

    Science.gov (United States)

    Pellegrinet, Luca; Rodilla, Veronica; Liu, Zhenyi; Chen, Shuang; Koch, Ute; Espinosa, Lluis; Kaestner, Klaus H; Kopan, Raphael; Lewis, Julian; Radtke, Freddy

    2011-04-01

    Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SCs), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiologic ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Transgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ER(T2)). Notch1 signaling was found to be activated in intestinal SCs. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of SCs (Olfm4(+), Lgr5(+), and Ascl2(+)). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Notch signaling in SCs and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SCs. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. IFMIF - Layout and arrangement of cells according to requirements of technical logistics, reliability and remote handling

    Energy Technology Data Exchange (ETDEWEB)

    Mittwollen, Martin, E-mail: martin.mittwollen@kit.edu [Karlsruhe Institute of Technology, Institute for Conveying Technology and Logistics, Karlsruhe (Germany); Eilert, Dirk; Kubaschewski, Martin; Madzharov, Vladimir [Karlsruhe Institute of Technology, Institute for Conveying Technology and Logistics, Karlsruhe (Germany); Tian Kuo [Karlsruhe Institute of Technology, Institute for Neutron Physics and Reactor Technology, Karlsruhe (Germany)

    2012-08-15

    Highlights: Black-Right-Pointing-Pointer In a first approach, layout and arrangement of the cells followed a predetermined plant layout. Black-Right-Pointing-Pointer Disadvantages in technical logistics, reliability and remote handling have been detected. Black-Right-Pointing-Pointer Deliberation with project teams opened space for improvements. Black-Right-Pointing-Pointer Layout and arrangement of cells have been improved by simplification of design. Black-Right-Pointing-Pointer Speed and reliability have been increased significantly. - Abstract: The International Fusion Material Irradiation Facility (IFMIF) is designed to study and qualify structural and functional materials which shall be used in future fusion nuclear power plants. During the current engineering validation and engineering design activities (EVEDA) phase the development of e.g. an optimized layout and arrangement of the cells (Access Cell, Test Cell, and Test Module Handling Cells) is of major interest. After defining different functions for the individual cells like e.g. large scale/fine scale disassembling of test modules a first layout has been developed. This design followed requirements like having a minimum of carrier changes to avoid sources of failures. On the other hand it has had to be a compact arrangement of cells due to restrictions from plant layout. A row of changes of transfer direction, and different crane systems were the consequence. Constructive discussion with project team results in the statement, that for reasons of being reliable and fast, layout and arrangement of cells goes first, plant layout then will follow. The chance for big improvements was taken and the result was a simplified design with strong reduced number of functional elements, and increased reliability and speed.

  18. Inflammasome-independent NLRP3 is required for epithelial-mesenchymal transition in colon cancer cells.

    Science.gov (United States)

    Wang, Hong; Wang, Yajing; Du, Qianming; Lu, Ping; Fan, Huimin; Lu, Jinrong; Hu, Rong

    2016-03-15

    Inflammasome NLRP3 plays a crucial role in the process of colitis and colitis--associated colon cancer. Even though much is known regarding the NLRP3 inflammasome that regulates pro-inflammatory cytokine release in innate immune cells, the role of NLRP3 in non-immune cells is still unclear. In this study, we showed that NLRP3 was highly expressed in mesenchymal-like colon cancer cells (SW620), and was upregulated by tumor necrosis factors-α (TNF-α) and transforming growth factor-β1 (TGF-β1) respectively, during EMT in colon cancer epithelial cells HCT116 and HT29. Knockdown of NLRP3 retained epithelial spindle-like morphology of HCT116 and HT29 cells and reversed the mesenchymal characteristic of SW620 cells, indicated by the decreased expression of vimentin and MMP9 and increased expression of E-cadherin. In addition, knockdown of NLRP3 in colorectal carcinoma cells displayed diminished cell migration and invasion. Interestingly, during the EMT process induced by TNF-α or TGF-β1, the cleaved caspase-1 and ASC speck were not detected, indicating that NLRP3 functions in an inflammasome-independent way. Further studies demonstrated that NLRP3 protein expression was regulated by NF-κB signaling in TNF-α or TGF-β1-induced EMT, as verified by the NF-κB inhibitor Bay 11-7082. Moreover, NLRP3 knockdown reduced the expression of Snail1, indicating that NLRP3 may promote EMT through regulating Snail1. In summary, our results showed that the NLRP3 expression, not the inflammasome activation, was required for EMT in colorectal cancer cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. C. elegans nucleostemin is required for larval growth and germline stem cell division.

    Directory of Open Access Journals (Sweden)

    Michelle M Kudron

    2008-08-01

    Full Text Available The nucleolus has shown to be integral for many processes related to cell growth and proliferation. Stem cells in particular are likely to depend upon nucleolus-based processes to remain in a proliferative state. A highly conserved nucleolar factor named nucleostemin is proposed to be a critical link between nucleolar function and stem-cell-specific processes. Currently, it is unclear whether nucleostemin modulates proliferation by affecting ribosome biogenesis or by another nucleolus-based activity that is specific to stem cells and/or highly proliferating cells. Here, we investigate nucleostemin (nst-1 in the nematode C. elegans, which enables us to examine nst-1 function during both proliferation and differentiation in vivo. Like mammalian nucleostemin, the NST-1 protein is localized to the nucleolus and the nucleoplasm; however, its expression is found in both differentiated and proliferating cells. Global loss of C. elegans nucleostemin (nst-1 leads to a larval arrest phenotype due to a growth defect in the soma, while loss of nst-1 specifically in the germ line causes germline stem cells to undergo a cell cycle arrest. nst-1 mutants exhibit reduced levels of rRNAs, suggesting defects in ribosome biogenesis. However, NST-1 is generally not present in regions of the nucleolus where rRNA transcription and processing occurs, so this reduction is likely secondary to a different defect in ribosome biogenesis. Transgenic studies indicate that NST-1 requires its N-terminal domain for stable expression and both its G1 GTPase and intermediate domains for proper germ line function. Our data support a role for C. elegans nucleostemin in cell growth and proliferation by promoting ribosome biogenesis.

  20. GIMAP6 is required for T cell maintenance and efficient autophagy in mice.

    Science.gov (United States)

    Pascall, John C; Webb, Louise M C; Eskelinen, Eeva-Liisa; Innocentin, Silvia; Attaf-Bouabdallah, Noudjoud; Butcher, Geoffrey W

    2018-01-01

    The GTPases of the immunity-associated proteins (GIMAP) GTPases are a family of proteins expressed strongly in the adaptive immune system. We have previously reported that in human cells one member of this family, GIMAP6, interacts with the ATG8 family member GABARAPL2, and is recruited to autophagosomes upon starvation, suggesting a role for GIMAP6 in the autophagic process. To study this possibility and the function of GIMAP6 in the immune system, we have established a mouse line in which the Gimap6 gene can be inactivated by Cre-mediated recombination. In mice bred to carry the CD2Cre transgene such that the Gimap6 gene was deleted within the T and B cell lineages there was a 50-70% reduction in peripheral CD4+ and CD8+ T cells. Analysis of splenocyte-derived proteins from these mice indicated increased levels of MAP1LC3B, particularly the lipidated LC3-II form, and S405-phosphorylation of SQSTM1. Electron microscopic measurements of Gimap6-/- CD4+ T cells indicated an increased mitochondrial/cytoplasmic volume ratio and increased numbers of autophagosomes. These results are consistent with autophagic disruption in the cells. However, Gimap6-/- T cells were largely normal in character, could be effectively activated in vitro and supported T cell-dependent antibody production. Treatment in vitro of CD4+ splenocytes from GIMAP6fl/flERT2Cre mice with 4-hydroxytamoxifen resulted in the disappearance of GIMAP6 within five days. In parallel, increased phosphorylation of SQSTM1 and TBK1 was observed. These results indicate a requirement for GIMAP6 in the maintenance of a normal peripheral adaptive immune system and a significant role for the protein in normal autophagic processes. Moreover, as GIMAP6 is expressed in a cell-selective manner, this indicates the potential existence of a cell-restricted mode of autophagic regulation.

  1. Merkel cell tumor of the skin treated with localized radiotherapy: are widely negative margins required?

    Directory of Open Access Journals (Sweden)

    David Parda

    2011-03-01

    Full Text Available Merkel’s cell carcinoma is a rare cutaneous tumor that can affect a wide variety of sites throughout the body. Commonly, it affects the skin alone and the management of limited disease can be confusing since the natural history of the disease involves distant metastasis. Traditional management has required wide local excision with negative margins of resection. We describe a case treated with local therapy alone and review the literature to suggest that complete microscopic excision may not be required if adjuvant radiotherapy is used.

  2. Mobile Robot Designed with Autonomous Navigation System

    Science.gov (United States)

    An, Feng; Chen, Qiang; Zha, Yanfang; Tao, Wenyin

    2017-10-01

    With the rapid development of robot technology, robots appear more and more in all aspects of life and social production, people also ask more requirements for the robot, one is that robot capable of autonomous navigation, can recognize the road. Take the common household sweeping robot as an example, which could avoid obstacles, clean the ground and automatically find the charging place; Another example is AGV tracking car, which can following the route and reach the destination successfully. This paper introduces a new type of robot navigation scheme: SLAM, which can build the environment map in a totally strange environment, and at the same time, locate its own position, so as to achieve autonomous navigation function.

  3. Autonomous reinforcement learning with experience replay.

    Science.gov (United States)

    Wawrzyński, Paweł; Tanwani, Ajay Kumar

    2013-05-01

    This paper considers the issues of efficiency and autonomy that are required to make reinforcement learning suitable for real-life control tasks. A real-time reinforcement learning algorithm is presented that repeatedly adjusts the control policy with the use of previously collected samples, and autonomously estimates the appropriate step-sizes for the learning updates. The algorithm is based on the actor-critic with experience replay whose step-sizes are determined on-line by an enhanced fixed point algorithm for on-line neural network training. An experimental study with simulated octopus arm and half-cheetah demonstrates the feasibility of the proposed algorithm to solve difficult learning control problems in an autonomous way within reasonably short time. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Novel functions of plant cyclin-dependent kinase inhibitors, ICK1/KRP1, can act non-cell-autonomously and inhibit entry into mitosis

    DEFF Research Database (Denmark)

    Weinl, Christina; Marquardt, Sebastian; Kuijt, Suzanne J H

    2005-01-01

    numbers of cells consistent with a function of CKIs in blocking the G1-S cell cycle transition. Here, we demonstrate that at least one inhibitor from Arabidopsis, ICK1/KRP1, can also block entry into mitosis but allows S-phase progression causing endoreplication. Our data suggest that plant CKIs act...... independently from ICK1/KRP1-induced endoreplication. Strikingly, we found that endoreplicated cells were able to reenter mitosis, emphasizing the high degree of flexibility of plant cells during development. Moreover, we show that in contrast with animal CDK inhibitors, ICK1/KRP1 can move between cells...

  5. Radioiodine therapy of functional autonomy using the functional autonomous volume

    International Nuclear Information System (INIS)

    Seeger, T.; Emrich, D.; Sandrock, D.

    1995-01-01

    In order to determine the effective radiation dose to be delivered by 131 I in functional autonomy we have used the functional autonomous volume calculated from the global 99m Tc thyroid uptake under exogenous or endogenous suppression before and 3 to 7 months after treatment. The radiation dose to the autonomous volume was calculated retrospectively in 131 patients with unifocal, multifocal and disseminated autonomy (75 hyperthyroid, 56 euthyroid) who received 131 I treatment of 200-300 Gy to the total volume of the gland. It could be shown that at least 350 Gy to the autonomous volume are required to reach the desired effect of treatment which was dependent only on the radiation dose delivered to the functional autonomous volume. (orig.) [de

  6. Swarm autonomic agents with self-destruct capability

    Science.gov (United States)

    Hinchey, Michael G. (Inventor); Sterritt, Roy (Inventor)

    2011-01-01

    Systems, methods and apparatus are provided through which in some embodiments an autonomic entity manages a system by generating one or more stay alive signals based on the functioning status and operating state of the system. In some embodiments, an evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy. The evolvable neural interface receives and generates heartbeat monitor signals and pulse monitor signals that are used to generate a stay alive signal that is used to manage the operations of the synthetic neural system. In another embodiment an asynchronous Alice signal (Autonomic license) requiring valid credentials of an anonymous autonomous agent is initiated. An unsatisfactory Alice exchange may lead to self-destruction of the anonymous autonomous agent for self-protection.

  7. Msx genes define a population of mural cell precursors required for head blood vessel maturation.

    Science.gov (United States)

    Lopes, Miguel; Goupille, Olivier; Saint Cloment, Cécile; Lallemand, Yvan; Cumano, Ana; Robert, Benoît

    2011-07-01

    Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.

  8. Vav1 GEF activity is required for T cell mediated allograft rejection.

    Science.gov (United States)

    Haubert, Dirk; Li, Jianping; Saveliev, Alexander; Calzascia, Thomas; Sutter, Esther; Metzler, Barbara; Kaiser, Daniel; Tybulewicz, Victor L J; Weckbecker, Gisbert

    2012-06-01

    The GDP exchange factor (GEF) Vav1 is a central signal transducer downstream of the T cell receptor and has been identified as a key factor for T cell activation in the context of allograft rejection. Vav1 has been shown to transduce signals both dependent and independent of its GEF function. The most promising approach to disrupt Vav1 activity by pharmacological inhibition would be to target its GEF function. However, the contribution of Vav1 GEF activity for allogeneic T cell activation has not been clarified yet. To address this question, we used knock-in mice bearing a mutated Vav1 with disrupted GEF activity but intact GEF-independent functions. T cells from these mice showed strongly reduced proliferation and activation in response to allogeneic stimulation. Furthermore, lack of Vav1 GEF activity strongly abrogated the in vivo expansion of T cells in a systemic graft-versus-host model. In a cardiac transplantation model, mice with disrupted Vav1 GEF activity show prolonged allograft survival. These findings demonstrate a strong requirement for Vav1 GEF activity for allogeneic T cell activation and graft rejection suggesting that disruption of Vav1 GEF activity alone is sufficient to induce significant immunosuppression. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA.

    Directory of Open Access Journals (Sweden)

    Rachel Flynn

    Full Text Available Defining the molecular interactions required to program activated CD8 T cells to survive and become memory cells may allow us to understand how to augment anti-viral immunity. HVEM (herpes virus entry mediator is a member of the tumor necrosis factor receptor (TNFR family that interacts with ligands in the TNF family, LIGHT and Lymphotoxin-α, and in the Ig family, B and T lymphocyte attenuator (BTLA and CD160. The Ig family members initiate inhibitory signaling when engaged with HVEM, but may also activate survival gene expression. Using a model of vaccinia virus infection, we made the unexpected finding that deficiency in HVEM or BTLA profoundly impaired effector CD8 T cell survival and development of protective immune memory. Mixed adoptive transfer experiments indicated that BTLA expressed in CD8α+ dendritic cells functions as a trans-activating ligand that delivers positive co-signals through HVEM expressed in T cells. Our data demonstrate a critical role of HVEM-BTLA bidirectional cosignaling system in antiviral defenses by driving the differentiation of memory CD8 T cells.

  10. Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin.

    Science.gov (United States)

    Gouignard, Nadège; Maccarana, Marco; Strate, Ina; von Stedingk, Kristoffer; Malmström, Anders; Pera, Edgar M

    2016-06-01

    Of all live births with congenital anomalies, approximately one-third exhibit deformities of the head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE). Studies in mice have extended our understanding of DS-epi1 in connective tissue maintenance; however, its role in fetal development is not understood. We demonstrate that DS-epi1 is important for the generation of isolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos. The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures. Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin. Thus, our work indicates a functional link between DS and NC cell migration. We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS, which might facilitate the diagnosis and development of therapies for this distressing condition. Moreover, the presented correlations between human DS-epi1 expression and gene sets of mesenchymal character, invasion and metastasis in

  11. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching.

    Science.gov (United States)

    Manis, J P; Gu, Y; Lansford, R; Sonoda, E; Ferrini, R; Davidson, L; Rajewsky, K; Alt, F W

    1998-06-15

    Immunoglobulin (Ig) heavy chain (HC) class switch recombination (CSR) is a late B cell process that involves intrachromosomal DNA rearrangement. Ku70 and Ku80 form a DNA end-binding complex required for DNA double strand break repair and V(D)J recombination. Ku70(-/-) (K70T) mice, like recombination activating gene (RAG)-1- or RAG-2-deficient (R1T or R2T) mice, have impaired B and T cell development at an early progenitor stage, which is thought to result at least in part from defective V(D)J recombination (Gu, Y., K.J. Seidl, G.A. Rathbun, C. Zhu, J.P. Manis, N. van der Stoep, L. Davidson, H.L. Cheng, J.M. Sekiguchi, K. Frank, et al. 1997. Immunity. 7:653-665; Ouyang, H., A. Nussenzweig, A. Kurimasa, V.C. Soares, X. Li, C. Cordon-Cardo, W. Li, N. Cheong, M. Nussenzweig, G. Iliakis, et al. 1997. J. Exp. Med. 186:921-929). Therefore, to examine the potential role of Ku70 in CSR, we generated K70T mice that carry a germline Ig HC locus in which the JH region was replaced with a functionally rearranged VH(D)JH and Ig lambda light chain transgene (referred to as K70T/HL mice). Previously, we have shown that B cells from R1T or R2T mice carrying these rearranged Ig genes (R1T/HL or R2T/HL mice) can undergo CSR to IgG isotypes (Lansford, R., J. Manis, E. Sonoda, K. Rajewsky, and F. Alt. 1998. Int. Immunol. 10:325-332). K70T/HL mice had significant numbers of peripheral surface IgM+ B cells, which generated serum IgM levels similar to those of R2T/HL mice. However, in contrast to R2T/HL mice, K70T/HL mice had no detectable serum IgG isotypes. In vitro culture of K70T/HL B cells with agents that induce CSR in normal or R2T/HL B cells did lead to the induction of germline CH transcripts, indicating that initial signaling pathways for CSR were intact in K70T/HL cells. However, treatment with such agents did not lead to detectable CSR by K70T/HL B cells, and instead, led to cell death within 72 h. We conclude that Ku70 is required for the generation of B cells that have

  12. Cell-specific differences in the requirements for translation quality control

    DEFF Research Database (Denmark)

    Reynolds, Noah M; Ling, Jiqiang; Roy, Hervé

    2010-01-01

    Protein synthesis has an overall error rate of approximately 10(-4) for each mRNA codon translated. The fidelity of translation is mainly determined by two events: synthesis of cognate amino acid:tRNA pairs by aminoacyl-tRNA synthetases (aaRSs) and accurate selection of aminoacyl-tRNAs (aa-tRNAs)...... divergent requirements for quality control in different cell compartments and suggest that the limits of translational accuracy may be largely determined by cellular physiology....

  13. Intercellular transfer of P-glycoprotein from the drug resistant human bladder cancer cell line BIU-87 does not require cell-to-cell contact.

    Science.gov (United States)

    Zhou, Hui-liang; Zheng, Yong-jun; Cheng, Xiao-zhi; Lv, Yi-song; Gao, Rui; Mao, Hou-ping; Chen, Qin

    2013-09-01

    The efflux activity of transmembrane P-glycoprotein prevents various therapeutic drugs from reaching lethal concentrations in cancer cells, resulting in multidrug resistance. We investigated whether drug resistant bladder cancer cells could transfer functional P-glycoprotein to sensitive parental cells. Drug sensitive BIU-87 bladder cancer cells were co-cultured for 48 hours with BIU-87/ADM, a doxorubicin resistant derivative of the same cell line, in a Transwell® system that prevented cell-to-cell contact. The presence of P-glycoprotein in recipient cell membranes was established using fluorescein isothiocyanate, laser scanning confocal microscopy and Western blot. P-glycoprotein mRNA levels were compared between cell types. Rhodamine 123 efflux assay was done to confirm that P-glycoprotein was biologically active. The amount of P-glycoprotein protein in BIU-87 cells co-cultured with BIU-87/ADM was significantly higher than in BIU-87 cells (0.44 vs 0.25) and BIU-87/H33342 cells (0.44 vs 0.26, each p transfer. P-glycoprotein mRNA expression was significantly higher in BIU-87/ADM cells than in co-cultured BIU-87 cells (1.28 vs 0.30), BIU-87/H33342 (0.28) and BIU-87 cells (0.25, each p <0.001), ruling out a genetic mechanism. After 30 minutes of efflux, rhodamine 123 fluorescence intensity was significantly lower in BIU-87/ADM cells (5.55 vs 51.45, p = 0.004) and co-cultured BIU-87 cells than in BIU-87 cells (14.22 vs 51.45, p <0.001), indicating that P-glycoprotein was functional. Bladder cancer cells can acquire functional P-glycoprotein through a nongenetic mechanism that does not require direct cell contact. This mechanism is consistent with a microparticle mediated process. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  14. Long-Term Dynamics of Autonomous Fractional Differential Equations

    Science.gov (United States)

    Liu, Tao; Xu, Wei; Xu, Yong; Han, Qun

    This paper aims to investigate long-term dynamic behaviors of autonomous fractional differential equations with effective numerical method. The long-term dynamic behaviors predict where systems are heading after long-term evolution. We make some modification and transplant cell mapping methods to autonomous fractional differential equations. The mapping time duration of cell mapping is enlarged to deal with the long memory effect. Three illustrative examples, i.e. fractional Lotka-Volterra equation, fractional van der Pol oscillator and fractional Duffing equation, are studied with our revised generalized cell mapping method. We obtain long-term dynamics, such as attractors, basins of attraction, and saddles. Compared with some existing stability and numerical results, the validity of our method is verified. Furthermore, we find that the fractional order has its effect on the long-term dynamics of autonomous fractional differential equations.

  15. Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients

    International Nuclear Information System (INIS)

    Orme, I.M.; Collins, F.M.

    1983-01-01

    The results of this study demonstrate that spleen cells taken from mice at the height of the primary immune response to intravenous infection with Mycobacterium tuberculosis possess the capacity to transfer adoptive protection to M. tuberculosis-infected recipients, but only if these recipients are first rendered T cell-deficient, either by thymectomy and gamma irradiation, or by sublethal irradiation. A similar requirement was necessary to demonstrate the adoptive protection of the lungs after exposure to an acute aerosol-delivered M. tuberculosis infection. In both infectious models successful adoptive immunotherapy was shown to be mediated by T lymphocytes, which were acquired in the donor animals in response to the immunizing infection. It is proposed that the results of this study may serve as a basic model for the subsequent analysis of the nature of the T cell-mediated immune response to both systemic and aerogenic infections with M. tuberculosis

  16. Solar cell development requires effective metrology: lock-in thermography can help

    International Nuclear Information System (INIS)

    Tarin, M.; Overstreet, R.

    2013-01-01

    The environmental and political benefits of renewable energy sources are understood by any informed observer with an interest in the future sustainability of our planet. Solar cells are getting a lot of attention - not only because they are a clean source of renewable energy, but also because their energy input is essentially free. Through the use of photovoltaic (PV) technology, solar cells convert the sun's rays directly into electricity. According to John Boyd, a technology analyst at Semiconductor Insights, 'a solar array 150 x 150 km could, in principle, meet all of North America's energy needs.' Assuming adequate installation space, and a solution for power grid load balancing, the main problem remaining to be solved is achieving grid parity - the point at which the cost of generating PV power is competitive with that of generating power using existing power plants. Currently, the cost of generating PV power is approximately $0.20/kWh globally. This is still roughly twice the rate of coal-based alternatives. The current generation of silicon solar cells typically achieves conversion efficiencies between 15% and 25%, while typical metallic thin film cells have efficiencies in the 5% to 20% range, depending on materials used. R and D efforts are aimed at increasing the efficiency of both solar cell technologies and reducing PV cell power generation costs to around $0.05/kWh. The primary challenges in reducing the cost of PV power generation exist in the production phase of the development cycle. Too many defects in the semiconducting material structure go undetected before solar cells are put into use. Identifying these defects requires efficient, cost effective test and measurement methods for characterizing a cell's performance and its electronic structure.(author)

  17. Notch signaling activation in human embryonic stem cells is required for embryonic but not trophoblastic lineage commitment

    OpenAIRE

    Yu, Xiaobing; Zou, Jizhong; Ye, Zhaohui; Hammond, Holly; Chen, Guibin; Tokunaga, Akinori; Mali, Prashant; Li, Yue-Ming; Civin, Curt; Gaiano, Nicholas; Cheng, Linzhao

    2008-01-01

    The Notch signaling pathway plays important roles in cell fate determination during embryonic development and adult life. In this study, we focus on the role of Notch signaling in governing cell fate choices in human embryonic stem (hES) cells. Using genetic and pharmacological approaches, we achieved both blockade and conditional activation of Notch signaling in several hES cell lines. We report here that activation of Notch signaling is required for undifferentiated hES cells to form the pr...

  18. Cybersecurity for aerospace autonomous systems

    Science.gov (United States)

    Straub, Jeremy

    2015-05-01

    High profile breaches have occurred across numerous information systems. One area where attacks are particularly problematic is autonomous control systems. This paper considers the aerospace information system, focusing on elements that interact with autonomous control systems (e.g., onboard UAVs). It discusses the trust placed in the autonomous systems and supporting systems (e.g., navigational aids) and how this trust can be validated. Approaches to remotely detect the UAV compromise, without relying on the onboard software (on a potentially compromised system) as part of the process are discussed. How different levels of autonomy (task-based, goal-based, mission-based) impact this remote characterization is considered.

  19. Decentralized Control of Autonomous Vehicles

    Science.gov (United States)

    2003-01-01

    Autonomous Vehicles by John S. Baras, Xiaobo Tan, Pedram Hovareshti CSHCN TR 2003-8 (ISR TR 2003-14) Report Documentation Page Form ApprovedOMB No. 0704...AND SUBTITLE Decentralized Control of Autonomous Vehicles 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 Decentralized Control of Autonomous Vehicles ∗ John S. Baras, Xiaobo Tan, and Pedram

  20. Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements

    International Nuclear Information System (INIS)

    Band, V.; Zajchowski, D.; Kulesa, V.; Sager, R.

    1990-01-01

    Human papilloma virus (HPV) types 16 and 18 are most commonly associated with cervical carcinoma in patients and induce immortalization of human keratinocytes in culture. HPV has not been associated with breast cancer. This report describes the immortalization of normal human mammary epithelial cells (76N) by plasmid pHPV18 or pHPV16, each containing the linearized viral genome. Transfectants were grown continuously for more than 60 passages, whereas 76N cells senesce after 18-20 passages. The transfectants also differ from 76N cells in cloning in a completely defined medium called D2 and growing a minimally supplemented defined medium (D3) containing epidermal growth factor. All transfectant tested contain integrated HPV DNA, express HPV RNA, and produce HPV E7 protein. HPV transfectants do not form tumors in a nude mouse assay. It is concluded that products of the HPV genome induce immortalization of human breast epithelial cells and reduce their growth factor requirements. This result raises the possibility that HPV might be involved in breast cancer. Furthermore, other tissue-specific primary epithelial cells that are presently difficult to grown and investigate may also be immortalized by HPV

  1. Immune cells are required for cutaneous ulceration in a swine model of chancroid.

    Science.gov (United States)

    San Mateo, L R; Toffer, K L; Orndorff, P E; Kawula, T H

    1999-09-01

    Cutaneous lesions of the human sexually transmitted genital ulcer disease chancroid are characterized by the presence of intraepidermal pustules, keratinocyte cytopathology, and epidermal and dermal erosion. These lesions are replete with neutrophils, macrophages, and CD4(+) T cells and contain very low numbers of cells of Haemophilus ducreyi, the bacterial agent of chancroid. We examined lesion formation by H. ducreyi in a pig model by using cyclophosphamide (CPA)-induced immune cell deficiency to distinguish between host and bacterial contributions to chancroid ulcer formation. Histologic presentation of H. ducreyi-induced lesions in CPA-treated pigs differed from ulcers that developed in immune-competent animals in that pustules did not form and surface epithelia remained intact. However, these lesions had significant suprabasal keratinocyte cytotoxicity. These results demonstrate that the host immune response was required for chancroid ulceration, while bacterial products were at least partially responsible for the keratinocyte cytopathology associated with chancroid lesions in the pig. The low numbers of H. ducreyi present in lesions in humans and immune-competent pigs have prevented localization of these organisms within skin. However, H. ducreyi organisms were readily visualized in lesion biopsies from infected CPA-treated pigs by immunoelectron microscopy. These bacteria were extracellular and associated with necrotic host cells in the epidermis and dermis. The relative abundance of H. ducreyi in inoculated CPA-treated pig skin suggests control of bacterial replication by host immune cells during natural human infection.

  2. Feeding cells induced by phytoparasitic nematodes require γ-tubulin ring complex for microtubule reorganization.

    Directory of Open Access Journals (Sweden)

    Mohamed Youssef Banora

    2011-12-01

    Full Text Available Reorganization of the microtubule network is important for the fast isodiametric expansion of giant-feeding cells induced by root-knot nematodes. The efficiency of microtubule reorganization depends on the nucleation of new microtubules, their elongation rate and activity of microtubule severing factors. New microtubules in plants are nucleated by cytoplasmic or microtubule-bound γ-tubulin ring complexes. Here we investigate the requirement of γ-tubulin complexes for giant feeding cells development using the interaction between Arabidopsis and Meloidogyne spp. as a model system. Immunocytochemical analyses demonstrate that γ-tubulin localizes to both cortical cytoplasm and mitotic microtubule arrays of the giant cells where it can associate with microtubules. The transcripts of two Arabidopsis γ-tubulin (TUBG1 and TUBG2 and two γ-tubulin complex proteins genes (GCP3 and GCP4 are upregulated in galls. Electron microscopy demonstrates association of GCP3 and γ-tubulin as part of a complex in the cytoplasm of giant cells. Knockout of either or both γ-tubulin genes results in the gene dose-dependent alteration of the morphology of feeding site and failure of nematode life cycle completion. We conclude that the γ-tubulin complex is essential for the control of microtubular network remodelling in the course of initiation and development of giant-feeding cells, and for the successful reproduction of nematodes in their plant hosts.

  3. [Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison].

    Science.gov (United States)

    Kuhlmann-Gottke, Johanna; Duchow, Karin

    2015-11-01

    At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act.

  4. Commensal Microbiota Are Required for Systemic Inflammation Triggered by Necrotic Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Jennifer A. Young

    2013-06-01

    Full Text Available The relationship between dendritic cells (DCs and commensal microflora in shaping systemic immune responses is not well understood. Here, we report that mice deficient for the Fas-associated death domain in DCs developed systemic inflammation associated with elevated proinflammatory cytokines and increased myeloid and B cells. These mice exhibited reduced DCs in gut-associated lymphoid tissues due to RIP3-dependent necroptosis, whereas DC functions remained intact. Induction of systemic inflammation required DC necroptosis and commensal microbiota signals that activated MyD88-dependent pathways in other cell types. Systemic inflammation was abrogated with the administration of broad-spectrum antibiotics or complete, but not DC-specific, deletion of MyD88. Thus, we have identified a previously unappreciated role for commensal microbiota in priming immune cells for inflammatory responses against necrotic cells. These studies demonstrate the impact intestinal microflora have on the immune system and their role in eliciting proper immune responses to harmful stimuli.

  5. Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates.

    Science.gov (United States)

    Mundell, Nathan A; Labosky, Patricia A

    2011-02-01

    Neural crest (NC) progenitors generate a wide array of cell types, yet molecules controlling NC multipotency and self-renewal and factors mediating cell-intrinsic distinctions between multipotent versus fate-restricted progenitors are poorly understood. Our earlier work demonstrated that Foxd3 is required for maintenance of NC progenitors in the embryo. Here, we show that Foxd3 mediates a fate restriction choice for multipotent NC progenitors with loss of Foxd3 biasing NC toward a mesenchymal fate. Neural derivatives of NC were lost in Foxd3 mutant mouse embryos, whereas abnormally fated NC-derived vascular smooth muscle cells were ectopically located in the aorta. Cranial NC defects were associated with precocious differentiation towards osteoblast and chondrocyte cell fates, and individual mutant NC from different anteroposterior regions underwent fate changes, losing neural and increasing myofibroblast potential. Our results demonstrate that neural potential can be separated from NC multipotency by the action of a single gene, and establish novel parallels between NC and other progenitor populations that depend on this functionally conserved stem cell protein to regulate self-renewal and multipotency.

  6. Priming Drivers before Handover in Semi-Autonomous Cars

    NARCIS (Netherlands)

    van der Heiden, R.M.A.; Iqbal, Shamsi T.; Janssen, C.P.

    2017-01-01

    Semi-autonomous vehicles occasionally require control to be handed over to the driver in situations where the vehicle is unable to operate safely. Currently, such handover requests require the driver to take control almost instantaneously. We investigate how auditory pre-alerts that occur well

  7. Activated Rac1 requires gp130 for Stat3 activation, cell proliferation and migration

    Energy Technology Data Exchange (ETDEWEB)

    Arulanandam, Rozanne; Geletu, Mulu [Departments of Microbiology and Immunology and Pathology and Molecular Medicine, and Queen' s University Cancer Institute, Queen' s University, Botterell Hall, Rm. 713, Kingston, Ontario, Canada K7L 3N6 (Canada); Feracci, Helene [Universite Bordeaux 1, Centre de Recherche Paul Pascal, CNRS UPR 8641, 33600 Pessac (France); Raptis, Leda, E-mail: raptisl@queensu.ca [Departments of Microbiology and Immunology and Pathology and Molecular Medicine, and Queen' s University Cancer Institute, Queen' s University, Botterell Hall, Rm. 713, Kingston, Ontario, Canada K7L 3N6 (Canada)

    2010-03-10

    Rac1 (Rac) is a member of the Rho family of small GTPases which controls cell migration by regulating the organization of actin filaments. Previous results suggested that mutationally activated forms of the Rho GTPases can activate the Signal Transducer and Activator of Transcription-3 (Stat3), but the exact mechanism is a matter of controversy. We recently demonstrated that Stat3 activity of cultured cells increases dramatically following E-cadherin engagement. To better understand this pathway, we now compared Stat3 activity levels in mouse HC11 cells before and after expression of the mutationally activated Rac1 (Rac{sup V12}), at different cell densities. The results revealed for the first time a dramatic increase in protein levels and activity of both the endogenous Rac and Rac{sup V12} with cell density, which was due to inhibition of proteasomal degradation. In addition, Rac{sup V12}-expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that Rac{sup V12} is able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that Rac{sup V12} expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity, indicating that these cytokines may be responsible for the Stat3 activation by Rac{sup V12}. The upregulation of IL6 family cytokines was required for cell migration and proliferation induced by Rac{sup V12}, as shown by gp130 knockdown experiments, thus demonstrating that the gp130/Stat3 axis represents an essential effector of activated Rac for the regulation of key cellular functions.

  8. Efficient retina formation requires suppression of both Activin and BMP signaling pathways in pluripotent cells

    Directory of Open Access Journals (Sweden)

    Kimberly A. Wong

    2015-03-01

    Full Text Available Retina formation requires the correct spatiotemporal patterning of key regulatory factors. While it is known that repression of several signaling pathways lead to specification of retinal fates, addition of only Noggin, a known BMP antagonist, can convert pluripotent Xenopus laevis animal cap cells to functional retinal cells. The aim of this study is to determine the intracellular molecular events that occur during this conversion. Surprisingly, blocking BMP signaling alone failed to mimic Noggin treatment. Overexpressing Noggin in pluripotent cells resulted in a concentration-dependent suppression of both Smad1 and Smad2 phosphorylation, which act downstream of BMP and Activin signaling, respectively. This caused a decrease in downstream targets: endothelial marker, xk81, and mesodermal marker, xbra. We treated pluripotent cells with dominant-negative receptors or the chemical inhibitors, dorsomorphin and SB431542, which each target either the BMP or Activin signaling pathway. We determined the effect of these treatments on retina formation using the Animal Cap Transplant (ACT assay; in which treated pluripotent cells were transplanted into the eye field of host embryos. We found that inhibition of Activin signaling, in the presence of BMP signaling inhibition, promotes efficient retinal specification in Xenopus tissue, mimicking the affect of adding Noggin alone. In whole embryos, we found that the eye field marker, rax, expanded when adding both dominant-negative Smad1 and Smad2, as did treating the cells with both dorsomorphin and SB431542. Future studies could translate these findings to a mammalian culture assay, in order to more efficiently produce retinal cells in culture.

  9. Activated Rac1 requires gp130 for Stat3 activation, cell proliferation and migration

    International Nuclear Information System (INIS)

    Arulanandam, Rozanne; Geletu, Mulu; Feracci, Helene; Raptis, Leda

    2010-01-01

    Rac1 (Rac) is a member of the Rho family of small GTPases which controls cell migration by regulating the organization of actin filaments. Previous results suggested that mutationally activated forms of the Rho GTPases can activate the Signal Transducer and Activator of Transcription-3 (Stat3), but the exact mechanism is a matter of controversy. We recently demonstrated that Stat3 activity of cultured cells increases dramatically following E-cadherin engagement. To better understand this pathway, we now compared Stat3 activity levels in mouse HC11 cells before and after expression of the mutationally activated Rac1 (Rac V12 ), at different cell densities. The results revealed for the first time a dramatic increase in protein levels and activity of both the endogenous Rac and Rac V12 with cell density, which was due to inhibition of proteasomal degradation. In addition, Rac V12 -expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that Rac V12 is able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that Rac V12 expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity, indicating that these cytokines may be responsible for the Stat3 activation by Rac V12 . The upregulation of IL6 family cytokines was required for cell migration and proliferation induced by Rac V12 , as shown by gp130 knockdown experiments, thus demonstrating that the gp130/Stat3 axis represents an essential effector of activated Rac for the regulation of key cellular functions.

  10. Nrf2 is required to maintain the self-renewal of glioma stem cells

    International Nuclear Information System (INIS)

    Zhu, Jianhong; Wang, Handong; Sun, Qing; Ji, Xiangjun; Zhu, Lin; Cong, Zixiang; Zhou, Yuan; Liu, Huandong; Zhou, Mengliang

    2013-01-01

    Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioma stem cells (GSCs). Self-renewal is a complex biological process necessary for maintaining the glioma stem cells. Nuclear factor rythroid 2-related factor 2(Nrf2) plays a significant role in protecting cells from endogenous and exogenous stresses. Nrf2 is a key nuclear transcription factor that regulates antioxidant response element (ARE)-containing genes. Previous studies have demonstrated the significant role of Nrf2 in the proliferation of glioblastoma, and in their resistance to radioactive therapies. We examined the effect of knocking down Nrf2 in GSCs. Nrf2 expression was down-regulated by shRNA transinfected with lentivirus. Expression levels of Nestin, Nrf2, BMI-1, Sox2 and Cyclin E were assessed by western blotting, quantitative polymerase chain reaction (qPCR) and immunohistochemistry analysis. The capacity for self-renewal in vitro was assessed by genesis of colonies. The capacity for self-renewal in vivo was analyzed by tumor genesis of xenografts in nude mice. Knockdown of Nrf2 inhibited the proliferation of GSCs, and significantly reduced the expression of BMI-1, Sox2 and CyclinE. Knocking down of Nrf2 changed the cell cycle distribution of GSCs by causing an uncharacteristic increase in the proportion of cells in the G2 phase and a decrease in the proportion of cells in the S phase of the cell cycle. Nrf2 is required to maintain the self-renewal of GSCs, and its down-regulation can attenuate the self-renewal of GSCs significantly

  11. Effects of copper on CHO cells: cellular requirements and product quality considerations.

    Science.gov (United States)

    Yuk, Inn H; Russell, Stephen; Tang, Yun; Hsu, Wei-Ting; Mauger, Jacob B; Aulakh, Rigzen P S; Luo, Jun; Gawlitzek, Martin; Joly, John C

    2015-01-01

    Recent reports highlight the impact of copper on lactate metabolism: CHO cell cultures with higher initial copper levels shift to net lactate consumption and yield lower final lactate and higher titers. These studies investigated the effects of copper on metabolite and transcript profiles, but did not measure in detail the dependences of cell culture performance and product quality on copper concentrations. To more thoroughly map these dependences, we explored the effects of various copper treatments on four recombinant CHO cell lines. In the first cell line, when extracellular copper remained above the limit of detection (LOD), cultures shifted to net lactate consumption and yielded comparable performances irrespective of the differences in copper levels; when extracellular copper dropped below LOD (∼13 nM), cultures failed to shift to net lactate consumption, and yielded significantly lower product titers. Across the four cell lines, the ability to grow and consume lactate seemed to depend on the presence of a minimum level of copper, beyond which there were no further gains in culture performance. Although this minimum cellular copper requirement could not be directly quantified, we estimated its probable range for the first cell line by applying several assumptions. Even when different copper concentrations did not affect cell culture performance, they affected product quality profiles: higher initial copper concentrations increased the basic variants in the recombinant IgG1 products. Therefore, in optimizing chemically defined media, it is important to select a copper concentration that is adequate and achieves desired product quality attributes. © 2014 American Institute of Chemical Engineers.

  12. Physics Simulation Software for Autonomous Propellant Loading and Gas House Autonomous System Monitoring

    Science.gov (United States)

    Regalado Reyes, Bjorn Constant

    2015-01-01

    1. Kennedy Space Center (KSC) is developing a mobile launching system with autonomous propellant loading capabilities for liquid-fueled rockets. An autonomous system will be responsible for monitoring and controlling the storage, loading and transferring of cryogenic propellants. The Physics Simulation Software will reproduce the sensor data seen during the delivery of cryogenic fluids including valve positions, pressures, temperatures and flow rates. The simulator will provide insight into the functionality of the propellant systems and demonstrate the effects of potential faults. This will provide verification of the communications protocols and the autonomous system control. 2. The High Pressure Gas Facility (HPGF) stores and distributes hydrogen, nitrogen, helium and high pressure air. The hydrogen and nitrogen are stored in cryogenic liquid state. The cryogenic fluids pose several hazards to operators and the storage and transfer equipment. Constant monitoring of pressures, temperatures and flow rates are required in order to maintain the safety of personnel and equipment during the handling and storage of these commodities. The Gas House Autonomous System Monitoring software will be responsible for constantly observing and recording sensor data, identifying and predicting faults and relaying hazard and operational information to the operators.

  13. Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Chung Hyung-Min

    2009-08-01

    Full Text Available Abstract Background Studies have provided important findings about the roles of Notch signaling in neural development. Unfortunately, however, most of these studies have investigated the neural stem cells (NSCs of mice or other laboratory animals rather than humans, mainly owing to the difficulties associated with obtaining human brain samples. It prompted us to focus on neuroectodermal spheres (NESs which are derived from human embryonic stem cell (hESC and densely inhabited by NSCs. We here investigated the role of Notch signaling with the hESC-derived NESs. Results From hESCs, we derived NESs, the in-vitro version of brain-derived neurospheres. NES formation was confirmed by increased levels of various NSC marker genes and the emergence of rosette structures in which neuroprogenitors are known to reside. We found that Notch signaling, which maintains stem cell characteristics of in-vivo-derived neuroprogenitors, is active in these hESC-derived NESs, similar to their in-vivo counterpart. Expression levels of Notch signaling molecules such as NICD, DLLs, JAG1, HES1 and HES5 were increased in the NESs. Inhibition of the Notch signaling by a γ-secretase inhibitor reduced rosette structures, expression levels of NSC marker genes and proliferation potential in the NESs, and, if combined with withdrawal of growth factors, triggered differentiation toward neurons. Conclusion Our results indicate that the hESC-derived NESs, which share biochemical features with brain-derived neurospheres, maintain stem cell characteristics mainly through Notch signaling, which suggests that the hESC-derived NESs could be an in-vitro model for in-vivo neurogenesis.

  14. Mutational analysis of the RNA-binding domain of the Prunus necrotic ringspot virus (PNRSV) movement protein reveals its requirement for cell-to-cell movement

    OpenAIRE

    Herranz, M. Carmen; Sánchez Navarro, Jesús A.; Saurí Peris, Ana; Mingarro Muñoz, Ismael; Pallás Benet, Vicente

    2005-01-01

    The movement protein (MP) of Prunus necrotic ringspot virus (PNRSV) is required for cell-to-cell movement. MP subcellular localization studies using a GFP fusion protein revealed highly punctate structures between neighboring cells, believed to represent plasmodesmata. Deletion of the RNA-binding domain (RBD) of PNRSV MP abolishes the cell-to-cell movement. A mutational analysis on this RBD was performed in order to identify in vivo the features that govern viral transport. Loss of positive c...

  15. Autonomous Aerobraking: A Design, Development, and Feasibility Study

    Science.gov (United States)

    Prince, Jill L. H.; Powell, Richard W.; Murri, Dan

    2011-01-01

    Aerobraking has been used four times to decrease the apoapsis of a spacecraft in a captured orbit around a planetary body with a significant atmosphere utilizing atmospheric drag to decelerate the spacecraft. While aerobraking requires minimum fuel, the long time required for aerobraking requires both a large operations staff, and large Deep Space Network resources. A study to automate aerobraking has been sponsored by the NASA Engineering and Safety Center to determine initial feasibility of equipping a spacecraft with the onboard capability for autonomous aerobraking, thus saving millions of dollars incurred by a large aerobraking operations workforce and continuous DSN coverage. This paper describes the need for autonomous aerobraking, the development of the Autonomous Aerobraking Development Software that includes an ephemeris estimator, an atmospheric density estimator, and maneuver calculation, and the plan forward for continuation of this study.

  16. The Autonomous Student: A Footnote.

    Science.gov (United States)

    Long, Jancis

    1987-01-01

    An argument that rationality is a learned behavior, rather than a natural facility, is developed vis-a-vis certain educational theories. The difficulties students face in maintaining a rational stance in an autonomous classroom are also discussed. (JL)

  17. Structural Discrimination and Autonomous Vehicles

    DEFF Research Database (Denmark)

    Liu, Hin-Yan

    2016-01-01

    This paper examines the potential for structural discrimination to be woven into the fabric of autonomous vehicle developments, which remain underexplored and undiscussed. The prospect for structural discrimination arises as a result of the coordinated modes of autonomous vehicle behaviour...... individual identity, and potentially relative worth, to autonomous vehicles engaging in a crash damage calculus. At the risk of introducing these ideas into the development of autonomous vehicles, this paper hopes to spark a debate to foreclose these eventualities....... that is prescribed by its code. This leads to the potential for individuated outcomes to be networked and thereby multiplied consistently to any number of vehicles implementing such a code. The aggregated effects of such algorithmic policy preferences will thus cumulate in the reallocation of benefits and burdens...

  18. Flocking algorithm for autonomous flying robots.

    Science.gov (United States)

    Virágh, Csaba; Vásárhelyi, Gábor; Tarcai, Norbert; Szörényi, Tamás; Somorjai, Gergő; Nepusz, Tamás; Vicsek, Tamás

    2014-06-01

    Animal swarms displaying a variety of typical flocking patterns would not exist without the underlying safe, optimal and stable dynamics of the individuals. The emergence of these universal patterns can be efficiently reconstructed with agent-based models. If we want to reproduce these patterns with artificial systems, such as autonomous aerial robots, agent-based models can also be used in their control algorithms. However, finding the proper algorithms and thus understanding the essential characteristics of the emergent collective behaviour requires thorough and realistic modeling of the robot and also the environment. In this paper, we first present an abstract mathematical model of an autonomous flying robot. The model takes into account several realistic features, such as time delay and locality of communication, inaccuracy of the on-board sensors and inertial effects. We present two decentralized control algorithms. One is based on a simple self-propelled flocking model of animal collective motion, the other is a collective target tracking algorithm. Both algorithms contain a viscous friction-like term, which aligns the velocities of neighbouring agents parallel to each other. We show that this term can be essential for reducing the inherent instabilities of such a noisy and delayed realistic system. We discuss simulation results on the stability of the control algorithms, and perform real experiments to show the applicability of the algorithms on a group of autonomous quadcopters. In our case, bio-inspiration works in two ways. On the one hand, the whole idea of trying to build and control a swarm of robots comes from the observation that birds tend to flock to optimize their behaviour as a group. On the other hand, by using a realistic simulation framework and studying the group behaviour of autonomous robots we can learn about the major factors influencing the flight of bird flocks.

  19. Goblet Cell Hyperplasia Requires High Bicarbonate Transport To Support Mucin Release.

    Science.gov (United States)

    Gorrieri, Giulia; Scudieri, Paolo; Caci, Emanuela; Schiavon, Marco; Tomati, Valeria; Sirci, Francesco; Napolitano, Francesco; Carrella, Diego; Gianotti, Ambra; Musante, Ilaria; Favia, Maria; Casavola, Valeria; Guerra, Lorenzo; Rea, Federico; Ravazzolo, Roberto; Di Bernardo, Diego; Galietta, Luis J V

    2016-10-27

    Goblet cell hyperplasia, a feature of asthma and other respiratory diseases, is driven by the Th-2 cytokines IL-4 and IL-13. In human bronchial epithelial cells, we find that IL-4 induces the expression of many genes coding for ion channels and transporters, including TMEM16A, SLC26A4, SLC12A2, and ATP12A. At the functional level, we find that IL-4 enhances calcium- and cAMP-activated chloride/bicarbonate secretion, resulting in high bicarbonate concentration and alkaline pH in the fluid covering the apical surface of epithelia. Importantly, mucin release, elicited by purinergic stimulation, requires the presence of bicarbonate in the basolateral solution and is defective in cells derived from cystic fibrosis patients. In conclusion, our results suggest that Th-2 cytokines induce a profound change in expression and function in multiple ion channels and transporters that results in enhanced bicarbonate transport ability. This change is required as an important mechanism to favor release and clearance of mucus.

  20. BMP antagonism by Noggin is required in presumptive notochord cells for mammalian foregut morphogenesis.

    Science.gov (United States)

    Fausett, Sarah R; Brunet, Lisa J; Klingensmith, John

    2014-07-01

    Esophageal atresia with tracheoesophageal fistula (EA/TEF) is a serious human birth defect, in which the esophagus ends before reaching the stomach, and is aberrantly connected with the trachea. Several mouse models of EA/TEF have recently demonstrated that proper dorsal/ventral (D/V) patterning of the primitive anterior foregut endoderm is essential for correct compartmentalization of the trachea and esophagus. Here we elucidate the pathogenic mechanisms underlying the EA/TEF that occurs in mice lacking the BMP antagonist Noggin, which display correct dorsal/ventral patterning. To clarify the mechanism of this malformation, we use spatiotemporal manipulation of Noggin and BMP receptor 1A conditional alleles during foregut development. Surprisingly, we find that the expression of Noggin in the compartmentalizing endoderm is not required to generate distinct tracheal and esophageal tubes. Instead, we show that Noggin and BMP signaling attenuation are required in the early notochord to correctly resolve notochord cells from the dorsal foregut endoderm, which in turn, appears to be a prerequisite for foregut compartmentalization. Collectively, our findings support an emerging model for a mechanism underlying EA/TEF in which impaired notochord resolution from the early endoderm causes the foregut to be hypo-cellular just prior to the critical period of compartmentalization. Our further characterizations suggest that Noggin may regulate a cell rearrangement process that involves reciprocal E-cadherin and Zeb1 expression in the resolving notochord cells. Copyright © 2014. Published by Elsevier Inc.

  1. Simple autonomous Mars walker

    Science.gov (United States)

    Larimer, Stanley J.; Lisec, Thomas R.; Spiessbach, Andrew J.

    1989-01-01

    Under a contract with NASA's Jet Propulsion Laboratory, Martin Marietta has developed several alternative rover concepts for unmanned exploration of the planet Mars. One of those concepts, the 'Walking Beam', is the subject of this paper. This concept was developed with the goal of achieving many of the capabilities of more sophisticated articulated-leg walkers with a much simpler, more robust, less computationally demanding and more power efficient design. It consists of two large-base tripods nested one within the other which alternately translate with respect to each other along a 5-meter beam to propel the vehicle. The semiautonomous navigation system relies on terrain geometry sensors and tacticle feedback from each foot to autonomously select a path which avoids hazards along a route designated from earth. Both mobility and navigation features of this concept are discussed including a top-level description of the vehicle's physical characteristics, deployment strategy, mobility elements, sensor suite, theory of operation, navigation and control processes, and estimated performance.

  2. Is paramecium swimming autonomic?

    Science.gov (United States)

    Bandyopadhyay, Promode R.; Toplosky, Norman; Hansen, Joshua

    2010-11-01

    We seek to explore if the swimming of paramecium has an underlying autonomic mechanism. Such robotic elements may be useful in capturing the disturbance field in an environment in real time. Experimental evidence is emerging that motion control neurons of other animals may be present in paramecium as well. The limit cycle determined using analog simulation of the coupled nonlinear oscillators of olivo-cerebellar dynamics (ieee joe 33, 563-578, 2008) agrees with the tracks of the cilium of a biological paramecium. A 4-motor apparatus has been built that reproduces the kinematics of the cilium motion. The motion of the biological cilium has been analyzed and compared with the results of the finite element modeling of forces on a cilium. The modeling equates applied torque at the base of the cilium with drag, the cilium stiffness being phase dependent. A low friction pendulum apparatus with a multiplicity of electromagnetic actuators is being built for verifying the maps of the attractor basin computed using the olivo-cerebellar dynamics for different initial conditions. Sponsored by ONR 33.

  3. AUTONOMOUS GAUSSIAN DECOMPOSITION

    Energy Technology Data Exchange (ETDEWEB)

    Lindner, Robert R.; Vera-Ciro, Carlos; Murray, Claire E.; Stanimirović, Snežana; Babler, Brian [Department of Astronomy, University of Wisconsin, 475 North Charter Street, Madison, WI 53706 (United States); Heiles, Carl [Radio Astronomy Lab, UC Berkeley, 601 Campbell Hall, Berkeley, CA 94720 (United States); Hennebelle, Patrick [Laboratoire AIM, Paris-Saclay, CEA/IRFU/SAp-CNRS-Université Paris Diderot, F-91191 Gif-sur Yvette Cedex (France); Goss, W. M. [National Radio Astronomy Observatory, P.O. Box O, 1003 Lopezville, Socorro, NM 87801 (United States); Dickey, John, E-mail: rlindner@astro.wisc.edu [University of Tasmania, School of Maths and Physics, Private Bag 37, Hobart, TAS 7001 (Australia)

    2015-04-15

    We present a new algorithm, named Autonomous Gaussian Decomposition (AGD), for automatically decomposing spectra into Gaussian components. AGD uses derivative spectroscopy and machine learning to provide optimized guesses for the number of Gaussian components in the data, and also their locations, widths, and amplitudes. We test AGD and find that it produces results comparable to human-derived solutions on 21 cm absorption spectra from the 21 cm SPectral line Observations of Neutral Gas with the EVLA (21-SPONGE) survey. We use AGD with Monte Carlo methods to derive the H i line completeness as a function of peak optical depth and velocity width for the 21-SPONGE data, and also show that the results of AGD are stable against varying observational noise intensity. The autonomy and computational efficiency of the method over traditional manual Gaussian fits allow for truly unbiased comparisons between observations and simulations, and for the ability to scale up and interpret the very large data volumes from the upcoming Square Kilometer Array and pathfinder telescopes.

  4. AUTONOMOUS GAUSSIAN DECOMPOSITION

    International Nuclear Information System (INIS)

    Lindner, Robert R.; Vera-Ciro, Carlos; Murray, Claire E.; Stanimirović, Snežana; Babler, Brian; Heiles, Carl; Hennebelle, Patrick; Goss, W. M.; Dickey, John

    2015-01-01

    We present a new algorithm, named Autonomous Gaussian Decomposition (AGD), for automatically decomposing spectra into Gaussian components. AGD uses derivative spectroscopy and machine learning to provide optimized guesses for the number of Gaussian components in the data, and also their locations, widths, and amplitudes. We test AGD and find that it produces results comparable to human-derived solutions on 21 cm absorption spectra from the 21 cm SPectral line Observations of Neutral Gas with the EVLA (21-SPONGE) survey. We use AGD with Monte Carlo methods to derive the H i line completeness as a function of peak optical depth and velocity width for the 21-SPONGE data, and also show that the results of AGD are stable against varying observational noise intensity. The autonomy and computational efficiency of the method over traditional manual Gaussian fits allow for truly unbiased comparisons between observations and simulations, and for the ability to scale up and interpret the very large data volumes from the upcoming Square Kilometer Array and pathfinder telescopes

  5. Design of Autonomous Gel Actuators

    Directory of Open Access Journals (Sweden)

    Shuji Hashimoto

    2011-01-01

    Full Text Available In this paper, we introduce autonomous gel actuators driven by chemical energy. The polymer gels prepared here have cyclic chemical reaction networks. With a cyclic reaction, the polymer gels generate periodical motion. The periodic motion of the gel is produced by the chemical energy of the oscillatory Belouzov-Zhabotinsky (BZ reaction. We have succeeded in making synthetic polymer gel move autonomously like a living organism. This experimental fact represents the great possibility of the chemical robot.

  6. Mortalin antibody-conjugated quantum dot transfer from human mesenchymal stromal cells to breast cancer cells requires cell–cell interaction

    Energy Technology Data Exchange (ETDEWEB)

    Pietilä, Mika [National Institute of Advanced industrial Sciences and Technology, Tsukuba, Ibaraki 305 8562 (Japan); Lehenkari, Petri [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, Aapistie 7, P.O. Box 5000, FIN-90014 (Finland); Institute of Clinical Medicine, Division of Surgery, University of Oulu and Clinical Research Centre, Department of Surgery and Intensive Care, Oulu University Hospital, Aapistie 5a, P.O. Box 5000, FIN-90014 (Finland); Kuvaja, Paula [Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, Aapistie 7, P.O. Box 5000, FIN-90014 (Finland); Department of Pathology, Oulu University Hospital, P.O. Box 50, FIN-90029 OYS, Oulu (Finland); Kaakinen, Mika [Biocenter Oulu, University of Oulu, P.O. Box 5000, FI-90014 (Finland); Kaul, Sunil C.; Wadhwa, Renu [National Institute of Advanced industrial Sciences and Technology, Tsukuba, Ibaraki 305 8562 (Japan); Uemura, Toshimasa, E-mail: t.uemura@aist.go.jp [National Institute of Advanced industrial Sciences and Technology, Tsukuba, Ibaraki 305 8562 (Japan)

    2013-11-01

    The role of tumor stroma in regulation of breast cancer growth has been widely studied. However, the details on the type of heterocellular cross-talk between stromal and breast cancer cells (BCCs) are still poorly known. In the present study, in order to investigate the intercellular communication between human mesenchymal stromal cells (hMSCs) and breast cancer cells (BCCs, MDA-MB-231), we recruited cell-internalizing quantum dots (i-QD) generated by conjugation of cell-internalizing anti-mortalin antibody and quantum dots (QD). Co-culture of illuminated and color-coded hMSCs (QD655) and BCCs (QD585) revealed the intercellular transfer of QD655 signal from hMSCs to BCCs. The amount of QD double positive BCCs increased gradually within 48 h of co-culture. We found prominent intercellular transfer of QD655 in hanging drop co-culture system and it was non-existent when hMSCs and BBCs cells were co-cultured in trans-well system lacking imminent cell–cell contact. Fluorescent and electron microscope analyses also supported that the direct cell-to-cell interactions may be required for the intercellular transfer of QD655 from hMSCs to BCCs. To the best of our knowledge, the study provides a first demonstration of transcellular crosstalk between stromal cells and BCCs that involve direct contact and may also include a transfer of mortalin, an anti-apoptotic and growth-promoting factor enriched in cancer cells.

  7. Endogenous laminin is required for human airway smooth muscle cell maturation

    Directory of Open Access Journals (Sweden)

    Tran Thai

    2006-09-01

    Full Text Available Abstract Background Airway smooth muscle (ASM contraction underlies acute bronchospasm in asthma. ASM cells can switch between a synthetic-proliferative phenotype and a contractile phenotype. While the effects of extracellular matrix (ECM components on modulation of ASM cells to a synthetic phenotype have been reported, the role of ECM components on maturation of ASM cells to a contractile phenotype in adult lung is unclear. As both changes in ECM components and accumulation of contractile ASM are features of airway wall remodelling in asthma, we examined the role of the ECM protein, laminin, in the maturation of contractile phenotype in human ASM cells. Methods Human ASM cells were made senescence-resistant by stable expression of human telomerase reverse transcriptase. Maturation to a contractile phenotype was induced by 7-day serum deprivation, as assessed by immunoblotting for desmin and calponin. The role of laminin on ASM maturation was investigated by comparing the effects of exogenous laminin coated on culture plates, and of soluble laminin peptide competitors. Endogenous expression of laminin chains during ASM maturation was also measured. Results Myocyte binding to endogenously expressed laminin was required for ASM phenotype maturation, as laminin competing peptides (YIGSR or GRGDSP significantly reduced desmin and calponin protein accumulation that otherwise occurs with prolonged serum deprivation. Coating of plastic cell culture dishes with different purified laminin preparations was not sufficient to further promote accumulation of desmin or calponin during 7-day serum deprivation. Expression of α2, β1 and γ1 laminin chains by ASM cells was specifically up-regulated during myocyte maturation, suggesting a key role for laminin-2 in the development of the contractile phenotype. Conclusion While earlier reports suggest exogenously applied laminin slows the spontaneous modulation of ASM to a synthetic phenotype, we show for the

  8. Feasibility of implementation of an autonomous hybrid system for PEM fuel cells to electrify localities in rural Cuba; Factibilidad de implementacion de un sistema hibrido autonomo con celda de combustible PEM para electrificar localidades rurales en Cuba

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez Torres, Yamir [Centro de Estudios de Tecnologias Energeticas Renovables (CETER), Ciudad de la Habana (Cuba)] e-mail: yamir@ceter.cujae.edu.cu

    2009-09-15

    The use of PEM fuel cells to produce electric energy in autonomous systems is closely linked with the production and storage of hydrogen. Eventually joined with sources of renewable energy, this creates an ecologically clean and sustainable system. In several developing countries, localities exist that do not have electricity but have significant unexploited renewable energy power, where an autonomous hybrid system can be designed to electrify these population centers. This work presents a hybrid electricity scheme with a PEM fuel cell to produce hydrogen and electricity in order to electrify rural zones far from the national power grid in Cuba. The electric demand of the zone and available energy power was calculated using the informatics modeling and simulation programs HOMER, PVSYST and Matlab 1,2,3. Variability in wind and photovoltage power was determined based on daylight hours and seasonal periods throughout the year as well as their effect on the production of hydrogen and electricity. It was shown that the energy demand is met even for the most adverse scenarios. This work offers a detailed description of the behavior of the system and evidence of no effect on the environment, enabling the electrification and wellbeing of residents of the locality. [Spanish] El uso de celdas de combustible PEM para la produccion de energia electrica en sistemas autonomos esta estrechamente ligado a la produccion y almacenamiento de hidrogeno. Esto eventualmente unido a las fuentes renovables de energia forma un sistema ecologicamente limpio y sustentable. En varios paises subdesarrollados existen localidades que no cuentan con electricidad y que tienen importantes potenciales energeticos renovables no explotados actualmente en los cuales se puede disenar un sistema hibrido autonomo para electrificar estas poblaciones. En este trabajo se presenta el esquema de un sistema hibrido autonomo con celda de combustible PEM, para la produccion de hidrogeno y electricidad encaminado

  9. X-ray-enhanced cancer cell migration requires the linker of nucleoskeleton and cytoskeleton complex.

    Science.gov (United States)

    Imaizumi, Hiromasa; Sato, Katsutoshi; Nishihara, Asuka; Minami, Kazumasa; Koizumi, Masahiko; Matsuura, Nariaki; Hieda, Miki

    2018-04-01

    The linker of nucleoskeleton and cytoskeleton (LINC) complex is a multifunctional protein complex that is involved in various processes at the nuclear envelope, including nuclear migration, mechanotransduction, chromatin tethering and DNA damage response. We recently showed that a nuclear envelope protein, Sad1 and UNC84 domain protein 1 (SUN1), a component of the LINC complex, has a critical function in cell migration. Although ionizing radiation activates cell migration and invasion in vivo and in vitro, the underlying molecular mechanism remains unknown. Here, we examined the involvement of the LINC complex in radiation-enhanced cell migration and invasion. A sublethal dose of X-ray radiation promoted human breast cancer MDA-MB-231 cell migration and invasion, whereas carbon ion beam radiation suppressed these processes in a dose-dependent manner. Depletion of SUN1 and SUN2 significantly suppressed X-ray-enhanced cell migration and invasion. Moreover, depletion or overexpression of each SUN1 splicing variant revealed that SUN1_888 containing 888 amino acids of SUN1 but not SUN1_916 was required for X-ray-enhanced migration and invasion. In addition, the results suggested that X-ray irradiation affected the expression level of SUN1 splicing variants and a SUN protein binding partner, nesprins. Taken together, our findings supported that the LINC complex contributed to photon-enhanced cell migration and invasion. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  10. HCN channels are not required for mechanotransduction in sensory hair cells of the mouse inner ear.

    Directory of Open Access Journals (Sweden)

    Geoffrey C Horwitz

    Full Text Available The molecular composition of the hair cell transduction channel has not been identified. Here we explore the novel hypothesis that hair cell transduction channels include HCN subunits. The HCN family of ion channels includes four members, HCN1-4. They were originally identified as the molecular correlates of the hyperpolarization-activated, cyclic nucleotide gated ion channels that carry currents known as If, IQ or Ih. However, based on recent evidence it has been suggested that HCN subunits may also be components of the elusive hair cell transduction channel. To investigate this hypothesis we examined expression of mRNA that encodes HCN1-4 in sensory epithelia of the mouse inner ear, immunolocalization of HCN subunits 1, 2 and 4, uptake of the transduction channel permeable dye, FM1-43 and electrophysiological measurement of mechanotransduction current. Dye uptake and transduction current were assayed in cochlear and vestibular hair cells of wildtype mice exposed to HCN channel blockers or a dominant-negative form of HCN2 that contained a pore mutation and in mutant mice that lacked HCN1, HCN2 or both. We found robust expression of HCNs 1, 2 and 4 but little evidence that localized HCN subunits in hair bundles, the site of mechanotransduction. Although high concentrations of the HCN antagonist, ZD7288, blocked 50-70% of the transduction current, we found no reduction of transduction current in either cochlear or vestibular hair cells of HCN1- or HCN2- deficient mice relative to wild-type mice. Furthermore, mice that lacked both HCN1 and HCN2 also had normal transduction currents. Lastly, we found that mice exposed to the dominant-negative mutant form of HCN2 had normal transduction currents as well. Taken together, the evidence suggests that HCN subunits are not required for mechanotransduction in hair cells of the mouse inner ear.

  11. Requirement of myomaker-mediated stem cell fusion for skeletal muscle hypertrophy.

    Science.gov (United States)

    Goh, Qingnian; Millay, Douglas P

    2017-02-10

    Fusion of skeletal muscle stem/progenitor cells is required for proper development and regeneration, however the significance of this process during adult muscle hypertrophy has not been explored. In response to muscle overload after synergist ablation in mice, we show that myomaker, a muscle specific membrane protein essential for myoblast fusion, is activated mainly in muscle progenitors and not myofibers. We rendered muscle progenitors fusion-incompetent through genetic deletion of myomaker in muscle stem cells and observed a complete reduction of overload-induced hypertrophy. This blunted hypertrophic response was associated with a reduction in Akt and p70s6k signaling and protein synthesis, suggesting a link between myonuclear accretion and activation of pro-hypertrophic pathways. Furthermore, fusion-incompetent muscle exhibited increased fibrosis after muscle overload, indicating a protective role for normal stem cell activity in reducing myofiber strain associated with hypertrophy. These findings reveal an essential contribution of myomaker-mediated stem cell fusion during physiological adult muscle hypertrophy.

  12. Progesterone production requires activation of caspase-3 in preovulatory granulosa cells in a serum starvation model.

    Science.gov (United States)

    An, Li-Sha; Yuan, Xiao-Hua; Hu, Ying; Shi, Zi-Yun; Liu, Xiao-Qin; Qin, Li; Wu, Gui-Qing; Han, Wei; Wang, Ya-Qin; Ma, Xu

    2012-11-01

    Granulosa cells proliferate, differentiate, and undergo apoptosis throughout follicular development. Previous studies have demonstrated that stimulation of progesterone production is accompanied by caspase-3 activation. Moreover, we previously reported that arsenic enhanced caspase-3 activity coupled with progesterone production. Inhibition of caspase-3 activity can significantly inhibit progesterone production induced by arsenic or follicle-stimulating hormone (FSH). Here, we report that serum starvation induces caspase-3 activation coupled with augmentation of progesterone production. Serum starvation also increased the levels of cytochrome P450 cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory (StAR) protein, both of which may contribute to progesterone synthesis in preovulatory granulosa cells. Inhibition of caspase-3 activity resulted in a decrease in progesterone production. Deactivation of caspase-3 activity by caspase-3 specific inhibitor also resulted in decreases in P450scc and StAR expression, which may partly contribute to the observed decrease in progesterone production. Our study demonstrates for the first time that progesterone production in preovulatory granulosa cells is required for caspase-3 activation in a serum starvation model. Inhibition of caspase-3 activity can result in decreased expression of the steroidogenic proteins P450scc and StAR. Our work provides further details on the relationship between caspase-3 activation and steroidogenesis and indicates that caspase-3 plays a critical role in progesterone production by granulosa cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Maintenance of neural progenitor cell stemness in 3D hydrogels requires matrix remodelling

    Science.gov (United States)

    Madl, Christopher M.; Lesavage, Bauer L.; Dewi, Ruby E.; Dinh, Cong B.; Stowers, Ryan S.; Khariton, Margarita; Lampe, Kyle J.; Nguyen, Duong; Chaudhuri, Ovijit; Enejder, Annika; Heilshorn, Sarah C.

    2017-12-01

    Neural progenitor cell (NPC) culture within three-dimensional (3D) hydrogels is an attractive strategy for expanding a therapeutically relevant number of stem cells. However, relatively little is known about how 3D material properties such as stiffness and degradability affect the maintenance of NPC stemness in the absence of differentiation factors. Over a physiologically relevant range of stiffness from ~0.5 to 50 kPa, stemness maintenance did not correlate with initial hydrogel stiffness. In contrast, hydrogel degradation was both correlated with, and necessary for, maintenance of NPC stemness. This requirement for degradation was independent of cytoskeletal tension generation and presentation of engineered adhesive ligands, instead relying on matrix remodelling to facilitate cadherin-mediated cell-cell contact and promote β-catenin signalling. In two additional hydrogel systems, permitting NPC-mediated matrix remodelling proved to be a generalizable strategy for stemness maintenance in 3D. Our findings have identified matrix remodelling, in the absence of cytoskeletal tension generation, as a previously unknown strategy to maintain stemness in 3D.

  14. Endosomal sorting complexes required for ESCRTing cells toward death during neurogenesis, neurodevelopment and neurodegeneration.

    Science.gov (United States)

    Kaul, Zenia; Chakrabarti, Oishee

    2018-03-25

    The endosomal sorting complexes required for transport (ESCRT) proteins help in the recognition, sorting and degradation of ubiquitinated cargoes from the cell surface, long-lived proteins or aggregates, and aged organelles present in the cytosol. These proteins take part in the endo-lysosomal system of degradation. The ESCRT proteins also play an integral role in cytokinesis, viral budding and mRNA transport. Many neurodegenerative diseases are caused by toxic accumulation of cargo in the cell, which causes stress and ultimately leads to neuronal death. This accumulation of cargo occurs because of defects in the endo-lysosomal degradative pathway-loss of function of ESCRTs has been implicated in this mechanism. ESCRTs also take part in many survival processes, lack of which can culminate in neuronal cell death. While the role played by the ESCRT proteins in maintaining healthy neurons is known, their role in neurodegenerative diseases is still poorly understood. In this review, we highlight the importance of ESCRTs in maintaining healthy neurons and then suggest how perturbations in many of the survival mechanisms governed by these proteins could eventually lead to cell death; quite often these correlations are not so obviously laid out. Extensive neuronal death eventually culminates in neurodegeneration. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. The APC tumor suppressor is required for epithelial cell polarization and three-dimensional morphogenesis

    Science.gov (United States)

    Lesko, Alyssa C.; Goss, Kathleen H.; Yang, Frank F.; Schwertner, Adam; Hulur, Imge; Onel, Kenan; Prosperi, Jenifer R.

    2015-01-01

    The Adenomatous Polyposis Coli (APC) tumor suppressor has been previously implicated in the control of apical-basal polarity; yet, the consequence of APC loss-of-function in epithelial polarization and morphogenesis has not been characterized. To test the hypothesis that APC is required for the establishment of normal epithelial polarity and morphogenesis programs, we generated APC-knockdown epithelial cell lines. APC depletion resulted in loss of polarity and multi-layering on permeable supports, and enlarged, filled spheroids with disrupted polarity in 3D culture. Importantly, these effects of APC knockdown were independent of Wnt/β-catenin signaling, but were rescued with either full-length or a carboxy (c)-terminal segment of APC. Moreover, we identified a gene expression signature associated with APC knockdown that points to several candidates known to regulate cell-cell and cell-matrix communication. Analysis of epithelial tissues from mice and humans carrying heterozygous APC mutations further support the importance of APC as a regulator of epithelial behavior and tissue architecture. These data also suggest that the initiation of epithelial-derived tumors as a result of APC mutation or gene silencing may be driven by loss of polarity and dysmorphogenesis. PMID:25578398

  16. DNA adenine methylation is required to replicate both Vibrio cholerae chromosomes once per cell cycle.

    Science.gov (United States)

    Demarre, Gaëlle; Chattoraj, Dhruba K

    2010-05-06

    DNA adenine methylation is widely used to control many DNA transactions, including replication. In Escherichia coli, methylation serves to silence newly synthesized (hemimethylated) sister origins. SeqA, a protein that binds to hemimethylated DNA, mediates the silencing, and this is necessary to restrict replication to once per cell cycle. The methylation, however, is not essential for replication initiation per se but appeared so when the origins (oriI and oriII) of the two Vibrio cholerae chromosomes were used to drive plasmid replication in E. coli. Here we show that, as in the case of E. coli, methylation is not essential for oriI when it drives chromosomal replication and is needed for once-per-cell-cycle replication in a SeqA-dependent fashion. We found that oriII also needs SeqA for once-per-cell-cycle replication and, additionally, full methylation for efficient initiator binding. The requirement for initiator binding might suffice to make methylation an essential function in V. cholerae. The structure of oriII suggests that it originated from a plasmid, but unlike plasmids, oriII makes use of methylation for once-per-cell-cycle replication, the norm for chromosomal but not plasmid replication.

  17. DNA adenine methylation is required to replicate both Vibrio cholerae chromosomes once per cell cycle.

    Directory of Open Access Journals (Sweden)

    Gaëlle Demarre

    2010-05-01

    Full Text Available DNA adenine methylation is widely used to control many DNA transactions, including replication. In Escherichia coli, methylation serves to silence newly synthesized (hemimethylated sister origins. SeqA, a protein that binds to hemimethylated DNA, mediates the silencing, and this is necessary to restrict replication to once per cell cycle. The methylation, however, is not essential for replication initiation per se but appeared so when the origins (oriI and oriII of the two Vibrio cholerae chromosomes were used to drive plasmid replication in E. coli. Here we show that, as in the case of E. coli, methylation is not essential for oriI when it drives chromosomal replication and is needed for once-per-cell-cycle replication in a SeqA-dependent fashion. We found that oriII also needs SeqA for once-per-cell-cycle replication and, additionally, full methylation for efficient initiator binding. The requirement for initiator binding might suffice to make methylation an essential function in V. cholerae. The structure of oriII suggests that it originated from a plasmid, but unlike plasmids, oriII makes use of methylation for once-per-cell-cycle replication, the norm for chromosomal but not plasmid replication.

  18. Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration.

    Science.gov (United States)

    Takemura, Masahiko; Nakato, Hiroshi

    2017-01-15

    Stem cell division is activated to trigger regeneration in response to tissue damage. The molecular mechanisms by which this stem cell mitotic activity is properly repressed at the end of regeneration are poorly understood. Here, we show that a specific modification of heparan sulfate is crucial for regulating Drosophila intestinal stem cell (ISC) division during normal midgut homeostasis and regeneration. Loss of the extracellular heparan sulfate endosulfatase Sulf1 resulted in increased ISC division during normal homeostasis, which was caused by upregulation of mitogenic signaling including the JAK-STAT, EGFR and Hedgehog pathways. Using a regeneration model, we found that ISCs failed to properly halt division at the termination stage in Sulf1 mutants, showing that Sulf1 is required for terminating ISC division at the end of regeneration. We propose that post-transcriptional regulation of mitogen signaling by heparan sulfate structural modifications provides a new regulatory step for precise temporal control of stem cell activity during regeneration. © 2017. Published by The Company of Biologists Ltd.

  19. Stellate Cells in the Medial Entorhinal Cortex Are Required for Spatial Learning

    Directory of Open Access Journals (Sweden)

    Sarah A. Tennant

    2018-01-01

    Full Text Available Spatial learning requires estimates of location that may be obtained by path integration or from positional cues. Grid and other spatial firing patterns of neurons in the superficial medial entorhinal cortex (MEC suggest roles in behavioral estimation of location. However, distinguishing the contributions of path integration and cue-based signals to spatial behaviors is challenging, and the roles of identified MEC neurons are unclear. We use virtual reality to dissociate linear path integration from other strategies for behavioral estimation of location. We find that mice learn to path integrate using motor-related self-motion signals, with accuracy that decreases steeply as a function of distance. We show that inactivation of stellate cells in superficial MEC impairs spatial learning in virtual reality and in a real world object location recognition task. Our results quantify contributions of path integration to behavior and corroborate key predictions of models in which stellate cells contribute to location estimation.

  20. A sleep state in Drosophila larvae required for neural stem cell proliferation

    Science.gov (United States)

    Szuperak, Milan; Churgin, Matthew A; Borja, Austin J; Raizen, David M; Fang-Yen, Christopher

    2018-01-01

    Sleep during development is involved in refining brain circuitry, but a role for sleep in the earliest periods of nervous system elaboration, when neurons are first being born, has not been explored. Here we identify a sleep state in Drosophila larvae that coincides with a major wave of neurogenesis. Mechanisms controlling larval sleep are partially distinct from adult sleep: octopamine, the Drosophila analog of mammalian norepinephrine, is the major arousal neuromodulator in larvae, but dopamine is not required. Using real-time behavioral monitoring in a closed-loop sleep deprivation system, we find that sleep loss in larvae impairs cell division of neural progenitors. This work establishes a system uniquely suited for studying sleep during nascent periods, and demonstrates that sleep in early life regulates neural stem cell proliferation. PMID:29424688

  1. Equine herpesvirus type 1 (EHV-1) glycoprotein K is required for efficient cell-to-cell spread and virus egress

    International Nuclear Information System (INIS)

    Neubauer, Antonie; Osterrieder, Nikolaus

    2004-01-01

    The function of the equine herpesvirus type 1 (EHV-1) glycoprotein K (gK) homologue was investigated. Deletion of 88% of the UL53-homologous open reading frame in EHV-1 strain RacH resulted in a severe growth defect of the gK-negative virus (HΔgK) as reflected by a significant decrease in the production of infectious virus progeny on RK13 cells. The HΔgK virus induced only minute plaques, was unable to form syncytia, and its penetration efficiency into RK13 cells was reduced by approximately 40%. To further analyze gK function and intracellular trafficking, gK of strain RacH was replaced by a C-terminally truncated gK-green fluorescent protein fusion protein (gK-GFP). The generated recombinant virus was shown to replicate well on non-complementing cells, and virus penetration and syncytium formation were comparable to parental RacH. A reduction in plaque size and slightly decreased intra- and extracellular virus titers, however, were observed. The gK-GFP fusion protein was expressed with early-late kinetics, and multiple forms of the protein exhibiting M r s between 50,000 and 85,000 were detected by Western blot analysis. The various gK-GFP forms were shown to be N-glycosylated, associated with membranes of the Golgi apparatus, and were incorporated into extracellular virions. Complete processing of gK-GFP was only observed within the context of viral infection. From the results, we concluded that EHV-1 gK is required for efficient virus growth in vitro and that the carboxy-terminal amino acids are not required for its function, because the gK-GFP fusion protein was able to complement for EHV-1 growth in the absence of authentic gK

  2. Differential requirement for the CD45 splicing regulator hnRNPLL for accumulation of NKT and conventional T cells.

    Directory of Open Access Journals (Sweden)

    Mehmet Yabas

    Full Text Available Natural killer T (NKT cells represent an important regulatory T cell subset that develops in the thymus and contains immature (NK1.1(lo and mature (NK1.1(hi cell subsets. Here we show in mice that an inherited mutation in heterogeneous ribonucleoprotein L-like protein (hnRNPLL(thunder, that shortens the survival of conventional T cells, has no discernible effect on NKT cell development, homeostasis or effector function. Thus, Hnrpll deficiency effectively increases the NKT∶T cell ratio in the periphery. However, Hnrpll mutation disrupts CD45RA, RB and RC exon silencing of the Ptprc mRNA in both NKT and conventional T cells, and leads to a comparably dramatic shift to high molecular weight CD45 isoforms. In addition, Hnrpll mutation has a cell intrinsic effect on the expression of the developmentally regulated cell surface marker NK1.1 on NKT cells in the thymus and periphery but does not affect cell numbers. Therefore our results highlight both overlapping and divergent roles for hnRNPLL between conventional T cells and NKT cells. In both cell subsets it is required as a trans-acting factor to regulate alternative splicing of the Ptprc mRNA, but it is only required for survival of conventional T cells.

  3. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells

    Directory of Open Access Journals (Sweden)

    Zou Jie

    2013-01-01

    Full Text Available Abstract Background Notch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL. Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL. Methods T-ALL cell lines (Jurkat, Sup-T1 transfected with HIF-1α or Notch1 small interference RNA (siRNA were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot. Results Hypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2 and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression. Conclusions Notch1 signalling is required for hypoxia/HIF-1α-induced proliferation

  4. Autonomous Dome for a Robotic Telescope

    Science.gov (United States)

    Kumar, A.; Sengupta, A.; Ganesh, S.

    2016-12-01

    The Physical Research Laboratory operates a 50 cm robotic observatory at Mount Abu (Rajsthan, India). This Automated Telescope for Variability Studies (ATVS) makes use of the Remote Telescope System 2 (RTS2) for autonomous operations. The observatory uses a 3.5 m dome from Sirius Observatories. We have developed electronics using Arduino electronic circuit boards with home grown logic and software to control the dome operations. We are in the process of completing the drivers to link our Arduino based dome controller with RTS2. This document is a short description of the various phases of the development and their integration to achieve the required objective.

  5. Developments and challenges for autonomous unmanned vehicles

    CERN Document Server

    Finn, Anthony

    2010-01-01

    It is widely anticipated that autonomous vehicles will have a transformational impact on military forces and will play a key role in many future force structures. As a result, many tasks have already been identified that unmanned systems could undertake more readily than humans. However, for this to occur, such systems will need to be agile, versatile, persistent, reliable, survivable and lethal. This will require many of the vehicles 'cognitive' or higher order functions to be more fully developed, whereas to date only the 'component' or physical functions have been successfully automated and

  6. Mind bomb-1 in dendritic cells is specifically required for Notch-mediated T helper type 2 differentiation.

    Directory of Open Access Journals (Sweden)

    Hyun-Woo Jeong

    Full Text Available In dendritic cell (DC-CD4(+ T cell interaction, Notch signaling has been implicated in the CD4(+ T cell activation, proliferation, and subset differentiation. However, there has been a lot of debate on the exact role of Notch signaling. Here, we observed that expression of Mind bomb-1 (Mib1, a critical regulator of Notch ligands for the activation of Notch signaling, increases gradually as precursor cells differentiate into DCs in mice. To clarify the role of Mib1 in DC-CD4(+ T cell interactions, we generated Mib1-null bone marrow-derived DCs. These cells readily expressed Notch ligands but failed to initiate Notch activation in the adjacent cells. Nevertheless, Mib1-null DCs were able to prime the activation and proliferation of CD4(+ T cells, suggesting that Notch activation in CD4(+ T cells is not required for these processes. Intriguingly, stimulation of CD4(+ T cells with Mib1-null DCs resulted in dramatically diminished Th2 cell populations, while preserving Th1 cell populations, both in vitro and in vivo. Our results demonstrate that Mib1 in DCs is critical for the activation of Notch signaling in CD4(+ T cells, and Notch signaling reinforces Th2 differentiation, but is not required for the activation or proliferation of the CD4(+ T cells.

  7. Compact autonomous navigation system (CANS)

    Science.gov (United States)

    Hao, Y. C.; Ying, L.; Xiong, K.; Cheng, H. Y.; Qiao, G. D.

    2017-11-01

    Autonomous navigation of Satellite and constellation has series of benefits, such as to reduce operation cost and ground station workload, to avoid the event of crises of war and natural disaster, to increase spacecraft autonomy, and so on. Autonomous navigation satellite is independent of ground station support. Many systems are developed for autonomous navigation of satellite in the past 20 years. Along them American MANS (Microcosm Autonomous Navigation System) [1] of Microcosm Inc. and ERADS [2] [3] (Earth Reference Attitude Determination System) of Honeywell Inc. are well known. The systems anticipate a series of good features of autonomous navigation and aim low cost, integrated structure, low power consumption and compact layout. The ERADS is an integrated small 3-axis attitude sensor system with low cost and small volume. It has the Earth center measurement accuracy higher than the common IR sensor because the detected ultraviolet radiation zone of the atmosphere has a brightness gradient larger than that of the IR zone. But the ERADS is still a complex system because it has to eliminate many problems such as making of the sapphire sphere lens, birefringence effect of sapphire, high precision image transfer optical fiber flattener, ultraviolet intensifier noise, and so on. The marginal sphere FOV of the sphere lens of the ERADS is used to star imaging that may be bring some disadvantages., i.e. , the image energy and attitude measurements accuracy may be reduced due to the tilt image acceptance end of the fiber flattener in the FOV. Besides Japan, Germany and Russia developed visible earth sensor for GEO [4] [5]. Do we have a way to develop a cheaper/easier and more accurate autonomous navigation system that can be used to all LEO spacecraft, especially, to LEO small and micro satellites? To return this problem we provide a new type of the system—CANS (Compact Autonomous Navigation System) [6].

  8. Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality

    DEFF Research Database (Denmark)

    Buchou, Thierry; Vernet, Muriel; Blond, Olivier

    2003-01-01

    in mice leads to postimplantation lethality. Mutant embryos were reduced in size at embryonic day 6.5 (E6.5). They did not exhibit signs of apoptosis but did show reduced cell proliferation. Mutant embryos were resorbed at E7.5. In vitro, CK2beta(-/-) morula development stopped after the blastocyst stage...

  9. B cell-autonomous somatic mutation deficit following bone marrow transplant = [B cel-autonoom gebrek in somatische mutatie na beenmergtransplantatie

    NARCIS (Netherlands)

    Glas, A.M.

    2000-01-01

    The bone marrow is the major haematopoietic organ and is critically involved in the production of all formed blood elements in postnatal life. The bone marrow contains rapidly dividing cells and therefore is sensitive to DNA damaging agents. In certain types of cancers where a high dose of

  10. Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6.

    Science.gov (United States)

    Hall, M O; Prieto, A L; Obin, M S; Abrams, T A; Burgess, B L; Heeb, M J; Agnew, B J

    2001-10-01

    The function and viability of vertebrate photoreceptors requires the daily phagocytosis of photoreceptor outer segments (OS) by the adjacent retinal pigment epithelium (RPE). We demonstrate here a critical role in this process for Gas6 and by implication one of its receptor protein tyrosine kinases (RTKs), Mertk (Mer). Gas6 specifically and selectively stimulates the phagocytosis of OS by normal cultured rat RPE cells. The magnitude of the response is dose-dependent and shows an absolute requirement for calcium. By contrast the Royal College of Surgeons (RCS) rat RPE cells, in which a mutation in the gene Mertk results in the expression of a truncated, non-functional receptor, does not respond to Gas6. These data strongly suggest that activation of Mertk by its ligand, Gas6, is the specific signaling pathway responsible for initiating the ingestion of shed OS. Moreover, photoreceptor degeneration in the RCS rat retina, which lacks Mertk, and in humans with a mutation in Mertk, strongly suggests that the Gas6/Mertk signaling pathway is essential for photoreceptor viability. We believe that this is the first demonstration of a specific function for Gas6 in the eye. Copyright 2001 Academic Press.

  11. Structural requirements for cub domain containing protein 1 (CDCP1 and Src dependent cell transformation.

    Directory of Open Access Journals (Sweden)

    Gwendlyn Kollmorgen

    Full Text Available Cub domain containing protein 1 (CDCP1 is strongly expressed in tumors derived from lung, colon, ovary, or kidney. It is a membrane protein that is phosphorylated and then bound by Src family kinases. Although expression and phosphorylation of CDCP1 have been investigated in many tumor cell lines, the CDCP1 features responsible for transformation have not been fully evaluated. This is in part due to the lack of an experimental system in which cellular transformation depends on expression of exogenous CDCP1 and Src. Here we use retrovirus mediated co-overexpression of c-Src and CDCP1 to induce focus formation of NIH3T3 cells. Employing different mutants of CDCP1 we show that for a full transformation capacity, the intact amino- and carboxy-termini of CDCP1 are essential. Mutation of any of the core intracellular tyrosine residues (Y734, Y743, or Y762 abolished transformation, and mutation of a palmitoylation motif (C689,690G strongly reduced it. Src kinase binding to CDCP1 was not required since Src with a defective SH2 domain generated even more CDCP1 dependent foci whereas Src myristoylation was necessary. Taken together, the focus formation assay allowed us to define structural requirements of CDCP1/Src dependent transformation and to characterize the interaction of CDCP1 and Src.

  12. Developing Autonomous Learning in First Year University Students Using Perspectives from Positive Psychology

    Science.gov (United States)

    Macaskill, Ann; Denovan, Andrew

    2013-01-01

    Autonomous learning is a commonly occurring learning outcome from university study, and it is argued that students require confidence in their own abilities to achieve this. Using approaches from positive psychology, this study aimed to develop confidence in first-year university students to facilitate autonomous learning. Psychological character…

  13. Development and implementation of algorithms in a population of cooperative autonomous mobile robots

    CSIR Research Space (South Africa)

    Namoshe, M

    2007-10-01

    Full Text Available An increase in the number of mobile robot users has lead to the design and implementation of cooperative autonomous mobile robots. Autonomous robots require the ability to build maps of an unknown environment while simultaneously using these maps...

  14. Increased ATP generation in the host cell is required for efficient vaccinia virus production

    Directory of Open Access Journals (Sweden)

    Hsu Che-Fang

    2009-09-01

    Full Text Available Abstract To search for cellular genes up-regulated by vaccinia virus (VV infection, differential display-reverse transcription-polymerase chain reaction (ddRT-PCR assays were used to examine the expression of mRNAs from mock-infected and VV-infected HeLa cells. Two mitochondrial genes for proteins that are part of the electron transport chain that generates ATP, ND4 and CO II, were up-regulated after VV infection. Up-regulation of ND4 level by VV infection was confirmed by Western blotting analysis. Up-regulation of ND4 was reduced by the MAPK inhibitor, apigenin, which has been demonstrated elsewhere to inhibit VV replication. The induction of ND4 expression occurred after viral DNA replication since ara C, an inhibitor of poxviral DNA replication, could block this induction. ATP production was increased in the host cells after VV infection. Moreover, 4.5 μM oligomycin, an inhibitor of ATP production, reduced the ATP level 13 hr after virus infection to that of mock-infected cells and inhibited viral protein expression and virus production, suggesting that increased ATP production is required for efficient VV production. Our results further suggest that induction of ND4 expression is through a Bcl-2 independent pathway.

  15. Cathepsin L is required for endothelial progenitor cell-induced neovascularization

    Energy Technology Data Exchange (ETDEWEB)

    Urbich, Carmen; Heeschen, Christopher; Aicher, Alexandra; Sasaki, Ken-ichiro; Bruhl, Thomas; Hofmann, Wolf K.; Peters, Christoph; Reinheckel, Thomas; Pennacchio, Len A.; Abolmaali, Nasreddin D.; Chavakis, Emmanouil; Zeiher, Andreas M.; Dimmeler, Stefanie

    2004-01-15

    Infusion of endothelial progenitor cells (EPCs), but not of mature endothelial cells (ECs), promotes neovascularization after ischemia. We performed a gene expression profiling of EPCs and ECs to identify genes, which might be important for the neovascularization capacity of EPCs. Intriguingly, the protease cathepsin L (CathL) was highly expressed in EPCs as opposed to ECs and is essential for matrix degradation and invasion by EPCs in vitro. CathL deficient mice showed impaired functional recovery after hind limb ischemia supporting the concept for an important role of CathL in postnatal neovascularization. Infused CathL deficient progenitor cells failed to home to sites of ischemia and to augment neovascularization. In contrast, over expression of CathL in mature ECs significantly enhanced their invasive activity and induced their neovascularization capacity in vivo. Taken together, CathL plays a crucial role for the integration of circulating EPCs into the ischemic tissue and is required for neovascularization mediated by EPCs.

  16. Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products.

    Science.gov (United States)

    Salmikangas, P; Flory, E; Reinhardt, J; Hinz, T; Maciulaitis, R

    2010-01-01

    The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

  17. An Interbacterial NAD(P)+ Glycohydrolase Toxin Requires Elongation Factor Tu for Delivery to Target Cells

    Energy Technology Data Exchange (ETDEWEB)

    Whitney, John C.; Quentin, Dennis; Sawai, Shin; LeRoux, Michele; Harding, Brittany N.; Ledvina, Hannah E.; Tran, Bao Q.; Robinson, Howard; Goo, Young Ah; Goodlett, David R.; Raunser, Stefan; Mougous, Joseph D.

    2015-10-08

    Type VI secretion (T6S) influences the composition of microbial communities by catalyzing the delivery of toxins between adjacent bacterial cells. Here, we demonstrate that a T6S integral membrane toxin from Pseudomonas aeruginosa, Tse6, acts on target cells by degrading the universally essential dinucleotides NAD+ and NADP+. Structural analyses of Tse6 show that it resembles mono-ADP-ribosyltransferase proteins, such as diphtheria toxin, with the exception of a unique loop that both excludes proteinaceous ADP-ribose acceptors and contributes to hydrolysis. We find that entry of Tse6 into target cells requires its binding to an essential housekeeping protein, translation elongation factor Tu (EF-Tu). These proteins participate in a larger assembly that additionally directs toxin export and provides chaperone activity. Visualization of this complex by electron microscopy defines the architecture of a toxin-loaded T6S apparatus and provides mechanistic insight into intercellular membrane protein delivery between bacteria.

  18. Impairment of Cellulose Synthases Required for Arabidopsis Secondary Cell Wall Formation Enhances Disease Resistance[W

    Science.gov (United States)

    Hernández-Blanco, Camilo; Feng, Dong Xin; Hu, Jian; Sánchez-Vallet, Andrea; Deslandes, Laurent; Llorente, Francisco; Berrocal-Lobo, Marta; Keller, Harald; Barlet, Xavier; Sánchez-Rodríguez, Clara; Anderson, Lisa K.; Somerville, Shauna; Marco, Yves; Molina, Antonio

    2007-01-01

    Cellulose is synthesized by cellulose synthases (CESAs) contained in plasma membrane–localized complexes. In Arabidopsis thaliana, three types of CESA subunits (CESA4/IRREGULAR XYLEM5 [IRX5], CESA7/IRX3, and CESA8/IRX1) are required for secondary cell wall formation. We report that mutations in these proteins conferred enhanced resistance to the soil-borne bacterium Ralstonia solanacearum and the necrotrophic fungus Plectosphaerella cucumerina. By contrast, susceptibility to these pathogens was not altered in cell wall mutants of primary wall CESA subunits (CESA1, CESA3/ISOXABEN RESISTANT1 [IXR1], and CESA6/IXR2) or POWDERY MILDEW–RESISTANT5 (PMR5) and PMR6 genes. Double mutants indicated that irx-mediated resistance was independent of salicylic acid, ethylene, and jasmonate signaling. Comparative transcriptomic analyses identified a set of common irx upregulated genes, including a number of abscisic acid (ABA)–responsive, defense-related genes encoding antibiotic peptides and enzymes involved in the synthesis and activation of antimicrobial secondary metabolites. These data as well as the increased susceptibility of ABA mutants (abi1-1, abi2-1, and aba1-6) to R. solanacearum support a direct role of ABA in resistance to this pathogen. Our results also indicate that alteration of secondary cell wall integrity by inhibiting cellulose synthesis leads to specific activation of novel defense pathways that contribute to the generation of an antimicrobial-enriched environment hostile to pathogens. PMID:17351116

  19. Pulse power requirements for large aperture optical switches based on plasma electrode Pockels cells

    International Nuclear Information System (INIS)

    Rhodes, M.A.; Taylor, J.

    1992-06-01

    We discuss very large-aperture optical switches (greater than 30 x 30 cm) as an enabling technology for inertial confinement fusion drivers based on multipass laser amplifiers. Large-scale laser fusion drivers such as the Nova laser have been based on single-pass amplifier designs in part because of the unavailability of a suitable large-aperture switch. We are developing an optical switch based on a Pockels cell employing plasma-electrodes. A plasma-electrode Pockels cell (PEPC) is a longitudinal-mode Pockels cell in which a plasma discharge is formed on each side of an electro-optic crystal (typically KDP or deuterated KDP, often designated KD*P). The plasmas formed on either side of the crystal act as transparent electrodes for a switching-pulse and are intended to allow uniform charging of the entire crystal. The switching-pulse is a nominally rectangular high-voltage pulse equal to the half-wave voltage V x ( 8 kV for KD*P or 17 kV for KDP) and is applied across the crystal via the plasma-electrodes. When the crystal is charged to V x , the polarization of an incoming, linearly polarized, laser beam is rotated by 90 degree. When used in conjunction with an appropriate, passive polarizer, an optical switch is thus realized. A switch with a clear aperture of 37 x 37 cm is now in construction for the Beamlet laser which will serve as a test bed for this switch as well as other technologies required for an advanced NOVA laser design. In this paper, we discuss the unique power electronics requirements of PEPC optical switches

  20. Mapping autonomously replicating sequence elements in a 73-kb ...

    Indian Academy of Sciences (India)

    Autonomously replicating sequence (ARS) elements are the genetic determinants of replication origin function in yeasts. They can be easily identified as the plasmids containing them transform yeast cells at a high frequency. As the first step towards identifying all potential replication origins in a 73-kb region of the long arm ...

  1. Autonomous vehicles: from paradigms to technology

    Science.gov (United States)

    Ionita, Silviu

    2017-10-01

    Mobility is a basic necessity of contemporary society and it is a key factor in global economic development. The basic requirements for the transport of people and goods are: safety and duration of travel, but also a number of additional criteria are very important: energy saving, pollution, passenger comfort. Due to advances in hardware and software, automation has penetrated massively in transport systems both on infrastructure and on vehicles, but man is still the key element in vehicle driving. However, the classic concept of ‘human-in-the-loop’ in terms of ‘hands on’ in driving the cars is competing aside from the self-driving startups working towards so-called ‘Level 4 autonomy’, which is defined as “a self-driving system that does not requires human intervention in most scenarios”. In this paper, a conceptual synthesis of the autonomous vehicle issue is made in connection with the artificial intelligence paradigm. It presents a classification of the tasks that take place during the driving of the vehicle and its modeling from the perspective of traditional control engineering and artificial intelligence. The issue of autonomous vehicle management is addressed on three levels: navigation, movement in traffic, respectively effective maneuver and vehicle dynamics control. Each level is then described in terms of specific tasks, such as: route selection, planning and reconfiguration, recognition of traffic signs and reaction to signaling and traffic events, as well as control of effective speed, distance and direction. The approach will lead to a better understanding of the way technology is moving when talking about autonomous cars, smart/intelligent cars or intelligent transport systems. Keywords: self-driving vehicle, artificial intelligence, deep learning, intelligent transport systems.

  2. Effect of Spermidine Analogues on Cell Growth of Escherichia coli Polyamine Requiring Mutant MA261.

    Directory of Open Access Journals (Sweden)

    Taketo Yoshida

    Full Text Available The effects of spermidine analogues [norspermidine (NSPD, 33, spermidine (SPD, 34, homospermidine (HSPD, 44 and aminopropylcadaverine (APCAD, 35] on cell growth were studied using Escherichia coli polyamine-requiring mutant MA261. Cell growth was compared at 32°C, 37°C, and 42°C. All four analogues were taken up mainly by the PotABCD spermidine-preferential uptake system. The degree of stimulation of cell growth at 32°C and 37°C was NSPD ≥ SPD ≥ HSPD > APCAD, and SPD ≥ HSPD ≥ NSPD > APCAD, respectively. However, at 42°C, it was HSPD » SPD > NSPD > APCAD. One reason for this is HSPD was taken up effectively compared with other triamines. In addition, since natural polyamines (triamines and teteraamines interact mainly with RNA, and the structure of RNA is more flexible at higher temperatures, HSPD probably stabilized RNA more tightly at 42°C. We have thus far found that 20 kinds of protein syntheses are stimulated by polyamines at the translational level. Among them, synthesis of OppA, RpoE and StpA was more strongly stimulated by HSPD at 42°C than at 37°C. Stabilization of the initiation region of oppA and rpoE mRNA was tighter by HSPD at 42°C than 37°C determined by circular dichroism (CD. The degree of polyamine stimulation of OppA, RpoE and StpA synthesis by NSPD, SPD and APCAD was smaller than that by HSPD at 42°C. Thus, the degree of stimulation of cell growth by spermidine analogues at the different temperatures is dependent on the stimulation of protein synthesis by some components of the polyamine modulon.

  3. ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells.

    Directory of Open Access Journals (Sweden)

    Qing Lu

    Full Text Available Estrogen promotes the proliferation and migration of vascular endothelial cells (ECs, which likely underlies its ability to accelerate re-endothelialization and reduce adverse remodeling after vascular injury. In previous studies, we have shown that the protective effects of E2 (the active endogenous form of estrogen in vascular injury require the estrogen receptor alpha (ERα. ERα transduces the effects of estrogen via a classical DNA binding, "genomic" signaling pathway and via a more recently-described "rapid" signaling pathway that is mediated by a subset of ERα localized to the cell membrane. However, which of these pathways mediates the effects of estrogen on endothelial cells is poorly understood. Here we identify a triple point mutant version of ERα (KRR ERα that is specifically defective in rapid signaling, but is competent to regulate transcription through the "genomic" pathway. We find that in ECs expressing wild type ERα, E2 regulates many genes involved in cell migration and proliferation, promotes EC migration and proliferation, and also blocks the adhesion of monocytes to ECs. ECs expressing KRR mutant ERα, however, lack all of these responses. These observations establish KRR ERα as a novel tool that could greatly facilitate future studies into the vascular and non-vascular functions of ERα rapid signaling. Further, they support that rapid signaling through ERα is essential for many of the transcriptional and physiological responses of ECs to E2, and that ERα rapid signaling in ECs, in vivo, may be critical for the vasculoprotective and anti-inflammatory effects of estrogen.

  4. Low Immunogenic Endothelial Cells Maintain Morphological and Functional Properties Required for Vascular Tissue Engineering.

    Science.gov (United States)

    Lau, Skadi; Eicke, Dorothee; Carvalho Oliveira, Marco; Wiegmann, Bettina; Schrimpf, Claudia; Haverich, Axel; Blasczyk, Rainer; Wilhelmi, Mathias; Figueiredo, Constança; Böer, Ulrike

    2018-03-01

    functional properties required for vascular tissue engineering. This extends the spectrum of available cell sources from autologous to allogeneic sources, thereby accelerating the generation of tissue-engineered vascular grafts in acute clinical cases.

  5. The Bering Autonomous Target Detection

    DEFF Research Database (Denmark)

    Jørgensen, John Leif; Denver, Troelz; Betto, Maurizio

    2003-01-01

    An autonomous asteroid target detection and tracking method has been developed. The method features near omnidirectionality and focus on high speed operations and completeness of search of the near space rather than the traditional faint object search methods, employed presently at the larger...... telescopes. The method has proven robust in operation and is well suited for use onboard spacecraft. As development target for the method and the associated instrumentation the asteroid research mission Bering has been used. Onboard a spacecraft, the autonomous detection is centered around the fully...... autonomous star tracker the Advanced Stellar Compass (ASC). One feature of this instrument is that potential targets are registered directly in terms of date, right ascension, declination, and intensity, which greatly facilitates both tracking search and registering. Results from ground and inflight tests...

  6. Autonomous Industrial Mobile Manipulation (AIMM)

    DEFF Research Database (Denmark)

    Hvilshøj, Mads; Bøgh, Simon; Nielsen, Oluf Skov

    2012-01-01

    Purpose - The purpose of this paper is to provide a review of the interdisciplinary research field Autonomous Industrial Mobile Manipulation (AIMM), with an emphasis on physical implementations and applications. Design/methodology/approach - Following an introduction to AIMM, this paper investiga......Purpose - The purpose of this paper is to provide a review of the interdisciplinary research field Autonomous Industrial Mobile Manipulation (AIMM), with an emphasis on physical implementations and applications. Design/methodology/approach - Following an introduction to AIMM, this paper......; sustainability, configuration, adaptation, autonomy, positioning, manipulation and grasping, robot-robot interaction, human-robot interaction, process quality, dependability, and physical properties. Findings - The concise yet comprehensive review provides both researchers (academia) and practitioners (industry......) with a quick and gentle overview of AIMM. Furthermore, the paper identifies key open issues and promising research directions to realize real-world integration and maturation of the AIMM technology. Originality/value - This paper reviews the interdisciplinary research field Autonomous Industrial Mobile...

  7. Implementation of a photovoltaic/electrolyzer/fuel cell autonomous system; Implementacao de um sistema autonomo fotovoltaico/eletrolisador/celula a combustivel

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Ennio Peres da; Apolinario, Fernando Rezende; Furlan, Andre Luis [Universidade Estadual de Campinas (IFGW/UNICAMP), SP (Brazil). Inst. de Fisica Gleb Wataghin. Lab. de Hidrogenio], Emails: lh2ennio@ifi.unicamp.br, rezende@ifi.unicamp.br; Souza, Rubem Cesar Rodrigues [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil). Centro de Desenvolvimento Energetico Amazonico], Email: rubem_souza@yahoo.com.br; Pinto, Adailton de Souza [Centrais Eletricas do Norte do Brasil S.A. (ELETRONORTE), Brasilia, DF (Brazil)], Email: adailton@eln.gov.br

    2006-07-01

    This article presents a project whose main objective is to analyze the technical feasibility of using a system based on the production of hydrogen (H{sub 2}) for storing the energy generated for photovoltaic systems. The work involves the design, physical implementation and the performance evaluation of a system for hydrogen electrolytic generation with solar-photovoltaic energy, the treatment os gas, its storage and it use in fuel cell systems. This work will be performed in cooperation between researchers from the Laboratorio de Hidrogenio (LH2) of the UNICAMP and of the Centro de Desenvolvimento Energetico Amazonico (CDEAM) of the UFAM, and is financing by ELETRONORTE.

  8. SAP is required for the development of innate phenotype in H2-M3-restricted CD8+ T cells1

    Science.gov (United States)

    Bediako, Yaw; Bian, Yao; Zhang, Hong; Cho, Hoonsik; Stein, Paul L.; Wang, Chyung-Ru

    2012-01-01

    H2-M3-restricted T cells have a pre-activated surface phenotype, rapidly expand and produce cytokines upon stimulation and as such, are classified as innate T cells. Unlike most innate T cells, M3-restricted T cells also express CD8αβ co-receptors and a diverse TCR repertoire: hallmarks of conventional MHC Ia-restricted CD8+ T cells. Although iNKT cells are also innate lymphocytes, they are selected exclusively on hematopoietic cells (HC), while M3-restricted T cells can be selected on either hematopoietic or thymic epithelial cells (TEC). Moreover, their phenotypes differ depending on what cells mediate their selection. Though there is a clear correlation between selection on HC and development of innate phenotype, the underlying mechanism remains unclear. SAP is required for the development of iNKT cells and mediates signals from SLAM receptors that are exclusively expressed on HC. Based on their dual selection pathway, M3-restricted T cells present a unique model for studying the development of innate T cell phenotype. Using both polyclonal and transgenic mouse models we demonstrate that while M3-restricted T cells are capable of developing in the absence of SAP, SAP is required for HC-mediated selection, development of pre-activated phenotype and heightened effector functions of M3-restricted T cells. These findings are significant because they directly demonstrate the need for SAP in HC-mediated acquisition of innate T cell phenotype and suggest that due to their SAP-dependent HC-mediated selection, M3-restricted T cells develop a pre-activated phenotype and an intrinsic ability to proliferate faster upon stimulation, allowing for an important role in the early response to infection. PMID:23041566

  9. Autonomic Regulation of Splanchnic Circulation

    Directory of Open Access Journals (Sweden)

    Kathleen A Fraser

    1991-01-01

    Full Text Available The role of the autonomic nervous system in circulatory regulation of the splanchnic organs (stomach, small intestine, colon, liver, pancreas and spleen is reviewed. In general, the sympathetic nervous system is primarily involved in vasoconstriction, while the parasympathetic contributes to vasodilation. Vasoconstriction in the splanchnic circulation appears to be mediated by alpha-2 receptors and vasodilation by activation of primary afferent nerves with subsequent release of vasodilatory peptides, or by stimulation of beta-adrenergic receptors. As well, an important function of the autonomic nervous system is to provide a mechanism by which splanchnic vascular reserve can be mobilized during stress to maintain overall cardiovascular homeostasis.

  10. Political accountability and autonomous weapons

    Directory of Open Access Journals (Sweden)

    James Igoe Walsh

    2015-09-01

    Full Text Available Autonomous weapons would have the capacity to select and attack targets without direct human input. One important objection to the introduction of such weapons is that they will make it more difficult to identify and hold accountable those responsible for undesirable outcomes such as mission failures and civilian casualties. I hypothesize that individuals can modify their attribution of responsibility in predicable ways to accommodate this new technology. The results of a survey experiment are consistent with this; subjects continue to find responsible and hold accountable political and military leaders when autonomous weapons are used, but also attribute responsibility to the designers and programmers of such weapons.

  11. Gas House Autonomous System Monitoring

    Science.gov (United States)

    Miller, Luke; Edsall, Ashley

    2015-01-01

    Gas House Autonomous System Monitoring (GHASM) will employ Integrated System Health Monitoring (ISHM) of cryogenic fluids in the High Pressure Gas Facility at Stennis Space Center. The preliminary focus of development incorporates the passive monitoring and eventual commanding of the Nitrogen System. ISHM offers generic system awareness, adept at using concepts rather than specific error cases. As an enabler for autonomy, ISHM provides capabilities inclusive of anomaly detection, diagnosis, and abnormality prediction. Advancing ISHM and Autonomous Operation functional capabilities enhances quality of data, optimizes safety, improves cost effectiveness, and has direct benefits to a wide spectrum of aerospace applications.

  12. Advances in Autonomous Systems for Missions of Space Exploration

    Science.gov (United States)

    Gross, A. R.; Smith, B. D.; Briggs, G. A.; Hieronymus, J.; Clancy, D. J.

    New missions of space exploration will require unprecedented levels of autonomy to successfully accomplish their objectives. Both inherent complexity and communication distances will preclude levels of human involvement common to current and previous space flight missions. With exponentially increasing capabilities of computer hardware and software, including networks and communication systems, a new balance of work is being developed between humans and machines. This new balance holds the promise of meeting the greatly increased space exploration requirements, along with dramatically reduced design, development, test, and operating costs. New information technologies, which take advantage of knowledge-based software, model-based reasoning, and high performance computer systems, will enable the development of a new generation of design and development tools, schedulers, and vehicle and system health monitoring and maintenance capabilities. Such tools will provide a degree of machine intelligence and associated autonomy that has previously been unavailable. These capabilities are critical to the future of space exploration, since the science and operational requirements specified by such missions, as well as the budgetary constraints that limit the ability to monitor and control these missions by a standing army of ground- based controllers. System autonomy capabilities have made great strides in recent years, for both ground and space flight applications. Autonomous systems have flown on advanced spacecraft, providing new levels of spacecraft capability and mission safety. Such systems operate by utilizing model-based reasoning that provides the capability to work from high-level mission goals, while deriving the detailed system commands internally, rather than having to have such commands transmitted from Earth. This enables missions of such complexity and communications distance as are not otherwise possible, as well as many more efficient and low cost

  13. Towards Competitive Commercial Autonomous Robots: The Configuration Problem

    DEFF Research Database (Denmark)

    Kjærgaard, Morten; Andersen, Nils Axel; Ravn, Ole

    2011-01-01

    knowledge about the underlying algorithms. The framework also makes it possible for the robot to autonomously calibrate itself, resulting in higher stability of the robot and less development time required. The work is a result of an industrial research project aimed at lowering development costs...

  14. approximate controllability of a non-autonomous differential equation

    Indian Academy of Sciences (India)

    53

    for a non-autonomous functional differential equation using the theory of linear ... approximate controllability of various functional differential equations in abstract ...... the operator A(t) and into the requirement that x(t) ∈ D(A) for all t ≥ 0.

  15. Safety analysis of autonomous excavator functionality

    International Nuclear Information System (INIS)

    Seward, D.; Pace, C.; Morrey, R.; Sommerville, I.

    2000-01-01

    This paper presents an account of carrying out a hazard analysis to define the safety requirements for an autonomous robotic excavator. The work is also relevant to the growing generic class of heavy automated mobile machinery. An overview of the excavator design is provided and the concept of a safety manager is introduced. The safety manager is an autonomous module responsible for all aspects of system operational safety, and is central to the control system's architecture. Each stage of the hazard analysis is described, i.e. system model creation, hazard definition and hazard analysis. Analysis at an early stage of the design process, and on a system that interfaces directly to an unstructured environment, exposes certain issues relevant to the application of current hazard analysis methods. The approach taken in the analysis is described. Finally, it is explained how the results of the hazard analysis have influenced system design, in particular, safety manager specifications. Conclusions are then drawn about the applicability of hazard analysis of requirements in general, and suggestions are made as to how the approach can be taken further

  16. Security-Enhanced Autonomous Network Management

    Science.gov (United States)

    Zeng, Hui

    2015-01-01

    Ensuring reliable communication in next-generation space networks requires a novel network management system to support greater levels of autonomy and greater awareness of the environment and assets. Intelligent Automation, Inc., has developed a security-enhanced autonomous network management (SEANM) approach for space networks through cross-layer negotiation and network monitoring, analysis, and adaptation. The underlying technology is bundle-based delay/disruption-tolerant networking (DTN). The SEANM scheme allows a system to adaptively reconfigure its network elements based on awareness of network conditions, policies, and mission requirements. Although SEANM is generically applicable to any radio network, for validation purposes it has been prototyped and evaluated on two specific networks: a commercial off-the-shelf hardware test-bed using Institute of Electrical Engineers (IEEE) 802.11 Wi-Fi devices and a military hardware test-bed using AN/PRC-154 Rifleman Radio platforms. Testing has demonstrated that SEANM provides autonomous network management resulting in reliable communications in delay/disruptive-prone environments.

  17. Industry requirements for introduction of alternative energies with emphasis on hydrogen fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Delabbio, F. [Rio Tinto, Canadian Exploration Ltd., Toronto, ON (Canada); Starbuck, D. [Newmont Mining Corp., Denver, CO (United States); Akerman, A. [CVRD-Inco, Toronto, ON (Canada); Betournay, M.C. [Natural Resources Canada, Ottawa, ON (Canada). CANMET Mining and Mineral Sciences Laboratories

    2007-07-01

    This paper discussed issues related to the use of alternate sources of energy in underground mining applications. Hydrogen power systems were examined in relation to operational drivers, available commercial supplies, site supplies, health and safety issues, capital and operating costs, mine production, and the role of government. Hydrogen power systems are being considered for mining applications in an effort to reduce greenhouse gas (GHG) emissions and reduce cooling and ventilation requirements. This article examined a range of issues that must be addressed before alternate energy systems such as hydrogen fuel cell technology can be used in larger-scale underground mining applications. The mining industry supports the development of new technologies. However, the introduction of alternate energy technologies must proceed in steps which include proof of concept testing, the development of generic infrastructure, power systems and regulations, and whole operating system studies. 13 refs., 1 fig.

  18. Construction of concrete hot cells; requirements for shielding windows for concrete walls with different densities

    International Nuclear Information System (INIS)

    1987-10-01

    The shielding windows form part of the basic equipment of hot cells for remote handling, as defined in standard DIN 25 420 part 1. The draft standard in hand is intended to specify the design and manufacture requirements, especially with regard to main dimensions, sight quality, shielding effects, and radiation resistance. The standard refers to three types of shielding window with surface area design (product of density and wall thickness) corresponding to concrete walls of the densities 2.4, 3.4, and 4.0 g/cm 3 . The windows fit to three types of concrete of common usage, and the design is made for Co-60 radiation, with attenuation factors of about 10 4 , 10 6 , or 10 7 . For concrete walls with densities between these data, a shielding window suitable to the next higher density data is to be chosen. (orig./HP) [de

  19. Dystroglycan is required for polarizing the epithelial cells and the oocyte in Drosophila

    DEFF Research Database (Denmark)

    Deng, Wu-Min; Schneider, Martina; Frock, Richard

    2003-01-01

    The transmembrane protein Dystroglycan is a central element of the dystrophin-associated glycoprotein complex, which is involved in the pathogenesis of many forms of muscular dystrophy. Dystroglycan is a receptor for multiple extracellular matrix (ECM) molecules such as Laminin, agrin and perlecan......, and plays a role in linking the ECM to the actin cytoskeleton; however, how these interactions are regulated and their basic cellular functions are poorly understood. Using mosaic analysis and RNAi in the model organism Drosophila melanogaster, we show that Dystroglycan is required cell......, possibly by organizing the Laminin ECM. These data suggest that the primary function of Dystroglycan in oogenesis is to organize cellular polarity; and this study sets the stage for analyzing the Dystroglycan complex by using the power of Drosophila molecular genetics....

  20. Alloantigen-specific suppressor T cells are not inhibited by cyclosporin A, but do require IL 2 for activation

    International Nuclear Information System (INIS)

    Bucy, R.P.

    1986-01-01

    Alloantigen-specific suppressor T cells are activated from normal murine spleen cells in mixed lymphocyte reactions (MLR). These T cells are radioresistant and suppress the activation of cytotoxic T lymphocytes (CTL) in second primary MLR cultures. This report demonstrates that cyclosporin A (CsA) blocks the activation of these suppressor cells at a dose of 1 microgram/ml. However, reconstitution of CsA blocked cultures with IL 2 restores the activation of the suppressor T cells, but fails to significantly restore the activation of CTL in these same cultures. This differential activation requirement was used to establish T cell lines that demonstrate enriched suppressor cell activity but depletion of CTL activity. These findings are discussed in terms of the mechanism of action of CsA in these distinct T cell subsets and the relevance to models of allograft unresponsiveness

  1. Large, but not small, antigens require time- and temperature-dependent processing in accessory cells before they can be recognized by T cells

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1986-01-01

    We have studied if antigens of different size and structure all require processing in antigen-presenting cells of guinea-pigs before they can be recognized by T cells. The method of mild paraformaldehyde fixation was used to stop antigen-processing in the antigen-presenting cells. As a measure...... of antigen presentation we used the proliferative response of appropriately primed T cells during a co-culture with the paraformaldehyde-fixed and antigen-exposed presenting cells. We demonstrate that the large synthetic polypeptide antigen, dinitrophenyl-poly-L-lysine, requires processing. After an initial......-dependent and consequently energy-requiring. Processing is strongly inhibited by the lysosomotrophic drug, chloroquine, suggesting a lysosomal involvement in antigen processing. The existence of a minor, non-lysosomal pathway is suggested, since small amounts of antigen were processed even at 10 degrees C, at which...

  2. Expert system isssues in automated, autonomous space vehicle rendezvous

    Science.gov (United States)

    Goodwin, Mary Ann; Bochsler, Daniel C.

    1987-01-01

    The problems involved in automated autonomous rendezvous are briefly reviewed, and the Rendezvous Expert (RENEX) expert system is discussed with reference to its goals, approach used, and knowledge structure and contents. RENEX has been developed to support streamlining operations for the Space Shuttle and Space Station program and to aid definition of mission requirements for the autonomous portions of rendezvous for the Mars Surface Sample Return and Comet Nucleus Sample return unmanned missions. The experience with REMEX to date and recommendations for further development are presented.

  3. Co-stimulation by anti-immunoglobulin is required for B cell activation by CD40Llow T cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    cell Ag specificity by using anti-CD3/T cell receptor (TcR) monoclonal antibodies (mAb) to activate T cells. To study the role of sIg engagement in the responsiveness of B cells to T help, we pre-treated small resting B cells with soluble anti-kappa mAb prior to contact with an activated Th1 clone...... strongly. Low buoyant density B cells also responded to CD40Llow Th cells. There was no B cell response to resting Th cells. mAb against CD54/intercellular adhesion molecule-1 or major histocompatibility complex (MHC) class II completely inhibited B cell responses to CD40Llow Th1 cells, equivalent...

  4. Highly stable loading of Mcm proteins onto chromatin in living cells requires replication to unload

    Science.gov (United States)

    Kuipers, Marjorie A.; Stasevich, Timothy J.; Sasaki, Takayo; Wilson, Korey A.; Hazelwood, Kristin L.; McNally, James G.; Davidson, Michael W.

    2011-01-01

    The heterohexameric minichromosome maintenance protein complex (Mcm2-7) functions as the eukaryotic helicase during DNA replication. Mcm2-7 loads onto chromatin during early G1 phase but is not converted into an active helicase until much later during S phase. Hence, inactive Mcm complexes are presumed to remain stably bound from early G1 through the completion of S phase. Here, we investigated Mcm protein dynamics in live mammalian cells. We demonstrate that Mcm proteins are irreversibly loaded onto chromatin cumulatively throughout G1 phase, showing no detectable exchange with a gradually diminishing soluble pool. Eviction of Mcm requires replication; during replication arrest, Mcm proteins remained bound indefinitely. Moreover, the density of immobile Mcms is reduced together with chromatin decondensation within sites of active replication, which provides an explanation for the lack of colocalization of Mcm with replication fork proteins. These results provide in vivo evidence for an exceptionally stable lockdown mechanism to retain all loaded Mcm proteins on chromatin throughout prolonged cell cycles. PMID:21220507

  5. Autonomic dysfunction in cirrhosis and portal hypertension

    DEFF Research Database (Denmark)

    Dümcke, Christine Winkler; Møller, Søren

    2008-01-01

    Liver cirrhosis and portal hypertension are frequently associated with signs of circulatory dysfunction and peripheral polyneuropathy, which includes defects of the autonomic nervous system. Autonomic dysfunction, which is seen in both alcoholic and non-alcoholic liver cirrhosis and increases...

  6. Energy homeostasis, autonomic activity and obesity

    NARCIS (Netherlands)

    Scheurink, AJW; Balkan, B; Nyakas, C; vanDijk, G; Steffens, AB; Bohus, B

    1995-01-01

    Obesity is often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The present paper summarizes the results of a number of studies designed to investigate autonomic functioning in normal, genetically, and experimentally obese rats, Particular emphasis is given

  7. Connected and autonomous vehicles 2040 vision.

    Science.gov (United States)

    2014-07-01

    The Pennsylvania Department of Transportation (PennDOT) commissioned a one-year project, Connected and Autonomous : Vehicles 2040 Vision, with researchers at Carnegie Mellon University (CMU) to assess the implications of connected and : autonomous ve...

  8. Improving Human/Autonomous System Teaming Through Linguistic Analysis

    Science.gov (United States)

    Meszaros, Erica L.

    2016-01-01

    An area of increasing interest for the next generation of aircraft is autonomy and the integration of increasingly autonomous systems into the national airspace. Such integration requires humans to work closely with autonomous systems, forming human and autonomous agent teams. The intention behind such teaming is that a team composed of both humans and autonomous agents will operate better than homogenous teams. Procedures exist for licensing pilots to operate in the national airspace system and current work is being done to define methods for validating the function of autonomous systems, however there is no method in place for assessing the interaction of these two disparate systems. Moreover, currently these systems are operated primarily by subject matter experts, limiting their use and the benefits of such teams. Providing additional information about the ongoing mission to the operator can lead to increased usability and allow for operation by non-experts. Linguistic analysis of the context of verbal communication provides insight into the intended meaning of commonly heard phrases such as "What's it doing now?" Analyzing the semantic sphere surrounding these common phrases enables the prediction of the operator's intent and allows the interface to supply the operator's desired information.

  9. Overlapping Requirements for Tet2 and Tet3 in Normal Development and Hematopoietic Stem Cell Emergence

    Directory of Open Access Journals (Sweden)

    Cheng Li

    2015-08-01

    Full Text Available The Tet family of methylcytosine dioxygenases (Tet1, Tet2, and Tet3 convert 5-methylcytosine to 5-hydroxymethylcytosine. To date, functional overlap among Tet family members has not been examined systematically in the context of embryonic development. To clarify the potential for overlap among Tet enzymes during development, we mutated the zebrafish orthologs of Tet1, Tet2, and Tet3 and examined single-, double-, and triple-mutant genotypes. Here, we identify Tet2 and Tet3 as the major 5-methylcytosine dioxygenases in the zebrafish embryo and uncover a combined requirement for Tet2 and Tet3 in hematopoietic stem cell (HSC emergence. We demonstrate that Notch signaling in the hemogenic endothelium is regulated by Tet2/3 prior to HSC emergence and show that restoring expression of the downstream gata2b/scl/runx1 transcriptional network can rescue HSCs in tet2/3 double mutant larvae. Our results reveal essential, overlapping functions for tet genes during embryonic development and uncover a requirement for 5hmC in regulating HSC production.

  10. Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton.

    Directory of Open Access Journals (Sweden)

    Cheng Cui

    2013-11-01

    Full Text Available Planar cell polarity (PCP regulates cell alignment required for collective cell movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question of the role of the cilium in PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and collective cell movement, but the underlying mechanism is unknown. Here we show Wdpcp can regulate PCP by direct modulation of the actin cytoskeleton. These studies were made possible by recovery of a Wdpcp mutant mouse model. Wdpcp-deficient mice exhibit phenotypes reminiscent of Bardet-Biedl/Meckel-Gruber ciliopathy syndromes, including cardiac outflow tract and cochlea defects associated with PCP perturbation. We observed Wdpcp is localized to the transition zone, and in Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the transition zone, indicating Wdpcp is required for recruitment of proteins essential for ciliogenesis. Wdpcp is also found in the cytoplasm, where it is localized in the actin cytoskeleton and in focal adhesions. Wdpcp interacts with Sept2 and is colocalized with Sept2 in actin filaments, but in Wdpcp-deficient cells, Sept2 was lost from the actin cytoskeleton, suggesting Wdpcp is required for Sept2 recruitment to actin filaments. Significantly, organization of the actin filaments and focal contacts were markedly changed in Wdpcp-deficient cells. This was associated with decreased membrane ruffling, failure to establish cell polarity, and loss of directional cell migration. These results suggest the PCP defects in Wdpcp mutants are not caused by loss of cilia, but by direct disruption of the actin cytoskeleton. Consistent with this, Wdpcp mutant cochlea has normal kinocilia and yet exhibits PCP defects. Together, these findings provide the first evidence, to our knowledge, that a PCP component required for ciliogenesis can directly modulate the actin

  11. GPS/DR Error Estimation for Autonomous Vehicle Localization.

    Science.gov (United States)

    Lee, Byung-Hyun; Song, Jong-Hwa; Im, Jun-Hyuck; Im, Sung-Hyuck; Heo, Moon-Beom; Jee, Gyu-In

    2015-08-21

    Autonomous vehicles require highly reliable navigation capabilities. For example, a lane-following method cannot be applied in an intersection without lanes, and since typical lane detection is performed using a straight-line model, errors can occur when the lateral distance is estimated in curved sections due to a model mismatch. Therefore, this paper proposes a localization method that uses GPS/DR error estimation based on a lane detection method with curved lane models, stop line detection, and curve matching in order to improve the performance during waypoint following procedures. The advantage of using the proposed method is that position information can be provided for autonomous driving through intersections, in sections with sharp curves, and in curved sections following a straight section. The proposed method was applied in autonomous vehicles at an experimental site to evaluate its performance, and the results indicate that the positioning achieved accuracy at the sub-meter level.

  12. GPS/DR Error Estimation for Autonomous Vehicle Localization

    Directory of Open Access Journals (Sweden)

    Byung-Hyun Lee

    2015-08-01

    Full Text Available Autonomous vehicles require highly reliable navigation capabilities. For example, a lane-following method cannot be applied in an intersection without lanes, and since typical lane detection is performed using a straight-line model, errors can occur when the lateral distance is estimated in curved sections due to a model mismatch. Therefore, this paper proposes a localization method that uses GPS/DR error estimation based on a lane detection method with curved lane models, stop line detection, and curve matching in order to improve the performance during waypoint following procedures. The advantage of using the proposed method is that position information can be provided for autonomous driving through intersections, in sections with sharp curves, and in curved sections following a straight section. The proposed method was applied in autonomous vehicles at an experimental site to evaluate its performance, and the results indicate that the positioning achieved accuracy at the sub-meter level.

  13. More Effective Use of Urban Space by Autonomous Double Parking

    Directory of Open Access Journals (Sweden)

    Rafael Estepa

    2017-01-01

    Full Text Available The new capabilities of autonomous cars can be used to mitigate to a large extent safety concerns and nuisance traditionally associated with double parking. In this paper double parking for autonomous cars is proposed as a new approach to temporarily increase parking capacity in locations in clear need for extra provision when best alternatives cannot be found. The basic requirements, operation, and procedures of the proposed solution are outlined. A curbside parking has been simulated implementing the suggested double parking operation and important advantages have been identified for drivers, the environment, and the city. Double parking can increase over 50% the parking capacity of a given area. Autonomous car owners would (at least double their probabilities of finding parking compared to traditional drivers, saving cruising time and emissions. However, significant work and technological advances are still needed in order to make this feasible in the near future.

  14. Mapping of ESE-1 subdomains required to initiate mammary epithelial cell transformation via a cytoplasmic mechanism

    Directory of Open Access Journals (Sweden)

    Tentler John J

    2011-08-01

    Full Text Available Abstract Background The ETS family transcription factor ESE-1 is often overexpressed in human breast cancer. ESE-1 initiates transformation of MCF-12A cells via a non-transcriptional, cytoplasmic process that is mediated by a unique 40-amino acid serine and aspartic acid rich (SAR subdomain, whereas, ESE-1's nuclear transcriptional property is required to maintain the transformed phenotype of MCF7, ZR-75-1 and T47D breast cancer cells. Results To map the minimal functional nuclear localization (NLS and nuclear export (NES signals, we fused in-frame putative NLS and NES motifs between GFP and the SAR domain. Using these GFP constructs as reporters of subcellular localization, we mapped a single NLS to six basic amino acids (242HGKRRR247 in the AT-hook and two CRM1-dependent NES motifs, one to the pointed domain (NES1: 102LCNCALEELRL112 and another to the DNA binding domain (DBD, (NES2: 275LWEFIRDILI284. Moreover, analysis of a putative NLS located in the DBD (316GQKKKNSN323 by a similar GFP-SAR reporter or by internal deletion of the DBD, revealed this sequence to lack NLS activity. To assess the role of NES2 in regulating ESE-1 subcellular localization and subsequent transformation potency, we site-specifically mutagenized NES2, within full-length GFP-ESE-1 and GFP-NES2-SAR reporter constructs. These studies show that site-specific mutation of NES2 completely abrogates ESE-1 transforming activity. Furthermore, we show that exclusive cytoplasmic targeting of the SAR domain is sufficient to initiate transformation, and we report that an intact SAR domain is required, since block mutagenesis reveals that an intact SAR domain is necessary to maintain its full transforming potency. Finally, using a monoclonal antibody targeting the SAR domain, we demonstrate that the SAR domain contains a region accessible for protein - protein interactions. Conclusions These data highlight that ESE-1 contains NLS and NES signals that play a critical role in

  15. Requirement for CD40 ligand, CD4(+) T cells, and B cells in an infectious mononucleosis-like syndrome

    DEFF Research Database (Denmark)

    Brooks, J W; Hamilton-Easton, A M; Christensen, J P

    1999-01-01

    (+) CD8(+) population that is found in mice with different major histocompatibility complex (MHC) haplotypes. Aspects of the CD8(+)-T-cell response are substantially modified in mice that lack B cells, CD4(+) T cells, or the CD40 ligand (CD40L). The B-cell-deficient mice show no increase in Vbeta4(+) CD8......(+) T cells. Similar abrogation of the Vbeta4(+) CD8(+) response is seen following antibody-mediated depletion of the CD4(+) subset, through the numbers of CD8(+) CD62L(lo) cells are still significantly elevated. Virus-specific CD4(+)-T-cell frequencies are minimal in the CD40L(-/-) mice, and the Vbeta4......(+) CD8(+) population remains unexpanded. Apparently B-cell-CD4(+)-T-cell interactions play a part in the gammaHV-68 induction of both splenomegaly and non-MHC-restricted Vbeta4(+) CD8(+)-T-cell expansion....

  16. Streptococcus pneumoniae PBP2x mid-cell localization requires the C-terminal PASTA domains and is essential for cell shape maintenance

    NARCIS (Netherlands)

    Peters, Katharina; Schweizer, Inga; Beilharz, Katrin; Stahlmann, Christoph; Veening, Jan-Willem; Hakenbeck, Regine; Denapaite, Dalia

    The transpeptidase activity of the essential penicillin-binding protein 2x (PBP2x) of Streptococcus pneumoniae is believed to be important for murein biosynthesis required for cell division. To study the molecular mechanism driving localization of PBP2x in live cells, we constructed a set of

  17. What on "irf" is this gene 4? Irf4 transcription-factor-dependent dendritic cells are required for T helper 2 cell responses in murine skin.

    Science.gov (United States)

    Flutter, Barry; Nestle, Frank O

    2013-10-17

    Interferon regulatory factors play an important role in the transcriptional regulation of immunity. In this issue of Immunity, Kumamoto et al. (2013) and Gao et al. (2013) identify an Irf4-dependent migratory dendritic cell subset required for T helper 2 cell polarization following cutaneous challenge. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Formal Verification of Autonomous Vehicle Platooning

    OpenAIRE

    Kamali, Maryam; Dennis, Louise A.; McAree, Owen; Fisher, Michael; Veres, Sandor M.

    2016-01-01

    The coordination of multiple autonomous vehicles into convoys or platoons is expected on our highways in the near future. However, before such platoons can be deployed, the new autonomous behaviors of the vehicles in these platoons must be certified. An appropriate representation for vehicle platooning is as a multi-agent system in which each agent captures the "autonomous decisions" carried out by each vehicle. In order to ensure that these autonomous decision-making agents in vehicle platoo...

  19. The scaffold protein MEK Partner 1 is required for the survival of estrogen receptor positive breast cancer cells

    Directory of Open Access Journals (Sweden)

    Marina Mihaela

    2012-07-01

    Full Text Available Abstract MEK Partner 1 (MP1 or MAPKSP1 is a scaffold protein that has been reported to function in multiple signaling pathways, including the ERK, PAK and mTORC pathways. Several of these pathways influence the biology of breast cancer, but MP1’s functional significance in breast cancer cells has not been investigated. In this report, we demonstrate a requirement for MP1 expression in estrogen receptor (ER positive breast cancer cells. MP1 is widely expressed in both ER-positive and negative breast cancer cell lines, and in non-tumorigenic mammary epithelial cell lines. However, inhibition of its expression using siRNA duplexes resulted in detachment and apoptosis of several ER-positive breast cancer cell lines, but not ER-negative breast cancer cells or non-tumorigenic mammary epithelial cells. Inhibition of MP1 expression in ER-positive MCF-7 cells did not affect ERK activity, but resulted in reduced Akt1 activity and reduced ER expression and activity. Inhibition of ER expression did not result in cell death, suggesting that decreased ER expression is not the cause of cell death. In contrast, pharmacological inhibition of PI3K signaling did induce cell death in MCF-7 cells, and expression of a constitutively active form of Akt1 partially rescued the cell death observed when the MP1 gene was silenced in these cells. Together, these results suggest that MP1 is required for pro-survival signaling from the PI3K/Akt pathway in ER-positive breast cancer cells.

  20. The Unfolded Protein Response Is Induced by the Cell Wall Integrity Mitogen-activated Protein Kinase Signaling Cascade and Is Required for Cell Wall Integrity in Saccharomyces cerevisiae

    OpenAIRE

    Scrimale, Thomas; Didone, Louis; de Mesy Bentley, Karen L.; Krysan, Damian J.

    2009-01-01

    The yeast cell wall is an extracellular structure that is dependent on secretory and membrane proteins for its construction. We investigated the role of protein quality control mechanisms in cell wall integrity and found that the unfolded protein response (UPR) and, to a lesser extent, endoplasmic reticulum (ER)-associated degradation (ERAD) pathways are required for proper cell wall construction. Null mutation of IRE1, double mutation of ERAD components (hrd1Δ and ubc7Δ) and ire1Δ, or expres...

  1. SAP expression in invariant NKT cells is required for cognate help to support B-cell responses.

    Science.gov (United States)

    Detre, Cynthia; Keszei, Marton; Garrido-Mesa, Natividad; Kis-Toth, Katalin; Castro, Wilson; Agyemang, Amma F; Veerapen, Natacha; Besra, Gurdyal S; Carroll, Michael C; Tsokos, George C; Wang, Ninghai; Leadbetter, Elizabeth A; Terhorst, Cox

    2012-07-05

    One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP(-/-).B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP(-/-).BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP(fl/fl).tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell-mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.

  2. Hazard Map for Autonomous Navigation

    DEFF Research Database (Denmark)

    Riis, Troels

    This dissertation describes the work performed in the area of using image analysis in the process of landing a spacecraft autonomously and safely on the surface of the Moon. This is suggested to be done using a Hazard Map. The correspondence problem between several Hazard Maps are investigated...

  3. Designing Assessment for Autonomous Learning

    Science.gov (United States)

    Hay, Marie; Mathers, Lucy

    2012-01-01

    This paper aims to disseminate and evaluate an autonomous learning framework developed through collaborative research with first- and second-year undergraduate students at De Montfort University. Central to the framework is the involvement of students in the assessment of their peers and themselves using dialogue about the assessment and feedback…

  4. Computing architecture for autonomous microgrids

    Science.gov (United States)

    Goldsmith, Steven Y.

    2015-09-29

    A computing architecture that facilitates autonomously controlling operations of a microgrid is described herein. A microgrid network includes numerous computing devices that execute intelligent agents, each of which is assigned to a particular entity (load, source, storage device, or switch) in the microgrid. The intelligent agents can execute in accordance with predefined protocols to collectively perform computations that facilitate uninterrupted control of the .

  5. Autonomous Landing on Moving Platforms

    KAUST Repository

    Mendoza Chavez, Gilberto

    2016-01-01

    -deployment and recovery of MAVs, but it remains a challenging task for both autonomous and piloted vehicles. Model Predictive Control (MPC) is a widely used and effective scheme to control constrained systems. One of its variants, output-feedback tube-based MPC, ensures

  6. Ambler - An autonomous rover for planetary exploration

    Science.gov (United States)

    Bares, John; Hebert, Martial; Kanade, Takeo; Krotkov, Eric; Mitchell, Tom

    1989-01-01

    The authors are building a prototype legged rover, called the Ambler (loosely an acronym for autonomous mobile exploration robot) and testing it on full-scale, rugged terrain of the sort that might be encountered on the Martian surface. They present an overview of their research program, focusing on locomotion, perception, planning, and control. They summarize some of the most important goals and requirements of a rover design and describe how locomotion, perception, and planning systems can satisfy these requirements. Since the program is relatively young (one year old at the time of writing) they identify issues and approaches and describe work in progress rather than report results. It is expected that many of the technologies developed will be applicable to other planetary bodies and to terrestrial concerns such as hazardous waste assessment and remediation, ocean floor exploration, and mining.

  7. Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells

    Science.gov (United States)

    Ding, Bi-Sen; Gomi, Kazunori; Rafii, Shahin; Crystal, Ronald G.; Walters, Matthew S.

    2015-01-01

    ABSTRACT Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, we found, by RNA sequencing analysis, that basal cells expressed multiple fibroblast growth factor (FGF) ligands (FGF2, FGF5, FGF11 and FGF13) and that only FGF2 and FGF5 were capable of functioning in a paracrine manner to activate classical FGF receptor (FGFR) signaling. Antibody-mediated blocking of FGFR1 during basal-cell–endothelial-cell co-culture significantly reduced the endothelial-cell-dependent basal cell growth. Stimulation of endothelial cells with basal-cell-derived growth factors induced endothelial cell expression of matrix metallopeptidase 14 (MMP14), and short hairpin RNA (shRNA)-mediated knockdown of endothelial cell MMP14 significantly reduced the endothelial-cell-dependent growth of basal cells. Overall, these data characterize a new growth-factor-mediated reciprocal ‘crosstalk’ between human airway basal cells and endothelial cells that regulates proliferation of basal cells. PMID:26116571

  8. Kinodynamic Motion Planning for Autonomous Vehicles

    Directory of Open Access Journals (Sweden)

    Jiwung Choi

    2014-06-01

    Full Text Available This article proposes a computationally effective motion planning algorithm for autonomous ground vehicles operating in a semi-structured environment with a mission specified by waypoints, corridor widths and obstacles. The algorithm switches between two kinds of planners, (i static planners and (ii moving obstacle avoidance manoeuvre planners, depending on the mobility of any detected obstacles. While the first is broken down into a path planner and a controller, the second generates a sequence of controls without global path planning. Each subsystem is implemented as follows. The path planner produces an optimal piecewise linear path by applying a variant of cell decomposition and dynamic programming. The piecewise linear path is smoothed by Bézier curves such that the maximum curvatures of the curves are minimized. The controller calculates the highest allowable velocity profile along the path, consistent with the limits on both tangential and radial acceleration and the steering command for the vehicle to track the trajectory using a pure pursuit method. The moving obstacle avoidance manoeuvre produces a sequence of time-optimal local velocities, by minimizing the cost as determined by the safety of the current velocity against obstacles in the velocity obstacle paradigm and the deviation of the current velocity relative to the desired velocity, to satisfy the waypoint constraint. The algorithms are shown to be robust and computationally efficient, and to demonstrate a viable methodology for autonomous vehicle control in the presence of unknown obstacles.

  9. Autonomic regulation of hepatic glucose production.

    Science.gov (United States)

    Bisschop, Peter H; Fliers, Eric; Kalsbeek, Andries

    2015-01-01

    Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine-based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process. © 2014 American Physiological Society.

  10. The Nanos3-3'UTR is required for germ cell specific NANOS3 expression in mouse embryos.

    Directory of Open Access Journals (Sweden)

    Hitomi Suzuki

    Full Text Available BACKGROUND: The regulation of gene expression via a 3' untranslated region (UTR plays essential roles in the discrimination of the germ cell lineage from somatic cells during embryogenesis. This is fundamental to the continuation of a species. Mouse NANOS3 is an essential protein required for the germ cell maintenance and is specifically expressed in these cells. However, the regulatory mechanisms that restrict the expression of this gene in the germ cells is largely unknown at present. METHODOLOGY/PRINCIPAL FINDINGS: In our current study, we show that differences in the stability of Nanos3 mRNA between germ cells and somatic cells is brought about in a 3'UTR-dependent manner in mouse embryos. Although Nanos3 is transcribed in both cell lineages, it is efficiently translated only in the germ lineage. We also find that the translational suppression of NANOS3 in somatic cells is caused by a 3'UTR-mediated mRNA destabilizing mechanism. Surprisingly, even when under the control of the CAG promoter which induces strong ubiquitous transcription in both germ cells and somatic cells, the addition of the Nanos3-3'UTR sequence to the coding region of exogenous gene was effective in restricting protein expression in germ cells. CONCLUSIONS/SIGNIFICANCE: Our current study thus suggests that Nanos3-3'UTR has an essential role in translational control in the mouse embryo.

  11. Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration.

    Science.gov (United States)

    Lee, Sang Goo; Huang, Mingqian; Obholzer, Nikolaus D; Sun, Shan; Li, Wenyan; Petrillo, Marco; Dai, Pu; Zhou, Yi; Cotanche, Douglas A; Megason, Sean G; Li, Huawei; Chen, Zheng-Yi

    2016-01-01

    Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.

  12. Autonomous Mission Operations for Sensor Webs

    Science.gov (United States)

    Underbrink, A.; Witt, K.; Stanley, J.; Mandl, D.

    2008-12-01

    We present interim results of a 2005 ROSES AIST project entitled, "Using Intelligent Agents to Form a Sensor Web for Autonomous Mission Operations", or SWAMO. The goal of the SWAMO project is to shift the control of spacecraft missions from a ground-based, centrally controlled architecture to a collaborative, distributed set of intelligent agents. The network of intelligent agents intends to reduce management requirements by utilizing model-based system prediction and autonomic model/agent collaboration. SWAMO agents are distributed throughout the Sensor Web environment, which may include multiple spacecraft, aircraft, ground systems, and ocean systems, as well as manned operations centers. The agents monitor and manage sensor platforms, Earth sensing systems, and Earth sensing models and processes. The SWAMO agents form a Sensor Web of agents via peer-to-peer coordination. Some of the intelligent agents are mobile and able to traverse between on-orbit and ground-based systems. Other agents in the network are responsible for encapsulating system models to perform prediction of future behavior of the modeled subsystems and components to which they are assigned. The software agents use semantic web technologies to enable improved information sharing among the operational entities of the Sensor Web. The semantics include ontological conceptualizations of the Sensor Web environment, plus conceptualizations of the SWAMO agents themselves. By conceptualizations of the agents, we mean knowledge of their state, operational capabilities, current operational capacities, Web Service search and discovery results, agent collaboration rules, etc. The need for ontological conceptualizations over the agents is to enable autonomous and autonomic operations of the Sensor Web. The SWAMO ontology enables automated decision making and responses to the dynamic Sensor Web environment and to end user science requests. The current ontology is compatible with Open Geospatial Consortium (OGC

  13. In situ profiling of eastern Arabian Sea coastal waters using a new autonomous vertical profiler

    Digital Repository Service at National Institute of Oceanography (India)

    Desa, E.S.; Madhan, R.; Dabholkar, N.A.; Prabhudesai, S.P.; Navelkar, G.S.; Mascarenhas, A.A.M.Q.; Afzulpurkar, S.; Phaldesai, M.; Maurya, P.

    The autonomous vertical profiler (AVP) presented here offers a fast, cost-effective, optimized approach to profiling in coastal waters. It consists of a hands-free, slightly buoyant, motor-driven in situ robot profiler that requires no operator...

  14. Autonomous mobile robot localization using Kalman filter

    Directory of Open Access Journals (Sweden)

    Mohd Nasir Nabil Zhafri

    2017-01-01

    Full Text Available Autonomous mobile robot field has gain interest among researchers in recent years. The ability of a mobile robot to locate its current position and surrounding environment is the fundamental in order for it to operate autonomously, which commonly known as localization. Localization of mobile robot are commonly affected by the inaccuracy of the sensors. These inaccuracies are caused by various factors which includes internal interferences of the sensor and external environment noises. In order to overcome these noises, a filtering method is required in order to improve the mobile robot’s localization. In this research, a 2- wheeled-drive (2WD mobile robot will be used as platform. The odometers, inertial measurement unit (IMU, and ultrasonic sensors are used for data collection. Data collected is processed using Kalman filter to predict and correct the error from these sensors reading. The differential drive model and measurement model which estimates the environmental noises and predict a correction are used in this research. Based on the simulation and experimental results, the x, y and heading was corrected by converging the error to10 mm, 10 mm and 0.06 rad respectively.

  15. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium

    NARCIS (Netherlands)

    Gerbe, F.; van Es, J.H.; Makrini, L.; Brulin, B.; Mellitzer, G.; Robine, S.; Romagnolo, B.; Shroyer, N.F.; Bourgaux, J.F.; Pignodel, C.; Clevers, H.; Jay, P.

    2011-01-01

    The unique morphology of tuft cells was first revealed by electron microscopy analyses in several endoderm-derived epithelia. Here, we explore the relationship of these cells with the other cell types of the intestinal epithelium and describe the first marker signature allowing their unambiguous

  16. Autonomous Cryogenics Loading Operations Simulation Software: Knowledgebase Autonomous Test Engineer

    Science.gov (United States)

    Wehner, Walter S., Jr.

    2013-01-01

    Working on the ACLO (Autonomous Cryogenics Loading Operations) project I have had the opportunity to add functionality to the physics simulation software known as KATE (Knowledgebase Autonomous Test Engineer), create a new application allowing WYSIWYG (what-you-see-is-what-you-get) creation of KATE schematic files and begin a preliminary design and implementation of a new subsystem that will provide vision services on the IHM (Integrated Health Management) bus. The functionality I added to KATE over the past few months includes a dynamic visual representation of the fluid height in a pipe based on number of gallons of fluid in the pipe and implementing the IHM bus connection within KATE. I also fixed a broken feature in the system called the Browser Display, implemented many bug fixes and made changes to the GUI (Graphical User Interface).

  17. Continuous signaling of CD79b and CD19 is required for the fitness of Burkitt lymphoma B cells.

    Science.gov (United States)

    He, Xiaocui; Kläsener, Kathrin; Iype, Joseena M; Becker, Martin; Maity, Palash C; Cavallari, Marco; Nielsen, Peter J; Yang, Jianying; Reth, Michael

    2018-04-18

    Expression of the B-cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B-cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine-based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B-cell co-receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co-receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B-cell surface, where it is found in close proximity to CD19 and signals in an ITAM-dependent manner. These data suggest that Igβ and CD19 are part of an alternative B-cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

  18. Autonomic computing enabled cooperative networked design

    CERN Document Server

    Wodczak, Michal

    2014-01-01

    This book introduces the concept of autonomic computing driven cooperative networked system design from an architectural perspective. As such it leverages and capitalises on the relevant advancements in both the realms of autonomic computing and networking by welding them closely together. In particular, a multi-faceted Autonomic Cooperative System Architectural Model is defined which incorporates the notion of Autonomic Cooperative Behaviour being orchestrated by the Autonomic Cooperative Networking Protocol of a cross-layer nature. The overall proposed solution not only advocates for the inc

  19. Requirement of cAMP signaling for Schwann cell differentiation restricts the onset of myelination.

    Directory of Open Access Journals (Sweden)

    Ketty Bacallao

    Full Text Available Isolated Schwann cells (SCs respond to cAMP elevation by adopting a differentiated post-mitotic state that exhibits high levels of Krox-20, a transcriptional enhancer of myelination, and mature SC markers such as the myelin lipid galactocerebroside (O1. To address how cAMP controls myelination, we performed a series of cell culture experiments which compared the differentiating responses of isolated and axon-related SCs to cAMP analogs and ascorbate, a known inducer of axon ensheathment, basal lamina formation and myelination. In axon-related SCs, cAMP induced the expression of Krox-20 and O1 without a concomitant increase in the expression of myelin basic protein (MBP and without promoting axon ensheathment, collagen synthesis or basal lamina assembly. When cAMP was provided together with ascorbate, a dramatic enhancement of MBP expression occurred, indicating that cAMP primes SCs to form myelin only under conditions supportive of basal lamina formation. Experiments using a combination of cell permeable cAMP analogs and type-selective adenylyl cyclase (AC agonists and antagonists revealed that selective transmembrane AC (tmAC activation with forskolin was not sufficient for full SC differentiation and that the attainment of an O1 positive state also relied on the activity of the soluble AC (sAC, a bicarbonate sensor that is insensitive to forskolin and GPCR activation. Pharmacological and immunological evidence indicated that SCs expressed sAC and that sAC activity was required for morphological differentiation and the expression of myelin markers such as O1 and protein zero. To conclude, our data indicates that cAMP did not directly drive myelination but rather the transition into an O1 positive state, which is perhaps the most critical cAMP-dependent rate limiting step for the onset of myelination. The temporally restricted role of cAMP in inducing differentiation independently of basal lamina formation provides a clear example of the

  20. The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Thozhukat Sathyapalan

    2017-11-01

    Full Text Available Background: There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS, and there is evidence that statins improve metabolic parameters in these patients. However, there are some data to show that statins increase the risk of incipient diabetes. Materials and methods: We have previously shown that 12 weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double-blind placebo controlled study, 40 medication-naïve patients with PCOS were randomised to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. Results: There was a significant reduction in HOMA-β (240 ± 3.2 vs 177 ± 2.3; P value <0.01 after 12 weeks of atorvastatin treatment, which was maintained by metformin in the subsequent 12 weeks. There were no changes in HOMA-β after the placebo or after subsequent metformin treatment. There was no linear correlation between reduction in HOMA-β with improvement of free androgen index (FAI (r2 = 0.02; P = 0.72, testosterone (r2 = 0.13; P = 0.49, SHBG (r2 = 0.22; P = 0.48, hsCRP (r2 = 0.19; P = 0.64, triglycerides (r2 = 0.09; P = 0.12, total cholesterol (r2 = 0.11; P = 0.32 or LDL-C (r2 = 0.19; P = 0.38. Conclusion: Treatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in β-cell requirement with improvement of insulin resistance rather than a reduction of β-cell function.

  1. The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome.

    Science.gov (United States)

    Sathyapalan, Thozhukat; Coady, Anne-Marie; Kilpatrick, Eric S; Atkin, Stephen L

    2017-11-01

    There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS), and there is evidence that statins improve metabolic parameters in these patients. However, there are some data to show that statins increase the risk of incipient diabetes. We have previously shown that 12 weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double-blind placebo controlled study, 40 medication-naïve patients with PCOS were randomised to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. There was a significant reduction in HOMA-β (240 ± 3.2 vs 177 ± 2.3; P value <0.01) after 12 weeks of atorvastatin treatment, which was maintained by metformin in the subsequent 12 weeks. There were no changes in HOMA-β after the placebo or after subsequent metformin treatment.There was no linear correlation between reduction in HOMA-β with improvement of free androgen index (FAI) ( r 2  = 0.02; P  = 0.72), testosterone ( r 2  = 0.13; P  = 0.49), SHBG ( r 2  = 0.22; P  = 0.48), hsCRP ( r 2  = 0.19; P  = 0.64), triglycerides ( r 2  = 0.09; P  = 0.12), total cholesterol ( r 2  = 0.11; P  = 0.32) or LDL-C ( r 2  = 0.19; P  = 0.38). Treatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in β-cell requirement with improvement of insulin resistance rather than a reduction of β-cell function. © 2017 The authors.

  2. Syntaxin binding protein 1 is not required for allergic inflammation via IgE-mediated mast cell activation.

    Directory of Open Access Journals (Sweden)

    Zhengli Wu

    Full Text Available Mast cells play a central role in both innate and acquired immunity. When activated by IgE-dependent FcεRI cross-linking, mast cells rapidly initiate a signaling cascade and undergo an extensive release of their granule contents, including inflammatory mediators. Some SNARE (soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor proteins and SM (Sec1/Munc18 family proteins are involved in mast cell degranulation. However, the function of syntaxin binding protein 1 (STXBP1, a member of SM family, in mast cell degranulation is currently unknown. In this study, we examined the role of STXBP1 in IgE-dependent mast cell activation. Liver-derived mast cells (LMCs from wild-type and STXBP1-deficient mice were cultured in vitro for the study of mast cell maturation, degranulation, cytokine and chemokine production, as well as MAPK, IκB-NFκB, and NFAT signaling pathways. In addition, in vivo models of passive cutaneous anaphylaxis and late-phase IgE-dependent inflammation were conducted in mast cell deficient W(sh mice that had been reconstituted with wild-type or STXBP1-deficient mast cells. Our findings indicate that STXBP1 is not required for any of these important functional mechanisms in mast cells both in vitro and in vivo. Our results demonstrate that STXBP1 is dispensable during IgE-mediated mast cell activation and in IgE-dependent allergic inflammatory reactions.

  3. Reactive Oxygen Species Are Required for Human Mesenchymal Stem Cells to Initiate Proliferation after the Quiescence Exit

    Directory of Open Access Journals (Sweden)

    O. G. Lyublinskaya

    2015-01-01

    Full Text Available The present study focuses on the involvement of reactive oxygen species (ROS in the process of mesenchymal stem cells “waking up” and entering the cell cycle after the quiescence. Using human endometrial mesenchymal stem cells (eMSCs, we showed that intracellular basal ROS level is positively correlated with the proliferative status of the cell cultures. Our experiments with the eMSCs synchronized in the G0 phase of the cell cycle revealed a transient increase in the ROS level upon the quiescence exit after stimulation of the cell proliferation. This increase was registered before the eMSC entry to the S-phase of the cell cycle, and elimination of this increase by antioxidants (N-acetyl-L-cysteine, Tempol, and Resveratrol blocked G1–S-phase transition. Similarly, a cell cycle arrest which resulted from the antioxidant treatment was observed in the experiments with synchronized human mesenchymal stem cells derived from the adipose tissue. Thus, we showed that physiologically relevant level of ROS is required for the initiation of human mesenchymal stem cell proliferation and that low levels of ROS due to the antioxidant treatment can block the stem cell self-renewal.

  4. Morphologic Changes in Autonomic Nerves in Diabetic Autonomic Neuropathy

    Directory of Open Access Journals (Sweden)

    Heung Yong Jin

    2015-12-01

    Full Text Available Diabetic neuropathy is one of the major complications of diabetes, and it increases morbidity and mortality in patients with both type 1 diabetes mellitus (T1DM and type 2 diabetes mellitus (T2DM. Because the autonomic nervous system, for example, parasympathetic axons, has a diffuse and wide distribution, we do not know the morphological changes that occur in autonomic neural control and their exact mechanisms in diabetic patients with diabetic autonomic neuropathy (DAN. Although the prevalence of sympathetic and parasympathetic neuropathy is similar in T1DM versus T2DM patients, sympathetic nerve function correlates with parasympathetic neuropathy only in T1DM patients. The explanation for these discrepancies might be that parasympathetic nerve function was more severely affected among T2DM patients. As parasympathetic nerve damage seems to be more advanced than sympathetic nerve damage, it might be that parasympathetic neuropathy precedes sympathetic neuropathy in T2DM, which was Ewing's concept. This could be explained by the intrinsic morphologic difference. Therefore, the morphological changes in the sympathetic and parasympathetic nerves of involved organs in T1DM and T2DM patients who have DAN should be evaluated. In this review, evaluation methods for morphological changes in the epidermal nerves of skin, and the intrinsic nerves of the stomach will be discussed.

  5. Insights into the background of autonomic medicine.

    Science.gov (United States)

    Laranjo, Sérgio; Geraldes, Vera; Oliveira, Mário; Rocha, Isabel

    2017-10-01

    Knowledge of the physiology underlying the autonomic nervous system is pivotal for understanding autonomic dysfunction in clinical practice. Autonomic dysfunction may result from primary modifications of the autonomic nervous system or be secondary to a wide range of diseases that cause severe morbidity and mortality. Together with a detailed history and physical examination, laboratory assessment of autonomic function is essential for the analysis of various clinical conditions and the establishment of effective, personalized and precise therapeutic schemes. This review summarizes the main aspects of autonomic medicine that constitute the background of cardiovascular autonomic dysfunction. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Introduction to autonomous manipulation case study with an underwater robot, SAUVIM

    CERN Document Server

    Marani, Giacomo

    2014-01-01

    Autonomous manipulation” is a challenge in robotic technologies. It refers to the capability of a mobile robot system with one or more manipulators that performs intervention tasks requiring physical contacts in unstructured environments and without continuous human supervision. Achieving autonomous manipulation capability is a quantum leap in robotic technologies as it is currently beyond the state of the art in robotics. This book addresses issues with the complexity of the problems encountered in autonomous manipulation including representation and modeling of robotic structures, kinematic and dynamic robotic control, kinematic and algorithmic singularity avoidance, dynamic task priority, workspace optimization and environment perception. Further development in autonomous manipulation should be able to provide robust improvements of the solutions for all of the above issues. The book provides an extensive tract on sensory-based autonomous manipulation for intervention tasks in unstructured environment...

  7. Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway.

    Science.gov (United States)

    Leung, E; Xue, A; Wang, Y; Rougerie, P; Sharma, V P; Eddy, R; Cox, D; Condeelis, J

    2017-05-11

    During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates. We found that tumor cells and macrophages, when plated together on the micro-patterned substrates, do not demonstrate sustained directional migration in only one direction (sustained directionality) but show random bi-directional walking. Sustained directionality of tumor cells as seen in vivo was established in vitro when beads coated with human umbilical vein endothelial cells were placed at one end of the micro-patterned 'ECM fibers' within the assay. We demonstrated that these endothelial cells supply the hepatocyte growth factor (HGF) required for the chemotactic gradient responsible for sustained directionality. Using this in vitro reconstituted streaming system, we found that directional streaming is dependent on, and most effectively blocked, by inhibiting the HGF/C-Met signaling pathway between endothelial cells and tumor cells. Key observations made with the in vitro reconstituted system implicating C-Met signaling were confirmed in vivo in mammary tumors using the in vivo invasion assay and intravital multiphoton imaging of tumor cell streaming. These results establish HGF/C-Met as a central organizing signal in blood vessel-directed tumor cell migration in vivo and highlight a promising role for C-Met inhibitors in blocking tumor cell streaming and metastasis in vivo, and for use in human trials.

  8. KRE5 Suppression Induces Cell Wall Stress and Alternative ER Stress Response Required for Maintaining Cell Wall Integrity in Candida glabrata

    Science.gov (United States)

    Sasaki, Masato; Ito, Fumie; Aoyama, Toshio; Sato-Okamoto, Michiyo; Takahashi-Nakaguchi, Azusa; Chibana, Hiroji; Shibata, Nobuyuki

    2016-01-01

    The maintenance of cell wall integrity in fungi is required for normal cell growth, division, hyphae formation, and antifungal tolerance. We observed that endoplasmic reticulum stress regulated cell wall integrity in Candida glabrata, which possesses uniquely evolved mechanisms for unfolded protein response mechanisms. Tetracycline-mediated suppression of KRE5, which encodes a predicted UDP-glucose:glycoprotein glucosyltransferase localized in the endoplasmic reticulum, significantly increased cell wall chitin content and decreased cell wall β-1,6-glucan content. KRE5 repression induced endoplasmic reticulum stress-related gene expression and MAP kinase pathway activation, including Slt2p and Hog1p phosphorylation, through the cell wall integrity signaling pathway. Moreover, the calcineurin pathway negatively regulated cell wall integrity, but not the reduction of β-1,6-glucan content. These results indicate that KRE5 is required for maintaining both endoplasmic reticulum homeostasis and cell wall integrity, and that the calcineurin pathway acts as a regulator of chitin-glucan balance in the cell wall and as an alternative mediator of endoplasmic reticulum stress in C. glabrata. PMID:27548283

  9. Requirement for noncognate interaction with T cells for the activation of B cell immunoglobulin secretion by IL-2

    DEFF Research Database (Denmark)

    Owens, T

    1991-01-01

    23.1+ TH1 clone E9.D4 in F23.1 (anti-T cell receptor V-beta 8)-coated microwells. This induced polyclonal B cell activation to enter cell cycle (thymidine incorporation) at 2 days and to secrete immunoglobulin at 5 days. An anti-IL-2 mAb (S4B6) inhibited antibody production completely. Anti-IL-2 did......The mechanism whereby noncognate contact with activated IL-2-producing Type 1 helper T cells (TH1) induces B cell activation was examined. Small resting B cells from C57B1/6 mice were cultured, in the absence of any ligand for surface Ig, with irradiated cells of the hapten-specific, CBA-derived, F...... not inhibit either LPS-induced B cell responses, or T cell activation (measured as IL-3 secretion). Anti-IL-2 receptor (anti-Tac) mAbs also inhibited T-dependent B cell responses, without affecting LPS responses. An anti-IFN-gamma mAb partially inhibited Ig secretion, without affecting entry into cycle. LPS...

  10. Cardiovascular autonomic neuropathy in diabetes

    DEFF Research Database (Denmark)

    Spallone, Vincenza; Ziegler, Dan; Freeman, Roy

    2011-01-01

    Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control...... in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: 1. one abnormal cardio-vagal test identifies possible or early CAN; 2. at least two abnormal cardio-vagal tests....... diagnosis of CAN clinical forms, 2. detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, OH, nondipping, QT interval prolongation), 3. risk stratification for diabetic complications and cardiovascular morbidity and mortality, and 4. modulation of targets of diabetes therapy...

  11. Autonomous Laser-Powered Vehicle

    Science.gov (United States)

    Stone, William C. (Inventor); Hogan, Bartholomew P. (Inventor)

    2017-01-01

    An autonomous laser-powered vehicle designed to autonomously penetrate through ice caps of substantial (e.g., kilometers) thickness by melting a path ahead of the vehicle as it descends. A high powered laser beam is transmitted to the vehicle via an onboard bare fiber spooler. After the beam enters through the dispersion optics, the beam expands into a cavity. A radiation shield limits backscatter radiation from heating the optics. The expanded beam enters the heat exchanger and is reflected by a dispersion mirror. Forward-facing beveled circular grooves absorb the reflected radiant energy preventing the energy from being reflected back towards the optics. Microchannels along the inner circumference of the beam dump heat exchanger maximize heat transfer. Sufficient amount of fiber is wound on the fiber spooler to permit not only a descent but also to permit a sample return mission by inverting the vehicle and melting its way back to the surface.

  12. Health, autonomic financing and transferences

    Directory of Open Access Journals (Sweden)

    David Cantarero Prieto

    2002-01-01

    Full Text Available The present paper has as objective to study the whole relative problem to the autonomous communities and regional heath care expenditure financing in Spain. This article has a dual purpose. First, the financing of the current health care attendance is approached in the Spanish regions passing magazine to its possible variants and we observe that the balance of our system is clearly inclined towards the side of the integration in the general pattern of financing («Fiscal Room» with specific conditions («Mixed System». Secondly, we examine the new situation in the mark of health care and its corresponding financing in the new model approved in 2001, in terms of the effects of tax assignment on autonomous communities.

  13. Autonomously managed high power systems

    International Nuclear Information System (INIS)

    Weeks, D.J.; Bechtel, R.T.

    1985-01-01

    The need for autonomous power management capabilities will increase as the power levels of spacecraft increase into the multi-100 kW range. The quantity of labor intensive ground and crew support consumed by the 9 kW Skylab cannot be afforded in support of a 75-300 kW Space Station or high power earth orbital and interplanetary spacecraft. Marshall Space Flight Center is managing a program to develop necessary technologies for high power system autonomous management. To date a reference electrical power system and automation approaches have been defined. A test facility for evaluation and verification of management algorithms and hardware has been designed with the first of the three power channel capability nearing completion

  14. Development of autonomous operation system

    International Nuclear Information System (INIS)

    Endou, Akira; Watanabe, Kenshiu; Miki, Tetsushi

    1992-01-01

    To enhance operation reliability of nuclear plants by removing human factors, study on an autonomous operation system has been carried out to substitute artificial intelligence (AI) for plant operators and, in addition, traditional controllers used in existing plants. For construction of the AI system, structurization of knowledge on the basis of the principles such as physical laws, function and structure of relevant objects and generalization of problem solving process are intended. A hierarchical distributed cooperative system configuration in employed because it is superior from the viewpoint of dynamical reorganization of system functions. This configuration is realized by an object-oriented multi-agent system. Construction of a prototype system was planned and the conceptual design was made for FBR plant in order to evaluate applicability of AI to the autonomous operation and to have a prospect for the realization of the system. The prototype system executes diagnosis, state evaluation, operation and control for the main plant subsystems. (author)

  15. Autonomous Agents as Artistic Collaborators

    DEFF Research Database (Denmark)

    Kadish, David

    In this paper, I ask whether it is possible to exert creative direction on the emergence of large scale patterns from the actions of autonomous or semi-autonomous actors. As an artist and an engineer, I undertake installations and projects with an intent to create, to make art or innovative...... structures. At the same time, one of my artistic interests is in ceding a great deal of creative control to a cluster of robotic actors, in the process interrogating the lack of control that we, as a species, exert over the world. Here, I explore this idea in the context of an ongoing project called...... that navigate the space as well. My work has implications for how we as a species address planetary-scale challenges and whether we can organize societies to find emergent solutions to complex problems. Behind my artistic interest is the idea that "creation" has no teleological impulse. The creative force from...

  16. A genome-wide screen identifies conserved protein hubs required for cadherin-mediated cell–cell adhesion

    Science.gov (United States)

    Toret, Christopher P.; D’Ambrosio, Michael V.; Vale, Ronald D.; Simon, Michael A.

    2014-01-01

    Cadherins and associated catenins provide an important structural interface between neighboring cells, the actin cytoskeleton, and intracellular signaling pathways in a variety of cell types throughout the Metazoa. However, the full inventory of the proteins and pathways required for cadherin-mediated adhesion has not been established. To this end, we completed a genome-wide (∼14,000 genes) ribonucleic acid interference (RNAi) screen that targeted Ca2+-dependent adhesion in DE-cadherin–expressing Drosophila melanogaster S2 cells in suspension culture. This novel screen eliminated Ca2+-independent cell–cell adhesion, integrin-based adhesion, cell spreading, and cell migration. We identified 17 interconnected regulatory hubs, based on protein functions and protein–protein interactions that regulate the levels of the core cadherin–catenin complex and coordinate cadherin-mediated cell–cell adhesion. Representative proteins from these hubs were analyzed further in Drosophila oogenesis, using targeted germline RNAi, and adhesion was analyzed in Madin–Darby canine kidney mammalian epithelial cell–cell adhesion. These experiments reveal roles for a diversity of cellular pathways that are required for cadherin function in Metazoa, including cytoskeleton organization, cell–substrate interactions, and nuclear and cytoplasmic signaling. PMID:24446484

  17. Nitric oxide production is not required for dihydrosphingosine-induced cell death in tobacco BY-2 cells.

    Science.gov (United States)

    Da Silva, Daniel; Lachaud, Christophe; Cotelle, Valérie; Brière, Christian; Grat, Sabine; Mazars, Christian; Thuleau, Patrice

    2011-05-01

    Sphinganine or dihydrosphingosine (d18:0, DHS), one of the most abundant free sphingoid Long Chain Base (LCB) in plants, is known to induce a calcium dependent programmed cell death (PCD) in tobacco BY-2 cells. In addition, we have recently shown that DHS triggers a production of H2O2, via the activation of NADPH oxidase(s). However, this production of H2O2 is not correlated with the DHS-induced cell death but would rather be associated with basal cell defense mechanisms. In the present study, we extend our current knowledge of the DHS signaling pathway, by demonstrating that DHS also promotes a production of nitric oxide (NO) in tobacco BY-2 cells. As for H2O2, this NO production is not necessary for cell death induction. 

  18. Autonomous driving in NMR.

    Science.gov (United States)

    Perez, Manuel

    2017-01-01

    The automatic analysis of NMR data has been a much-desired endeavour for the last six decades, as it is the case with any other analytical technique. This need for automation has only grown as advances in hardware; pulse sequences and automation have opened new research areas to NMR and increased the throughput of data. Full automatic analysis is a worthy, albeit hard, challenge, but in a world of artificial intelligence, instant communication and big data, it seems that this particular fight is happening with only one technique at a time (let this be NMR, MS, IR, UV or any other), when the reality of most laboratories is that there are several types of analytical instrumentation present. Data aggregation, verification and elucidation by using complementary techniques (e.g. MS and NMR) is a desirable outcome to pursue, although a time-consuming one if performed manually; hence, the use of automation to perform the heavy lifting for users is required to make the approach attractive for scientists. Many of the decisions and workflows that could be implemented under automation will depend on the two-way communication with databases that understand analytical data, because it is desirable not only to query these databases but also to grow them in as much of an automatic manner as possible. How these databases are designed, set up and the data inside classified will determine what workflows can be implemented. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Autonomous spacecraft rendezvous and docking

    Science.gov (United States)

    Tietz, J. C.; Almand, B. J.

    A storyboard display is presented which summarizes work done recently in design and simulation of autonomous video rendezvous and docking systems for spacecraft. This display includes: photographs of the simulation hardware, plots of chase vehicle trajectories from simulations, pictures of the docking aid including image processing interpretations, and drawings of the control system strategy. Viewgraph-style sheets on the display bulletin board summarize the simulation objectives, benefits, special considerations, approach, and results.

  20. Biology-Inspired Autonomous Control

    Science.gov (United States)

    2011-08-31

    insect brain, allow these animals to fly with damaged wings, order of body mass payloads (e.g., foraging bees with a load of pollen , blood satiated...The research focus addressed two broad, complementary research areas : autonomous systems concepts inspired by the behavior and neurobiology...UL 46 19b. TELEPHONE NUMBER (include area code) 850 883-1887 Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 iii Table of

  1. Fleet management for autonomous vehicles

    OpenAIRE

    Bsaybes, Sahar; Quilliot, Alain; Wagler, Annegret K.

    2016-01-01

    The VIPAFLEET project consists in developing models and algorithms for man- aging a fleet of Individual Public Autonomous Vehicles (VIPA). Hereby, we consider a fleet of cars distributed at specified stations in an industrial area to supply internal transportation, where the cars can be used in different modes of circulation (tram mode, elevator mode, taxi mode). One goal is to develop and implement suitable algorithms for each mode in order to satisfy all the requests under an economic point...

  2. Urban planning for autonomous vehicles

    OpenAIRE

    Fourie, Pieter J.; Ordoñez Medina, Sergio A.; Maheshwari, Tanvi; Wang, Biyu; Erath, Alexander; Cairns, Stephen; Axhausen, Kay W.

    2018-01-01

    In land-scarce Singapore, population growth and increasingly dense development are running up against limited remaining space for mobility infrastructure expansion. Autonomous Vehicles (AV) promise to relieve some of this pressure, through more efficient use of road space through platooning and intersection coordination, reducing the need for parking space, and reducing overall reliance on privately owned cars, realising Singapore’s vision of a “car-lite” future. In a collaborative resear...

  3. Failure Prediction for Autonomous Driving

    OpenAIRE

    Hecker, Simon; Dai, Dengxin; Van Gool, Luc

    2018-01-01

    The primary focus of autonomous driving research is to improve driving accuracy. While great progress has been made, state-of-the-art algorithms still fail at times. Such failures may have catastrophic consequences. It therefore is important that automated cars foresee problems ahead as early as possible. This is also of paramount importance if the driver will be asked to take over. We conjecture that failures do not occur randomly. For instance, driving models may fail more likely at places ...

  4. Autonomic computing meets SCADA security

    OpenAIRE

    Nazir, S; Patel, S; Patel, D

    2017-01-01

    © 2017 IEEE. National assets such as transportation networks, large manufacturing, business and health facilities, power generation, and distribution networks are critical infrastructures. The cyber threats to these infrastructures have increasingly become more sophisticated, extensive and numerous. Cyber security conventional measures have proved useful in the past but increasing sophistication of attacks dictates the need for newer measures. The autonomic computing paradigm mimics the auton...

  5. iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation

    Directory of Open Access Journals (Sweden)

    Ajitha Thanabalasuriar

    2016-09-01

    Full Text Available iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against bacterial infections, including S. pneumoniae. Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the specific iNKT cell ligand α-galactosylceramide or S. pneumoniae infection. In untreated mice, the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae induced CD1d-dependent rapid recruitment of neutrophils out of the vasculature. The neutrophils guided iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell recruitment by blocking CCL17 increased susceptibility to S. pneumoniae infection, suggesting a critical role for the influx of iNKT cells in host defense.

  6. Autonomic neuropathy in diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Alberto eVerrotti

    2014-12-01

    Full Text Available Diabetic autonomic neuropathy (DAN is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy (CAN defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent definition, different diagnostic method, different patient cohorts studied. The pathogenesis is still unclear and probably multifactorial. Once DAN becomes clinically evident, no form of therapy has been identified which can effectively stop or reverse it. Prevention strategies are based on strict glycemic control with intensive insulin treatment, multifactorial intervention and lifestyle modification including control of hypertension, dyslipidemia, stop smoking, weight loss and adequate physical exercise. The present review summarizes the latest knowledge regarding clinical presentation, epidemiology, pathogenesis and management of DAN, with some mention to childhood and adolescent population.

  7. Vinculin is required for cell polarization, migration, and extracellular matrix remodeling in 3D collagen.

    Science.gov (United States)

    Thievessen, Ingo; Fakhri, Nikta; Steinwachs, Julian; Kraus, Viola; McIsaac, R Scott; Gao, Liang; Chen, Bi-Chang; Baird, Michelle A; Davidson, Michael W; Betzig, Eric; Oldenbourg, Rudolf; Waterman, Clare M; Fabry, Ben

    2015-11-01

    Vinculin is filamentous (F)-actin-binding protein enriched in integrin-based adhesions to the extracellular matrix (ECM). Whereas studies in 2-dimensional (2D) tissue culture models have suggested that vinculin negatively regulates cell migration by promoting cytoskeleton-ECM coupling to strengthen and stabilize adhesions, its role in regulating cell migration in more physiologic, 3-dimensional (3D) environments is unclear. To address the role of vinculin in 3D cell migration, we analyzed the morphodynamics, migration, and ECM remodeling of primary murine embryonic fibroblasts (MEFs) with cre/loxP-mediated vinculin gene disruption in 3D collagen I cultures. We found that vinculin promoted 3D cell migration by increasing directional persistence. Vinculin was necessary for persistent cell protrusion, cell elongation, and stable cell orientation in 3D collagen, but was dispensable for lamellipodia formation, suggesting that vinculin-mediated cell adhesion to the ECM is needed to convert actin-based cell protrusion into persistent cell shape change and migration. Consistent with this finding, vinculin was necessary for efficient traction force generation in 3D collagen without affecting myosin II activity and promoted 3D collagen fiber alignment and macroscopical gel contraction. Our results suggest that vinculin promotes directionally persistent cell migration and tension-dependent ECM remodeling in complex 3D environments by increasing cell-ECM adhesion and traction force generation. © FASEB.

  8. Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+ T cells

    NARCIS (Netherlands)

    van Leeuwen, Ester M.; Gamadia, Laila E.; Baars, Paul A.; Remmerswaal, Ester B.; ten Berge, Ineke J.; van Lier, René A.

    2002-01-01

    Two prototypic types of virus-specific CD8(+) T cells can be found in latently infected individuals: CD45R0(+)CD27(+)CCR7(-) effector-memory, and CD45RA(+)CD27(-)CCR7(-) effector-type cells. It has recently been implied that CD45RA(+)CD27(-)CCR7(-) T cells are terminally differentiated effector