Sample records for accelerating ultimate pathways

  1. Ultimate Gradient Limitation in Niobium Superconducting Accelerating Cavities

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Checchin, Mattia; Grassellino, Anna; Martinello, Martina

    2016-06-01

    The present study is addressed to the theoretical description of the ultimate gradient limitation in SRF cavities. Our intent is to exploit experimental data to confirm models which provide feed-backs on how to improve the current state-of-art. New theoretical insight on the cavities limiting factor can be suitable to improve the quench field of N-doped cavities, and therefore to take advantage of high Q 0 at high gradients.

  2. Accelerating Adverse Outcome Pathway Development Using ...

    EPA Pesticide Factsheets

    The adverse outcome pathway (AOP) concept links molecular perturbations with organism and population-level outcomes to support high-throughput toxicity testing. International efforts are underway to define AOPs and store the information supporting these AOPs in a central knowledgebase, however, this process is currently labor-intensive and time-consuming. Publicly available data sources provide a wealth of information that could be used to define computationally-predicted AOPs (cpAOPs), which could serve as a basis for creating expert-derived AOPs in a much more efficient way. Computational tools for mining large datasets provide the means for extracting and organizing the information captured in these public data sources. Using cpAOPs as a starting point for expert-derived AOPs should accelerate AOP development. Coupling this with tools to coordinate and facilitate the expert development efforts will increase the number and quality of AOPs produced, which should play a key role in advancing the adoption of twenty-first century toxicity testing strategies. This review article describes how effective knowledge management and automated approaches to AOP development can enhance and accelerate the development and use of AOPs. As the principles documented in this review are put into practice, we anticipate that the quality and quantity of AOPs available will increase substantially. This, in turn, will aid in the interpretation of ToxCast and other high-throughput tox

  3. Accelerating Adverse Outcome Pathway (AOP) development ...

    EPA Pesticide Factsheets

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. However, the conventional process for assembly of these AOPs is time and resource intensive, and has been a rate limiting step for AOP use and development. Therefore computational approaches to accelerate the process need to be developed. We previously developed a method for generating computationally predicted AOPs (cpAOPs) by association mining and integration of data from publicly available databases. In this work, a cpAOP network of ~21,000 associations was established between 105 phenotypes from TG-GATEs rat liver data from different time points (including microarray, pathological effects and clinical chemistry data), 994 REACTOME pathways, 688 High-throughput assays from ToxCast and 194 chemicals. A second network of 128,536 associations was generated by connecting 255 biological target genes from ToxCast to 4,980 diseases from CTD using either HT screening activity from ToxCast for 286 chemicals or CTD gene expression changes in response to 2,330 chemicals. Both networks were separately evaluated through manual extraction of disease-specific cpAOPs and comparison with expert curation of the relevant literature. By employing data integration strategies that involve the weighting of n

  4. Mutational Pathway Determines Whether Drug Gradients Accelerate Evolution of Drug-Resistant Cells

    NASA Astrophysics Data System (ADS)

    Greulich, Philip; Waclaw, Bartłomiej; Allen, Rosalind J.

    2012-08-01

    Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anticancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a nonuniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combating the emergence of resistance.

  5. Caffeine accelerates recovery from general anesthesia via multiple pathways.

    PubMed

    Fong, Robert; Khokhar, Suhail; Chowdhury, Atif N; Xie, Kelvin G; Wong, Josiah Hiu-Yuen; Fox, Aaron P; Xie, Zheng

    2017-09-01

    Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A 2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP] i )-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A 2A receptor blockade and [cAMP] i elevation play a role in caffeine's ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP] i and adenosine receptor blockade play a role in this response. NEW & NOTEWORTHY Currently, there is no method to accelerate emergence from anesthesia. Patients "wake" when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that

  6. Building Integrated Pathways to Sustainable Careers: An Introduction to the Accelerated Opportunity Initiative

    ERIC Educational Resources Information Center

    Pleasants, Rachel

    2011-01-01

    "Accelerating Opportunity" responds to the nation's growing need for improved pathways from Adult Basic Education (ABE) to credentials of value in the labor market. It builds on promising practices developed in "Breaking Through," an initiative of Jobs for the Future and the National Council for Workforce Education, and…

  7. Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis.

    PubMed

    Liu, S; Tackmann, N R; Yang, J; Zhang, Y

    2017-03-01

    Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is frequently found in colorectal cancer. Loss of APC function results in deregulation of the Wnt/β-catenin signaling pathway causing overexpression of the c-MYC oncogene. In lymphoma, both p19ARF and ribosomal proteins RPL11 and RPL5 respond to c-MYC activation to induce p53. Their role in c-MYC-driven colorectal carcinogenesis is unclear, as p19ARF deletion does not accelerate APC loss-triggered intestinal tumorigenesis. To determine the contribution of the ribosomal protein (RP)-murine double minute 2 (MDM2)-p53 pathway to APC loss-induced tumorigenesis, we crossed mice bearing MDM2 C305F mutation, which disrupts RPL11- and RPL5-MDM2 binding, with Apc min/+ mice, which are prone to intestinal tumor formation. Interestingly, loss of RP-MDM2 binding significantly accelerated colorectal tumor formation while having no discernable effect on small intestinal tumor formation. Mechanistically, APC loss leads to overexpression of c-MYC, RPL11 and RPL5 in mouse colonic tumor cells irrespective of MDM2 C305F mutation. However, notable p53 stabilization and activation were observed only in Apc min/+ ;Mdm2 +/+ but not Apc min/+ ;Mdm2 C305F/C305F colon tumors. These data establish that the RP-MDM2-p53 pathway, in contrast to the p19ARF-MDM2-p53 pathway, is a critical mediator of colorectal tumorigenesis following APC loss.

  8. Cornerstones of Completion: State Policy Support for Accelerated, Structured Pathways to College Credentials and Transfer

    ERIC Educational Resources Information Center

    Couturier, Lara K.

    2012-01-01

    In spring 2012, after a year of intensive data analysis and planning, the colleges participating in Completion by Design announced strategies for creating clear, structured routes through college for more students, often referred to as accelerated, structured pathways to completion. These strategies contain elements unique to each college, but all…

  9. Microbially-accelerated consolidation of oil sands tailings. Pathway II: solid phase biogeochemistry.

    PubMed

    Siddique, Tariq; Kuznetsov, Petr; Kuznetsova, Alsu; Li, Carmen; Young, Rozlyn; Arocena, Joselito M; Foght, Julia M

    2014-01-01

    Consolidation of clay particles in aqueous tailings suspensions is a major obstacle to effective management of oil sands tailings ponds in northern Alberta, Canada. We have observed that microorganisms indigenous to the tailings ponds accelerate consolidation of mature fine tailings (MFT) during active metabolism by using two biogeochemical pathways. In Pathway I, microbes alter porewater chemistry to indirectly increase consolidation of MFT. Here, we describe Pathway II comprising significant, direct and complementary biogeochemical reactions with MFT mineral surfaces. An anaerobic microbial community comprising Bacteria (predominantly Clostridiales, Synergistaceae, and Desulfobulbaceae) and Archaea (Methanolinea/Methanoregula and Methanosaeta) transformed Fe(III) minerals in MFT to amorphous Fe(II) minerals during methanogenic metabolism of an added organic substrate. Synchrotron analyses suggested that ferrihydrite (5Fe2O3. 9H2O) and goethite (α-FeOOH) were the dominant Fe(III) minerals in MFT. The formation of amorphous iron sulfide (FeS) and possibly green rust entrapped and masked electronegative clay surfaces in amended MFT. Both Pathways I and II reduced the surface charge potential (repulsive forces) of the clay particles in MFT, which aided aggregation of clays and formation of networks of pores, as visualized using cryo-scanning electron microscopy (SEM). These reactions facilitated the egress of porewater from MFT and increased consolidation of tailings solids. These results have large-scale implications for management and reclamation of oil sands tailings ponds, a burgeoning environmental issue for the public and government regulators.

  10. Microbially-accelerated consolidation of oil sands tailings. Pathway II: solid phase biogeochemistry

    PubMed Central

    Siddique, Tariq; Kuznetsov, Petr; Kuznetsova, Alsu; Li, Carmen; Young, Rozlyn; Arocena, Joselito M.; Foght, Julia M.

    2014-01-01

    Consolidation of clay particles in aqueous tailings suspensions is a major obstacle to effective management of oil sands tailings ponds in northern Alberta, Canada. We have observed that microorganisms indigenous to the tailings ponds accelerate consolidation of mature fine tailings (MFT) during active metabolism by using two biogeochemical pathways. In Pathway I, microbes alter porewater chemistry to indirectly increase consolidation of MFT. Here, we describe Pathway II comprising significant, direct and complementary biogeochemical reactions with MFT mineral surfaces. An anaerobic microbial community comprising Bacteria (predominantly Clostridiales, Synergistaceae, and Desulfobulbaceae) and Archaea (Methanolinea/Methanoregula and Methanosaeta) transformed FeIII minerals in MFT to amorphous FeII minerals during methanogenic metabolism of an added organic substrate. Synchrotron analyses suggested that ferrihydrite (5Fe2O3. 9H2O) and goethite (α-FeOOH) were the dominant FeIII minerals in MFT. The formation of amorphous iron sulfide (FeS) and possibly green rust entrapped and masked electronegative clay surfaces in amended MFT. Both Pathways I and II reduced the surface charge potential (repulsive forces) of the clay particles in MFT, which aided aggregation of clays and formation of networks of pores, as visualized using cryo-scanning electron microscopy (SEM). These reactions facilitated the egress of porewater from MFT and increased consolidation of tailings solids. These results have large-scale implications for management and reclamation of oil sands tailings ponds, a burgeoning environmental issue for the public and government regulators. PMID:24711806

  11. Ultimate evidence for the ultimate regime

    NASA Astrophysics Data System (ADS)

    Smits, Alexander J.

    2018-04-01

    The ultimate regime of turbulence has been observed, more than half a century after its first prediction. Inspiration for achieving this technical feat came from the imperfections of an everyday pipe.

  12. The signaling pathways by which the Fas/FasL system accelerates oocyte aging.

    PubMed

    Zhu, Jiang; Lin, Fei-Hu; Zhang, Jie; Lin, Juan; Li, Hong; Li, You-Wei; Tan, Xiu-Wen; Tan, Jing-He

    2016-02-01

    In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca2+releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.

  13. Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

    PubMed

    Johnson, Norman A; Porter, Adam H

    2007-01-01

    Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.

  14. Visual Outcome in Meningiomas Around Anterior Visual Pathways Treated With Linear Accelerator Fractionated Stereotactic Radiotherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stiebel-Kalish, Hadas, E-mail: kalishhadas@gmail.com; Sackler School of Medicine, Tel Aviv University, Tel Aviv; Reich, Ehud

    Purpose: Meningiomas threatening the anterior visual pathways (AVPs) and not amenable for surgery are currently treated with multisession stereotactic radiotherapy. Stereotactic radiotherapy is available with a number of devices. The most ubiquitous include the gamma knife, CyberKnife, tomotherapy, and isocentric linear accelerator systems. The purpose of our study was to describe a case series of AVP meningiomas treated with linear accelerator fractionated stereotactic radiotherapy (FSRT) using the multiple, noncoplanar, dynamic conformal rotation paradigm and to compare the success and complication rates with those reported for other techniques. Patients and Methods: We included all patients with AVP meningiomas followed up atmore » our neuro-ophthalmology unit for a minimum of 12 months after FSRT. We compared the details of the neuro-ophthalmologic examinations and tumor size before and after FSRT and at the end of follow-up. Results: Of 87 patients with AVP meningiomas, 17 had been referred for FSRT. Of the 17 patients, 16 completed >12 months of follow-up (mean 39). Of the 16 patients, 11 had undergone surgery before FSRT and 5 had undergone FSRT as first-line management. Tumor control was achieved in 14 of the 16 patients, with three meningiomas shrinking in size after RT. Two meningiomas progressed, one in an area that was outside the radiation field. The visual function had improved in 6 or stabilized in 8 of the 16 patients (88%) and worsened in 2 (12%). Conclusions: Linear accelerator fractionated RT using the multiple noncoplanar dynamic rotation conformal paradigm can be offered to patients with meningiomas that threaten the anterior visual pathways as an adjunct to surgery or as first-line treatment, with results comparable to those reported for other stereotactic RT techniques.« less

  15. Ultimate concerns in late modernity: Archer, Bourdieu and reflexivity.

    PubMed

    Farrugia, David; Woodman, Dan

    2015-12-01

    Through a critique of Margaret Archer's theory of reflexivity, this paper explores the theoretical contribution of a Bourdieusian sociology of the subject for understanding social change. Archer's theory of reflexivity holds that conscious 'internal conversations' are the motor of society, central both to human subjectivity and to the 'reflexive imperative' of late modernity. This is established through critiques of Bourdieu, who is held to erase creativity and meaningful personal investments from subjectivity, and late modernity is depicted as a time when a 'situational logic of opportunity' renders embodied dispositions and the reproduction of symbolic advantages obsolete. Maintaining Archer's focus on 'ultimate concerns' in a context of social change, this paper argues that her theory of reflexivity is established through a narrow misreading and rejection of Bourdieu's work, which ultimately creates problems for her own approach. Archer's rejection of any pre-reflexive dimensions to subjectivity and social action leaves her unable to sociologically explain the genesis of 'ultimate concerns', and creates an empirically dubious narrative of the consequences of social change. Through a focus on Archer's concept of 'fractured reflexivity', the paper explores the theoretical necessity of habitus and illusio for understanding the social changes that Archer is grappling with. In late modernity, reflexivity is valorized just as the conditions for its successful operation are increasingly foreclosed, creating 'fractured reflexivity' emblematic of the complex contemporary interaction between habitus, illusio, and accelerating social change. © London School of Economics and Political Science 2015.

  16. Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway.

    PubMed

    Ludwig, Kirk; Enker, Warren E; Delaney, Conor P; Wolff, Bruce G; Du, Wei; Fort, John G; Cherubini, Maryann; Cucinotta, James; Techner, Lee

    2008-11-01

    To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection. This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients. The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded. Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo. Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative

  17. Ultimate Spectrum of Solar/Stellar Cosmic Rays

    NASA Astrophysics Data System (ADS)

    Struminsky, Alexei

    2015-08-01

    We reconstruct an ultimate spectrum of solar/stellar cosmic rays (SCR) in a given point in the heliosphere (stellar sphere) basing on maximal value of magnetic field strenght in active region and its characteristic linear dimension. An accelerator of given dimensions and magnetic field strengh may accelarate to a finite energy for a given time (a maximal energy of SCR). We will use spectrum of SCR proposed by Syrovatsky (1961) for relativistic and non-relativistic energies normaliszing it to galactic cosmic ray (GCR) intensity at maximal SCR energy. Maximal values of SCR flux propagating in the heliosphere are determined by equilibrium between pressure of interplanetary magnrtic field and dynamic pressure of SCR (Frier&Webber, 1963). The obtained spectra would be applied to explain the extreme solar particle event occurred in about 775 AD basing on the tree-ring chronology (Miyake et al., 2012).

  18. The Ultimate Monte Carlo: Studying Cross-Sections With Cosmic Rays

    NASA Technical Reports Server (NTRS)

    Wilson, Thomas L.

    2007-01-01

    The high-energy physics community has been discussing for years the need to bring together the three principal disciplines that study hadron cross-section physics - ground-based accelerators, cosmic-ray experiments in space, and air shower research. Only recently have NASA investigators begun discussing the use of space-borne cosmic-ray payloads to bridge the gap between accelerator physics and air shower work using cosmic-ray measurements. The common tool used in these three realms of high-energy hadron physics is the Monte Carlo (MC). Yet the obvious has not been considered - using a single MC for simulating the entire relativistic energy range (GeV to EeV). The task is daunting due to large uncertainties in accelerator, space, and atmospheric cascade measurements. These include inclusive versus exclusive cross-section measurements, primary composition, interaction dynamics, and possible new physics beyond the standard model. However, the discussion of a common tool or ultimate MC might be the very thing that could begin to unify these independent groups into a common purpose. The Offline ALICE concept of a Virtual MC at CERN s Large Hadron Collider (LHC) will be discussed as a rudimentary beginning of this idea, and as a possible forum for carrying it forward in the future as LHC data emerges.

  19. HEART Pathway Accelerated Diagnostic Protocol Implementation: Prospective Pre-Post Interrupted Time Series Design and Methods.

    PubMed

    Mahler, Simon A; Burke, Gregory L; Duncan, Pamela W; Case, Larry D; Herrington, David M; Riley, Robert F; Wells, Brian J; Hiestand, Brian C; Miller, Chadwick D

    2016-01-22

    Most patients presenting to US Emergency Departments (ED) with chest pain are hospitalized for comprehensive testing. These evaluations cost the US health system >$10 billion annually, but have a diagnostic yield for acute coronary syndrome (ACS) of <10%. The history/ECG/age/risk factors/troponin (HEART) Pathway is an accelerated diagnostic protocol (ADP), designed to improve care for patients with acute chest pain by identifying patients for early ED discharge. Prior efficacy studies demonstrate that the HEART Pathway safely reduces cardiac testing, while maintaining an acceptably low adverse event rate. The purpose of this study is to determine the effectiveness of HEART Pathway ADP implementation within a health system. This controlled before-after study will accrue adult patients with acute chest pain, but without ST-segment elevation myocardial infarction on electrocardiogram for two years and is expected to include approximately 10,000 patients. Outcomes measures include hospitalization rate, objective cardiac testing rates (stress testing and angiography), length of stay, and rates of recurrent cardiac care for participants. In pilot data, the HEART Pathway decreased hospitalizations by 21%, decreased hospital length (median of 12 hour reduction), without increasing adverse events or recurrent care. At the writing of this paper, data has been collected on >5000 patient encounters. The HEART Pathway has been fully integrated into health system electronic medical records, providing real-time decision support to our providers. We hypothesize that the HEART Pathway will safely reduce healthcare utilization. This study could provide a model for delivering high-value care to the 8-10 million US ED patients with acute chest pain each year. Clinicaltrials.gov NCT02056964; https://clinicaltrials.gov/ct2/show/NCT02056964 (Archived by WebCite at http://www.webcitation.org/6ccajsgyu).

  20. Plasma wakefield acceleration experiments at FACET II

    NASA Astrophysics Data System (ADS)

    Joshi, C.; Adli, E.; An, W.; Clayton, C. E.; Corde, S.; Gessner, S.; Hogan, M. J.; Litos, M.; Lu, W.; Marsh, K. A.; Mori, W. B.; Vafaei-Najafabadi, N.; O'shea, B.; Xu, Xinlu; White, G.; Yakimenko, V.

    2018-03-01

    During the past two decades of research, the ultra-relativistic beam-driven plasma wakefield accelerator (PWFA) concept has achieved many significant milestones. These include the demonstration of ultra-high gradient acceleration of electrons over meter-scale plasma accelerator structures, efficient acceleration of a narrow energy spread electron bunch at high-gradients, positron acceleration using wakes in uniform plasmas and in hollow plasma channels, and demonstrating that highly nonlinear wakes in the ‘blow-out regime’ have the electric field structure necessary for preserving the emittance of the accelerating bunch. A new 10 GeV electron beam facility, Facilities for Accelerator Science and Experimental Test (FACET) II, is currently under construction at SLAC National Accelerator Laboratory for the next generation of PWFA research and development. The FACET II beams will enable the simultaneous demonstration of substantial energy gain of a small emittance electron bunch while demonstrating an efficient transfer of energy from the drive to the trailing bunch. In this paper we first describe the capabilities of the FACET II facility. We then describe a series of PWFA experiments supported by numerical and particle-in-cell simulations designed to demonstrate plasma wake generation where the drive beam is nearly depleted of its energy, high efficiency acceleration of the trailing bunch while doubling its energy and ultimately, quantifying the emittance growth in a single stage of a PWFA that has optimally designed matching sections. We then briefly discuss other FACET II plasma-based experiments including in situ positron generation and acceleration, and several schemes that are promising for generating sub-micron emittance bunches that will ultimately be needed for both an early application of a PWFA and for a plasma-based future linear collider.

  1. Plasma wakefield acceleration experiments at FACET II

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Joshi, C.; Adli, E.; An, W.

    During the past two decades of research, the ultra-relativistic beam-driven plasma wakefield accelerator (PWFA) concept has achieved many significant milestones. These include the demonstration of ultra-high gradient acceleration of electrons over meter-scale plasma accelerator structures, efficient acceleration of a narrow energy spread electron bunch at high-gradients, positron acceleration using wakes in uniform plasmas and in hollow plasma channels, and demonstrating that highly nonlinear wakes in the 'blow-out regime' have the electric field structure necessary for preserving the emittance of the accelerating bunch. A new 10 GeV electron beam facility, Facilities for Accelerator Science and Experimental Test (FACET) II, is currentlymore » under construction at SLAC National Accelerator Laboratory for the next generation of PWFA research and development. The FACET II beams will enable the simultaneous demonstration of substantial energy gain of a small emittance electron bunch while demonstrating an efficient transfer of energy from the drive to the trailing bunch. In this paper we first describe the capabilities of the FACET II facility. We then describe a series of PWFA experiments supported by numerical and particle-in-cell simulations designed to demonstrate plasma wake generation where the drive beam is nearly depleted of its energy, high efficiency acceleration of the trailing bunch while doubling its energy and ultimately, quantifying the emittance growth in a single stage of a PWFA that has optimally designed matching sections. Here, we briefly discuss other FACET II plasma-based experiments including in situ positron generation and acceleration, and several schemes that are promising for generating sub-micron emittance bunches that will ultimately be needed for both an early application of a PWFA and for a plasma-based future linear collider.« less

  2. Plasma wakefield acceleration experiments at FACET II

    DOE PAGES

    Joshi, C.; Adli, E.; An, W.; ...

    2018-01-12

    During the past two decades of research, the ultra-relativistic beam-driven plasma wakefield accelerator (PWFA) concept has achieved many significant milestones. These include the demonstration of ultra-high gradient acceleration of electrons over meter-scale plasma accelerator structures, efficient acceleration of a narrow energy spread electron bunch at high-gradients, positron acceleration using wakes in uniform plasmas and in hollow plasma channels, and demonstrating that highly nonlinear wakes in the 'blow-out regime' have the electric field structure necessary for preserving the emittance of the accelerating bunch. A new 10 GeV electron beam facility, Facilities for Accelerator Science and Experimental Test (FACET) II, is currentlymore » under construction at SLAC National Accelerator Laboratory for the next generation of PWFA research and development. The FACET II beams will enable the simultaneous demonstration of substantial energy gain of a small emittance electron bunch while demonstrating an efficient transfer of energy from the drive to the trailing bunch. In this paper we first describe the capabilities of the FACET II facility. We then describe a series of PWFA experiments supported by numerical and particle-in-cell simulations designed to demonstrate plasma wake generation where the drive beam is nearly depleted of its energy, high efficiency acceleration of the trailing bunch while doubling its energy and ultimately, quantifying the emittance growth in a single stage of a PWFA that has optimally designed matching sections. Here, we briefly discuss other FACET II plasma-based experiments including in situ positron generation and acceleration, and several schemes that are promising for generating sub-micron emittance bunches that will ultimately be needed for both an early application of a PWFA and for a plasma-based future linear collider.« less

  3. On the Contribution of Curl-Free Current Patterns to the Ultimate Intrinsic Signal-to-Noise Ratio at Ultra-High Field Strength.

    PubMed

    Pfrommer, Andreas; Henning, Anke

    2017-05-01

    The ultimate intrinsic signal-to-noise ratio (SNR) is a coil independent performance measure to compare different receive coil designs. To evaluate this benchmark in a sample, a complete electromagnetic basis set is required. The basis set can be obtained by curl-free and divergence-free surface current distributions, which excite linearly independent solutions to Maxwell's equations. In this work, we quantitatively investigate the contribution of curl-free current patterns to the ultimate intrinsic SNR in a spherical head-sized model at 9.4 T. Therefore, we compare the ultimate intrinsic SNR obtained with having only curl-free or divergence-free current patterns, with the ultimate intrinsic SNR obtained from a combination of curl-free and divergence-free current patterns. The influence of parallel imaging is studied for various acceleration factors. Moreover results for different field strengths (1.5 T up to 11.7 T) are presented at specific voxel positions and acceleration factors. The full-wave electromagnetic problem is analytically solved using dyadic Green's functions. We show, that at ultra-high field strength (B 0 ⩾7T) a combination of curl-free and divergence-free current patterns is required to achieve the best possible SNR at any position in a spherical head-sized model. On 1.5- and 3T platforms, divergence-free current patterns are sufficient to cover more than 90% of the ultimate intrinsic SNR. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Power Supplies for High Energy Particle Accelerators

    NASA Astrophysics Data System (ADS)

    Dey, Pranab Kumar

    2016-06-01

    The on-going research and the development projects with Large Hadron Collider at CERN, Geneva, Switzerland has generated enormous enthusiasm and interest amongst all to know about the ultimate findings on `God's Particle'. This paper has made an attempt to unfold the power supply requirements and the methodology adopted to provide the stringent demand of such high energy particle accelerators during the initial stages of the search for the ultimate particles. An attempt has also been made to highlight the present status on the requirement of power supplies in some high energy accelerators with a view that, precautionary measures can be drawn during design and development from earlier experience which will be of help for the proposed third generation synchrotron to be installed in India at a huge cost.

  5. Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway.

    PubMed

    Yang, Rong-Hua; Qi, Shao-Hai; Shu, Bin; Ruan, Shu-Bin; Lin, Ze-Peng; Lin, Yan; Shen, Rui; Zhang, Feng-Gang; Chen, Xiao-Dong; Xie, Ju-Lin

    2016-08-01

    Chronic, non-healing wounds are a major complication of diabetes. Recently, various cell therapies have been reported for promotion of diabetic wound healing. Epidermal stem cells (ESCs) are considered a powerful tool for tissue therapy. However, the effect and the mechanism of the therapeutic properties of ESCs in the diabetic wound healing are unclear. Herein, to determine the ability of ESCs to diabetic wound healing, a dorsal skin defect in a streptozotocin (STZ)-induced diabetes mellitus (DM) mouse model was used. ESCs were isolated from mouse skin. We found that both the mRNA and protein levels of a Notch ligand Jagged1 (Jag1), Notch1 and Notch target gene Hairy Enhancer of Split-1 (Hes1) were significantly increased at the wound margins. In addition, we observed that Jag1 was high expressed in ESCs. Overexpression of Jag1 promotes ESCs migration, whereas knockdown Jag1 resulted in a significant reduction in ESCs migration in vitro Importantly, Jag1 overexpression improves diabetic wound healing in vivo These results provide evidence that ESCs accelerate diabetic wound healing via the Notch signalling pathway, and provide a promising potential for activation of the Notch pathway for the treatment of diabetic wound. © 2016 The Author(s).

  6. Roadmap for creating an accelerated three-year medical education program.

    PubMed

    Leong, Shou Ling; Cangiarella, Joan; Fancher, Tonya; Dodson, Lisa; Grochowski, Colleen; Harnik, Vicky; Hustedde, Carol; Jones, Betsy; Kelly, Christina; Macerollo, Allison; Reboli, Annette C; Rosenfeld, Melvin; Rundell, Kristen; Thompson, Tina; Whyte, Robert; Pusic, Martin

    2017-01-01

    Medical education is undergoing significant transformation. Many medical schools are moving away from the concept of seat time to competency-based education and introducing flexibility in the curriculum that allows individualization. In response to rising student debt and the anticipated physician shortage, 35% of US medical schools are considering the development of accelerated pathways. The roadmap described in this paper is grounded in the experiences of the Consortium of Accelerated Medical Pathway Programs (CAMPP) members in the development, implementation, and evaluation of one type of accelerated pathway: the three-year MD program. Strategies include developing a mission that guides curricular development - meeting regulatory requirements, attaining institutional buy-in and resources necessary to support the programs, including student assessment and mentoring - and program evaluation. Accelerated programs offer opportunities to innovate and integrate a mission benefitting students and the public. CAMPP: Consortium of accelerated medical pathway programs; GME: Graduate medical education; LCME: Liaison committee on medical education; NRMP: National residency matching program; UME: Undergraduate medical education.

  7. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ma, Lijie; Dong, Pingping; Liu, Longzi

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstratedmore » that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.« less

  8. Roadmap for creating an accelerated three-year medical education program

    PubMed Central

    Leong, Shou Ling; Cangiarella, Joan; Fancher, Tonya; Dodson, Lisa; Grochowski, Colleen; Harnik, Vicky; Hustedde, Carol; Jones, Betsy; Kelly, Christina; Macerollo, Allison; Reboli, Annette C.; Rosenfeld, Melvin; Rundell, Kristen; Thompson, Tina; Whyte, Robert; Pusic, Martin

    2017-01-01

    ABSTRACT Medical education is undergoing significant transformation. Many medical schools are moving away from the concept of seat time to competency-based education and introducing flexibility in the curriculum that allows individualization. In response to rising student debt and the anticipated physician shortage, 35% of US medical schools are considering the development of accelerated pathways. The roadmap described in this paper is grounded in the experiences of the Consortium of Accelerated Medical Pathway Programs (CAMPP) members in the development, implementation, and evaluation of one type of accelerated pathway: the three-year MD program. Strategies include developing a mission that guides curricular development – meeting regulatory requirements, attaining institutional buy-in and resources necessary to support the programs, including student assessment and mentoring – and program evaluation. Accelerated programs offer opportunities to innovate and integrate a mission benefitting students and the public. Abbreviations: CAMPP: Consortium of accelerated medical pathway programs; GME: Graduate medical education; LCME: Liaison committee on medical education; NRMP: National residency matching program; UME: Undergraduate medical education PMID:29117817

  9. Concussion Prevalence in Competitive Ultimate Frisbee Players

    PubMed Central

    Lazar, Damien J.; Lichtenstein, Jonathan D.; Tybor, David J.

    2018-01-01

    Background: Ultimate Frisbee (ultimate) is a fast-growing, popular sport played nationally by over 4 million athletes. While several studies have examined injury rates in ultimate, no work has investigated the prevalence of concussions specifically or players’ knowledge and management of those injuries. Purpose: To estimate the lifetime prevalence of concussions in ultimate and to assess players’ knowledge of concussions as well as their concussion management behaviors. Study Design: Descriptive epidemiology study. Methods: From June to November 2015, we collected ultimate-related concussion data via an anonymous web-based survey, the Concussion in Ultimate Frisbee Survey, from a convenience sample of 787 male and female ultimate players across the United States. Results: There were 553 male and 234 female respondents included in the analysis; 26.58% of men and 24.79% of women reported that they had sustained at least 1 concussion while playing ultimate, with 45.58% and 43.10% of those men and women, respectively, reporting multiple concussions. A total of 67.81% of men and 78.21% of women stated that they would remove themselves from play after sustaining a given concussion, although 45.99% of men and 37.62% of women indicated that they had returned to play in the same game or practice. Conclusion: Our preliminary data suggest that concussions do commonly occur in competitive ultimate and that better education and management of concussions in ultimate athletes are needed. This study is an important first step in deepening our understanding of these issues. PMID:29552572

  10. Ultimate Realities: Deterministic and Evolutionary

    ERIC Educational Resources Information Center

    Moxley, Roy A.

    2007-01-01

    References to ultimate reality commonly turn up in the behavioral literature as references to determinism. However, this determinism is often difficult to interpret. There are different kinds of determinisms as well as different kinds of ultimate realities for a behaviorist to consider. To clarify some of the issues involved, the views of ultimate…

  11. Ultimately short ballistic vertical graphene Josephson junctions

    PubMed Central

    Lee, Gil-Ho; Kim, Sol; Jhi, Seung-Hoon; Lee, Hu-Jong

    2015-01-01

    Much efforts have been made for the realization of hybrid Josephson junctions incorporating various materials for the fundamental studies of exotic physical phenomena as well as the applications to superconducting quantum devices. Nonetheless, the efforts have been hindered by the diffusive nature of the conducting channels and interfaces. To overcome the obstacles, we vertically sandwiched a cleaved graphene monoatomic layer as the normal-conducting spacer between superconducting electrodes. The atomically thin single-crystalline graphene layer serves as an ultimately short conducting channel, with highly transparent interfaces with superconductors. In particular, we show the strong Josephson coupling reaching the theoretical limit, the convex-shaped temperature dependence of the Josephson critical current and the exceptionally skewed phase dependence of the Josephson current; all demonstrate the bona fide short and ballistic Josephson nature. This vertical stacking scheme for extremely thin transparent spacers would open a new pathway for exploring the exotic coherence phenomena occurring on an atomic scale. PMID:25635386

  12. Ultimate Realities: Deterministic and Evolutionary

    PubMed Central

    Moxley, Roy A

    2007-01-01

    References to ultimate reality commonly turn up in the behavioral literature as references to determinism. However, this determinism is often difficult to interpret. There are different kinds of determinisms as well as different kinds of ultimate realities for a behaviorist to consider. To clarify some of the issues involved, the views of ultimate realities are treated as falling along a continuum, with extreme views of complete indeterminism and complete determinism at either end and various mixes in between. Doing so brings into play evolutionary realities and the movement from indeterminism to determinism, as in Peirce's evolutionary cosmology. In addition, this framework helps to show how the views of determinism by B. F. Skinner and other behaviorists have shifted over time. PMID:22478489

  13. Future Synchrotron Light Sources Based on Ultimate Storage Rings

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cai, Yunhai; /SLAC

    2012-04-09

    The main purpose of this talk is to describe how far one might push the state of the art in storage ring design. The talk will start with an overview of the latest developments and advances in the design of synchrotron light sources based on the concept of an 'ultimate' storage ring. The review will establish how bright a ring based light source might be, where the frontier of technological challenges are, and what the limits of accelerator physics are. Emphasis will be given to possible improvements in accelerator design and developments in technology toward the goal of achieving anmore » ultimate storage ring. An ultimate storage ring (USR), defined as an electron ring-based light source having an emittance in both transverse planes at the diffraction limit for the range of X-ray wavelengths of interest for a scientific community, would provide very high brightness photons having high transverse coherence that would extend the capabilities of X-ray imaging and probe techniques beyond today's performance. It would be a cost-effective, high-coherence 4th generation light source, competitive with one based on energy recovery linac (ERL) technology, serving a large number of users studying material, chemical, and biological sciences. Furthermore, because of the experience accumulated over many decades of ring operation, it would have the great advantage of stability and reliability. In this paper we consider the design of an USR having 10-pm-rad emittance. It is a tremendous challenge to design a storage ring having such an extremely low emittance, a factor of 100 smaller than those in existing light sources, especially such that it has adequate dynamic aperture and beam lifetime. In many ultra-low emittance designs, the injection acceptances are not large enough for accumulation of the electron beam, necessitating on-axis injection where stored electron bunches are completely replaced with newly injected ones. Recently, starting with the MAX-IV 7-bend achromatic

  14. The ultimate limits of the relativistic rocket equation. The Planck photon rocket

    NASA Astrophysics Data System (ADS)

    Haug, Espen Gaarder

    2017-07-01

    In this paper we look at the ultimate limits of a photon propulsion rocket. The maximum velocity for a photon propulsion rocket is just below the speed of light and is a function of the reduced Compton wavelength of the heaviest subatomic particles in the rocket. We are basically combining the relativistic rocket equation with Haug's new insight on the maximum velocity for anything with rest mass. An interesting new finding is that in order to accelerate any subatomic "fundamental" particle to its maximum velocity, the particle rocket basically needs two Planck masses of initial load. This might sound illogical until one understands that subatomic particles with different masses have different maximum velocities. This can be generalized to large rockets and gives us the maximum theoretical velocity of a fully-efficient and ideal rocket. Further, no additional fuel is needed to accelerate a Planck mass particle to its maximum velocity; this also might sound absurd, but it has a very simple and logical solution that is explained in this paper.

  15. An Automated Pipeline for Engineering Many-Enzyme Pathways: Computational Sequence Design, Pathway Expression-Flux Mapping, and Scalable Pathway Optimization.

    PubMed

    Halper, Sean M; Cetnar, Daniel P; Salis, Howard M

    2018-01-01

    Engineering many-enzyme metabolic pathways suffers from the design curse of dimensionality. There are an astronomical number of synonymous DNA sequence choices, though relatively few will express an evolutionary robust, maximally productive pathway without metabolic bottlenecks. To solve this challenge, we have developed an integrated, automated computational-experimental pipeline that identifies a pathway's optimal DNA sequence without high-throughput screening or many cycles of design-build-test. The first step applies our Operon Calculator algorithm to design a host-specific evolutionary robust bacterial operon sequence with maximally tunable enzyme expression levels. The second step applies our RBS Library Calculator algorithm to systematically vary enzyme expression levels with the smallest-sized library. After characterizing a small number of constructed pathway variants, measurements are supplied to our Pathway Map Calculator algorithm, which then parameterizes a kinetic metabolic model that ultimately predicts the pathway's optimal enzyme expression levels and DNA sequences. Altogether, our algorithms provide the ability to efficiently map the pathway's sequence-expression-activity space and predict DNA sequences with desired metabolic fluxes. Here, we provide a step-by-step guide to applying the Pathway Optimization Pipeline on a desired multi-enzyme pathway in a bacterial host.

  16. Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer.

    PubMed

    Zhao, Yawei; Cui, Lianzhi; Pan, Yue; Shao, Dan; Zheng, Xiao; Zhang, Fan; Zhang, Hansi; He, Kan; Chen, Li

    2017-12-01

    Cytotoxic chemotherapy is an effective and traditional treatment of ovarian cancer. However, chemotherapy-induced apoptosis may also trigger and ultimately accelerate the repopulation of the small number of adjacent surviving cells. This study mainly focused on the tumour cell repopulation caused by chemotherapy in ovarian cancer and the adjunctive/synergistic effect of Berberine on the prevention of tumour repopulation. The transwell system was used to mimic the co-culture of surviving ovarian cancer cells in the microenvironment of cytotoxic chemotherapy-treated dying cells. Tumour cell proliferation was observed by crystal violet staining. AA and PGE 2 levels were measured by ELISA, and changes of protein expression were analysed by Western blot. Chemotherapy drug VP16 treatment triggered AA pathway, leading to the elevated PGE 2 level, and ultimately enhanced the repopulation of ovarian cancer cells. Berberine can block the caspase 3-iPLA 2 -AA-COX-2-PGE 2 pathway by inhibiting the expression of iPLA 2 and COX-2. Berberine can also reverse the increased phosphorylation of FAK caused by abnormal PGE 2 level and thus reverse the repopulation of ovarian cancer cells after VP16 treatment. Our observation suggested that Berberine could inhibit the chemotherapy-induced repopulation of ovarian cancer cells by suppressing the AA pathway and phosphorylation of FAK. And these findings implicated a novel combined use of Berberine and chemotherapeutics, which might prevent ovarian cancer recurrence by abrogating early tumour repopulation. © 2017 John Wiley & Sons Ltd.

  17. Adherence to an Accelerated Diagnostic Protocol for Chest Pain: Secondary Analysis of the HEART Pathway Randomized Trial

    PubMed Central

    Mahler, Simon A.; Riley, Robert F.; Russell, Gregory B.; Hiestand, Brian C.; Hoekstra, James W.; Lefebvre, Cedric W.; Nicks, Bret A.; Cline, David M.; Askew, Kim L.; Bringolf, John; Elliott, Stephanie B.; Herrington, David M.; Burke, Gregory L.; Miller, Chadwick D.

    2015-01-01

    Objectives Accelerated diagnostic protocols (ADP), such as the HEART Pathway, are gaining popularity in emergency departments (EDs) as tools used to risk-stratify patients with acute chest pain. However, provider non-adherence may threaten the safety and effectiveness of ADPs. The objective of this study was to determine the frequency and impact of ADP non-adherence. Methods A secondary analysis of participants enrolled in the HEART Pathway RCT was conducted. This trial enrolled 282 adult ED patients with symptoms concerning for acute coronary syndrome without ST-elevation on electrocardiogram. Patients randomized to the HEART Pathway (N = 141) were included in this analysis. Outcomes included index visit disposition, non-adherence, and major adverse cardiac events (MACE) at 30 days. MACE was defined as death, myocardial infarction, or revascularization. Non-adherence was defined as: 1) under-testing: discharging a high-risk patient from the ED without objective testing (stress testing or coronary angiography); or 2) over-testing: admitting or obtaining objective testing on a low-risk patient. Results Non-adherence to the HEART Pathway occurred in 28 out of 141 patients (20%, 95% CI = 14% to 27%). Over-testing occurred in 19 of 141 patients (13.5%, 95% CI = 8% to 19%) and under-testing in 9 of 141 patients (6%, 95% CI = 3% to 12%). None of these 28 patients suffered MACE. The net effect of non-adherence was ten additional admissions among patients identified as low-risk and appropriate for early discharge (absolute decrease in discharge rate of 7%, 95% CI = 3% to 13%). Conclusions Real-time use of the HEART Pathway resulted in a non-adherence rate of 20%, mostly due to over-testing. None of these patients had MACE within 30 days. Non-adherence decreased the discharge rate, attenuating the HEART Pathway’s impact on health care use. PMID:26720295

  18. Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

    PubMed

    LoRusso, Patricia M; Canetta, Renzo; Wagner, John A; Balogh, Erin P; Nass, Sharyl J; Boerner, Scott A; Hohneker, John

    2012-11-15

    Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. ©2012 AACR.

  19. Optimized operation of dielectric laser accelerators: Multibunch

    NASA Astrophysics Data System (ADS)

    Hanuka, Adi; Schächter, Levi

    2018-06-01

    We present a self-consistent analysis to determine the optimal charge, gradient, and efficiency for laser driven accelerators operating with a train of microbunches. Specifically, we account for the beam loading reduction on the material occurring at the dielectric-vacuum interface. In the case of a train of microbunches, such beam loading effect could be detrimental due to energy spread, however this may be compensated by a tapered laser pulse. We ultimately propose an optimization procedure with an analytical solution for group velocity which equals to half the speed of light. This optimization results in a maximum efficiency 20% lower than the single bunch case, and a total accelerated charge of 1 06 electrons in the train. The approach holds promise for improving operations of dielectric laser accelerators and may have an impact on emerging laser accelerators driven by high-power optical lasers.

  20. [Accelerated postoperative recovery after colorectal surgery].

    PubMed

    Alfonsi, P; Schaack, E

    2007-01-01

    Accelerated recovery programs are clinical pathways which outline the stages, and streamline the means, and techniques aiming toward the desired end a rapid return of the patient to his pre-operative physical and psychological status. Recovery from colo-rectal surgery may be slowed by the patient's general health, surgical stress, post-surgical pain, and post-operative ileus. Both surgeons and anesthesiologists participate throughout the peri-operative period in a clinical pathway aimed at minimizing these delaying factors. Key elements of this pathway include avoidance of pre-operative colonic cleansing, early enteral feeding, and effective post-operative pain management permitting early ambulation (usually via thoracic epidural anesthesia). Pre-operative information and motivation of the patient is also a key to the success of this accelerated recovery program. Studies of such programs have shown decreased duration of post-operative ileus and hospital stay without an increase in complications or re-admissions. The elements of the clinical pathway must be regularly re-evaluated and updated according to local experience and published data.

  1. Community College Pathways: 2013-2014 Descriptive Report

    ERIC Educational Resources Information Center

    Sowers, Nicole; Yamada, Hiroyuki

    2015-01-01

    The Community College Pathways initiative consists of two pathways, Statway® and Quantway®, that accelerate post-secondary students' progress through their developmental mathematics sequence and a college-level course for credit. Launched in 2011, the Pathways have been remarkably successful, helping thousands of students achieve success in…

  2. Bootstrap calculation of ultimate strength temperature maxima for neutron irradiated ferritic/martensitic steels

    NASA Astrophysics Data System (ADS)

    Obraztsov, S. M.; Konobeev, Yu. V.; Birzhevoy, G. A.; Rachkov, V. I.

    2006-12-01

    The dependence of mechanical properties of ferritic/martensitic (F/M) steels on irradiation temperature is of interest because these steels are used as structural materials for fast, fusion reactors and accelerator driven systems. Experimental data demonstrating temperature peaks in physical and mechanical properties of neutron irradiated pure iron, nickel, vanadium, and austenitic stainless steels are available in the literature. A lack of such an information for F/M steels forces one to apply a computational mathematical-statistical modeling methods. The bootstrap procedure is one of such methods that allows us to obtain the necessary statistical characteristics using only a sample of limited size. In the present work this procedure is used for modeling the frequency distribution histograms of ultimate strength temperature peaks in pure iron and Russian F/M steels EP-450 and EP-823. Results of fitting the sums of Lorentz or Gauss functions to the calculated distributions are presented. It is concluded that there are two temperature (at 360 and 390 °C) peaks of the ultimate strength in EP-450 steel and single peak at 390 °C in EP-823.

  3. The Ultimate Fizz

    ERIC Educational Resources Information Center

    Heckscher, Mary

    2008-01-01

    Many recipes for elementary science activities suggest making carbon dioxide from baking soda and vinegar; however, they often do not give exact measurements of the ingredients. The author was able to turn this "drawback" into a plus by challenging her fifth-grade students to find the "ultimate fizz"--i.,e., "What amount of baking soda added to a…

  4. 29 CFR 18.704 - Opinion on ultimate issue.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Opinion on ultimate issue. 18.704 Section 18.704 Labor... ultimate issue. Testimony in the form of an opinion or inference otherwise admissible is not objectionable because it embraces an ultimate issue to be decided by the judge as trier of fact. ...

  5. Basic Fibroblast Growth Factor Accelerates Matrix Degradation Via a Neuro-Endocrine Pathway in Human Adult Articular Chondrocytes

    PubMed Central

    IM, HEE-JEONG; LI, XIN; MUDDASANI, PRASUNA; KIM, GUN-HEE; DAVIS, FRANCESCA; RANGAN, JAYANTHI; FORSYTH, CHRISTOPHER B.; ELLMAN, MICHAEL; THONAR, EUGENE JMA

    2010-01-01

    Pain-related neuropeptides released from synovial fibroblasts, such as substance P, have been implicated in joint destruction. Substance P-induced inflammatory processes are mediated via signaling through a G-protein-coupled receptor, that is, neurokinin-1 tachykinin receptor (NK1-R). We determined the pathophysiological link between substance P and its receptor in human adult articular cartilage homeostasis. We further examined if catabolic growth factors such as basic fibroblast growth factor (bFGF or FGF-2) or IL-1β accelerate matrix degradation via a neural pathway upregulation of substance P and NK1-R. We show here that substance P stimulates the production of cartilage-degrading enzymes, such as matrix metalloproteinase-13 (MMP-13), and suppresses proteoglycan deposition in human adult articular chondrocytes via NK1-R. Furthermore, we have demonstrated that substance P negates proteoglycan stimulation promoted by bone morphogenetic protein-7, suggesting the dual role of substance P as both a pro-catabolic and anti-anabolic mediator of cartilage homeostasis. We report that bFGF-mediated stimulation of substance P and its receptor NK1-R is, in part, through an IL-1β-dependent pathway. PMID:17960584

  6. Basic fibroblast growth factor accelerates matrix degradation via a neuro-endocrine pathway in human adult articular chondrocytes.

    PubMed

    Im, Hee-Jeong; Li, Xin; Muddasani, Prasuna; Kim, Gun-Hee; Davis, Francesca; Rangan, Jayanthi; Forsyth, Christopher B; Ellman, Michael; Thonar, Eugene J M A

    2008-05-01

    Pain-related neuropeptides released from synovial fibroblasts, such as substance P, have been implicated in joint destruction. Substance P-induced inflammatory processes are mediated via signaling through a G-protein-coupled receptor, that is, neurokinin-1 tachykinin receptor (NK(1)-R). We determined the pathophysiological link between substance P and its receptor in human adult articular cartilage homeostasis. We further examined if catabolic growth factors such as basic fibroblast growth factor (bFGF or FGF-2) or IL-1beta accelerate matrix degradation via a neural pathway upregulation of substance P and NK(1)-R. We show here that substance P stimulates the production of cartilage-degrading enzymes, such as matrix metalloproteinase-13 (MMP-13), and suppresses proteoglycan deposition in human adult articular chondrocytes via NK(1)-R. Furthermore, we have demonstrated that substance P negates proteoglycan stimulation promoted by bone morphogenetic protein-7, suggesting the dual role of substance P as both a pro-catabolic and anti-anabolic mediator of cartilage homeostasis. We report that bFGF-mediated stimulation of substance P and its receptor NK(1)-R is, in part, through an IL-1beta-dependent pathway. (c) 2007 Wiley-Liss, Inc.

  7. Laser Acceleration of Ions for Radiation Therapy

    NASA Astrophysics Data System (ADS)

    Tajima, Toshiki; Habs, Dietrich; Yan, Xueqing

    Ion beam therapy for cancer has proven to be a successful clinical approach, affording as good a cure as surgery and a higher quality of life. However, the ion beam therapy installation is large and expensive, limiting its availability for public benefit. One of the hurdles is to make the accelerator more compact on the basis of conventional technology. Laser acceleration of ions represents a rapidly developing young field. The prevailing acceleration mechanism (known as target normal sheath acceleration, TNSA), however, shows severe limitations in some key elements. We now witness that a new regime of coherent acceleration of ions by laser (CAIL) has been studied to overcome many of these problems and accelerate protons and carbon ions to high energies with higher efficiencies. Emerging scaling laws indicate possible realization of an ion therapy facility with compact, cost-efficient lasers. Furthermore, dense particle bunches may allow the use of much higher collective fields, reducing the size of beam transport and dump systems. Though ultimate realization of a laser-driven medical facility may take many years, the field is developing fast with many conceptual innovations and technical progress.

  8. Ultimate justification: Wittgenstein and medical ethics.

    PubMed

    Hughes, J

    1995-02-01

    Decisions must be justified. In medical ethics various grounds are given to justify decisions, but ultimate justification seems illusory and little considered. The philosopher Wittgenstein discusses the problem of ultimate justification in the context of general philosophy. His comments, nevertheless, are pertinent to ethics. From a discussion of Wittgensteinian notions, such as 'bedrock', the idea that 'ultimate' justification is grounded in human nature as such is derived. This discussion is relevant to medical ethics in at least five ways: it shows generally what type of certainty there is in practical ethics; it seems to imply some objective foundation to our ethical judgements; it squares with our experience of making ethical decisions; it shows something of the nature of moral arguments; and, finally, it has implications for teaching medicine and ethics.

  9. Ultimate justification: Wittgenstein and medical ethics.

    PubMed Central

    Hughes, J

    1995-01-01

    Decisions must be justified. In medical ethics various grounds are given to justify decisions, but ultimate justification seems illusory and little considered. The philosopher Wittgenstein discusses the problem of ultimate justification in the context of general philosophy. His comments, nevertheless, are pertinent to ethics. From a discussion of Wittgensteinian notions, such as 'bedrock', the idea that 'ultimate' justification is grounded in human nature as such is derived. This discussion is relevant to medical ethics in at least five ways: it shows generally what type of certainty there is in practical ethics; it seems to imply some objective foundation to our ethical judgements; it squares with our experience of making ethical decisions; it shows something of the nature of moral arguments; and, finally, it has implications for teaching medicine and ethics. PMID:7776343

  10. Pathway enrichment analysis approach based on topological structure and updated annotation of pathway.

    PubMed

    Yang, Qian; Wang, Shuyuan; Dai, Enyu; Zhou, Shunheng; Liu, Dianming; Liu, Haizhou; Meng, Qianqian; Jiang, Bin; Jiang, Wei

    2017-08-16

    Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology-based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality-based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well-known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r-project.org/web/packages/TPEA/. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Inflammation disrupts the LDL receptor pathway and accelerates the progression of vascular calcification in ESRD patients.

    PubMed

    Liu, Jing; Ma, Kun Ling; Gao, Min; Wang, Chang Xian; Ni, Jie; Zhang, Yang; Zhang, Xiao Liang; Liu, Hong; Wang, Yan Li; Liu, Bi Cheng

    2012-01-01

    Chronic inflammation plays a crucial role in the progression of vascular calcification (VC). This study was designed to investigate whether the low-density lipoprotein receptor (LDLr) pathway is involved in the progression of VC in patients with end-stage renal disease (ESRD) during inflammation. Twenty-eight ESRD patients were divided into control and inflamed groups according to plasma C-reactive protein (CRP) level. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used in the experiments. The expression of tumour necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) of the radial artery were increased in the inflamed group. Hematoxylin-eosin and alizarin red S staining revealed parallel increases in foam cell formation and calcium deposit formation in continuous cross-sections of radial arteries in the inflamed group compared to the control, which were closely correlated with increased LDLr, sterol regulatory element binding protein-2 (SREBP-2), bone morphogenetic proteins-2 (BMP-2), and collagen I protein expression, as shown by immunohistochemical and immunofluorescent staining. Confocal microscopy confirmed that inflammation enhanced the translocation of the SREBP cleavage-activating protein (SCAP)/SREBP-2 complex from the endoplasmic reticulum to the Golgi, thereby activating LDLr gene transcription. Inflammation increased alkaline phosphatase protein expression and reduced α-smooth muscle actin protein expression, contributing to the conversion of the vascular smooth muscle cells in calcified vessels from the fibroblastic to the osteogenic phenotype; osteogenic cells are the main cellular components involved in VC. Further analysis showed that the inflammation-induced disruption of the LDLr pathway was significantly associated with enhanced BMP-2 and collagen I expression. Inflammation accelerated the progression of VC in ESRD patients by disrupting the LDLr pathway, which may represent a

  12. The Ultimate Flag Games.

    ERIC Educational Resources Information Center

    Angel, Kenny; Sutton, Nancy

    This paper describes six Ultimate Flag Games which offer a change from traditional games and sports that are usually geared toward athletically inclined students. These new games, aimed at middle school through college students, allow for success from the least-skilled through the most athletically talented students. Players are ability grouped…

  13. Accelerating Adverse Outcome Pathway Development via Systems Approaches

    EPA Science Inventory

    The Adverse Outcome Pathway has emerged as an internationally harmonized mechanism for organizing biological information in a chemical agnostic manner. This construct is valuable for interpreting the results from high-throughput toxicity (HTT) assessment by providing a mechanisti...

  14. Converging Pathways in Lifespan Regulation

    PubMed Central

    Narasimhan, Sri Devi; Yen, Kelvin; Tissenbaum, Heidi A.

    2011-01-01

    The processes that determine an organism’s lifespan are complex and poorly understood. Yet single gene manipulations and environmental interventions can substantially delay age-related morbidity. In this review, we focus on the two most potent modulators of longevity: insulin/insulin-like growth factor 1 (IGF-1) signaling and dietary restriction. The remarkable molecular conservation of the components associated with insulin/IGF-1 signaling and dietary restriction allow us to understand longevity from a multi-species perspective. We summarize the most recent findings on insulin/IGF-1 signaling and examine the proteins and pathways that reveal a more genetic basis for dietary restriction. Although insulin/IGF-1 signaling and dietary restriction pathways are currently viewed as being independent, we suggest that these two pathways are more intricately connected than previously appreciated. We highlight that numerous interactions between these two pathways can occur at multiple levels. Ultimately, both the insulin/IGF-1 pathway and the pathway that mediates the effects of dietary restriction have evolved to respond to the nutritional status of an organism, which in turn affects its lifespan. PMID:19674551

  15. Education and Ultimate Meaning

    ERIC Educational Resources Information Center

    Schinkel, Anders

    2015-01-01

    Richard Peters and John White have both argued that education should contribute to the meaning people are able to find in or give to life. Both dismiss the idea of ultimate or profound meaning ("the meaning of life") in favour of ordinary meaning, or "meaning in life". Thus they exemplify the trend visible also in the general…

  16. The canonical Wnt signaling pathway in autism.

    PubMed

    Zhang, Yinghua; Yuan, Xiangshan; Wang, Zhongping; Li, Ruixi

    2014-01-01

    Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.

  17. Diffusive Shock Acceleration and Turbulent Reconnection

    NASA Astrophysics Data System (ADS)

    Garrel, Christian; Vlahos, Loukas; Isliker, Heinz; Pisokas, Theophilos

    2018-05-01

    Diffusive Shock Acceleration (DSA) cannot efficiently accelerate particles without the presence of self-consistently generated or pre-existing strong turbulence (δB/B ˜ 1) in the vicinity of the shock. The problem we address in this article is: if large amplitude magnetic disturbances are present upstream and downstream of a shock then Turbulent Reconnection (TR) will set in and will participate not only in the elastic scattering of particles but also in their heating and acceleration. We demonstrate that large amplitude magnetic disturbances and Unstable Current Sheets (UCS), spontaneously formed in the strong turbulence in the vicinity of a shock, can accelerate particles as efficiently as DSA in large scale systems and on long time scales. We start our analysis with "elastic" scatterers upstream and downstream and estimate the energy distribution of particles escaping from the shock, recovering the well known results from the DSA theory. Next we analyze the additional interaction of the particles with active scatterers (magnetic disturbances and UCS) upstream and downstream of the shock. We show that the asymptotic energy distribution of the particles accelerated by DSA/TR has very similar characteristics with the one due to DSA alone, but the synergy of DSA with TR is much more efficient: The acceleration time is an order of magnitude shorter and the maximum energy reached two orders of magnitude higher. We claim that DSA is the dominant acceleration mechanism in a short period before TR is established, and then strong turbulence will dominate the heating and acceleration of the particles. In other words, the shock serves as the mechanism to set up a strongly turbulent environment, in which the acceleration mechanism will ultimately be the synergy of DSA and TR.

  18. Ultimate RHIC Performance Estimates

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hahn, H.

    1986-11-10

    The RHIC performance estimates for pp operation given in the Conceptual Design report are intentionally conservative as to energy and luminosity. The ultimate RHIC performance was estimated by an ad-hoc comittee with F.Dell, H. Foelsche, H. Hahn, S.Y. Lee, G. Parzen, E. Raka, S. Tepikian, and P. Thompson as members. The present note summarizes the committee's conclusions.

  19. Reliability of Hull Girder Ultimate Strength of Steel Ships

    NASA Astrophysics Data System (ADS)

    Da-wei, Gao; Gui-jie, Shi

    2018-03-01

    Hull girder ultimate strength is an evaluation index reflecting the true safety margin or structural redundancy about container ships. Especially, after the hull girder fracture accident of the MOL COMFORT, the 8,000TEU class large container ship, on June 17 2013, larger container ship safety has been paid on much more attention. In this paper, different methods of calculating hull girder ultimate strength are firstly discussed and compared with. The bending ultimate strength can be analyzed by nonlinear finite element method (NFEM) and increment-iterative method, and also the shear ultimate strength can be analyzed by NFEM and simple equations. Then, the probability distribution of hull girder wave loads and still water loads of container ship are summarized. At last, the reliability of hull girder ultimate strength under bending moment and shear forces for three container ships is analyzed by using a first order method. The conclusions can be applied to give guidance for ship design and safety evaluation.

  20. Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy.

    PubMed

    Lee, Yun-Sil; Lehar, Adam; Sebald, Suzanne; Liu, Min; Swaggart, Kayleigh A; Talbot, C Conover; Pytel, Peter; Barton, Elisabeth R; McNally, Elizabeth M; Lee, Se-Jin

    2015-10-15

    Myostatin is a secreted signaling molecule that normally acts to limit muscle growth. As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss. One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression. To investigate this possibility, we examined the effect of blocking the myostatin pathway in dysferlin-deficient (Dysf(-/-)) mice, in which membrane repair is compromised, either by transgenic expression of follistatin in skeletal muscle or by systemic administration of the soluble form of the activin type IIB receptor (ACVR2B/Fc). Here, we show that myostatin inhibition by follistatin transgene expression in Dysf(-/-) mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration; this effect was not observed in dystrophin-deficient (mdx) mice, suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin. Dysf(-/-) mice injected with ACVR2B/Fc showed significant increases in muscle mass and amelioration of fibrotic changes normally seen in 8-month-old Dysf(-/-) mice. Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf(-/-) mice, indicating possible muscle damage induced by hypertrophy. These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis. © The Author 2015. Published by Oxford University Press.

  1. Ultimate fate of constrained voters

    NASA Astrophysics Data System (ADS)

    Vazquez, F.; Redner, S.

    2004-09-01

    We examine the ultimate fate of individual opinions in a socially interacting population of leftists, centrists and rightists. In an elemental interaction between agents, a centrist and a leftist can both become centrists or both become leftists with equal rates (and similarly for a centrist and a rightist). However leftists and rightists do not interact. This interaction step between pairs of agents is applied repeatedly until the system can no longer evolve. In the mean-field limit, we determine the exact probability that the system reaches consensus (either leftist, rightist or centrist) or a frozen mixture of leftists and rightists as a function of the initial composition of the population. We also determine the mean time until the final state is reached. Some implications of our results for the ultimate fate in a limit of the Axelrod model are discussed.

  2. GTA (ground test accelerator) Phase 1: Baseline design report

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Not Available

    1986-08-01

    The national Neutral Particle Beam (NPB) program has two objectives: to provide the necessary basis for a discriminator/weapon decision by 1992, and to develop the technology in stages that lead ultimately to a neutral particle beam weapon. The ground test accelerator (GTA) is the test bed that permits the advancement of the state-of-the-art under experimental conditions in an integrated automated system mode. An intermediate goal of the GTA program is to support the Integrated Space Experiments, while the ultimate goal is to support the 1992 decision. The GTA system and each of its major subsystems are described, and project schedulesmore » and resource requirements are provided. (LEW)« less

  3. The ultimate legs of Chilopoda (Myriapoda): a review on their morphological disparity and functional variability

    PubMed Central

    Kenning, Matthes; Müller, Carsten H.G.

    2017-01-01

    The arthropodium is the key innovation of arthropods. Its various modifications are the outcome of multiple evolutionary transformations, and the foundation of nearly endless functional possibilities. In contrast to hexapods, crustaceans, and even chelicerates, the spectrum of evolutionary transformations of myriapod arthropodia is insufficiently documented and rarely scrutinized. Among Myriapoda, Chilopoda (centipedes) are characterized by their venomous forcipules—evolutionarily transformed walking legs of the first trunk segment. In addition, the posterior end of the centipedes’ body, in particular the ultimate legs, exhibits a remarkable morphological heterogeneity. Not participating in locomotion, they hold a vast functional diversity. In many centipede species, elongation and annulation in combination with an augmentation of sensory structures indicates a functional shift towards a sensory appendage. In other species, thickening, widening and reinforcement with a multitude of cuticular protuberances and glandular systems suggests a role in both attack and defense. Moreover, sexual dimorphic characteristics indicate that centipede ultimate legs play a pivotal role in intraspecific communication, mate finding and courtship behavior. We address ambiguous identifications and designations of podomeres in order to point out controversial aspects of homology and homonymy. We provide a broad summary of descriptions, illustrations, ideas and observations published in past 160 years, and propose that studying centipede ultimate legs is not only essential in itself for filling gaps of knowledge in descriptive morphology, but also provides an opportunity to explore diverse pathways of leg transformations within Myriapoda. PMID:29158971

  4. Mapping the pathways of resistance to targeted therapies

    PubMed Central

    Wood, Kris C.

    2015-01-01

    Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacological approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients. PMID:26392071

  5. Ultimate Lateral Capacity of Rigid Pile in c- φ Soil

    NASA Astrophysics Data System (ADS)

    Zhang, Wei-min

    2018-03-01

    To date no analytical solution of the pile ultimate lateral capacity for the general c- φ soil has been obtained. In the present study, a new dimensionless embedded ratio was proposed and the analytical solutions of ultimate lateral capacity and rotation center of rigid pile in c- φ soils were obtained. The results showed that both the dimensionless ultimate lateral capacity and dimensionless rotation center were the univariate functions of the embedded ratio. Also, the ultimate lateral capacity in the c- φ soil was the combination of the ultimate lateral capacity ( f c ) in the clay, and the ultimate lateral capacity ( f φ ) in the sand. Therefore, the Broms chart for clay, solution for clay ( φ=0) put forward by Poulos and Davis, solution for sand ( c=0) obtained by Petrasovits and Awad, and Kondner's ultimate bending moment were all proven to be the special cases of the general solution in the present study. A comparison of the field and laboratory tests in 93 cases showed that the average ratios of the theoretical values to the experimental value ranged from 0.85 to 1.15. Also, the theoretical values displayed a good agreement with the test values.

  6. Particle acceleration and turbulence in cosmic Ray shocks: possible pathways beyond the Bohm limit

    NASA Astrophysics Data System (ADS)

    Malkov, M. A.; Diamond, P. H.

    2007-08-01

    Diffusive shock acceleration is discussed in terms of its potential to accelerate cosmic rays (CR) to 1018 eV (beyond the ``knee,'' as observations suggest) and in terms of the related observational signatures (spectral features). One idea to reach this energy is to resonantly generate a turbulent magnetic field via accelerated particles much in excess of the background field. We identify difficulties with this scenario and suggest two separate mechanisms that can work in concert with one another leading to a significant acceleration enhancement. The first mechanism is based on a nonlinear modification of the flow ahead of the shock supported by particles already accelerated to some specific (knee) momentum. The particles gain energy by bouncing off converging magnetic irregularities frozen into the flow in the shock precursor and not so much by re-crossing the shock itself. The acceleration rate is determined by the gradient of the flow velocity and turns out to be formally independent of the particle mean free path. The velocity gradient is set by the knee-particles. The acceleration rate of particles above the knee does not decrease with energy, unlike in the linear acceleration regime. The knee (spectrum steepening) forms because particles above it are effectively confined to the shock only if they are within limited domains in the momentum space, while other particles fall into ``loss-islands'', similar to the ``loss-cone'' of magnetic traps. This also maintains the steep velocity gradient and high acceleration rate. The second mechanism is based on the generation of Alfven waves at the gyroradius scale at the background field level, with a subsequent transfer to longer scales via interaction with strong acoustic turbulence in the shock precursor. The acoustic turbulence in turn, may be generated by Drury instability or by parametric instability of the Alfven (A) waves.

  7. Ultimate Educational Aims, Overridingness, and Personal Well-Being

    ERIC Educational Resources Information Center

    Haji, Ishtiyaque; Cuypers, Stefaan E.

    2011-01-01

    Discussion regarding education's aims, especially its ultimate aims, is a key topic in the philosophy of education. These aims or values play a pivotal role in regulating and structuring moral and other types of normative education. We outline two plausible strategies to identify and justify education's ultimate aims. The first associates these…

  8. Dusty-Plasma Particle Accelerator

    NASA Technical Reports Server (NTRS)

    Foster, John E.

    2005-01-01

    initiation of a low-current, high-voltage cathode spot. Plasma pressure associated with the cathode spot as well as the large voltage drop at the cathode spot accelerates the charged particles toward the substrate. The ultimate kinetic energy attained by particles exiting the particle holder depends in part on the magnitude of the cathode spot sheath potential difference, which is proportional to the magnitude of the voltage pulse, and the on the electric charge on the dust. The magnitude of the voltage pulse can be controlled directly, whereas the particle s electric charge can be controlled indirectly by controlling the operating parameters of the plasma apparatus.

  9. Cell Signaling Pathways that Regulate Ag Presentation

    PubMed Central

    Brutkiewicz, Randy R.

    2016-01-01

    Cell signaling pathways regulate much in the life of a cell: from shuttling cargo through intracellular compartments and onto the cell surface, how it should respond to stress, protecting itself from harm (environmental insults or infections), to ultimately, death by apoptosis. These signaling pathways are important for various aspects of the immune response as well. However, not much is known in terms of the participation of cell signaling pathways in Ag presentation--a necessary first step in the activation of innate and adaptive T cells. In this brief review, I will discuss the known signaling molecules (and pathways) that regulate how Ags are presented to T cells and the mechanism(s) if identified. Studies in this area have important implications in vaccine development and new treatment paradigms against infectious diseases, autoimmunity and cancer. PMID:27824592

  10. "Got Disc?" The "Ultimate" Experience in Physical Education

    ERIC Educational Resources Information Center

    Johnson, Tyler G.; Darst, Paul W.; Brusseau, Timothy A.

    2006-01-01

    A quality physical education program is one in which students are exposed to and can participate in a variety of sports and activities. One activity that is increasing in popularity in and outside of physical education is the game of "Ultimate." Opportunities to play Ultimate are increasing rapidly in intramural programs and community and…

  11. The Role of Substorms in Storm-time Particle Acceleration

    NASA Astrophysics Data System (ADS)

    Daglis, Ioannis A.; Kamide, Yohsuke

    The terrestrial magnetosphere has the capability to rapidly accelerate charged particles up to very high energies over relatively short times and distances. Acceleration of charged particles is an essential ingredient of both magnetospheric substorms and space storms. In the case of space storms, the ultimate result is a bulk flow of electric charge through the inner magnetosphere, commonly known as the ring current. Syun-Ichi Akasofu and Sydney Chapman, two of the early pioneers in space physics, postulated that the bulk acceleration of particles during storms is rather the additive result of partial acceleration during consecutive substorms. This paradigm has been heavily disputed during recent years. The new case is that substorm acceleration may be sufficient to produce individual high-energy particles that create auroras and possibly harm spacecraft, but it cannot produce the massive acceleration that constitutes a storm. This paper is a critical review of the long-standing issue of the storm-substorm relationship, or—in other words—the capability or necessity of substorms in facilitating or driving the build-up of the storm-time ring current. We mainly address the physical effect itself, i.e. the bulk acceleration of particles, and not the diagnostic of the process, i.e. the Dst index, which is rather often the case. Within the framework of particle acceleration, substorms retain their storm-importance due to the potential of substorm-induced impulsive electric fields in obtaining the massive ion acceleration needed for the storm-time ring current buildup.

  12. Pharma Opportunities and Risks Multiply as Regulatory Reform Remakes APAC: Expanded Accelerated Pathways Challenge Developer Value Story, Evidence Collection, and Market Access Strategies.

    PubMed

    Grignolo, Alberto; Mingping, Zhang

    2018-01-01

    Sweeping reforms in the largest markets of the Asia-Pacific region are transforming the regulatory and commercial landscape for foreign pharmaceutical companies. Japan, South Korea, and China are leading the charge, establishing mechanisms and infrastructure that both reflect and help drive international regulatory convergence and accelerate delivery of needed, innovative products to patients. In this rapidly evolving regulatory and commercial environment, drug developers can benefit from reforms and proliferating accelerated pathway (AP) frameworks, but only with regulatory and evidence-generation strategies tailored to the region. Otherwise, they will confront significant pricing and reimbursement headwinds. Although APAC economies are at different stages of development, they share a common imperative: to balance pharmaceutical innovation with affordability. Despite the complexity of meeting these sometimes conflicting demands, companies that focus on demonstrating and delivering value for money, and that price new treatments reasonably and sustainably, can succeed both for their shareholders and the region's patient population.

  13. Laser-driven proton acceleration with nanostructured targets

    NASA Astrophysics Data System (ADS)

    Vallières, Simon; Morabito, Antonia; Veltri, Simona; Scisciò, Massimiliano; Barberio, Marianna; Antici, Patrizio

    2017-05-01

    Laser-driven particle acceleration has become a growing field of research, in particular for its numerous interesting applications. One of the most common proton acceleration mechanism that is obtained on typically available multi-hundred TW laser systems is based on the irradiation of thin solid metal foils by the intense laser, generating the proton acceleration on its rear target surface. The efficiency of this acceleration scheme strongly depends on the type of target used. Improving the acceleration mechanism, i.e. enhancing parameters such as maximum proton energy, laminarity, efficiency, monocromaticy, and number of accelerated particles, is heavily depending on the laser-to-target absorption, where obviously cheap and easy to implement targets are best candidates. In this work, we present nanostructured targets that are able to increase the absorption of light compared to what can be achieved with a classical solid (non-nanostructured) target and are produced with a method that is much simpler and cheaper than conventional lithographic processes. Several layers of gold nanoparticles were deposited on solid targets (aluminum, Mylar and multiwalled carbon nanotube buckypaper) and allow for an increased photon absorption. This ultimately permits to increase the laser-to-particle energy transfer, and thus to enhance the yield in proton production. Experimental characterization results on the nanostructured films are presented (UV-Vis spectroscopy and AFM), along with preliminary experimental proton spectra obtained at the JLF-TITAN laser facility at LLNL.

  14. Hydrogen-Rich Water Intake Accelerates Oral Palatal Wound Healing via Activation of the Nrf2/Antioxidant Defense Pathways in a Rat Model

    PubMed Central

    Orihuela-Campos, Rita Cristina; Fukui, Makoto; Ito, Hiro-O

    2016-01-01

    The wound healing process attempts to restore the integrity and function of the injured tissue. Additionally, proinflammatory cytokines, growth factors, and oxidative stress play important roles in wound healing. The aim of this study was to determine whether hydrogen-rich water intake induces the activation of the Nrf2/antioxidant defense pathway in rat palatal tissue, thereby reducing systemic oxidative stress and proinflammatory cytokine levels and promoting healing-associated genes. A circular excisional wound was created in the oral palatal region, and the wound healing process was observed. The rats were divided into two experimental groups in which either hydrogen-rich water or distilled water was consumed. In the drinking hydrogen-rich water, the palatal wound healing process was accelerated compared to that in the control group. As molecular hydrogen upregulated the Nrf2 pathway, systemic oxidative stresses were decreased by the activation of antioxidant activity. Furthermore, hydrogen-rich water intake reduced proinflammatory cytokine levels and promoted the expression of healing-associated factors in rat palatal tissue. In conclusion, hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses. PMID:26798423

  15. Hydrogen-Rich Water Intake Accelerates Oral Palatal Wound Healing via Activation of the Nrf2/Antioxidant Defense Pathways in a Rat Model.

    PubMed

    Tamaki, Naofumi; Orihuela-Campos, Rita Cristina; Fukui, Makoto; Ito, Hiro-O

    2016-01-01

    The wound healing process attempts to restore the integrity and function of the injured tissue. Additionally, proinflammatory cytokines, growth factors, and oxidative stress play important roles in wound healing. The aim of this study was to determine whether hydrogen-rich water intake induces the activation of the Nrf2/antioxidant defense pathway in rat palatal tissue, thereby reducing systemic oxidative stress and proinflammatory cytokine levels and promoting healing-associated genes. A circular excisional wound was created in the oral palatal region, and the wound healing process was observed. The rats were divided into two experimental groups in which either hydrogen-rich water or distilled water was consumed. In the drinking hydrogen-rich water, the palatal wound healing process was accelerated compared to that in the control group. As molecular hydrogen upregulated the Nrf2 pathway, systemic oxidative stresses were decreased by the activation of antioxidant activity. Furthermore, hydrogen-rich water intake reduced proinflammatory cytokine levels and promoted the expression of healing-associated factors in rat palatal tissue. In conclusion, hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses.

  16. A mass filter based on an accelerating traveling wave.

    PubMed

    Wiedenbeck, Michael; Kasemset, Bodin; Kasper, Manfred

    2008-01-01

    We describe a novel mass filtering concept based on the acceleration of a pulsed ion beam through a stack of electrostatic plates. A precisely controlled traveling wave generated within such an ion guide will induce a mass-selective ion acceleration, with mass separation ultimately accomplished via a simple energy-filtering system. Crucial for successful filtering is that the velocity with which the traveling wave passes through the ion guide must be dynamically controlled in order to accommodate the acceleration of the target ion species. Mass selection is determined by the velocity and acceleration with which the wave traverses the ion guide, whereby the target species will acquire a higher kinetic energy than all other lighter as well as heaver species. Finite element simulations of this design demonstrate that for small masses a mass resolution M/DeltaM approximately 1000 can be achieved within an electrode stack containing as few as 20 plates. Some of the possible advantages and drawbacks which distinguish this concept from established mass spectrometric technologies are discussed.

  17. Constraints on the extremely high-energy cosmic ray accelerators from classical electrodynamics

    NASA Astrophysics Data System (ADS)

    Aharonian, F. A.; Belyanin, A. A.; Derishev, E. V.; Kocharovsky, V. V.; Kocharovsky, Vl. V.

    2002-07-01

    We formulate the general requirements, set by classical electrodynamics, on the sources of extremely high-energy cosmic rays (EHECRs). It is shown that the parameters of EHECR accelerators are strongly limited not only by the particle confinement in large-scale magnetic fields or by the difference in electric potentials (generalized Hillas criterion) but also by the synchrotron radiation, the electro-bremsstrahlung, or the curvature radiation of accelerated particles. Optimization of these requirements in terms of an accelerator's size and magnetic field strength results in the ultimate lower limit to the overall source energy budget, which scales as the fifth power of attainable particle energy. Hard γ rays accompanying generation of EHECRs can be used to probe potential acceleration sites. We apply the results to several populations of astrophysical objects-potential EHECR sources-and discuss their ability to accelerate protons to 1020 eV and beyond. The possibility of gain from ultrarelativistic bulk flows is addressed, with active galactic nuclei and gamma-ray bursts being the examples.

  18. Constraints on the extremely high-energy cosmic rays accelerators from classical electrodynamics

    NASA Astrophysics Data System (ADS)

    Belyanin, A.; Aharonian, F.; Derishev, E.; Kocharovsky, V.; Kocharovsky, V.

    We formulate the general requirements, set by classical electrodynamics, to the sources of extremely high-energy cosmic rays (EHECRs). It is shown that the parameters of EHECR accelerators are strongly limited not only by the particle confinement in large-scale magnetic field or by the difference in electric potentials (generalized Hillas criterion), but also by the synchrotron radiation, the electro-bremsstrahlung, or the curvature radiation of accelerated particles. Optimization of these requirements in terms of accelerator's size and magnetic field strength results in the ultimate lower limit to the overall source energy budget, which scales as the fifth power of attainable particle energy. Hard gamma-rays accompanying generation of EHECRs can be used to probe potential acceleration sites. We apply the results to several populations of astrophysical objects - potential EHECR sources - and discuss their ability to accelerate protons to 1020 eV and beyond. A possibility to gain from ultrarelativistic bulk flows is addressed, with Active Galactic Nuclei and Gamma-Ray Bursts being the examples.

  19. Human growth hormone may be detrimental when used to accelerate recovery from acute tendon-bone interface injuries.

    PubMed

    Baumgarten, Keith M; Oliver, Harvey A; Foley, Jack; Chen, Ding-Geng; Autenried, Peter; Duan, Shanzhong; Heiser, Patrick

    2013-05-01

    There have been few scientific studies that have examined usage of human growth hormone to accelerate recovery from injury. The hypothesis of this study was that human growth hormone would accelerate tendon-to-bone healing compared with control animals treated with placebo in a rat model of acute rotator cuff injury repair. Seventy-two rats underwent repair of acute rotator cuff injuries and were randomized into the following postoperative dosing regimens: placebo, and human growth hormone at 0.1, 1, 2, 5, and 10 mg/kg/day, administered subcutaneously once per day for fourteen days (Protocol 1). An additional twenty-four rats were randomized to receive either (1) placebo or (2) human growth hormone at 5 mg/kg, administered subcutaneously twice per day for seven days preoperatively and twenty-eight days postoperatively (Protocol 2). All rats were killed twenty-eight days postoperatively. Mechanical testing was performed. Ultimate stress, ultimate force, stiffness, energy to failure, and ultimate distension were determined. For Protocol 1, analysis of variance testing showed no significant difference between the groups with regard to ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension. In Protocol 2, ultimate force to failure was significantly worse in the human growth hormone group compared with the placebo group (21.1 ± 5.85 versus 26.3 ± 5.47 N; p = 0.035). Failure was more likely to occur through the bone than the tendon-bone interface in the human growth hormone group compared with the placebo group (p = 0.001). No significant difference was found for ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension between the groups in Protocol 2. In this rat model of acute tendon-bone injury repair, daily subcutaneous postoperative human growth hormone treatment for fourteen days failed to demonstrate a significant difference in any biomechanical parameter compared with placebo. Furthermore, subcutaneous

  20. Accelerator-Reactor Coupling for Energy Production in Advanced Nuclear Fuel Cycles

    NASA Astrophysics Data System (ADS)

    Heidet, Florent; Brown, Nicholas R.; Haj Tahar, Malek

    This article is a review of several accelerator-reactor interface issues and nuclear fuel cycle applications of accelerator-driven subcritical systems. The systems considered here have the primary goal of energy production, but that goal is accomplished via a specific application in various proposed nuclear fuel cycles, such as breed-and-burn of fertile material or burning of transuranic material. Several basic principles are reviewed, starting from the proton beam window including the target, blanket, reactor core, and up to the fuel cycle. We focus on issues of interest, such as the impact of the energy required to run the accelerator and associated systems on the potential electricity delivered to the grid. Accelerator-driven systems feature many of the constraints and issues associated with critical reactors, with the added challenges of subcritical operation and coupling to an accelerator. Reliable accelerator operation and avoidance of beam trips are critically important. One interesting challenge is measurement of blanket subcriticality level during operation. We also review the potential benefits of accelerator-driven systems in various nuclear fuel cycle applications. Ultimately, accelerator-driven subcritical systems with the goal of transmutation of transuranic material have lower 100,000-year radioactivity than a critical fast reactor with recycling of uranium and plutonium.

  1. AIP Career Pathways

    NASA Astrophysics Data System (ADS)

    Palchak, Amanda

    2012-02-01

    American Institute of Physics (AIP) Career Pathways is a new project funded by the National Science Foundation. One of the goals of AIP Career Pathways is to prepare students to compete for Science, Technology, Engineering, and Mathematics (STEM) careers with a bachelor's degree in physics. In order to do so, I reviewed and compiled useful resources on finding a STEM career with a bachelor's degree in physics. These resources not only supply the job seeker with job postings in STEM careers but also provide them with information on resumes, interviewing skills, and networking. Recently at the 2011 Industrial Physics Forum, I interviewed companies in the private sector to obtain a unique perspective on what types of skills potential employers expect an applicant to posses with a bachelor's degree in physics. Ultimately, these components will be used as supplements at student career workshops held at annual Society of Physics Students Zone Meetings.

  2. Ultimate Cost of Building Walls.

    ERIC Educational Resources Information Center

    Grimm, Clayford T.; Gross, James G.

    The need for economic analysis of building walls is discussed, and the factors influencing the ultimate cost of exterior walls are studied. The present worth method is used to analyze three types of exterior non-loadbearing panel or curtain walls. Anticipated costs are expressed in terms of their present value per square foot of wall area. The…

  3. Diagnostic Accuracy of a New High-Sensitivity Troponin I Assay and Five Accelerated Diagnostic Pathways for Ruling Out Acute Myocardial Infarction and Acute Coronary Syndrome.

    PubMed

    Greenslade, Jaimi H; Carlton, Edward W; Van Hise, Christopher; Cho, Elizabeth; Hawkins, Tracey; Parsonage, William A; Tate, Jillian; Ungerer, Jacobus; Cullen, Louise

    2018-04-01

    This diagnostic accuracy study describes the performance of 5 accelerated chest pain pathways, calculated with the new Beckman's Access high-sensitivity troponin I assay. High-sensitivity troponin I was measured with presentation and 2-hour blood samples in 1,811 patients who presented to an emergency department (ED) in Australia. Patients were classified as being at low risk according to 5 rules: modified accelerated diagnostic protocol to assess patients with chest pain symptoms using troponin as the only biomarker (m-ADAPT), the Emergency Department Assessment of Chest Pain Score (EDACS) pathway, the History, ECG, Age, Risk Factors, and Troponin (HEART) pathway, the No Objective Testing Rule, and the new Vancouver Chest Pain Rule. Endpoints were 30-day acute myocardial infarction and acute coronary syndrome. Measures of diagnostic accuracy for each rule were calculated. Data included 96 patients (5.3%) with acute myocardial infarction and 139 (7.7%) with acute coronary syndrome. The new Vancouver Chest Pain Rule and No Objective Testing Rule had high sensitivity for acute myocardial infarction (100%; 95% confidence interval [CI] 96.2% to 100% for both) and acute coronary syndrome (98.6% [95% CI 94.9% to 99.8%] and 99.3% [95% CI 96.1% to 100%]). The m-ADAPT, EDACS, and HEART pathways also yielded high sensitivity for acute myocardial infarction (96.9% [95% CI 91.1% to 99.4%] for m-ADAPT and 97.9% [95% CI 92.7% to 99.7%] for EDACS and HEART), but lower sensitivity for acute coronary syndrome (≤95.0% for all). The m-ADAPT, EDACS, and HEART rules classified more patients as being at low risk (64.3%, 62.5%, and 49.8%, respectively) than the new Vancouver Chest Pain Rule and No Objective Testing Rule (28.2% and 34.5%, respectively). In this cohort with a low prevalence of acute myocardial infarction and acute coronary syndrome, using the Beckman's Access high-sensitivity troponin I assay with the new Vancouver Chest Pain Rule or No Objective Testing Rule enabled

  4. Invited article: advanced drag-free concepts for future space-based interferometers: acceleration noise performance.

    PubMed

    Gerardi, D; Allen, G; Conklin, J W; Sun, K-X; DeBra, D; Buchman, S; Gath, P; Fichter, W; Byer, R L; Johann, U

    2014-01-01

    Future drag-free missions for space-based experiments in gravitational physics require a Gravitational Reference Sensor with extremely demanding sensing and disturbance reduction requirements. A configuration with two cubical sensors is the current baseline for the Laser Interferometer Space Antenna (LISA) and has reached a high level of maturity. Nevertheless, several promising concepts have been proposed with potential applications beyond LISA and are currently investigated at HEPL, Stanford, and EADS Astrium, Germany. The general motivation is to exploit the possibility of achieving improved disturbance reduction, and ultimately understand how low acceleration noise can be pushed with a realistic design for future mission. In this paper, we discuss disturbance reduction requirements for LISA and beyond, describe four different payload concepts, compare expected strain sensitivities in the "low-frequency" region of the frequency spectrum, dominated by acceleration noise, and ultimately discuss advantages and disadvantages of each of those concepts in achieving disturbance reduction for space-based detectors beyond LISA.

  5. Perspectives on the Use of Clinical Pathways in Oncology Care.

    PubMed

    Chiang, Anne C; Ellis, Peter; Zon, Robin

    2017-01-01

    Pathways and guidelines are valuable tools to provide evidence-based care in oncology. Pathways may be more restrictive than guidelines because they attempt (where possible) to reduce cost, add efficiency, and remove unwarranted variability. Pathways offer an opportunity to measure, report, and improve quality of care; they can drive to evidence-based targeted therapy where appropriate; they can enhance efficiency through standardization; and, finally, they can be a vehicle to enhance participation in clinical trials. Pathway implementation requires understanding and commitment on the part of the physician and leadership as they may initially disrupt workflow, but ultimately have the ability to enhance patient care. ASCO criteria have been published for the development and implementation of high-quality oncology pathway programs. Future challenges for pathways include incorporation of molecular testing and appropriate targeted care in a real-time precision oncology approach.

  6. Essay: Robert H. Siemann As Leader of the Advanced Accelerator Research Department

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Colby, Eric R.; Hogan, Mark J.; /SLAC

    Robert H. Siemann originally conceived of the Advanced Accelerator Research Department (AARD) as an academic, experimental group dedicated to probing the technical limitations of accelerators while providing excellent educational opportunities for young scientists. The early years of the Accelerator Research Department B, as it was then known, were dedicated to a wealth of mostly student-led experiments to examine the promise of advanced accelerator techniques. High-gradient techniques including millimeter-wave rf acceleration, beam-driven plasma acceleration, and direct laser acceleration were pursued, including tests of materials under rf pulsed heating and short-pulse laser radiation, to establish the ultimate limitations on gradient. As themore » department and program grew, so did the motivation to found an accelerator research center that brought experimentalists together in a test facility environment to conduct a broad range of experiments. The Final Focus Test Beam and later the Next Linear Collider Test Accelerator provided unique experimental facilities for AARD staff and collaborators to carry out advanced accelerator experiments. Throughout the evolution of this dynamic program, Bob maintained a department atmosphere and culture more reminiscent of a university research group than a national laboratory department. His exceptional ability to balance multiple roles as scientist, professor, and administrator enabled the creation and preservation of an environment that fostered technical innovation and scholarship.« less

  7. Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

    PubMed Central

    Ng, Qimin; Sanda, Gregory E.; Dey, Amit K.; Teague, Heather L.; Sorokin, Alexander V.; Dagur, Pradeep K.; Silverman, Joanna I.; Harrington, Charlotte L.; Rodante, Justin A.; Rose, Shawn M.; Varghese, Nevin J.; Belur, Agastya D.; Goyal, Aditya; Gelfand, Joel M.; Springer, Danielle A.; Bleck, Christopher K.E.; Thomas, Crystal L.; Yu, Zu-Xi; Winge, Mårten C.G.; Kruth, Howard S.; Marinkovich, M. Peter; Joshi, Aditya A.; Playford, Martin P.; Mehta, Nehal N.

    2018-01-01

    Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis. PMID:29321372

  8. Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, migration effects and accelerates cell cycle progression in multiple myeloma cells via activating the Akt pathway.

    PubMed

    Zheng, Dong; Chen, Ziang; Chen, Jingfu; Zhuang, Xiaomin; Feng, Jianqiang; Li, Juan

    2016-10-01

    Hydrogen sulfide (H2S), regarded as the third gaseous transmitter, mediates and induces various biological effects. The present study investigated the effects of H2S on multiple myeloma cell progression via amplifying the activation of Akt pathway in multiple myeloma cells. The level of H2S produced in multiple myeloma (MM) patients and healthy subjects was measured using enzyme-linked immunosorbent assay (ELISA). MM cells were treated with 500 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated-Akt (p-Akt), Bcl-2 and caspase-3 were measured by western blot assay. Cell viability was detected by Cell Counting Kit 8 (CCK-8). The cell cycle was analyzed by flow cytometry. Our results show that the concentration of H2S was higher in MM patients and that it increased in parallel with disease progression. Treating MM cells with 500 µmol/l NaHS for 24 h markedly increased the expression level of Bcl-2 and the activation of p-Akt, however, the expression level of caspase-3 was decreased, cell viability was increased, and cell cycle progression was accelerated in MM cells. NaHS also induced migration in MM cells in transwell migration assay. Furthermore, co-treatment of MM cells with 500 µmol/l NaHS and 50 µmol/l LY294002 for 24 h significantly overset these effects. In conclusion, our findings demonstrate that the Akt pathway contributes to NaHS-induced cell proliferation, migration and acceleration of cell cycle progression in MM cells.

  9. The ultimate disposition of depleted uranium

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Not Available

    1990-12-01

    Significant amounts of the depleted uranium (DU) created by past uranium enrichment activities have been sold, disposed of commercially, or utilized by defense programs. In recent years, however, the demand for DU has become quite small compared to quantities available, and within the US Department of Energy (DOE) there is concern for any risks and/or cost liabilities that might be associated with the ever-growing inventory of this material. As a result, Martin Marietta Energy Systems, Inc. (Energy Systems), was asked to review options and to develop a comprehensive plan for inventory management and the ultimate disposition of DU accumulated atmore » the gaseous diffusion plants (GDPs). An Energy Systems task team, under the chairmanship of T. R. Lemons, was formed in late 1989 to provide advice and guidance for this task. This report reviews options and recommends actions and objectives in the management of working inventories of partially depleted feed (PDF) materials and for the ultimate disposition of fully depleted uranium (FDU). Actions that should be considered are as follows. (1) Inspect UF{sub 6} cylinders on a semiannual basis. (2) Upgrade cylinder maintenance and storage yards. (3) Convert FDU to U{sub 3}O{sub 8} for long-term storage or disposal. This will include provisions for partial recovery of costs to offset those associated with DU inventory management and the ultimate disposal of FDU. Another recommendation is to drop the term tails'' in favor of depleted uranium'' or DU'' because the tails'' label implies that it is waste.'' 13 refs.« less

  10. Teaching the Toolkit: A Laboratory Series to Demonstrate the Evolutionary Conservation of Metazoan Cell Signaling Pathways

    ERIC Educational Resources Information Center

    LeClair, Elizabeth E.

    2008-01-01

    A major finding of comparative genomics and developmental genetics is that metazoans share certain conserved, embryonically deployed signaling pathways that instruct cells as to their ultimate fate. Because the DNA encoding these pathways predates the evolutionary split of most animal groups, it should in principle be possible to clone…

  11. Pollen Acceptance or Rejection: A Tale of Two Pathways.

    PubMed

    Doucet, Jennifer; Lee, Hyun Kyung; Goring, Daphne R

    2016-12-01

    While the molecular and cellular basis of self-incompatibility leading to self-pollen rejection in the Brassicaceae has been extensively studied, relatively little attention has been paid to compatible pollen recognition and the corresponding cellular responses in the stigmatic papillae. This is now changing because research has started to uncover steps in the Brassicaceae 'basal compatible pollen response pathway' in the stigma leading to pollen hydration and germination. Furthermore, recent studies suggest that self-incompatible pollen activates both the basal compatible pathway and the self-incompatibility pathway in the stigma, with the self-incompatibility response ultimately prevailing to reject self-pollen. We review here recent discoveries in both pathways and discuss how compatible pollen is accepted by the stigma versus the rejection of self-incompatible pollen. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Accelerator Reactor Coupling for Energy Production in Advanced Nuclear Fuel Cycles

    DOE PAGES

    Brown, Nicholas R.; Heidet, Florent; Haj Tahar, Malek

    2016-01-01

    This article is a review of several accelerator–reactor interface issues and nuclear fuel cycle applications of acceleratordriven subcritical systems. The systems considered here have the primary goal of energy production, but that goal is accomplished via a specific application in various proposed nuclear fuel cycles, such as breed-and-burn of fertile material or burning of transuranic material. Several basic principles are reviewed, starting from the proton beam window including the target, blanket, reactor core, and up to the fuel cycle. We focus on issues of interest, such as the impact of the energy required to run the accelerator and associated systemsmore » on the potential electricity delivered to the grid. Accelerator-driven systems feature many of the constraints and issues associated with critical reactors, with the added challenges of subcritical operation and coupling to an accelerator. Reliable accelerator operation and avoidance of beam trips are critically important. One interesting challenge is measurement of blanket subcriticality level during operation. We also review the potential benefits of accelerator-driven systems in various nuclear fuel cycle applications. Ultimately, accelerator-driven subcritical systems with the goal of transmutation of transuranic material have lower 100,000-year radioactivity than a critical fast reactor with recycling of uranium and plutonium.« less

  13. Probing the Ultimate Limits of Plasmonic Enhancement

    PubMed Central

    Ciracì, C.; Hill, R. T.; Mock, J. J.; Urzhumov, Y.; Fernández-Domínguez, A. I.; Maier, S. A.; Pendry, J. B.; Chilkoti, A.; Smith, D. R.

    2013-01-01

    Metals support surface plasmons at optical wavelengths and have the ability to localize light to sub-wavelength regions. The field enhancements that occur in these regions set the ultimate limitations on a wide range of nonlinear and quantum optical phenomena. Here we show that the dominant limiting factor is not the resistive loss of the metal, but the intrinsic nonlocality of its dielectric response. A semi-classical model of the electronic response of a metal places strict bounds on the ultimate field enhancement. We demonstrate the accuracy of this model by studying the optical scattering from gold nanoparticles spaced a few angstroms from a gold film. The bounds derived from the models and experiments impose limitations on all nanophotonic systems. PMID:22936772

  14. Physical Demands in Competitive Ultimate Frisbee.

    PubMed

    Krustrup, Peter; Mohr, Magni

    2015-12-01

    The objective was to study game demands in competitive ultimate Frisbee by performing match analysis during a game. Thirteen moderately trained (Yo-Yo intermittent recovery test levels 1 and 2 [Yo-Yo IR1 and IR2] performance: 1790 ± 382 m and 657 ± 225 m, respectively) competitive male ultimate Frisbee athletes played a game in which activity profile using Global Positioning System (GPS) technology and heart rate (HR) were recorded. Game HRmean and HRpeak were 82 ± 2% and 99 ± 1% of maximum heart rate, respectively. Total game distance was 4.70 ± 0.47 km, of which 0.63 ± 0.14 km was high-intensity running and 0.21 ± 0.11 km was sprinting. In the second half, 10% less (p ≤ 0.05) ground was covered with high-intensity running compared with the first half (0.28 ± 0.08 km vs. 0.31 ± 0.07 km). Less (43-47%; p ≤ 0.05) high-intensity running was performed in the third 9-minute period of each half compared with the first two 9-minute periods of the same half. Players performed 17.4 ± 5.7 sprints during the match. Yo-Yo IR2 performance correlated to the amount of high-intensity running in the last 9 minutes of both halves (r = 0.69, p ≤ 0.05), whereas Yo-Yo IR1 performance correlated with total sprint distance (r = 0.74, p ≤ 0.05). Ultimate Frisbee is an intense intermittent team sport with high cardiovascular loading and clear indications of fatigue toward the end of each half. Yo-Yo IR test performances correlate with physical match performance.

  15. 15 CFR 748.11 - Statement by Ultimate Consignee and Purchaser.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... ultimate consignee, provided the required statements are contained in Block 24 on the license application... copy submitted by the applicant must be of sufficient quality to ensure all assertions made on the...) Form or letter. The ultimate consignee and purchaser must complete either a statement on company...

  16. 15 CFR 748.11 - Statement by Ultimate Consignee and Purchaser.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... ultimate consignee, provided the required statements are contained in Block 24 on the license application... copy submitted by the applicant must be of sufficient quality to ensure all assertions made on the...) Form or letter. The ultimate consignee and purchaser must complete either a statement on company...

  17. Accelerating Adverse Outcome Pathway Development Using Publicly Available Data Sources

    EPA Science Inventory

    The adverse outcome pathway (AOP) concept links molecular perturbations with organism and population-level outcomes to support high-throughput toxicity testing. International efforts are underway to define AOPs and store the information supporting these AOPs in a central knowledg...

  18. Addressing the Common Pathway Underlying Hypertension and Diabetes in People Who Are Obese by Maximizing Health: The Ultimate Knowledge Translation Gap

    PubMed Central

    Dean, Elizabeth; Lomi, Constantina; Bruno, Selma; Awad, Hamzeh; O'Donoghue, Grainne

    2011-01-01

    In accordance with the WHO definition of health, this article examines the alarming discord between the epidemiology of hypertension, type 2 diabetes mellitus (T2DM), and obesity and the low profile of noninvasive (nondrug) compared with invasive (drug) interventions with respect to their prevention, reversal and management. Herein lies the ultimate knowledge translation gap and challenge in 21st century health care. Although lifestyle modification has long appeared in guidelines for medically managing these conditions, this evidence-based strategy is seldom implemented as rigorously as drug prescription. Biomedicine focuses largely on reducing signs and symptoms; the effects of the problem rather than the problem. This article highlights the evidence-based rationale supporting prioritizing the underlying causes and contributing factors for hypertension and T2DM, and, in turn, obesity. We argue that a primary focus on maximizing health could eliminate all three conditions, at best, or, at worst, minimize their severity, complications, and medication needs. To enable such knowledge translation and maximizing health outcome, the health care community needs to practice as an integrated team, and address barriers to effecting maximal health in all patients. Addressing the ultimate knowledge translation gap, by aligning the health care paradigm to 21st century needs, would constitute a major advance. PMID:21423684

  19. The application of artificial intelligent techniques to accelerator operations at McMaster University

    NASA Astrophysics Data System (ADS)

    Poehlman, W. F. S.; Garland, Wm. J.; Stark, J. W.

    1993-06-01

    In an era of downsizing and a limited pool of skilled accelerator personnel from which to draw replacements for an aging workforce, the impetus to integrate intelligent computer automation into the accelerator operator's repertoire is strong. However, successful deployment of an "Operator's Companion" is not trivial. Both graphical and human factors need to be recognized as critical areas that require extra care when formulating the Companion. They include interactive graphical user's interface that mimics, for the operator, familiar accelerator controls; knowledge of acquisition phases during development must acknowledge the expert's mental model of machine operation; and automated operations must be seen as improvements to the operator's environment rather than threats of ultimate replacement. Experiences with the PACES Accelerator Operator Companion developed at two sites over the past three years are related and graphical examples are given. The scale of the work involves multi-computer control of various start-up/shutdown and tuning procedures for Model FN and KN Van de Graaff accelerators. The response from licensing agencies has been encouraging.

  20. Intra-Beam Scattering, Impedance, and Instabilities in Ultimate Storage Rings

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bane, Karl; /SLAC

    We have investigated collective effects in an ultimate storage ring, i.e. one with diffraction limited emittances in both planes, using PEP-X as an example. In an ultimate ring intra-beam scattering (IBS) sets the limit of current that can be stored. In PEP-X, a 4.5 GeV ring running round beams at 200 mA in 3300 bunches, IBS doubles the emittances to 11.5 pm at the design current. The Touschek lifetime is 11 hours. Impedance driven collective effects tend not to be important since the beam current is relatively low. We have investigated collective effects in PEP-X, an ultimate storage ring, i.e.more » one with diffraction limited emittances (at one angstrom wavelength) in both planes. In an ultimate ring intra-beam scattering (IBS) sets the limit of current that can be stored. In PEP-X, IBS doubles the emittances to 11.5 pm at the design current of 200 mA, assuming round beams. The Touschek lifetime is quite large in PEP-X, 11.6 hours, and - near the operating point - increases with decreasing emittance. It is, however, a very sensitive function of momentum acceptance. In an ultimate ring like PEP-X impedance driven collective effects tend not to be important since the beam current is relatively low. Before ultimate PEP-X can be realized, the question of how to run a machine with round beams needs serious study. For example, in this report we assumed that the vertical emittance is coupling dominated. It may turn out that using vertical dispersion is a preferable way to generate round beams. The choice will affect IBS and the Touschek effect.« less

  1. Centaur Standard Shroud (CSS) static ultimate load structural tests

    NASA Technical Reports Server (NTRS)

    1975-01-01

    A series of tests were conducted on the jettisonable metallic shroud used on the Titan/Centaur launch vehicle to verify its structural capabilities and to evaluate its structural interaction with the Centaur stage. A flight configured shroud and the interfacing Titan/Centaur structural assemblies were subjected to tests consisting of combinations of applied axial and shear loads to design ultimate values, including a set of tests on thermal conditions and two dynamic response tests to verify the analytical stiffness model. The strength capabilities were demonstrated at ultimate (125 percent of design limit) loads. It was also verified that the spring rate of the flight configured shroud-to-Centaur forward structural deflections of the specimen became nonlinear, as expected, above limit load values. This test series qualification program verified that the Titan/Centaur shroud and the Centaur and Titan interface components are qualified structurally at design ultimate loads.

  2. N2-fixing red alder indirectly accelerates ecosystem nitrogen cycling

    USGS Publications Warehouse

    Perakis, Steven S.; Matkins, Joselin J.; Hibbs, David E.

    2012-01-01

    Symbiotic N2-fixing tree species can accelerate ecosystem N dynamics through decomposition via direct pathways by producing readily decomposed leaf litter and increasing N supply to decomposers, as well as via indirect pathways by increasing tissue and detrital N in non-fixing vegetation. To evaluate the relative importance of these pathways, we compared three-year decomposition and N dynamics of N2-fixing red alder leaf litter (2.34 %N) to both low-N (0.68 %N) and high-N (1.21 %N) litter of non-fixing Douglas-fir, and decomposed each litter source in four forests dominated by either red alder or Douglas-fir. We also used experimental N fertilization of decomposition plots to assess elevated N availability as a potential mechanism of N2-fixer effects on litter mass loss and N dynamics. Direct effects of N2-fixing red alder on decomposition occurred primarily as faster N release from red alder than Douglas-fir litter, but direct increases in N supply to decomposers via fertilization did not stimulate decomposition of any litter. Fixed N indirectly influenced detrital dynamics by increasing Douglas-fir tissue and litter N concentrations, which accelerated litter N release without accelerating mass loss. By increasing soil N, tissue N, and the rate of N release from litter of non-fixers, we conclude that N2-fixing vegetation can indirectly foster plant-soil feedbacks that contribute to the persistence of elevated N availability in terrestrial ecosystems.

  3. Emittance Growth in the DARHT-II Linear Induction Accelerator

    DOE PAGES

    Ekdahl, Carl; Carlson, Carl A.; Frayer, Daniel K.; ...

    2017-10-03

    The dual-axis radiographic hydrodynamic test (DARHT) facility uses bremsstrahlung radiation source spots produced by the focused electron beams from two linear induction accelerators (LIAs) to radiograph large hydrodynamic experiments driven by high explosives. Radiographic resolution is determined by the size of the source spot, and beam emittance is the ultimate limitation to spot size. On the DARHT-II LIA, we measure an emittance higher than predicted by theoretical simulations, and even though this accelerator produces submillimeter source spots, we are exploring ways to improve the emittance. Some of the possible causes for the discrepancy have been investigated using particle-in-cell codes. Finally,more » the simulations establish that the most likely source of emittance growth is a mismatch of the beam to the magnetic transport, which can cause beam halo.« less

  4. Emittance Growth in the DARHT-II Linear Induction Accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ekdahl, Carl; Carlson, Carl A.; Frayer, Daniel K.

    The dual-axis radiographic hydrodynamic test (DARHT) facility uses bremsstrahlung radiation source spots produced by the focused electron beams from two linear induction accelerators (LIAs) to radiograph large hydrodynamic experiments driven by high explosives. Radiographic resolution is determined by the size of the source spot, and beam emittance is the ultimate limitation to spot size. On the DARHT-II LIA, we measure an emittance higher than predicted by theoretical simulations, and even though this accelerator produces submillimeter source spots, we are exploring ways to improve the emittance. Some of the possible causes for the discrepancy have been investigated using particle-in-cell codes. Finally,more » the simulations establish that the most likely source of emittance growth is a mismatch of the beam to the magnetic transport, which can cause beam halo.« less

  5. Silicon wafer-based tandem cells: The ultimate photovoltaic solution?

    NASA Astrophysics Data System (ADS)

    Green, Martin A.

    2014-03-01

    Recent large price reductions with wafer-based cells have increased the difficulty of dislodging silicon solar cell technology from its dominant market position. With market leaders expected to be manufacturing modules above 16% efficiency at 0.36/Watt by 2017, even the cost per unit area (60-70/m2) will be difficult for any thin-film photovoltaic technology to significantly undercut. This may make dislodgement likely only by appreciably higher energy conversion efficiency approaches. A silicon wafer-based cell able to capitalize on on-going cost reductions within the mainstream industry, but with an appreciably higher than present efficiency, might therefore provide the ultimate PV solution. With average selling prices of 156 mm quasi-square monocrystalline Si photovoltaic wafers recently approaching 1 (per wafer), wafers now provide clean, low cost templates for overgrowth of thin, wider bandgap high performance cells, nearly doubling silicon's ultimate efficiency potential. The range of possible Si-based tandem approaches is reviewed together with recent results and ultimate prospects.

  6. Acceleration of bone regeneration by activating Wnt/β-catenin signalling pathway via lithium released from lithium chloride/calcium phosphate cement in osteoporosis

    NASA Astrophysics Data System (ADS)

    Li, Li; Peng, Xiaozhong; Qin, Yongbao; Wang, Renchong; Tang, Jingli; Cui, Xu; Wang, Ting; Liu, Wenlong; Pan, Haobo; Li, Bing

    2017-03-01

    By virtue of its excellent bioactivity and osteoconductivity, calcium phosphate cement (CPC) has been applied extensively in bone engineering. Doping a trace element into CPC can change physical characteristics and enhance osteogenesis. The trace element lithium has been demonstrated to stimulate the proliferation and differentiation of osteoblasts. We investigated the fracture-healing effect of osteoporotic defects with lithium-doped calcium phosphate cement (Li/CPC) and the underlying mechanism. Li/CPC bodies immersed in simulated body fluid converted gradually to hydroxyapatite. Li/CPC extracts stimulated the proliferation and differentiation of osteoblasts upon release of lithium ions (Li+) at 25.35 ± 0.12 to 50.74 ± 0.13 mg/l through activation of the Wnt/β-catenin pathway in vitro. We also examined the effect of locally administered Li+ on defects in rat tibia between CPC and Li/CPC in vivo. Micro-computed tomography and histological staining showed that Li/CPC had better osteogenesis by increasing bone mass and promoting repair in defects compared with CPC (P < 0.05). Li/CPC also showed better osteoconductivity and osseointegration. These findings suggest that local release of Li+ from Li/CPC may accelerate bone regeneration from injury through activation of the Wnt/β-catenin pathway in osteoporosis.

  7. Identification of JAK/STAT pathway regulators—Insights from RNAi screens

    PubMed Central

    Müller, Patrick; Boutros, Michael; Zeidler, Martin P.

    2008-01-01

    While many core JAK/STAT pathway components have been discovered in Drosophila via classical genetic approaches, the identification of pathway regulators has been more challenging. Recently two cell-based RNAi screens for JAK/STAT pathway regulators have been undertaken using libraries of double-stranded RNAs targeting a large proportion of the predicted Drosophila transcriptome. While both screens identified multiple regulators, only relatively few loci are common to both data sets. Here we compare the two screens and discuss these differences. Although many factors are likely to be contributory, differences in the assay design are of key importance. Low levels of stimulation favouring the identification of negative pathway regulators and high levels of stimulation favouring the identification of positively acting factors. Ultimately, the results from both screens are likely to be largely complementary and have identified a range of novel candidate regulators of JAK/STAT pathway activity as a starting point for new research directions in the future. PMID:18586112

  8. The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

    PubMed Central

    Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

    2014-01-01

    Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

  9. 26 CFR 48.6427-8 - Diesel fuel and kerosene; claims by ultimate purchasers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Diesel fuel and kerosene; claims by ultimate... kerosene; claims by ultimate purchasers. (a) Overview. This section provides rules under which ultimate purchasers of taxed diesel fuel and kerosene may claim the income tax credits or payments allowed by section...

  10. 26 CFR 48.6427-8 - Diesel fuel and kerosene; claims by ultimate purchasers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Diesel fuel and kerosene; claims by ultimate... kerosene; claims by ultimate purchasers. (a) Overview. This section provides rules under which ultimate purchasers of taxed diesel fuel and kerosene may claim the income tax credits or payments allowed by section...

  11. 26 CFR 48.6427-8 - Diesel fuel and kerosene; claims by ultimate purchasers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Diesel fuel and kerosene; claims by ultimate... kerosene; claims by ultimate purchasers. (a) Overview. This section provides rules under which ultimate purchasers of taxed diesel fuel and kerosene may claim the income tax credits or payments allowed by section...

  12. 26 CFR 48.6427-8 - Diesel fuel and kerosene; claims by ultimate purchasers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Diesel fuel and kerosene; claims by ultimate... kerosene; claims by ultimate purchasers. (a) Overview. This section provides rules under which ultimate purchasers of taxed diesel fuel and kerosene may claim the income tax credits or payments allowed by section...

  13. Physics of Limiting Phenomena in Superconducting Microwave Resonators: Vortex Dissipation, Ultimate Quench and Quality Factor Degradation Mechanisms

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Checchin, Mattia

    Superconducting niobium accelerating cavities are devices operating in radio-frequency and able to accelerate charged particles up to energy of tera-electron-volts. Such accelerating structures are though limited in terms of quality factor and accelerating gradient, that translates--in some cases--in higher capital costs of construction and operation of superconducting rf accelerators. Looking forward for a new generation of more affordable accelerators, the physical description of limiting mechanisms in superconducting microwave resonators is discussed. In particular, the physics behind the dissipation introduced by vortices in the superconductor, the ultimate quench limitations and the quality factor degradation mechanism after a quench are described inmore » detail. One of the limiting factor of the quality factor is the dissipation introduced by trapped magnetic flux vortices. The radio-frequency complex response of trapped vortices in superconductors is derived by solving the motion equation for a magnetic flux line, assuming a bi-dimensional and mean free path-dependent Lorentzian-shaped pinning potential. The resulting surface resistance shows the bell-shaped trend as a function of the mean free path, in agreement with the experimental data observed. Such bell-shaped trend of the surface resistance is described in terms of the interplay of the two limiting regimes identified as pinning and flux flow regimes, for low and large mean free path values respectively. The model predicts that the dissipation regime--pinning- or flux-flow-dominated--can be tuned either by acting on the frequency or on the electron mean free path value. The effect of different configurations of pinning sites and strength on the vortex surface resistance are also discussed. Accelerating cavities are also limited by the quench of the superconductive state, which limits the maximum accelerating gradient achievable. The accelerating field limiting factor is usually associate d to the

  14. Physics of limiting phenomena in superconducting microwave resonators: Vortex dissipation, ultimate quench and quality factor degradation mechanisms

    NASA Astrophysics Data System (ADS)

    Checchin, Mattia

    Superconducting niobium accelerating cavities are devices operating in radiofrequency and able to accelerate charged particles up to energy of tera-electron-volts. Such accelerating structures are though limited in terms of quality factor and accelerating gradient, that translates--in some cases--in higher capital costs of construction and operation of superconducting rf accelerators. Looking forward for a new generation of more affordable accelerators, the physical description of limiting mechanisms in superconducting microwave resonators is discussed. In particular, the physics behind the dissipation introduced by vortices in the superconductor, the ultimate quench limitations and the quality factor degradation mechanism after a quench are described in detail. One of the limiting factor of the quality factor is the dissipation introduced by trapped magnetic flux vortices. The radio-frequency complex response of trapped vortices in superconductors is derived by solving the motion equation for a magnetic flux line, assuming a bi-dimensional and mean free path-dependent Lorentzian-shaped pinning potential. The resulting surface resistance shows the bell-shaped trend as a function of the mean free path, in agreement with the experimental data observed. Such bell-shaped trend of the surface resistance is described in terms of the interplay of the two limiting regimes identified as pinning and flux flow regimes, for low and large mean free path values respectively. The model predicts that the dissipation regime--pinning- or flux-flow-dominated--can be tuned either by acting on the frequency or on the electron mean free path value. The effect of different configurations of pinning sites and strength on the vortex surface resistance are also discussed. Accelerating cavities are also limited by the quench of the superconductive state, which limits the maximum accelerating gradient achievable. The accelerating field limiting factor is usually associated to the superheating

  15. Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development.

    PubMed

    Wang, J; Martin, J F

    2017-10-01

    The evolutionarily conserved Hippo signaling pathway is a vital regulator of organ size that fine-tunes cell proliferation, apoptosis, and differentiation. A number of important studies have revealed critical roles of Hippo signaling and its effectors Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ binding motif) in tissue development, homeostasis, and regeneration, as well as in tumorigenesis. In addition, recent studies have shown evidence of crosstalk between the Hippo pathway and other key signaling pathways, such as Wnt signaling, that not only regulates developmental processes but also contributes to disease pathogenesis. In this review, we summarize the major discoveries in the field of Hippo signaling and what has been learned about its regulation and crosstalk with other signaling pathways, with a particular focus on recent findings involving the Hippo-Yap pathway in craniofacial and tooth development. New and exciting studies of the Hippo pathway are anticipated that will significantly improve our understanding of the molecular mechanisms of human craniofacial and tooth development and disease and will ultimately lead to the development of new therapies.

  16. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants.

    PubMed

    Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S; Wentzell, Jill S; Kretzschmar, Doris; Giebultowicz, Jadwiga M

    2012-03-01

    Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per(01)) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni(1)), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni(1) mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per(01)sni(1) flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per(01) mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws(1)), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants

    PubMed Central

    Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S.; Wentzell, Jill S.; Kretzschmar, Doris; Giebultowicz, Jadwiga M.

    2012-01-01

    Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per01) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni1), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni1 mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per01 sni1 flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per01 mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws1), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. PMID:22227001

  18. Ultimate Longitudinal Strength of Composite Ship Hulls

    NASA Astrophysics Data System (ADS)

    Zhang, Xiangming; Huang, Lingkai; Zhu, Libao; Tang, Yuhang; Wang, Anwen

    2017-01-01

    A simple analytical model to estimate the longitudinal strength of ship hulls in composite materials under buckling, material failure and ultimate collapse is presented in this paper. Ship hulls are regarded as assemblies of stiffened panels which idealized as group of plate-stiffener combinations. Ultimate strain of the plate-stiffener combination is predicted under buckling or material failure with composite beam-column theory. The effects of initial imperfection of ship hull and eccentricity of load are included. Corresponding longitudinal strengths of ship hull are derived in a straightforward method. A longitudinally framed ship hull made of symmetrically stacked unidirectional plies under sagging is analyzed. The results indicate that present analytical results have a good agreement with FEM method. The initial deflection of ship hull and eccentricity of load can dramatically reduce the bending capacity of ship hull. The proposed formulations provide a simple but useful tool for the longitudinal strength estimation in practical design.

  19. Accelerating Adverse Outcome Pathway (AOP) development via computationally predicted AOP networks

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. Ho...

  20. Combined wind turbine fatigue and ultimate load reduction by individual blade control

    NASA Astrophysics Data System (ADS)

    Han, Y.; Leithead, W. E.

    2014-06-01

    If each blade of the wind turbine has individual pitch actuator, there is possibility of employing the pitch system to mitigate structural loads through advanced control methods. Previously, considerable reduction of blade lifetime equivalent fatigue loads has been achieved by Individual Blade Control (IBC) and in addition, it has also been shown the potential in blade ultimate loads reduction. However, both fatigue and ultimate loads impact on the design and life of wind turbine blades. In this paper, the design and application of IBC that concurrently reduce both blade fatigue and ultimate loads is investigated. The contributions of blade load spectral components, which are 1P, 2P and edgewise mode from blade in-plane and/or out-of-plane bending moments, are firstly explored. Four different control options for reducing various combinations of these load components are compared. In response to the different spectral peaks of both fatigue and ultimate loads, the controller has been designed so that it can act on different frequency components which vary with wind speed. The performance of the IBC controller on fatigue and ultimate load reduction is assessed by simulating a 5MW exemplar wind turbine. Simulation results show that with a proper selection of controlling inputs at different wind speed, the use of a single combined IBC can achieve satisfactory reduction on both fatigue and ultimate loads.

  1. Excess glycogen does not resolve high ultimate pH of oxidative muscle.

    PubMed

    England, Eric M; Matarneh, Sulaiman K; Oliver, Emily M; Apaoblaza, Ariel; Scheffler, Tracy L; Shi, Hao; Gerrard, David E

    2016-04-01

    Skeletal muscle glycogen content can impact the extent of postmortem pH decline. Compared to glycolytic muscles, oxidative muscles contain lower glycogen levels antemortem which may contribute to the higher ultimate pH. In an effort to explore further the participation of glycogen in postmortem metabolism, we postulated that increasing the availability of glycogen would drive additional pH decline in oxidative muscles to equivalent pH values similar to the ultimate pH of glycolytic muscles. Glycolysis and pH declines were compared in porcine longissimus lumborum (glycolytic) and masseter (oxidative) muscles using an in vitro system in the presence of excess glycogen. The ultimate pH of the system containing longissimus lumborum reached a value similar to that observed in intact muscle. The pH decline of the system containing masseter samples stopped prematurely resulting in a higher ultimate pH which was similar to that of intact masseter muscle. To investigate further, we titrated powdered longissimus lumborum and masseter samples in the reaction buffer. As the percentage of glycolytic sample increased, the ultimate pH decreased. These data show that oxidative muscle produces meat with a high ultimate pH regardless of glycogen content and suggest that inherent muscle factors associated with glycolytic muscle control the extent of pH decline in pig muscles. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Accelerating Opportunity: A Portrait of Students and Their Program Experiences from the 2014 Student Survey

    ERIC Educational Resources Information Center

    Spaulding, Shayne; Martin-Caughey, Ananda

    2015-01-01

    This report presents findings from a survey of students enrolled in Accelerating Opportunity (AO) career pathways in spring 2014. AO provides grants to help community colleges create career pathway programs to enroll students with low basic skills into for-credit career and technical education courses to improve educational and employment…

  3. Female puberty acceleration by male odour in mice: neural pathway and behavioural consequences.

    PubMed

    Jouhanneau, Mélanie; Szymanski, Laura A; Keller, Matthieu

    2014-08-01

    In female mice, exposure to male chemosignals results in early puberty onset characterized by advanced vaginal opening and higher uterine weight. Evidence suggests that the male chemosignals responsible for acceleration of female puberty are androgen-dependent, but not all of the compounds that contribute to puberty acceleration have been identified. The male chemosignals are primarily detected and processed by the vomeronasal system including the vomeronasal organ, the accessory olfactory bulb and the medial amygdala. By contrast, the mechanism by which this olfactory information is integrated in the hypothalamus is poorly understood. In this context, the recent identification of the neuropeptide kisspeptin as a gatekeeper of puberty onset may provide a good candidate neuropeptide system for the transmission of chemosensory information to the gonadotrope axis.

  4. Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice.

    PubMed

    Zeng, Yi; Wang, Ping-Han; Zhang, Mao; Du, Jun-Rong

    2016-02-01

    The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury. Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury. Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls. The present results suggest that aging-related inflammation and the development of early-stage CKD are likely associated with the downregulation of Klotho and induction of the RIG-I/NF-κB signaling pathway in 12-month-old SAMP8 mice. Moreover, aged SAMP8 mice with cognitive deficits and renal damage may be a potential mouse model for investigating the kidney-brain axis in the aging process.

  5. Apparent cosmic acceleration from Type Ia supernovae

    NASA Astrophysics Data System (ADS)

    Dam, Lawrence H.; Heinesen, Asta; Wiltshire, David L.

    2017-11-01

    Parameters that quantify the acceleration of cosmic expansion are conventionally determined within the standard Friedmann-Lemaître-Robertson-Walker (FLRW) model, which fixes spatial curvature to be homogeneous. Generic averages of Einstein's equations in inhomogeneous cosmology lead to models with non-rigidly evolving average spatial curvature, and different parametrizations of apparent cosmic acceleration. The timescape cosmology is a viable example of such a model without dark energy. Using the largest available supernova data set, the JLA catalogue, we find that the timescape model fits the luminosity distance-redshift data with a likelihood that is statistically indistinguishable from the standard spatially flat Λ cold dark matter cosmology by Bayesian comparison. In the timescape case cosmic acceleration is non-zero but has a marginal amplitude, with best-fitting apparent deceleration parameter, q_{0}=-0.043^{+0.004}_{-0.000}. Systematic issues regarding standardization of supernova light curves are analysed. Cuts of data at the statistical homogeneity scale affect light-curve parameter fits independent of cosmology. A cosmological model dependence of empirical changes to the mean colour parameter is also found. Irrespective of which model ultimately fits better, we argue that as a competitive model with a non-FLRW expansion history, the timescape model may prove a useful diagnostic tool for disentangling selection effects and astrophysical systematics from the underlying expansion history.

  6. How UV photolysis accelerates the biodegradation and mineralization of sulfadiazine (SD).

    PubMed

    Pan, Shihui; Yan, Ning; Liu, Xinyue; Wang, Wenbing; Zhang, Yongming; Liu, Rui; Rittmann, Bruce E

    2014-11-01

    Sulfadiazine (SD), one of broad-spectrum antibiotics, exhibits limited biodegradation in wastewater treatment due to its chemical structure, which requires initial mono-oxygenation reactions to initiate its biodegradation. Intimately coupling UV photolysis with biodegradation, realized with the internal loop photobiodegradation reactor, accelerated SD biodegradation and mineralization by 35 and 71 %, respectively. The main organic products from photolysis were 2-aminopyrimidine (2-AP), p-aminobenzenesulfonic acid (ABS), and aniline (An), and an SD-photolysis pathway could be identified using C, N, and S balances. Adding An or ABS (but not 2-AP) into the SD solution during biodegradation experiments (no UV photolysis) gave SD removal and mineralization rates similar to intimately coupled photolysis and biodegradation. An SD biodegradation pathway, based on a diverse set of the experimental results, explains how the mineralization of ABS and An (but not 2-AP) provided internal electron carriers that accelerated the initial mono-oxygenation reactions of SD biodegradation. Thus, multiple lines of evidence support that the mechanism by which intimately coupled photolysis and biodegradation accelerated SD removal and mineralization was through producing co-substrates whose oxidation produced electron equivalents that stimulated the initial mono-oxygenation reactions for SD biodegradation.

  7. Accelerating pathway evolution by increasing the gene dosage of chromosomal segments.

    PubMed

    Tumen-Velasquez, Melissa; Johnson, Christopher W; Ahmed, Alaa; Dominick, Graham; Fulk, Emily M; Khanna, Payal; Lee, Sarah A; Schmidt, Alicia L; Linger, Jeffrey G; Eiteman, Mark A; Beckham, Gregg T; Neidle, Ellen L

    2018-06-18

    Experimental evolution is a critical tool in many disciplines, including metabolic engineering and synthetic biology. However, current methods rely on the chance occurrence of a key step that can dramatically accelerate evolution in natural systems, namely increased gene dosage. Our studies sought to induce the targeted amplification of chromosomal segments to facilitate rapid evolution. Since increased gene dosage confers novel phenotypes and genetic redundancy, we developed a method, Evolution by Amplification and Synthetic Biology (EASy), to create tandem arrays of chromosomal regions. In Acinetobacter baylyi , EASy was demonstrated on an important bioenergy problem, the catabolism of lignin-derived aromatic compounds. The initial focus on guaiacol (2-methoxyphenol), a common lignin degradation product, led to the discovery of Amycolatopsis genes ( gcoAB ) encoding a cytochrome P450 enzyme that converts guaiacol to catechol. However, chromosomal integration of gcoAB in Pseudomonas putida or A. baylyi did not enable guaiacol to be used as the sole carbon source despite catechol being a growth substrate. In ∼1,000 generations, EASy yielded alleles that in single chromosomal copy confer growth on guaiacol. Different variants emerged, including fusions between GcoA and CatA (catechol 1,2-dioxygenase). This study illustrates the power of harnessing chromosomal gene amplification to accelerate the evolution of desirable traits.

  8. 75 FR 60133 - Agency Information Collection Activities: Declaration of Ultimate Consignee That Articles Were...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-29

    ... Activities: Declaration of Ultimate Consignee That Articles Were Exported for Temporary Scientific or... the Declaration of Ultimate Consignee That Articles Were Exported for Temporary Scientific or...: Title: Declaration of Ultimate Consignee That Articles Were Exported for Temporary Scientific or...

  9. Synergistic Action of FOXP3 and TSC1 Pathways During Tumor Progression

    DTIC Science & Technology

    2015-10-01

    invasive carcinoma and, ultimately, metastatic disease [1-3]. Mouse models of PIN (mPIN) generated by a single- mutant gene in prostate do not progress...downstream target) is sufficient to significantly reduce the initiation of prostate cancer in the Pten conditional knockout mouse model [19-21...the possibility that these two genetic hits cooperate to promote tumor progression, and mouse models show that this cooperation accelerates

  10. Ultimate Strength of Ferro-Geopolymer Composite Built-Up I Joist

    NASA Astrophysics Data System (ADS)

    Vipin, K. T.; Ganesan, N.; Indira, P. V.

    2017-07-01

    An experimental study was carried out to study the behaviour of ferro-geopolymer built-up I- joist with different types of mesh reinforcements under flexure. Mesh reinforcements considered in this study are square welded meshes, square woven meshes and hexagonal meshes. First crack load as well as ultimate strength of ferro-geopolymer built-up I-joist in flexure was obtained. An attempt was made to predict the first crack load and ultimate moment capacity of the specimen.

  11. Ultimate Limit State Assessment of Timber Bolt Connection Subjected to Double Unequal Shears

    NASA Astrophysics Data System (ADS)

    Musilek, Josef; Plachy, Jan

    2017-10-01

    Nowadays the problems occur when a structure engineer need to assess the ultimate limit state of timber bolt connection which is subjected to double unequal shears. This assessment of ultimate limit state shows the reliability of these connections. In assessing the reliability of this connection in ultimate limit state is a problem, because the formulas and equations that are currently available in design standards and available literature, describing only connections loaded symmetrically - this mean that they describe the timber bolt connection subjected to double equal shears. This fact causes problems because structural engineers have no available support, according to which they could assess reliability of the connection in terms of the ultimate limit state. They must therefore often report following an asymmetrically loaded connections carry about using formulas, which are primarily designed for checking connections loaded symmetrically. This leads logically to the fact that it is not respected by the actual behaviour of the connection in the ultimate limit state. Formulas derived in this paper provide the possibility to assess the ultimate limit state for such connection. The formulas derived in this article allow to carry out a reliability assessment of the ultimate limit state of timber bolt connection subjected to double shear. The using of the formulas derived in this paper leads to better description of the behaviour of this type of connection and also to the more economic design. An example of using these derived formulas is shown. There is shown in this example, how to assess the reliability of timber bolt connection subjected to double unequal shears in terms of ultimate limit states.

  12. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

    PubMed

    Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

    2015-02-10

    For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into

  13. Cosmic Ray Acceleration by a Versatile Family of Galactic Wind Termination Shocks

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bustard, Chad; Zweibel, Ellen G.; Cotter, Cory, E-mail: bustard@wisc.edu

    2017-01-20

    There are two distinct breaks in the cosmic ray (CR) spectrum: the so-called “knee” around 3 × 10{sup 15} eV and the so-called “ankle” around 10{sup 18} eV. Diffusive shock acceleration (DSA) at supernova remnant (SNR) shock fronts is thought to accelerate galactic CRs to energies below the knee, while an extragalactic origin is presumed for CRs with energies beyond the ankle. CRs with energies between 3 × 10{sup 15} and 10{sup 18} eV, which we dub the “shin,” have an unknown origin. It has been proposed that DSA at galactic wind termination shocks, rather than at SNR shocks, maymore » accelerate CRs to these energies. This paper uses the galactic wind model of Bustard et al. to analyze whether galactic wind termination shocks may accelerate CRs to shin energies within a reasonable acceleration time and whether such CRs can subsequently diffuse back to the Galaxy. We argue for acceleration times on the order of 100 Myr rather than a few billion years, as assumed in some previous works, and we discuss prospects for magnetic field amplification at the shock front. Ultimately, we generously assume that the magnetic field is amplified to equipartition. This formalism allows us to obtain analytic formulae, applicable to any wind model, for CR acceleration. Even with generous assumptions, we find that very high wind velocities are required to set up the necessary conditions for acceleration beyond 10{sup 17} eV. We also estimate the luminosities of CRs accelerated by outflow termination shocks, including estimates for the Milky Way wind.« less

  14. 78 FR 69101 - Agency Information Collection Activities: Declaration of the Ultimate Consignee That Articles...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-18

    ... Activities: Declaration of the Ultimate Consignee That Articles Were Exported for Temporary Scientific or... the Declaration of the Ultimate Consignee that Articles were Exported for Temporary Scientific or...: Title: Declaration of the Ultimate Consignee that Articles were Exported for Temporary Scientific or...

  15. The downregulation of thioredoxin accelerated Neuro2a cell apoptosis induced by advanced glycation end product via activating several pathways.

    PubMed

    Ren, Xiang; Ma, Haiying; Qiu, Yuanyuan; Liu, Bo; Qi, Hui; Li, Zeyu; Kong, Hui; Kong, Li

    2015-08-01

    Thioredoxin (Trx), a 12 kDa protein, has different functions in different cellular environments, playing important anti-oxidative and anti-apoptotic roles and regulating the expression of transcription factors. Advanced glycation end products (AGEs) are a heterogeneous group of irreversible adducts from glucose-protein condensation reactions and are considered crucial to the development of diabetic nephropathy, retinopathy, neurodegeneration and atherosclerosis. The aim of this study was to use a Trx inhibitor to investigate the effects and mechanism of Trx down-regulation on AGE-induced Neuro2a cell apoptosis. Neuro2a cells were cultured in vitro and treated with different conditions. The apoptosis and proliferation of Neuro2a cells were detected using flow cytometry, DNA-Ladder and CCK8 assays. Rho 123 was used to detect the mitochondrial membrane potential. ROS generation and caspase3 activity were detected using a DCFH-DA probe and micro-plate reader. Western blotting and real-time PCR were used to detect the expression of proteins and genes. We found that the down-regulation of thioredoxin could accelerate AGE-induced apoptosis in Neuro2a cells. A possible underlying mechanism is that the down-regulation of thioredoxin stimulated the up-regulation of ASK1, p-JNK, PTEN, and Txnip, as well as the down-regulation of p-AKT, ultimately increasing ROS levels and caspase3 activity. Copyright © 2015. Published by Elsevier Ltd.

  16. ULTIMATE: a deployable multiple integral field unit for Subaru

    NASA Astrophysics Data System (ADS)

    Ellis, S. C.; Zhelem, Ross; Brown, David; Staszak, Nicholas F.; Lidman, Chris; Nataf, David M.; Casey, Andrew R.; Xavier, Pascal; Sheinis, Andrew; Gillingham, Peter; Tims, Julia; Lawrence, Jon; Bryant, Julia; Sharp, Rob

    2016-08-01

    ULTIMATE is an instrument concept under development at the AAO, for the Subaru Telescope, which will have the unique combination of ground layer adaptive optics feeding multiple deployable integral field units. This will allow ULTIMATE to probe unexplored parameter space, enabling science cases such as the evolution of galaxies at z 0:5 to 1.5, and the dark matter content of the inner part of our Galaxy. ULTIMATE will use Starbugs to position between 7 and 13 IFUs over a 14 × 8 arcmin field-of-view, pro- vided by a new wide-field corrector. All Starbugs can be positioned simultaneously, to an accuracy of better than 5 milli-arcsec within the typical slew-time of the telescope, allowing for very efficient re-configuration between observations. The IFUs will feed either the near-infrared nuMOIRCS or the visible/ near-infrared PFS spectrographs, or both. Future possible upgrades include the possibility of purpose built spectrographs and incorporating OH suppression using fibre Bragg gratings. We describe the science case and resulting design requirements, the baseline instrument concept, and the expected performance of the instrument.

  17. T-cell costimulatory pathways in allograft rejection and tolerance.

    PubMed

    Rothstein, David M; Sayegh, Mohamed H

    2003-12-01

    The destiny of activated T cells is critical to the ultimate fate of immune response. After encountering antigen, naïve T cells receive signal 1 through the T-cell receptor (TCR)-major histocompatibility complex (MHC) plus antigenic peptide complex and signal 2 through "positive" costimulatory molecules leading to full activation. "Negative" T-cell costimulatory pathways, on the other hand, function to downregulate immune responses. The purpose of this article is to review the current state of knowledge and recent advances in our understanding of the functions of the positive and negative T-cell costimulatory pathways in alloimmune responses. Specifically, we discuss the functions of the CD28:B7 and the tumor necrosis factor receptor (TNFR):tumor necrosis factor (TNF) family of molecules in allograft rejection and tolerance. We address the following important questions: are T-cell costimulatory pathways merely redundant or do they provide distinct and unique functions? What are the important and unique interactions between the various pathways? And, what are the effects and mechanisms of targeting of these pathways in different types and patterns of allograft rejection and tolerance models?

  18. Testing Gravity and Cosmic Acceleration with Galaxy Clustering

    NASA Astrophysics Data System (ADS)

    Kazin, Eyal; Tinker, J.; Sanchez, A. G.; Blanton, M.

    2012-01-01

    The large-scale structure contains vast amounts of cosmological information that can help understand the accelerating nature of the Universe and test gravity on large scales. Ongoing and future sky surveys are designed to test these using various techniques applied on clustering measurements of galaxies. We present redshift distortion measurements of the Sloan Digital Sky Survey II Luminous Red Galaxy sample. We find that when combining the normalized quadrupole Q with the projected correlation function wp(rp) along with cluster counts (Rapetti et al. 2010), results are consistent with General Relativity. The advantage of combining Q and wp is the addition of the bias information, when using the Halo Occupation Distribution framework. We also present improvements to the standard technique of measuring Hubble expansion rates H(z) and angular diameter distances DA(z) when using the baryonic acoustic feature as a standard ruler. We introduce clustering wedges as an alternative basis to the multipole expansion and show that it yields similar constraints. This alternative basis serves as a useful technique to test for systematics, and ultimately improve measurements of the cosmic acceleration.

  19. Acceleration modules in linear induction accelerators

    NASA Astrophysics Data System (ADS)

    Wang, Shao-Heng; Deng, Jian-Jun

    2014-05-01

    The Linear Induction Accelerator (LIA) is a unique type of accelerator that is capable of accelerating kilo-Ampere charged particle current to tens of MeV energy. The present development of LIA in MHz bursting mode and the successful application into a synchrotron have broadened LIA's usage scope. Although the transformer model is widely used to explain the acceleration mechanism of LIAs, it is not appropriate to consider the induction electric field as the field which accelerates charged particles for many modern LIAs. We have examined the transition of the magnetic cores' functions during the LIA acceleration modules' evolution, distinguished transformer type and transmission line type LIA acceleration modules, and re-considered several related issues based on transmission line type LIA acceleration module. This clarified understanding should help in the further development and design of LIA acceleration modules.

  20. 26 CFR 48.6427-11 - Kerosene; claims by registered ultimate vendors (blending).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-11 Kerosene... certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments allowed...

  1. 26 CFR 48.6427-11 - Kerosene; claims by registered ultimate vendors (blending).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-11 Kerosene... certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments allowed...

  2. 26 CFR 48.6427-11 - Kerosene; claims by registered ultimate vendors (blending).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-11 Kerosene... certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments allowed...

  3. 26 CFR 48.6427-11 - Kerosene; claims by registered ultimate vendors (blending).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-11 Kerosene... certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments allowed...

  4. Acceleration of the Fast Solar Wind by Solitary Waves in Coronal Holes

    NASA Technical Reports Server (NTRS)

    Ofman, Leon

    2001-01-01

    The purpose of this investigation is to develop a new model for the acceleration of the fast solar wind by nonlinear. time-dependent multidimensional MHD simulations of waves in solar coronal holes. Preliminary computational studies indicate that nonlinear waves are generated in coronal holes by torsional Alfv\\'{e}n waves. These waves in addition to thermal conduction may contribute considerably to the accelerate the solar wind. Specific goals of this proposal are to investigate the generation of nonlinear solitary-like waves and their effect on solar wind acceleration by numerical 2.5D MHD simulation of coronal holes with a broad range of plasma and wave parameters; to study the effect of random disturbances at the base of a solar coronal hole on the fast solar wind acceleration with a more advanced 2.5D MHD model and to compare the results with the available observations; to extend the study to a full 3D MHD simulation of fast solar wind acceleration with a more realistic model of a coronal hole and solar boundary conditions. The ultimate goal of the three year study is to model the, fast solar wind in a coronal hole, based on realistic boundary conditions in a coronal hole near the Sun, and the coronal hole structure (i.e., density, temperature. and magnetic field geometry,) that will become available from the recently launched SOHO spacecraft.

  5. Acceleration of the Fast Solar Wind by Solitary Waves in Coronal Holes

    NASA Technical Reports Server (NTRS)

    Ofman, Leon

    2000-01-01

    The purpose of this investigation is to develop a new model for the acceleration of the fast solar wind by nonlinear, time-dependent multidimensional MHD simulations of waves in solar coronal holes. Preliminary computational studies indicate that solitary-like waves are generated in coronal holes nonlinearly by torsional Alfven waves. These waves in addition to thermal conduction may contribute considerably to the accelerate the solar wind. Specific goals of this proposal are to investigate the generation of nonlinear solitary-like waves and their effect on solar wind acceleration by numerical 2.5D MHD simulation of coronal holes with a broad range of plasma and wave parameters; to study the effect of random disturbances at the base of a solar coronal hole on the fast solar wind acceleration with a more advanced 2.5D MHD model and to compare the results with the available observations; to extend the study to a full 3D MHD simulation of fast solar wind acceleration with a more realistic model of a coronal hole and solar boundary conditions. The ultimate goal of the three year study is to model the fast solar wind in a coronal hole, based on realistic boundary conditions in a coronal hole near the Sun, and the coronal hole structure (i.e., density, temperature, and magnetic field geometry) that will become available from the recently launched SOHO spacecraft.

  6. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors.

    PubMed

    Taniguchi, Toshiyasu; Tischkowitz, Marc; Ameziane, Najim; Hodgson, Shirley V; Mathew, Christopher G; Joenje, Hans; Mok, Samuel C; D'Andrea, Alan D

    2003-05-01

    Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.

  7. Caveat emptor: limitations of the automated reconstruction of metabolic pathways in Plasmodium.

    PubMed

    Ginsburg, Hagai

    2009-01-01

    The functional reconstruction of metabolic pathways from an annotated genome is a tedious and demanding enterprise. Automation of this endeavor using bioinformatics algorithms could cope with the ever-increasing number of sequenced genomes and accelerate the process. Here, the manual reconstruction of metabolic pathways in the functional genomic database of Plasmodium falciparum--Malaria Parasite Metabolic Pathways--is described and compared with pathways generated automatically as they appear in PlasmoCyc, metaSHARK and the Kyoto Encyclopedia for Genes and Genomes. A critical evaluation of this comparison discloses that the automatic reconstruction of pathways generates manifold paths that need an expert manual verification to accept some and reject most others based on manually curated gene annotation.

  8. The converter mechanism of particle acceleration and the maximum energy of cosmic rays

    NASA Astrophysics Data System (ADS)

    Kocharovsky, Vl. V.; Aharonian, F. A.; Derishev, E. V.; Kocharovsky, V. V.

    We consider the fundamental limits on the energy of particles accelerated by electromagnetic forces in various astrophysical objects [1]. We show that accelerator's parameters are strongly limited not only by the particle confinement in large-scale magnetic field or by the difference in electric potentials (generalized Hillas criterion) but also by the curvature and other types of radiative losses of accelerated particles. Optimization of these requirements in terms of accelerator's size and the magnetic field strength results in the ultimate lower limit on the overall source energy budget, which scales as the fifth power of attainable particle energy. It is demonstrated that the curvature gamma-rays accompanying the acceleration gives further restrictions for potential acceleration sites. We compare different acceleration mechanisms and show, that the converter mechanism, which we suggested earlier [2], is the least sensitive to the geometry of the magnetic field in accelerators and allows to reach cosmic-ray energies close to the fundamental limit. The converter mechanism works most efficiently in relativistic shocks or shear flows. It utilizes multiple conversions of charged particles into neutral ones (protons to neutrons and electrons/positrons to photons) and back by means of photon-induced reactions or inelastic nucleon- nucleon collisions. We discuss the properties of gamma-ray radiation, which accompanies acceleration of cosmic rays via the converter mechanism and can provide an evidence for the latter. 1. F.A. Aharonian, A.A. Belyanin, E.V. Derishev, V.V. Kocharovsky, and Vl.V. Kocharovsky, Phys. Rev. D 66, 023005 (2002). 2. E.V. Derishev, F.A. Aharonian, V.V. Kocharovsky, and Vl.V. Kocharovsky, Phys. Rev. D 68, 043003 (2003).

  9. NOTCH pathway inactivation promotes bladder cancer progression

    PubMed Central

    Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel; Martínez-Fernández, Mónica; Cañamero, Marta; Roncador, Giovanna; Martinez-Torrecuadrada, Jorge L.; Grivas, Dimitrios; de la Pompa, Jose Luis; Valencia, Alfonso; Paramio, Jesús M.; Real, Francisco X.; Serrano, Manuel

    2015-01-01

    NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features. PMID:25574842

  10. Acellular dermal matrix scaffolds coated with connective tissue growth factor accelerate diabetic wound healing by increasing fibronectin through PKC signalling pathway.

    PubMed

    Yan, Wenxia; Liu, Hanping; Deng, Xiaoyuan; Jin, Ying; Wang, Ning; Chu, Jing

    2018-03-01

    The regional injection of connective tissue growth factor (CTGF) for diabetic wound healing requires multiple components and results in a substantial loss of its biological activity. Acellular dermal matrix (ADM) scaffolds are optimal candidates for delivering these factors to local ischaemic environments. In this study, we explored whether CTGF loaded on ADM scaffolds can enhance fibronectin (FN) expression to accelerate diabetic wound healing via the protein kinase C (PKC) signalling pathway. The performance of CTGF and CTGF + PKC inhibitor, which were loaded on ADM scaffolds to treat dorsal skin wounds in streptozotocin-induced diabetic mice, was evaluated with naked ADM as a control. Wound closure showed that ADM scaffolds loaded with CTGF induced greater diabetic wound healing in the early stage of the wound in diabetic mice. Moreover, ADM scaffolds loaded with CTGF obviously increased the expression of FN both at the mRNA and protein levels, whereas the expression of FN was significantly reduced in the inhibitor group. Furthermore, the ADM + CTGF group, which produce FN, obviously promoted alpha-smooth muscle actin and transforming growth factor-beta expression and enhanced neovasculature and collagen synthesis at the wound sites. ADM scaffolds loaded with CTGF + PKC inhibitor delayed diabetic wound healing, indicating that FN expression was mediated by the PKC signalling pathway. Our findings offer new perspectives for the treatment of diabetic wound healing and suggest a rationale for the clinical evaluation of CTGF use in diabetic wound healing. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Emittance Growth in the DARHT-II Linear Induction Accelerator

    NASA Astrophysics Data System (ADS)

    Ekdahl, Carl; Carlson, Carl A.; Frayer, Daniel K.; McCuistian, B. Trent; Mostrom, Christopher B.; Schulze, Martin E.; Thoma, Carsten H.

    2017-11-01

    The Dual-Axis Radiographic Hydrotest (DARHT) facility uses bremsstrahlung radiation source spots produced by the focused electron beams from two linear induction accelerators (LIAs) to radiograph large hydrodynamic experiments driven by high explosives. Radiographic resolution is determined by the size of the source spot, and beam emittance is the ultimate limitation to spot size. Some of the possible causes for the emittance growth in the DARHT LIA have been investigated using particle-in-cell (PIC) codes, and are discussed in this article. The results suggest that the most likely source of emittance growth is a mismatch of the beam to the magnetic transport, which can cause beam halo.

  12. Accelerator system and method of accelerating particles

    NASA Technical Reports Server (NTRS)

    Wirz, Richard E. (Inventor)

    2010-01-01

    An accelerator system and method that utilize dust as the primary mass flux for generating thrust are provided. The accelerator system can include an accelerator capable of operating in a self-neutralizing mode and having a discharge chamber and at least one ionizer capable of charging dust particles. The system can also include a dust particle feeder that is capable of introducing the dust particles into the accelerator. By applying a pulsed positive and negative charge voltage to the accelerator, the charged dust particles can be accelerated thereby generating thrust and neutralizing the accelerator system.

  13. Theorizing a model information pathway to mitigate the menstrual taboo.

    PubMed

    Yagnik, Arpan

    2017-12-13

    The impact of menstruation on the society is directly seen in the educational opportunities, quality of life and professional endeavors of females. However, lack of menstrual hygiene management has indirect implication on the balance and development of the society and nation. This study is set in the Indian context. The researcher identifies actors with a potential of mitigating menstrual taboo and then theorizes an optimal information pathway to mitigate menstrual taboo. Diffusion of innovation, framing and agenda setting theories contribute as frameworks in the creation of an optimal pathway to dissolve the menstrual taboo. The actors identified in this model are scholars, health activists, students, NGOs, media, government, corporations and villages or communities. The determinants for the direction and the order of the pathway to diffuse knowledge and confidence among these actors are the ultimate goal and sustainability of the model, strengths and weaknesses of actors, and actors' extent of influence. Considering the absence of an existing alternate, this model pathway provides a solid framework purely from a theoretical perspective. Theoretically, this model pathway is possible, practical and optimal. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Ultimate pier and contraction scour prediction in cohesive soils at selected bridges in Illinois

    USGS Publications Warehouse

    Straub, Timothy D.; Over, Thomas M.; Domanski, Marian M.

    2013-01-01

    The Scour Rate In COhesive Soils-Erosion Function Apparatus (SRICOS-EFA) method includes an ultimate scour prediction that is the equilibrium maximum pier and contraction scour of cohesive soils over time. The purpose of this report is to present the results of testing the ultimate pier and contraction scour methods for cohesive soils on 30 bridge sites in Illinois. Comparison of the ultimate cohesive and noncohesive methods, along with the Illinois Department of Transportation (IDOT) cohesive soil reduction-factor method and measured scour are presented. Also, results of the comparison of historic IDOT laboratory and field values of unconfined compressive strength of soils (Qu) are presented. The unconfined compressive strength is used in both ultimate cohesive and reduction-factor methods, and knowing how the values from field methods compare to the laboratory methods is critical to the informed application of the methods. On average, the non-cohesive method results predict the highest amount of scour, followed by the reduction-factor method results; and the ultimate cohesive method results predict the lowest amount of scour. The 100-year scour predicted for the ultimate cohesive, noncohesive, and reduction-factor methods for each bridge site and soil are always larger than observed scour in this study, except 12% of predicted values that are all within 0.4 ft of the observed scour. The ultimate cohesive scour prediction is smaller than the non-cohesive scour prediction method for 78% of bridge sites and soils. Seventy-six percent of the ultimate cohesive predictions show a 45% or greater reduction from the non-cohesive predictions that are over 10 ft. Comparing the ultimate cohesive and reduction-factor 100-year scour predictions methods for each bridge site and soil, the scour predicted by the ultimate cohesive scour prediction method is less than the reduction-factor 100-year scour prediction method for 51% of bridge sites and soils. Critical shear stress

  15. A method for early determination of meat ultimate pH.

    PubMed

    Young, O A; West, J; Hart, A L; van Otterdijk, F F H

    2004-02-01

    A patented method of rapidly determining the ultimate pH from approximate glycolytic potential of muscles of slaughtered animals has been devised. The method is based on the rapid hydrolysis of muscle glycogen to glucose by the enzyme amyloglucosidase and subsequent measurement of the liberated glucose. In acetate buffer at pH 4.5, glucose concentration can be determined in 30 s with domestic meters for diabetes control. The meter response differed from that of glucose in blood, but was linear with concentration. In slurries comprising homogenised meat in acetate buffer and added glucose, a similar linear response was obtained. Amyloglucosidase was capable of rapidly hydrolysing glycogen to glucose in such slurries. In the 24 h following slaughter, a decrease in glycogen, as determined by glucose, occurred in parallel with the decline in pH. At the same time, lactate progressively accumulated as expected. Values for the approximate glycolytic potential and (by calibration) ultimate pH, were obtained on prerigor muscle within 7 min of muscle sampling in an industrial environment. The method is suitable for on-line application in beef abattoirs particularly those employing hot boning where ultimate must be known at the grading point.

  16. External validation of the emergency department assessment of chest pain score accelerated diagnostic pathway (EDACS-ADP).

    PubMed

    Flaws, Dylan; Than, Martin; Scheuermeyer, Frank Xavier; Christenson, James; Boychuk, Barbara; Greenslade, Jaimi H; Aldous, Sally; Hammett, Christopher J; Parsonage, William A; Deely, Joanne M; Pickering, John W; Cullen, Louise

    2016-09-01

    The emergency department assessment of chest pain score accelerated diagnostic pathway (EDACS-ADP) facilitates low-risk ED chest pain patients early to outpatient investigation. We aimed to validate this rule in a North American population. We performed a retrospective validation of the EDACS-ADP using 763 chest pain patients who presented to St Paul's Hospital, Vancouver, Canada, between June 2000 and January 2003. Patients were classified as low risk if they had an EDACS <16, no new ischaemia on ECG and non-elevated serial 0-hour and 2-hour cardiac troponin concentrations. The primary outcome was the number of patients who had a predetermined major adverse cardiac event (MACE) at 30 days after presentation. Of the 763 patients, 317 (41.6%) were classified as low risk by the EDACS-ADP. The sensitivity, specificity, negative predictive value and positive predictive value of the EDACS-ADP for 30-day MACE were 100% (95% CI 94.2% to 100%), 46.4% (95% CI 42.6% to 50.2%), 100% (95% CI 98.5% to 100.0%) and 17.5% (95% CI 14.1% to 21.3%), respectively. This study validated the EDACS-ADP in a novel context and supports its safe use in a North American population. It confirms that EDACS-ADP can facilitate progression to early outpatient investigation in up to 40% of ED chest pain patients within 2 hours. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  17. An overview of bioinformatics methods for modeling biological pathways in yeast

    PubMed Central

    Hou, Jie; Acharya, Lipi; Zhu, Dongxiao

    2016-01-01

    The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein–protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae. In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways in S. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed. PMID:26476430

  18. The Ultimate Factor of Safety for Aircraft and Spacecraft Its History, Applications and Misconceptions

    NASA Technical Reports Server (NTRS)

    Zipay, John J.; Modlin, C. Thomas, Jr.; Larsen, Curtis E.

    2016-01-01

    The ultimate factor of safety (FOSULT) concept used in aircraft and spacecraft has evolved over many decades. Currently an FOSULT 1.5 is the FAR-mandated value for aircraft while an FOSULT of 1.4 has been used in various spacecraft. This paper was motivated by the desire to concisely explain the origins, proper interpretation and application of the ultimate factor of safety concept, since the authors have seen throughout their careers many misconceptions and incorrect applications of this concept. The history of the ultimate factor of safety concept is briefly summarized, the proper application of the factor of safety in aircraft design, structural analysis and operations is covered in detail, examples of limit load exceedance in aircraft and spacecraft are discussed, the evolution of the 1.4 FOSULT for spacecraft is described and some misconceptions regarding the ultimate factor of safety concept are addressed. It is hoped that this paper can be a summary resource for engineers to understand the origin, purpose and proper application of the ultimate factor of safety.

  19. Accelerating Quinoline Biodegradation and Oxidation with Endogenous Electron Donors.

    PubMed

    Bai, Qi; Yang, Lihui; Li, Rongjie; Chen, Bin; Zhang, Lili; Zhang, Yongming; Rittmann, Bruce E

    2015-10-06

    Quinoline, a recalcitrant heterocyclic compound, is biodegraded by a series of reactions that begin with mono-oxygenations, which require an intracellular electron donor. Photolysis of quinoline can generate readily biodegradable products, such as oxalate, whose bio-oxidation can generate endogenous electron donors that ought to accelerate quinoline biodegradation and, ultimately, mineralization. To test this hypothesis, we compared three protocols for the biodegradation of quinoline: direct biodegradation (B), biodegradation after photolysis of 1 h (P1h+B) or 2 h (P2h+B), and biodegradation by adding oxalate commensurate to the amount generated from photolysis of 1 h (O1+B) or 2 h (O2+B). The experimental results show that P1h+B and P2h+B accelerated quinoline biodegradation by 19% and 50%, respectively, compared to B. Protocols O1+B and O2+B also gave 19% and 50% increases, respectively. During quinoline biodegradation, its first intermediate, 2-hydroxyquinoline, accumulated gradually in parallel to quinoline loss but declined once quinoline was depleted. Mono-oxygenation of 2-hydroxyquinoline competed with mono-oxygenation of quinoline, but the inhibition was relieved when extra electrons donors were added from oxalate, whether formed by UV photolysis or added exogenously. Rapid oxalate oxidation stimulated both mono-oxygenations, which accelerated the overall quinoline oxidation that provided the bulk of the electron donor.

  20. Ultimate dynamics of the Kirschner-Panetta model: Tumor eradication and related problems

    NASA Astrophysics Data System (ADS)

    Starkov, Konstantin E.; Krishchenko, Alexander P.

    2017-10-01

    In this paper we consider the ultimate dynamics of the Kirschner-Panetta model which was created for studying the immune response to tumors under special types of immunotherapy. New ultimate upper bounds for compact invariant sets of this model are given, as well as sufficient conditions for the existence of a positively invariant polytope. We establish three types of conditions for the nonexistence of compact invariant sets in the domain of the tumor-cell population. Our main results are two types of conditions for global tumor elimination depending on the ratio between the proliferation rate of the immune cells and their mortality rate. These conditions are described in terms of simple algebraic inequalities imposed on model parameters and treatment parameters. Our theoretical studies of ultimate dynamics are complemented by numerical simulation results.

  1. Revisiting perceptions of quality of hospice care: managing for the ultimate referral.

    PubMed

    Churchman, Richard; York, Grady S; Woodard, Beth; Wainright, Charles; Rau-Foster, Mary

    2014-08-01

    Hospice services provided in the final months of life are delivered through complex interpersonal relationships between caregivers, patients, and families. Often, service value and quality are defined by these interpersonal interactions. This understanding provides hospice leaders with an enormous opportunity to create processes that provide the optimal level of care during the last months of life. The authors argue that the ultimate referral is attained when a family member observes the care of a loved one, and the family member conveys a desire to receive the same quality of services their loved one received at that facility. The point of this article is to provide evidence that supports the methods to ultimately enhance the patient's and family's experience and increase the potential for the ultimate referral. © The Author(s) 2013.

  2. 26 CFR 48.6427-10 - Kerosene; claims by registered ultimate vendors (blocked pumps).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-10 Kerosene... which certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments...

  3. 26 CFR 48.6427-10 - Kerosene; claims by registered ultimate vendors (blocked pumps).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-10 Kerosene... which certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments...

  4. 26 CFR 48.6427-10 - Kerosene; claims by registered ultimate vendors (blocked pumps).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-10 Kerosene... which certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments...

  5. 26 CFR 48.6427-10 - Kerosene; claims by registered ultimate vendors (blocked pumps).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Kerosene; claims by registered ultimate vendors... Administrative Provisions of Special Application to Retailers and Manufacturers Taxes § 48.6427-10 Kerosene... which certain registered ultimate vendors of taxed kerosene may claim the income tax credits or payments...

  6. Biomechanical and Histopathologic Effects of Pulsed-Light Accelerated Epithelium-On/-Off Corneal Collagen Cross-Linking.

    PubMed

    Zhang, Xiaoyu; Sun, Ling; Shen, Yang; Tian, Mi; Zhao, Jing; Zhao, Yu; Li, Meiyan; Zhou, Xingtao

    2017-07-01

    This study aimed to compare the biomechanical and histopathologic effects of transepithelial and accelerated epithelium-off pulsed-light accelerated corneal collagen cross-linking (CXL). A total of 24 New Zealand rabbits were analyzed after sham operation (control) or transepithelial or epithelium-off operation (45 mW/cm for both). The transepithelial group was treated with pulsed-light ultraviolet A for 5 minutes 20 seconds, and the epithelium-off group was treated for 90 seconds. Biomechanical testing, including ultimate stress, Young modulus, and the physiological modulus, was analyzed. Histological changes were evaluated by light microscopy and transmission electron microscopy. The stress-strain curve was nonlinear in both accelerated transepithelial and epithelium-off CXL groups. The stress and elastic moduli were all significantly higher in both experimental groups compared with the control group (P < 0.05), whereas there were no significant differences between the 2 treatment groups (P > 0.05). Six months after the operation, hematoxylin and eosin staining and transmission electron microscopy showed that the subcutaneous collagen fibers were arranged in a regular pattern, and the fiber density was higher in the experimental groups. Both transepithelial and accelerated epithelium-off CXL produced biomechanical and histopathologic improvements, which were not significantly different between the 2 pulsed-light accelerated CXL treatments.

  7. Increasing scientific confidence in adverse outcome pathways: Application of tailored Bradford-Hill considerations for evaluating weight of evidence

    EPA Science Inventory

    Systematic consideration of scientific support is a critical element in developing and, ultimately, using adverse outcome pathways (AOPs) for various regulatory applications. Though weight of evidence (WoE) analysis has been proposed as a basis for assessment of the maturity and...

  8. 7 CFR 4274.308 - Eligibility requirements-Ultimate recipients.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... making a loan to one of its members. (c) Any delinquent debt to the Federal Government by the ultimate... authority to incur the debt and carry out the purpose of the loan. (b) To be eligible to receive loans from... rates and terms. (4) Must, along with its principal officers (including their immediate family), hold no...

  9. Ultimate computing. Biomolecular consciousness and nano Technology

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hameroff, S.R.

    1987-01-01

    The book advances the premise that the cytoskeleton is the cell's nervous system, the biological controller/computer. If indeed cytoskeletal dynamics in the nanoscale (billionth meter, billionth second) are the texture of intracellular information processing, emerging ''NanoTechnologies'' (scanning tunneling microscopy, Feynman machines, von Neumann replicators, etc.) should enable direct monitoring, decoding and interfacing between biological and technological information devices. This in turn could result in important biomedical applications and perhaps a merger of mind and machine: Ultimate Computing.

  10. Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein.

    PubMed

    Vu, Trang T; Zhou, Ji; Leslie, Beverly A; Stafford, Alan R; Fredenburgh, James C; Ni, Ran; Qiao, Shengjun; Vaezzadeh, Nima; Jahnen-Dechent, Willi; Monia, Brett P; Gross, Peter L; Weitz, Jeffrey I

    2015-04-23

    Factor (F) XII, a key component of the contact system, triggers clotting via the intrinsic pathway, and is implicated in propagating thrombosis. Although nucleic acids are potent activators, it is unclear how the contact system is regulated to prevent uncontrolled clotting. Previously, we showed that histidine-rich glycoprotein (HRG) binds FXIIa and attenuates its capacity to trigger coagulation. To investigate the role of HRG as a regulator of the intrinsic pathway, we compared RNA- and DNA-induced thrombin generation in plasma from HRG-deficient and wild-type mice. Thrombin generation was enhanced in plasma from HRG-deficient mice, and accelerated clotting was restored to normal with HRG reconstitution. Although blood loss after tail tip amputation was similar in HRG-deficient and wild-type mice, carotid artery occlusion after FeCl3 injury was accelerated in HRG-deficient mice, and HRG administration abrogated this effect. To confirm that HRG modulates the contact system, we used DNase, RNase, and antisense oligonucleotides to characterize the FeCl3 model. Whereas DNase or FVII knockdown had no effect, carotid occlusion was abrogated with RNase or FXII knockdown, confirming that FeCl3-induced thrombosis is triggered by RNA in a FXII-dependent fashion. Therefore, in a nucleic acid-driven model, HRG inhibits thrombosis by modulating the intrinsic pathway of coagulation. © 2015 by The American Society of Hematology.

  11. Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein

    PubMed Central

    Vu, Trang T.; Zhou, Ji; Leslie, Beverly A.; Stafford, Alan R.; Fredenburgh, James C.; Ni, Ran; Qiao, Shengjun; Vaezzadeh, Nima; Jahnen-Dechent, Willi; Monia, Brett P.; Gross, Peter L.; Weitz, Jeffrey I.

    2015-01-01

    Factor (F) XII, a key component of the contact system, triggers clotting via the intrinsic pathway, and is implicated in propagating thrombosis. Although nucleic acids are potent activators, it is unclear how the contact system is regulated to prevent uncontrolled clotting. Previously, we showed that histidine-rich glycoprotein (HRG) binds FXIIa and attenuates its capacity to trigger coagulation. To investigate the role of HRG as a regulator of the intrinsic pathway, we compared RNA- and DNA-induced thrombin generation in plasma from HRG-deficient and wild-type mice. Thrombin generation was enhanced in plasma from HRG-deficient mice, and accelerated clotting was restored to normal with HRG reconstitution. Although blood loss after tail tip amputation was similar in HRG-deficient and wild-type mice, carotid artery occlusion after FeCl3 injury was accelerated in HRG-deficient mice, and HRG administration abrogated this effect. To confirm that HRG modulates the contact system, we used DNase, RNase, and antisense oligonucleotides to characterize the FeCl3 model. Whereas DNase or FVII knockdown had no effect, carotid occlusion was abrogated with RNase or FXII knockdown, confirming that FeCl3-induced thrombosis is triggered by RNA in a FXII-dependent fashion. Therefore, in a nucleic acid–driven model, HRG inhibits thrombosis by modulating the intrinsic pathway of coagulation. PMID:25691157

  12. Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice

    PubMed Central

    He, Shuang; Zhao, Tiechan; Guo, Hao; Meng, Yanzhi; Qin, Gangjian; Goukassian, David A.; Han, Jihong; Gao, Xuimei; Zhu, Yan

    2016-01-01

    Diabetic mellitus (DM) patients are at an increased risk of developing peripheral arterial disease (PAD). Danhong injection (DHI) is a Chinese patent medicine widely used for several cardiovascular indications but the mechanism of action is not well-understood. We investigated the therapeutic potential of DHI on experimental PAD in mice with chemically induced as well as genetic (KKAy) type 2 DM and the overlapping signaling pathways regulating both therapeutic angiogenesis and glucose homeostasis. Compared with normal genetic background wild type (WT) mice, both DM mice showed impaired perfusion recovery in hind-limb ischemia (HLI) model. DHI treatment significantly accelerated perfusion recovery, lowered blood glucose and improved glucose tolerance in both DM models. Bioluminescent imaging demonstrated a continuous ischemia-induced vascular endothelial growth factor receptor 2 (VEGFR-2) gene expressions with a peak time coincident with the maximal DHI stimulation. Flow cytometry analysis showed a DHI-mediated increase in endothelial progenitor cell (EPC) mobilization from bone marrow to circulating peripheral blood. DHI administration upregulated the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor-2 (VEGFR-2) in ischemic muscle. A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of VEGF-A/VEGFR-2 and peroxisome proliferator-activated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes. We confirmed that upregulation of VEGF-A/VEGFR-2 by DHI promoted PPARδ gene expression in both type 2 diabetic mice. Our findings demonstrated that a multi-component Chinese medicine DHI effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of VEGF-A/VEGFR-2 and PPARδ signaling pathways. PMID

  13. Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice.

    PubMed

    He, Shuang; Zhao, Tiechan; Guo, Hao; Meng, Yanzhi; Qin, Gangjian; Goukassian, David A; Han, Jihong; Gao, Xuimei; Zhu, Yan

    2016-01-01

    Diabetic mellitus (DM) patients are at an increased risk of developing peripheral arterial disease (PAD). Danhong injection (DHI) is a Chinese patent medicine widely used for several cardiovascular indications but the mechanism of action is not well-understood. We investigated the therapeutic potential of DHI on experimental PAD in mice with chemically induced as well as genetic (KKAy) type 2 DM and the overlapping signaling pathways regulating both therapeutic angiogenesis and glucose homeostasis. Compared with normal genetic background wild type (WT) mice, both DM mice showed impaired perfusion recovery in hind-limb ischemia (HLI) model. DHI treatment significantly accelerated perfusion recovery, lowered blood glucose and improved glucose tolerance in both DM models. Bioluminescent imaging demonstrated a continuous ischemia-induced vascular endothelial growth factor receptor 2 (VEGFR-2) gene expressions with a peak time coincident with the maximal DHI stimulation. Flow cytometry analysis showed a DHI-mediated increase in endothelial progenitor cell (EPC) mobilization from bone marrow to circulating peripheral blood. DHI administration upregulated the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor-2 (VEGFR-2) in ischemic muscle. A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of VEGF-A/VEGFR-2 and peroxisome proliferator-activated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes. We confirmed that upregulation of VEGF-A/VEGFR-2 by DHI promoted PPARδ gene expression in both type 2 diabetic mice. Our findings demonstrated that a multi-component Chinese medicine DHI effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of VEGF-A/VEGFR-2 and PPARδ signaling pathways.

  14. The optimisation of low-acceleration interstellar relativistic rocket trajectories using genetic algorithms

    NASA Astrophysics Data System (ADS)

    Fung, Kenneth K. H.; Lewis, Geraint F.; Wu, Xiaofeng

    2017-04-01

    A vast wealth of literature exists on the topic of rocket trajectory optimisation, particularly in the area of interplanetary trajectories due to its relevance today. Studies on optimising interstellar and intergalactic trajectories are usually performed in flat spacetime using an analytical approach, with very little focus on optimising interstellar trajectories in a general relativistic framework. This paper examines the use of low-acceleration rockets to reach galactic destinations in the least possible time, with a genetic algorithm being employed for the optimisation process. The fuel required for each journey was calculated for various types of propulsion systems to determine the viability of low-acceleration rockets to colonise the Milky Way. The results showed that to limit the amount of fuel carried on board, an antimatter propulsion system would likely be the minimum technological requirement to reach star systems tens of thousands of light years away. However, using a low-acceleration rocket would require several hundreds of thousands of years to reach these star systems, with minimal time dilation effects since maximum velocities only reached about 0.2 c . Such transit times are clearly impractical, and thus, any kind of colonisation using low acceleration rockets would be difficult. High accelerations, on the order of 1 g, are likely required to complete interstellar journeys within a reasonable time frame, though they may require prohibitively large amounts of fuel. So for now, it appears that humanity's ultimate goal of a galactic empire may only be possible at significantly higher accelerations, though the propulsion technology requirement for a journey that uses realistic amounts of fuel remains to be determined.

  15. The ultimate efficiency of photosensitive systems

    NASA Technical Reports Server (NTRS)

    Buoncristiani, A. M.; Byvik, C. E.; Smith, B. T.

    1981-01-01

    These systems have in common two important but not independent features: they can produce a storable fuel, and they are sensitive only to radiant energy with a characteristic absorption spectrum. General analyses of the conversion efficiencies were made using the operational characteristics of each particular system. An efficiency analysis of a generalized system consisting of a blackbody source, a radiant energy converter having a threshold energy and operating temperature, and a reservoir is reported. This analysis is based upon the first and second laws of thermodynamics, and leads to a determination of the limiting or ultimate efficiency for an energy conversion system having a characteristic threshold.

  16. 75 FR 76746 - Agency Information Collection Activities: Declaration of Ultimate Consignee That Articles Were...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-09

    ... Activities: Declaration of Ultimate Consignee That Articles Were Exported for Temporary Scientific or... That Articles Were Exported for Temporary Scientific or Educational Purposes. This is a proposed... forms of information. Title: Declaration of Ultimate Consignee That Articles Were Exported for Temporary...

  17. An overview of bioinformatics methods for modeling biological pathways in yeast.

    PubMed

    Hou, Jie; Acharya, Lipi; Zhu, Dongxiao; Cheng, Jianlin

    2016-03-01

    The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein-protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways inS. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  18. Optimization and Prediction of Ultimate Tensile Strength in Metal Active Gas Welding.

    PubMed

    Ampaiboon, Anusit; Lasunon, On-Uma; Bubphachot, Bopit

    2015-01-01

    We investigated the effect of welding parameters on ultimate tensile strength of structural steel, ST37-2, welded by Metal Active Gas welding. A fractional factorial design was used for determining the significance of six parameters: wire feed rate, welding voltage, welding speed, travel angle, tip-to-work distance, and shielded gas flow rate. A regression model to predict ultimate tensile strength was developed. Finally, we verified optimization of the process parameters experimentally. We achieved an optimum tensile strength (558 MPa) and wire feed rate, 19 m/min, had the greatest effect, followed by tip-to-work distance, 7 mm, welding speed, 200 mm/min, welding voltage, 30 V, and travel angle, 60°. Shield gas flow rate, 10 L/min, was slightly better but had little effect in the 10-20 L/min range. Tests showed that our regression model was able to predict the ultimate tensile strength within 4%.

  19. Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. I. Normal responses

    NASA Technical Reports Server (NTRS)

    Minor, L. B.; Lasker, D. M.; Backous, D. D.; Hullar, T. E.; Shelhamer, M. J. (Principal Investigator)

    1999-01-01

    The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in five squirrel monkeys with intact vestibular function. The VOR evoked by steps of acceleration in darkness (3,000 degrees /s(2) reaching a velocity of 150 degrees /s) began after a latency of 7.3 +/- 1.5 ms (mean +/- SD). Gain of the reflex during the acceleration was 14.2 +/- 5.2% greater than that measured once the plateau head velocity had been reached. A polynomial regression was used to analyze the trajectory of the responses to steps of acceleration. A better representation of the data was obtained from a polynomial that included a cubic term in contrast to an exclusively linear fit. For sinusoidal rotations of 0.5-15 Hz with a peak velocity of 20 degrees /s, the VOR gain measured 0.83 +/- 0.06 and did not vary across frequencies or animals. The phase of these responses was close to compensatory except at 15 Hz where a lag of 5.0 +/- 0.9 degrees was noted. The VOR gain did not vary with head velocity at 0.5 Hz but increased with velocity for rotations at frequencies of >/=4 Hz (0. 85 +/- 0.04 at 4 Hz, 20 degrees /s; 1.01 +/- 0.05 at 100 degrees /s, P < 0.0001). No responses to these rotations were noted in two animals that had undergone bilateral labyrinthectomy indicating that inertia of the eye had a negligible effect for these stimuli. We developed a mathematical model of VOR dynamics to account for these findings. The inputs to the reflex come from linear and nonlinear pathways. The linear pathway is responsible for the constant gain across frequencies at peak head velocity of 20 degrees /s and also for the phase lag at higher frequencies being less than that expected based on the reflex delay. The frequency- and velocity-dependent nonlinearity in VOR gain is accounted for by the dynamics of the nonlinear pathway. A transfer function that increases the gain of this pathway with frequency and a term related to the third power of head

  20. New challenges for text mining: mapping between text and manually curated pathways

    PubMed Central

    Oda, Kanae; Kim, Jin-Dong; Ohta, Tomoko; Okanohara, Daisuke; Matsuzaki, Takuya; Tateisi, Yuka; Tsujii, Jun'ichi

    2008-01-01

    Background Associating literature with pathways poses new challenges to the Text Mining (TM) community. There are three main challenges to this task: (1) the identification of the mapping position of a specific entity or reaction in a given pathway, (2) the recognition of the causal relationships among multiple reactions, and (3) the formulation and implementation of required inferences based on biological domain knowledge. Results To address these challenges, we constructed new resources to link the text with a model pathway; they are: the GENIA pathway corpus with event annotation and NF-kB pathway. Through their detailed analysis, we address the untapped resource, ‘bio-inference,’ as well as the differences between text and pathway representation. Here, we show the precise comparisons of their representations and the nine classes of ‘bio-inference’ schemes observed in the pathway corpus. Conclusions We believe that the creation of such rich resources and their detailed analysis is the significant first step for accelerating the research of the automatic construction of pathway from text. PMID:18426550

  1. Topical N-Acetylcysteine Accelerates Wound Healing in Vitro and in Vivo via the PKC/Stat3 Pathway

    PubMed Central

    Tsai, Min-Ling; Huang, Hui-Pei; Hsu, Jeng-Dong; Lai, Yung-Rung; Hsiao, Yu-Ping; Lu, Fung-Jou; Chang, Horng-Rong

    2014-01-01

    N-Acetylcysteine (Nac) is an antioxidant administered in both oral and injectable forms. In this study, we used Nac topically to treat burn wounds in vitro and in vivo to investigate mechanisms of action. In vitro, we monitored glutathione levels, cell proliferation, migration, scratch-wound healing activities and the epithelialization-related proteins, matrixmetalloproteinase-1 (MMP-1) and proteins involved in regulating the expression of MMP-1 in CCD-966SK cells treated with Nac. Various Nac concentrations (0.1, 0.5, and 1.0 mM) increased glutathione levels, cell viability, scratch-wound healing activities and migration abilities of CCD-966SK cells in a dose-dependent manner. The MMP-1 expression of CCD-966SK cells treated with 1.0 mM Nac for 24 h was significantly increased. Levels of phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), janus kinase 1 (Jak1), signal transducer and activator of transcription 3 (Stat3), c-Fos and Jun, but not extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), were also significantly increased in a dose-dependent manner compared to the controls. In addition, Nac induced collagenous expression of MMP-1 via the PKC/Stat3 signaling pathway. In vivo, a burn wound healing rat model was applied to assess the stimulation activity and histopathological effects of Nac, with 3.0% Nac-treated wounds being found to show better characteristics on re-epithelialization. Our results demonstrated that Nac can potentially promote wound healing activity, and may be a promising drug to accelerate burn wound healing. PMID:24798751

  2. Effect of load eccentricity and substructure deformation on ultimate strength of shuttle orbiter thermal protection system

    NASA Technical Reports Server (NTRS)

    Sawyer, J. W.

    1981-01-01

    The effect of load eccentricity and substructure deformation on the ultimate strength and stress displacement properties of the shuttle orbiter thermal protection system (TPS) was determined. The LI-900 Reusable Surface Insulation (RSI) tiles mounted on the .41 cm thick Strain Isolator Pad (SIP) were investigated. Substructure deformations reduce the ultimate strength of the SIP/tile TPS and increase the scatter in the ultimate strength data. Substructure deformations that occur unsymmetric to the tile can cause the tile to rotate when subjected to a uniform applied load. Load eccentricity reduces SIP/tile TPS ultimate strength and causes tile rotation.

  3. Optimum swimming pathways of fish spawning migrations in rivers

    USGS Publications Warehouse

    McElroy, Brandon; DeLonay, Aaron; Jacobson, Robert

    2012-01-01

    Fishes that swim upstream in rivers to spawn must navigate complex fluvial velocity fields to arrive at their ultimate locations. One hypothesis with substantial implications is that fish traverse pathways that minimize their energy expenditure during migration. Here we present the methodological and theoretical developments necessary to test this and similar hypotheses. First, a cost function is derived for upstream migration that relates work done by a fish to swimming drag. The energetic cost scales with the cube of a fish's relative velocity integrated along its path. By normalizing to the energy requirements of holding a position in the slowest waters at the path's origin, a cost function is derived that depends only on the physical environment and not on specifics of individual fish. Then, as an example, we demonstrate the analysis of a migration pathway of a telemetrically tracked pallid sturgeon (Scaphirhynchus albus) in the Missouri River (USA). The actual pathway cost is lower than 105 random paths through the surveyed reach and is consistent with the optimization hypothesis. The implication—subject to more extensive validation—is that reproductive success in managed rivers could be increased through manipulation of reservoir releases or channel morphology to increase abundance of lower-cost migration pathways.

  4. Regions of absolute ultimate boundedness for discrete-time systems.

    NASA Technical Reports Server (NTRS)

    Siljak, D. D.; Weissenberger, S.

    1972-01-01

    This paper considers discrete-time systems of the Lur'e-Postnikov class where the linear part is not asymptotically stable and the nonlinear characteristic satisfies only partially the usual sector condition. Estimates of the resulting finite regions of absolute ultimate boundedness are calculated by means of a quadratic Liapunov function.

  5. The Ultimate Sampling Dilemma in Experience-Based Decision Making

    ERIC Educational Resources Information Center

    Fiedler, Klaus

    2008-01-01

    Computer simulations and 2 experiments demonstrate the ultimate sampling dilemma, which constitutes a serious obstacle to inductive inferences in a probabilistic world. Participants were asked to take the role of a manager who is to make purchasing decisions based on positive versus negative feedback about 3 providers in 2 different product…

  6. Wilderness education: The ultimate commitment to quality wilderness stewardship

    Treesearch

    Gregory F. Hansen; Tom Carlson

    2007-01-01

    The effective planning, implementation, and monitoring of a wilderness education program will ultimately produce measurable results that can be instrumental in achieving wilderness management goals and objectives. This paper will provide a simple step-by-step overview of how to develop and maintain a successful wilderness education program through planning,...

  7. Cancer cachexia: mediators, signaling, and metabolic pathways.

    PubMed

    Fearon, Kenneth C H; Glass, David J; Guttridge, Denis C

    2012-08-08

    Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response.

    PubMed

    Osorio, Fernando G; Bárcena, Clea; Soria-Valles, Clara; Ramsay, Andrew J; de Carlos, Félix; Cobo, Juan; Fueyo, Antonio; Freije, José M P; López-Otín, Carlos

    2012-10-15

    Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging.

  9. Academic Provenance: Mapping Geoscience Students' Academic Pathways to their Career Trajectories

    NASA Astrophysics Data System (ADS)

    Houlton, H. R.; Gonzales, L. M.; Keane, C. M.

    2011-12-01

    Targeted recruitment and retention efforts for the geosciences have become increasingly important with the growing concerns about program visibility on campuses, and given that geoscience degree production remains low relative to the demand for new geoscience graduates. Furthermore, understanding the career trajectories of geoscience degree recipients is essential for proper occupational placement. A theoretical framework was developed by Houlton (2010) to focus recruitment and retention efforts. This "pathway model" explicitly maps undergraduate students' geoscience career trajectories, which can be used to refine existing methods for recruiting students into particular occupations. Houlton's (2010) framework identified three main student population groups: Natives, Immigrants or Refugees. Each student followed a unique pathway, which consisted of six pathway steps. Each pathway step was comprised of critical incidents that influenced students' overall career trajectories. An aggregate analysis of students' pathways (Academic Provenance Analysis) showed that different populations' pathways exhibited a deviation in career direction: Natives indicated intentions to pursue industry or government sectors, while Immigrants intended to pursue academic or research-based careers. We expanded on Houlton's (2010) research by conducting a follow-up study to determine if the original participants followed the career trajectories they initially indicated in the 2010 study. A voluntary, 5-question, short-answer survey was administered via email. We investigated students' current pathway steps, pathway deviations, students' goals for the near future and their ultimate career ambitions. This information may help refine Houlton's (2010) "pathway model" and may aid geoscience employers in recruiting the new generation of professionals for their respective sectors.

  10. Molecular mechanism of TGF-β signaling pathway in colon carcinogenesis and status of curcumin as chemopreventive strategy.

    PubMed

    Ramamoorthi, Ganesan; Sivalingam, Nageswaran

    2014-08-01

    Colon cancer is one of the third most common cancer in man, the second most common cancer in women worldwide, and the second leading cause of mortality in the USA. There are a number of molecular pathways that have been implicated in colon carcinogenesis, including TGF-β/Smad signaling pathway. TGF-β (transforming growth factor-beta) signaling pathway has the potential to regulate various biological processes including cell growth, differentiation, apoptosis, extracellular matrix modeling, and immune response. TGF-β signaling pathway acts as a tumor suppressor, but alterations in TGF-β signaling pathway promotes colon cancer cell growth, migration, invasion, angiogenesis, and metastasis. Here we review the role of TGF-β signaling cascade in colon carcinogenesis and multiple molecular targets of curcumin in colon carcinogenesis. Elucidation of the molecular mechanism of curcumin on TGF-β signaling pathway-induced colon carcinogenesis may ultimately lead to novel and more effective treatments for colon cancer.

  11. Reduced Design Load Basis for Ultimate Blade Loads Estimation in Multidisciplinary Design Optimization Frameworks

    NASA Astrophysics Data System (ADS)

    Pavese, Christian; Tibaldi, Carlo; Larsen, Torben J.; Kim, Taeseong; Thomsen, Kenneth

    2016-09-01

    The aim is to provide a fast and reliable approach to estimate ultimate blade loads for a multidisciplinary design optimization (MDO) framework. For blade design purposes, the standards require a large amount of computationally expensive simulations, which cannot be efficiently run each cost function evaluation of an MDO process. This work describes a method that allows integrating the calculation of the blade load envelopes inside an MDO loop. Ultimate blade load envelopes are calculated for a baseline design and a design obtained after an iteration of an MDO. These envelopes are computed for a full standard design load basis (DLB) and a deterministic reduced DLB. Ultimate loads extracted from the two DLBs with the two blade designs each are compared and analyzed. Although the reduced DLB supplies ultimate loads of different magnitude, the shape of the estimated envelopes are similar to the one computed using the full DLB. This observation is used to propose a scheme that is computationally cheap, and that can be integrated inside an MDO framework, providing a sufficiently reliable estimation of the blade ultimate loading. The latter aspect is of key importance when design variables implementing passive control methodologies are included in the formulation of the optimization problem. An MDO of a 10 MW wind turbine blade is presented as an applied case study to show the efficacy of the reduced DLB concept.

  12. Heterostyly accelerates diversification via reduced extinction in primroses.

    PubMed

    de Vos, Jurriaan M; Hughes, Colin E; Schneeweiss, Gerald M; Moore, Brian R; Conti, Elena

    2014-06-07

    The exceptional species diversity of flowering plants, exceeding that of their sister group more than 250-fold, is especially evident in floral innovations, interactions with pollinators and sexual systems. Multiple theories, emphasizing flower-pollinator interactions, genetic effects of mating systems or high evolvability, predict that floral evolution profoundly affects angiosperm diversification. However, consequences for speciation and extinction dynamics remain poorly understood. Here, we investigate trajectories of species diversification focusing on heterostyly, a remarkable floral syndrome where outcrossing is enforced via cross-compatible floral morphs differing in placement of their respective sexual organs. Heterostyly evolved at least 20 times independently in angiosperms. Using Darwin's model for heterostyly, the primrose family, we show that heterostyly accelerates species diversification via decreasing extinction rates rather than increasing speciation rates, probably owing to avoidance of the negative genetic effects of selfing. However, impact of heterostyly appears to differ over short and long evolutionary time-scales: the accelerating effect of heterostyly on lineage diversification is manifest only over long evolutionary time-scales, whereas recent losses of heterostyly may prompt ephemeral bursts of speciation. Our results suggest that temporal or clade-specific conditions may ultimately determine the net effects of specific traits on patterns of species diversification.

  13. Heterostyly accelerates diversification via reduced extinction in primroses

    PubMed Central

    de Vos, Jurriaan M.; Hughes, Colin E.; Schneeweiss, Gerald M.; Moore, Brian R.; Conti, Elena

    2014-01-01

    The exceptional species diversity of flowering plants, exceeding that of their sister group more than 250-fold, is especially evident in floral innovations, interactions with pollinators and sexual systems. Multiple theories, emphasizing flower–pollinator interactions, genetic effects of mating systems or high evolvability, predict that floral evolution profoundly affects angiosperm diversification. However, consequences for speciation and extinction dynamics remain poorly understood. Here, we investigate trajectories of species diversification focusing on heterostyly, a remarkable floral syndrome where outcrossing is enforced via cross-compatible floral morphs differing in placement of their respective sexual organs. Heterostyly evolved at least 20 times independently in angiosperms. Using Darwin's model for heterostyly, the primrose family, we show that heterostyly accelerates species diversification via decreasing extinction rates rather than increasing speciation rates, probably owing to avoidance of the negative genetic effects of selfing. However, impact of heterostyly appears to differ over short and long evolutionary time-scales: the accelerating effect of heterostyly on lineage diversification is manifest only over long evolutionary time-scales, whereas recent losses of heterostyly may prompt ephemeral bursts of speciation. Our results suggest that temporal or clade-specific conditions may ultimately determine the net effects of specific traits on patterns of species diversification. PMID:24759859

  14. Adaptive Acceleration of Visually Evoked Smooth Eye Movements in Mice

    PubMed Central

    2016-01-01

    The optokinetic response (OKR) consists of smooth eye movements following global motion of the visual surround, which suppress image slip on the retina for visual acuity. The effective performance of the OKR is limited to rather slow and low-frequency visual stimuli, although it can be adaptably improved by cerebellum-dependent mechanisms. To better understand circuit mechanisms constraining OKR performance, we monitored how distinct kinematic features of the OKR change over the course of OKR adaptation, and found that eye acceleration at stimulus onset primarily limited OKR performance but could be dramatically potentiated by visual experience. Eye acceleration in the temporal-to-nasal direction depended more on the ipsilateral floccular complex of the cerebellum than did that in the nasal-to-temporal direction. Gaze-holding following the OKR was also modified in parallel with eye-acceleration potentiation. Optogenetic manipulation revealed that synchronous excitation and inhibition of floccular complex Purkinje cells could effectively accelerate eye movements in the nasotemporal and temporonasal directions, respectively. These results collectively delineate multiple motor pathways subserving distinct aspects of the OKR in mice and constrain hypotheses regarding cellular mechanisms of the cerebellum-dependent tuning of movement acceleration. SIGNIFICANCE STATEMENT Although visually evoked smooth eye movements, known as the optokinetic response (OKR), have been studied in various species for decades, circuit mechanisms of oculomotor control and adaptation remain elusive. In the present study, we assessed kinematics of the mouse OKR through the course of adaptation training. Our analyses revealed that eye acceleration at visual-stimulus onset primarily limited working velocity and frequency range of the OKR, yet could be dramatically potentiated during OKR adaptation. Potentiation of eye acceleration exhibited different properties between the nasotemporal and

  15. Ultimate Load Behaviour of Reinforced Concrete Beam with Corroded Reinforcement

    NASA Astrophysics Data System (ADS)

    Kanchana Devi, A.; Ramajaneyulu, K.; Sundarkumar, S.; Ramesh, G.; Bharat Kumar, B. H.; Krishna Moorthy, T. S.

    2017-12-01

    Corrosion of reinforcement reduces the load carrying capacity, energy dissipation and ductility of Reinforced Concrete (RC) members. In the present study, reinforcements of RC beam are subjected to 10, 25, and 30% corrosion and the respective RC beams are tested to evaluate their ultimate load behaviour. A huge drop in energy dissipation capacity of the RC beam is observed beyond the corrosion level of 10%. Further, nonlinear finite element analysis is employed to assess the load-displacement behaviour and ultimate load of RC beam. The corrosion induced damage to the reinforcement is represented in the finite element model by modifying its mechanical properties based on the results reported in the literature. The resultant load versus displacement curves of reinforced concrete beams are obtained. Good correlation is observed between the finite element analysis results and that obtained from experimental investigation on the control beam. The experimental results are also compared with the finite element analysis results for RC beams with corroded reinforcement. In order to understand the effect of corrosion on the mechanical properties of reinforcement, the corroded reinforcements are modelled in nonlinear finite element analysis by (i) reducing the area of reinforcement alone (ii) by reducing both area and mechanical properties and (iii) reducing the mechanical properties without reducing the area of steel as reported in literature. The results obtained for the beam with corroded reinforcement confirms reduction in yield stress and ultimate stress of the reinforcement steel.

  16. Pathway-engineering for highly-aligned block copolymer arrays.

    PubMed

    Choo, Youngwoo; Majewski, Paweł W; Fukuto, Masafumi; Osuji, Chinedum O; Yager, Kevin G

    2017-12-21

    While the ultimate driving force in self-assembly is energy minimization and the corresponding evolution towards equilibrium, kinetic effects can also play a very strong role. These kinetic effects, such as trapping in metastable states, slow coarsening kinetics, and pathway-dependent assembly, are often viewed as complications to be overcome. Here, we instead exploit these effects to engineer a desired final nano-structure in a block copolymer thin film, by selecting a particular ordering pathway through the self-assembly energy landscape. In particular, we combine photothermal shearing with high-temperature annealing to yield hexagonal arrays of block copolymer cylinders that are aligned in a single prescribed direction over macroscopic sample dimensions. Photothermal shearing is first used to generate a highly-aligned horizontal cylinder state, with subsequent thermal processing used to reorient the morphology to the vertical cylinder state in a templated manner. Finally, we demonstrate the successful transfer of engineered morphologies into inorganic replicas.

  17. First muon acceleration using a radio-frequency accelerator

    NASA Astrophysics Data System (ADS)

    Bae, S.; Choi, H.; Choi, S.; Fukao, Y.; Futatsukawa, K.; Hasegawa, K.; Iijima, T.; Iinuma, H.; Ishida, K.; Kawamura, N.; Kim, B.; Kitamura, R.; Ko, H. S.; Kondo, Y.; Li, S.; Mibe, T.; Miyake, Y.; Morishita, T.; Nakazawa, Y.; Otani, M.; Razuvaev, G. P.; Saito, N.; Shimomura, K.; Sue, Y.; Won, E.; Yamazaki, T.

    2018-05-01

    Muons have been accelerated by using a radio-frequency accelerator for the first time. Negative muonium atoms (Mu- ), which are bound states of positive muons (μ+) and two electrons, are generated from μ+'s through the electron capture process in an aluminum degrader. The generated Mu- 's are initially electrostatically accelerated and injected into a radio-frequency quadrupole linac (RFQ). In the RFQ, the Mu- 's are accelerated to 89 keV. The accelerated Mu- 's are identified by momentum measurement and time of flight. This compact muon linac opens the door to various muon accelerator applications including particle physics measurements and the construction of a transmission muon microscope.

  18. Acceleration and focusing of plasma flows

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Griswold, Martin Elias

    The acceleration of flowing plasmas is a fundamental problem that is useful in a wide variety of technological applications. We consider the problem from the perspective of plasma propulsion. Gridded ion thrusters and Hall thrusters are the most commonly used devices to create flowing plasma for space propulsion, but both suffer from fundamental limitations. Gridded ion sources create good quality beams in terms of energy spread and spatial divergence, but the Child-Langmuir law in the non-neutral acceleration region limits the maximum achievable current density. Hall thrusters avoid this limitation by accelerating ions in quasi-neutral plasma but, as a result, producemore » plumes with high spatial divergence and large energy spread. In addition the more complicated magnetized plasma in the Hall Thruster produces oscillations that can reduce the efficiency of the thruster by increasing electron transport to the anode. We present investigations of three techniques to address the fundamental limitations on the performance of each thruster. First, we propose a method to increase the time-averaged current density (and thus thrust density) produced by a gridded ion source above the Child-Langmuir limit by introducing time-varying boundary conditions. Next, we use an electrostatic plasma lens to focus the Hall thruster plume, and finally we develop a technique to suppress a prominent oscillation that degrades the performance of Hall thrusters. The technique to loosen the constraints on current density from gridded ion thrusters actually applies much more broadly to any space charge limited flow. We investigate the technique with a numerical simulation and by proving a theoretical upper bound. While we ultimately conclude that the approach is not suitable for space propulsion, our results proved useful in another area, providing a benchmark for research into the spontaneously time-dependent current that arises in microdiodes. Next, we experimentally demonstrate a novel

  19. 49 Stories That Make an Ultimate STEM Lesson Plan

    ERIC Educational Resources Information Center

    Mehta, Swati; Mehta, Rohit; Berzina-Pitcher, Inese; Seals, Christopher; Mishra, Punya

    2016-01-01

    In this paper we reviewed what 49 large urban public school district STEM teachers enrolled in a year-long graduate certificate and fellowship program at a large Midwestern university considered as their amazing teaching moments. They were asked to share their amazing teaching moments that would make an Ultimate Lesson Plan in STEM. In smaller…

  20. A Small RNA-Catalytic Argonaute Pathway Tunes Germline Transcript Levels to Ensure Embryonic Divisions

    PubMed Central

    Gerson-Gurwitz, Adina; Wang, Shaohe; Sathe, Shashank; Green, Rebecca; Yeo, Gene W.; Oegema, Karen; Desai, Arshad

    2016-01-01

    SUMMARY Multiple division cycles without growth are a characteristic feature of early embryogenesis. The female germline loads proteins and RNAs into oocytes to support these divisions, which lack many quality control mechanisms operating in somatic cells undergoing growth. Here we describe a small RNA-Argonaute pathway that ensures early embryonic divisions in C. elegans by employing catalytic slicing activity to broadly tune, instead of silence, germline gene expression. Misregulation of one target, a kinesin-13 microtubule depolymerase, underlies a major phenotype associated with pathway loss. Tuning of target transcript levels is guided by density of homologous small RNAs, whose generation must ultimately be related to target sequence. Thus, the tuning action of a small RNA-catalytic Argonaute pathway generates oocytes capable of supporting embryogenesis. We speculate that the specialized nature of germline chromatin led to emergence of small RNA-catalytic Argonaute pathways in the female germline as a post-transcriptional control layer to optimize oocyte composition. PMID:27020753

  1. PARTICLE ACCELERATOR

    DOEpatents

    Teng, L.C.

    1960-01-19

    ABS>A combination of two accelerators, a cyclotron and a ring-shaped accelerator which has a portion disposed tangentially to the cyclotron, is described. Means are provided to transfer particles from the cyclotron to the ring accelerator including a magnetic deflector within the cyclotron, a magnetic shield between the ring accelerator and the cyclotron, and a magnetic inflector within the ring accelerator.

  2. Repurposing the Saccharomyces cerevisiae peroxisome for compartmentalizing multi-enzyme pathways

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    DeLoache, William; Russ, Zachary; Samson, Jennifer

    The peroxisome of Saccharomyces cerevisiae was targeted for repurposing in order to create a synthetic organelle that provides a generalizable compartment for engineered metabolic pathways. Compartmentalization of enzymes into organelles is a promising strategy for limiting metabolic crosstalk, improving pathway efficiency, and ultimately modifying the chemical environment to be distinct from that of the cytoplasm. We focused on the Saccharomyces cerevisiae peroxisome, as this organelle is not required for viability when grown on conventional media. We identified an enhanced peroxisomal targeting signal type 1 (PTS1) for rapidly importing non-native cargo proteins. Additionally, we performed the first systematic in vivo measurementsmore » of nonspecific metabolite permeability across the peroxisomal membrane using a polymer exclusion assay and characterized the size dependency of metabolite trafficking. Finally, we applied these new insights to compartmentalize a two-enzyme pathway in the peroxisome and characterize the expression regimes where compartmentalization leads to improved product titer. This work builds a foundation for using the peroxisome as a synthetic organelle, highlighting both promise and future challenges on the way to realizing this goal.« less

  3. Can Perspective-Taking Reduce Crime? Examining a Pathway Through Empathic-Concern and Guilt-Proneness

    PubMed Central

    Martinez, Andres G.; Stuewig, Jeffrey; Tangney, June

    2015-01-01

    We describe and test a theoretical model in which individual differences in perspective-taking eventuate in crime reduction. Specifically, it is hypothesized that perspective-taking propensities influence the tendency to feel empathic-concern, thereby heightening proneness for guilt, which then ultimately inhibits criminal behavior (perspective-taking → empathic-concern → guilt-proneness → crime desistance). Data from two sources were analyzed: (1) a cross-sectional college sample and (2) a longitudinal sample of jail inmates. Overall, results lend credence to this model. Perspective-taking propensities ultimately “put the brakes” on criminal behavior via an affective pathway of empathic-concern and guilt-proneness. Discussion focuses on the nature of perspective-taking, its generative role in moral emotions, as well as potential applications for crime prevention. PMID:25324328

  4. Acceleration Modes and Transitions in Pulsed Plasma Accelerators

    NASA Technical Reports Server (NTRS)

    Polzin, Kurt A.; Greve, Christine M.

    2018-01-01

    Pulsed plasma accelerators typically operate by storing energy in a capacitor bank and then discharging this energy through a gas, ionizing and accelerating it through the Lorentz body force. Two plasma accelerator types employing this general scheme have typically been studied: the gas-fed pulsed plasma thruster and the quasi-steady magnetoplasmadynamic (MPD) accelerator. The gas-fed pulsed plasma accelerator is generally represented as a completely transient device discharging in approximately 1-10 microseconds. When the capacitor bank is discharged through the gas, a current sheet forms at the breech of the thruster and propagates forward under a j (current density) by B (magnetic field) body force, entraining propellant it encounters. This process is sometimes referred to as detonation-mode acceleration because the current sheet representation approximates that of a strong shock propagating through the gas. Acceleration of the initial current sheet ceases when either the current sheet reaches the end of the device and is ejected or when the current in the circuit reverses, striking a new current sheet at the breech and depriving the initial sheet of additional acceleration. In the quasi-steady MPD accelerator, the pulse is lengthened to approximately 1 millisecond or longer and maintained at an approximately constant level during discharge. The time over which the transient phenomena experienced during startup typically occur is short relative to the overall discharge time, which is now long enough for the plasma to assume a relatively steady-state configuration. The ionized gas flows through a stationary current channel in a manner that is sometimes referred to as the deflagration-mode of operation. The plasma experiences electromagnetic acceleration as it flows through the current channel towards the exit of the device. A device that had a short pulse length but appeared to operate in a plasma acceleration regime different from the gas-fed pulsed plasma

  5. Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers.

    PubMed

    Gong, Ping; Hong, Huixiao; Perkins, Edward J

    2015-01-01

    Antagonism of ionotropic GABA receptors (iGABARs) can occur at three distinct types of receptor binding sites causing chemically induced epileptic seizures. Here we review three adverse outcome pathways, each characterized by a specific molecular initiating event where an antagonist competitively binds to active sites, negatively modulates allosteric sites or noncompetitively blocks ion channel on the iGABAR. This leads to decreased chloride conductance, followed by depolarization of affected neurons, epilepsy-related death and ultimately decreased population. Supporting evidence for causal linkages from the molecular to population levels is presented and differential sensitivity to iGABAR antagonists in different GABA receptors and organisms discussed. Adverse outcome pathways are poised to become important tools for linking mechanism-based biomarkers to regulated outcomes in next-generation risk assessment.

  6. Multiple proximate and ultimate causes of natal dispersal in white-tailed deer

    USGS Publications Warehouse

    Long, E.S.; Diefenbach, D.R.; Rosenberry, C.S.; Wallingford, B.D.

    2008-01-01

    Proximate and ultimate causes of dispersal in vertebrates vary, and relative importance of these causes is poorly understood. Among populations, inter- and intrasexual social cues for dispersal are thought to reduce inbreeding and local mate competition, respectively, and specific emigration cue may affect dispersal distance, such that inbreeding avoidance dispersal tends to be farther than dispersal to reduce local competition. To investigate potential occurrence of multiple proximate and ultimate causes of dispersal within populations, we radio-marked 363 juvenile male white-tailed deer (Odocoileus virginianus) in 2 study areas in Pennsylvania. Natal dispersal probability and distance were monitored over a 3-year period when large-scale management changes reduced density of adult females and increased density of adult males. Most dispersal (95-97%) occurred during two 12-week periods: spring, when yearling males still closely associate with related females, and prior to fall breeding season, when yearling males closely associate with other breeding-age males. Following changes to sex and age structure that reduced potential for inbreeding and increased potential for mate competition, annual dispersal probability did not change; however, probability of spring dispersal decreased, whereas probability of fall dispersal increased. Spring dispersal distances were greater than fall dispersal distances, suggesting that adaptive inbreeding avoidance dispersal requires greater distance than mate competition dispersal where opposite-sex relatives are philopatric and populations are not patchily distributed. Both inbreeding avoidance and mate competition are important ultimate causes of dispersal of white-tailed deer, but ultimate motivations for dispersal are proximately cued by different social mechanisms and elicit different responses in dispersers.

  7. A novel approach on accelerated ageing towards reliability optimization of high concentration photovoltaic cells

    NASA Astrophysics Data System (ADS)

    Tsanakas, John A.; Jaffre, Damien; Sicre, Mathieu; Elouamari, Rachid; Vossier, Alexis; de Salins, Jean-Edouard; Bechou, Laurent; Levrier, Bruno; Perona, Arnaud; Dollet, Alain

    2014-09-01

    This paper presents a preliminary study upon a novel approach proposed for highly accelerated ageing and reliability optimization of high concentrating photovoltaic (HCPV) cells and assemblies. The intended approach aims to overcome several limitations of some current accelerated ageing tests (AAT) adopted up today, proposing the use of an alternative experimental set-up for performing faster and more realistic thermal cycles, under real sun, without the involvement of environmental chamber. The study also includes specific characterization techniques, before and after each AAT sequence, which respectively provide the initial and final diagnosis on the condition of the tested sample. The acquired data from these diagnostic/characterization methods are then used as indices to determine both quantitatively and qualitatively the severity of degradation and, thus, the ageing level for each tested HCPV assembly or cell sample. Ultimate goal of such "initial diagnosis - AAT - final diagnosis" sequences is to provide the basis for a future work on the reliability analysis of the main degradation mechanisms and confident prediction of failure propagation in HCPV cells, by means of acceleration factor (AF) and mean-time-to-failure (MTTF) estimations.

  8. Getting “Just Deserts” or Seeing the “Silver Lining”: The Relation between Judgments of Immanent and Ultimate Justice

    PubMed Central

    Harvey, Annelie J.; Callan, Mitchell J.

    2014-01-01

    People can perceive misfortunes as caused by previous bad deeds (immanent justice reasoning) or resulting in ultimate compensation (ultimate justice reasoning). Across two studies, we investigated the relation between these types of justice reasoning and identified the processes (perceptions of deservingness) that underlie them for both others (Study 1) and the self (Study 2). Study 1 demonstrated that observers engaged in more ultimate (vs. immanent) justice reasoning for a “good” victim and greater immanent (vs. ultimate) justice reasoning for a “bad” victim. In Study 2, participants' construals of their bad breaks varied as a function of their self-worth, with greater ultimate (immanent) justice reasoning for participants with higher (lower) self-esteem. Across both studies, perceived deservingness of bad breaks or perceived deservingness of ultimate compensation mediated immanent and ultimate justice reasoning respectively. PMID:25036011

  9. Transcending matter: physics and ultimate meaning.

    PubMed

    Paulson, Steve; Frank, Adam; Kaiser, David; Maudlin, Tim; Natarajan, Priyamvada

    2015-12-01

    From the discovery of new galaxies and nearly undetectable dark energy to the quantum entanglement of particles across the universe, new findings in physics naturally elicit a sense of awe and wonder. For the founders of modern physics-from Einstein and Bohr to Heisenberg, Pauli, and Bohm-a fascination with deeper questions of meaning and ultimate reality led some of them to explore esoteric traditions and metaphysics. More recently, however, physicists have largely shunned such philosophical and spiritual associations. What can contemporary physics offer us in the quest to understand our place in the universe? Has physics in some ways become a religion unto itself that rejects the search for existential meaning? Discussion of these and related questions is presented in this paper. © 2015 New York Academy of Sciences.

  10. Accelerated nursing students and theater students: creating a safe environment by acting the part.

    PubMed

    Cangelosi, Pamela R

    2008-01-01

    Traditional approaches to teaching basic nursing skills are being questioned for accelerated, or second-degree, nursing students. Since accelerated nursing students have demonstrated the ability to quickly assimilate new information and to transfer skills from a previous career into a new field, it is thought that they may benefit from teaching strategies that promote experiential learning. Through a hermeneutic phenomenological approach, this study inquired into the experiences of 22 accelerated baccalaureate nursing students to determine if narrative learning in a campus laboratory setting helped them integrate content from classroom and clinical practica and move quickly along the pathway to the competencies that are needed for safe nursing practice. Data analysis revealed the teaching/learning significance of narratives for these students and is identified in the theme, "Creating a Safe Environment".

  11. 37. ALTERNATE DESIGN, SIMILAR TO THAT ULTIMATELY SELECTED, BUT USING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    37. ALTERNATE DESIGN, SIMILAR TO THAT ULTIMATELY SELECTED, BUT USING STEPPED TOWERS, AND WITH PYLONS CAPPED BY LANTERNS Pen-and-ink drawing by project architect Alfred Eichler, ca. 1934. - Sacramento River Bridge, Spanning Sacramento River at California State Highway 275, Sacramento, Sacramento County, CA

  12. Accelerators: Sparking Innovation and Transdisciplinary Team Science in Disparities Research.

    PubMed

    Horowitz, Carol R; Shameer, Khader; Gabrilove, Janice; Atreja, Ashish; Shepard, Peggy; Goytia, Crispin N; Smith, Geoffrey W; Dudley, Joel; Manning, Rachel; Bickell, Nina A; Galvez, Maida P

    2017-02-23

    Development and implementation of effective, sustainable, and scalable interventions that advance equity could be propelled by innovative and inclusive partnerships. Readied catalytic frameworks that foster communication, collaboration, a shared vision, and transformative translational research across scientific and non-scientific divides are needed to foster rapid generation of novel solutions to address and ultimately eliminate disparities. To achieve this, we transformed and expanded a community-academic board into a translational science board with members from public, academic and private sectors. Rooted in team science, diverse board experts formed topic-specific "accelerators", tasked with collaborating to rapidly generate new ideas, questions, approaches, and projects comprising patients, advocates, clinicians, researchers, funders, public health and industry leaders. We began with four accelerators-digital health, big data, genomics and environmental health-and were rapidly able to respond to funding opportunities, transform new ideas into clinical and community programs, generate new, accessible, actionable data, and more efficiently and effectively conduct research. This innovative model has the power to maximize research quality and efficiency, improve patient care and engagement, optimize data democratization and dissemination among target populations, contribute to policy, and lead to systems changes needed to address the root causes of disparities.

  13. Real-time orthorectification by FPGA-based hardware acceleration

    NASA Astrophysics Data System (ADS)

    Kuo, David; Gordon, Don

    2010-10-01

    Orthorectification that corrects the perspective distortion of remote sensing imagery, providing accurate geolocation and ease of correlation to other images is a valuable first-step in image processing for information extraction. However, the large amount of metadata and the floating-point matrix transformations required to operate on each pixel make this a computation and I/O (Input/Output) intensive process. As result much imagery is either left unprocessed or loses timesensitive value in the long processing cycle. However, the computation on each pixel can be reduced substantially by using computational results of the neighboring pixels and accelerated by special pipelined hardware architecture in one to two orders of magnitude. A specialized coprocessor that is implemented inside an FPGA (Field Programmable Gate Array) chip and surrounded by vendorsupported hardware IP (Intellectual Property) shares the computation workload with CPU through PCI-Express interface. The ultimate speed of one pixel per clock (125 MHz) is achieved by the pipelined systolic array architecture. The optimal partition between software and hardware, the timing profile among image I/O and computation, and the highly automated GUI (Graphical User Interface) that fully exploits this speed increase to maximize overall image production throughput will also be discussed. The software that runs on a workstation with the acceleration hardware orthorectifies 16 Megapixels per second, which is 16 times faster than without the hardware. It turns the production time from months to days. A real-life successful story of an imaging satellite company that adopted such workstations for their orthorectified imagery production will be presented. The potential candidacy of the image processing computation that can be accelerated more efficiently by the same approach will also be analyzed.

  14. A cell-free framework for rapid biosynthetic pathway prototyping and enzyme discovery.

    PubMed

    Karim, Ashty S; Jewett, Michael C

    2016-07-01

    Speeding up design-build-test (DBT) cycles is a fundamental challenge facing biochemical engineering. To address this challenge, we report a new cell-free protein synthesis driven metabolic engineering (CFPS-ME) framework for rapid biosynthetic pathway prototyping. In our framework, cell-free cocktails for synthesizing target small molecules are assembled in a mix-and-match fashion from crude cell lysates either containing selectively enriched pathway enzymes from heterologous overexpression or directly producing pathway enzymes in lysates by CFPS. As a model, we apply our approach to n-butanol biosynthesis showing that Escherichia coli lysates support a highly active 17-step CoA-dependent n-butanol pathway in vitro. The elevated degree of flexibility in the cell-free environment allows us to manipulate physiochemical conditions, access enzymatic nodes, discover new enzymes, and prototype enzyme sets with linear DNA templates to study pathway performance. We anticipate that CFPS-ME will facilitate efforts to define, manipulate, and understand metabolic pathways for accelerated DBT cycles without the need to reengineer organisms. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  15. How Does the ASAP Model Align with Guided Pathways Implementation in Community Colleges?

    ERIC Educational Resources Information Center

    MDRC, 2016

    2016-01-01

    Community colleges that are exploring ways to dramatically improve outcomes for their students frequently seek a better understanding of the relationship between two "branded" approaches receiving significant publicity: Accelerated Study in Associate Programs (ASAP) and guided pathways. ASAP was created by the City University of New York…

  16. Integrated care pathways for airway diseases (AIRWAYS-ICPs).

    PubMed

    Bousquet, J; Addis, A; Adcock, I; Agache, I; Agusti, A; Alonso, A; Annesi-Maesano, I; Anto, J M; Bachert, C; Baena-Cagnani, C E; Bai, C; Baigenzhin, A; Barbara, C; Barnes, P J; Bateman, E D; Beck, L; Bedbrook, A; Bel, E H; Benezet, O; Bennoor, K S; Benson, M; Bernabeu-Wittel, M; Bewick, M; Bindslev-Jensen, C; Blain, H; Blasi, F; Bonini, M; Bonini, S; Boulet, L P; Bourdin, A; Bourret, R; Bousquet, P J; Brightling, C E; Briggs, A; Brozek, J; Buhl, R; Bush, A; Caimmi, D; Calderon, M; Calverley, P; Camargos, P A; Camuzat, T; Canonica, G W; Carlsen, K H; Casale, T B; Cazzola, M; Cepeda Sarabia, A M; Cesario, A; Chen, Y Z; Chkhartishvili, E; Chavannes, N H; Chiron, R; Chuchalin, A; Chung, K F; Cox, L; Crooks, G; Crooks, M G; Cruz, A A; Custovic, A; Dahl, R; Dahlen, S E; De Blay, F; Dedeu, T; Deleanu, D; Demoly, P; Devillier, P; Didier, A; Dinh-Xuan, A T; Djukanovic, R; Dokic, D; Douagui, H; Dubakiene, R; Eglin, S; Elliot, F; Emuzyte, R; Fabbri, L; Fink Wagner, A; Fletcher, M; Fokkens, W J; Fonseca, J; Franco, A; Frith, P; Furber, A; Gaga, M; Garcés, J; Garcia-Aymerich, J; Gamkrelidze, A; Gonzales-Diaz, S; Gouzi, F; Guzmán, M A; Haahtela, T; Harrison, D; Hayot, M; Heaney, L G; Heinrich, J; Hellings, P W; Hooper, J; Humbert, M; Hyland, M; Iaccarino, G; Jakovenko, D; Jardim, J R; Jeandel, C; Jenkins, C; Johnston, S L; Jonquet, O; Joos, G; Jung, K S; Kalayci, O; Karunanithi, S; Keil, T; Khaltaev, N; Kolek, V; Kowalski, M L; Kull, I; Kuna, P; Kvedariene, V; Le, L T; Lodrup Carlsen, K C; Louis, R; MacNee, W; Mair, A; Majer, I; Manning, P; de Manuel Keenoy, E; Masjedi, M R; Melen, E; Melo-Gomes, E; Menzies-Gow, A; Mercier, G; Mercier, J; Michel, J P; Miculinic, N; Mihaltan, F; Milenkovic, B; Molimard, M; Momas, I; Montilla-Santana, A; Morais-Almeida, M; Morgan, M; N'Diaye, M; Nafti, S; Nekam, K; Neou, A; Nicod, L; O'Hehir, R; Ohta, K; Paggiaro, P; Palkonen, S; Palmer, S; Papadopoulos, N G; Papi, A; Passalacqua, G; Pavord, I; Pigearias, B; Plavec, D; Postma, D S; Price, D; Rabe, K F; Radier Pontal, F; Redon, J; Rennard, S; Roberts, J; Robine, J M; Roca, J; Roche, N; Rodenas, F; Roggeri, A; Rolland, C; Rosado-Pinto, J; Ryan, D; Samolinski, B; Sanchez-Borges, M; Schünemann, H J; Sheikh, A; Shields, M; Siafakas, N; Sibille, Y; Similowski, T; Small, I; Sola-Morales, O; Sooronbaev, T; Stelmach, R; Sterk, P J; Stiris, T; Sud, P; Tellier, V; To, T; Todo-Bom, A; Triggiani, M; Valenta, R; Valero, A L; Valiulis, A; Valovirta, E; Van Ganse, E; Vandenplas, O; Vasankari, T; Vestbo, J; Vezzani, G; Viegi, G; Visier, L; Vogelmeier, C; Vontetsianos, T; Wagstaff, R; Wahn, U; Wallaert, B; Whalley, B; Wickman, M; Williams, D M; Wilson, N; Yawn, B P; Yiallouros, P K; Yorgancioglu, A; Yusuf, O M; Zar, H J; Zhong, N; Zidarn, M; Zuberbier, T

    2014-08-01

    The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

  17. How Stuttering Develops: The Multifactorial Dynamic Pathways Theory.

    PubMed

    Smith, Anne; Weber, Christine

    2017-09-18

    We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. We review evidence related to how stuttering develops, including genetic/epigenetic factors; motor, linguistic, and emotional features; and advances in neuroimaging studies. We update evidence for our earlier claim: Although stuttering ultimately reflects impairment in speech sensorimotor processes, its course over the life span is strongly conditioned by linguistic and emotional factors. Our current account places primary emphasis on the dynamic developmental context in which stuttering emerges and follows its course during the preschool years. Rapid changes in many neurobehavioral systems are ongoing, and critical interactions among these systems likely play a major role in determining persistence of or recovery from stuttering. Stuttering, or childhood onset fluency disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; American Psychiatric Association [APA], 2013), is a neurodevelopmental disorder that begins when neural networks supporting speech, language, and emotional functions are rapidly developing. The multifactorial dynamic pathways theory motivates experimental and clinical work to determine the specific factors that contribute to each child's pathway to the diagnosis of stuttering and those most likely to promote recovery.

  18. The kynurenine pathway in schizophrenia and bipolar disorder.

    PubMed

    Erhardt, Sophie; Schwieler, Lilly; Imbeault, Sophie; Engberg, Göran

    2017-01-01

    The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1β that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. Copyright

  19. Covariant Uniform Acceleration

    NASA Astrophysics Data System (ADS)

    Friedman, Yaakov; Scarr, Tzvi

    2013-04-01

    We derive a 4D covariant Relativistic Dynamics Equation. This equation canonically extends the 3D relativistic dynamics equation , where F is the 3D force and p = m0γv is the 3D relativistic momentum. The standard 4D equation is only partially covariant. To achieve full Lorentz covariance, we replace the four-force F by a rank 2 antisymmetric tensor acting on the four-velocity. By taking this tensor to be constant, we obtain a covariant definition of uniformly accelerated motion. This solves a problem of Einstein and Planck. We compute explicit solutions for uniformly accelerated motion. The solutions are divided into four Lorentz-invariant types: null, linear, rotational, and general. For null acceleration, the worldline is cubic in the time. Linear acceleration covariantly extends 1D hyperbolic motion, while rotational acceleration covariantly extends pure rotational motion. We use Generalized Fermi-Walker transport to construct a uniformly accelerated family of inertial frames which are instantaneously comoving to a uniformly accelerated observer. We explain the connection between our approach and that of Mashhoon. We show that our solutions of uniformly accelerated motion have constant acceleration in the comoving frame. Assuming the Weak Hypothesis of Locality, we obtain local spacetime transformations from a uniformly accelerated frame K' to an inertial frame K. The spacetime transformations between two uniformly accelerated frames with the same acceleration are Lorentz. We compute the metric at an arbitrary point of a uniformly accelerated frame. We obtain velocity and acceleration transformations from a uniformly accelerated system K' to an inertial frame K. We introduce the 4D velocity, an adaptation of Horwitz and Piron s notion of "off-shell." We derive the general formula for the time dilation between accelerated clocks. We obtain a formula for the angular velocity of a uniformly accelerated object. Every rest point of K' is uniformly accelerated, and

  20. Mitochondrial pathways governing stress resistance, life, and death in the fungal aging model Podospora anserina.

    PubMed

    Osiewacz, Heinz D; Brust, Diana; Hamann, Andrea; Kunstmann, Birgit; Luce, Karin; Müller-Ohldach, Mathis; Scheckhuber, Christian Q; Servos, Jörg; Strobel, Ingmar

    2010-06-01

    Work from more than 50 years of research has unraveled a number of molecular pathways that are involved in controlling aging of the fungal model system Podospora anserina. Early research revealed that wild-type strain aging is linked to gross reorganization of the mitochondrial DNA. Later it was shown that aging of P. anserina does also take place, although at a slower pace, when the wild-type specific mitochondrial DNA rearrangements do not occur. Now it is clear that a network of different pathways is involved in the control of aging. Branches of these pathways appear to be connected and constitute a hierarchical system of responses. Although cross talk between the individual pathways seems to be fundamental in the coordination of the overall system, the precise underlying interactions remain to be unraveled. Such a systematic approach aims at a holistic understanding of the process of biological aging, the ultimate goal of modern systems biology.

  1. HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation.

    PubMed

    Yang, Rui; Wu, Yanan; Wang, Mei; Sun, Zhongfeng; Zou, Jiahua; Zhang, Yundong; Cui, Hongjuan

    2015-04-10

    Histone deacetylase 9 (HDAC9), a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions. We found that HDAC9 is over-expressed in prognostically poor glioblastoma patients. Knockdown HDAC9 decreased proliferation in vitro and tumor formation in vivo. HDAC9 accelerated cell cycle in part by potentiating the EGFR signaling pathway. Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway. Knockdown of HDAC9 decreased the expression of TAZ. We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo. We demonstrated that HDAC9 promotes tumor formation of glioblastoma via TAZ-mediated EGFR pathway activation, and provide the evidence for promising target for the treatment of glioblastoma.

  2. Ultimate explanations and suboptimal choice.

    PubMed

    Vasconcelos, Marco; Machado, Armando; Pandeirada, Josefa N S

    2018-07-01

    Researchers have unraveled multiple cases in which behavior deviates from rationality principles. We propose that such deviations are valuable tools to understand the adaptive significance of the underpinning mechanisms. To illustrate, we discuss in detail an experimental protocol in which animals systematically incur substantial foraging losses by preferring a lean but informative option over a rich but non-informative one. To understand how adaptive mechanisms may fail to maximize food intake, we review a model inspired by optimal foraging principles that reconciles sub-optimal choice with the view that current behavioral mechanisms were pruned by the optimizing action of natural selection. To move beyond retrospective speculation, we then review critical tests of the model, regarding both its assumptions and its (sometimes counterintuitive) predictions, all of which have been upheld. The overall contention is that (a) known mechanisms can be used to develop better ultimate accounts and that (b) to understand why mechanisms that generate suboptimal behavior evolved, we need to consider their adaptive value in the animal's characteristic ecology. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Analyzing radial acceleration with a smartphone acceleration sensor

    NASA Astrophysics Data System (ADS)

    Vogt, Patrik; Kuhn, Jochen

    2013-03-01

    This paper continues the sequence of experiments using the acceleration sensor of smartphones (for description of the function and the use of the acceleration sensor, see Ref. 1) within this column, in this case for analyzing the radial acceleration.

  4. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response

    PubMed Central

    Osorio, Fernando G.; Bárcena, Clea; Soria-Valles, Clara; Ramsay, Andrew J.; de Carlos, Félix; Cobo, Juan; Fueyo, Antonio; Freije, José M.P.; López-Otín, Carlos

    2012-01-01

    Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24−/− and LmnaG609G/G609G mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging. PMID:23019125

  5. Enhanced recovery pathways in pancreatic surgery: State of the art

    PubMed Central

    Pecorelli, Nicolò; Nobile, Sara; Partelli, Stefano; Cardinali, Luca; Crippa, Stefano; Balzano, Gianpaolo; Beretta, Luigi; Falconi, Massimo

    2016-01-01

    Pancreatic surgery is being offered to an increasing number of patients every year. Although postoperative outcomes have significantly improved in the last decades, even in high-volume centers patients still experience significant postoperative morbidity and full recovery after surgery takes longer than we think. In recent years, enhanced recovery pathways incorporating a large number of evidence-based perioperative interventions have proved to be beneficial in terms of improved postoperative outcomes, and accelerated patient recovery in the context of gastrointestinal, genitourinary and orthopedic surgery. The role of these pathways for pancreatic surgery is still unclear as high-quality randomized controlled trials are lacking. To date, non-randomized studies have shown that care pathways for pancreaticoduodenectomy and distal pancreatectomy are safe with no difference in postoperative morbidity, leading to early discharge and no increase in hospital readmissions. Hospital costs are reduced due to better organization of care and resource utilization. However, further research is needed to clarify the effect of enhanced recovery pathways on patient recovery and post-discharge outcomes following pancreatic resection. Future studies should be prospective and follow recent recommendations for the design and reporting of enhanced recovery pathways. PMID:27605881

  6. Community Petascale Project for Accelerator Science and Simulation: Advancing Computational Science for Future Accelerators and Accelerator Technologies

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spentzouris, P.; /Fermilab; Cary, J.

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessarymore » accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors. ComPASS is in the first year of executing its plan to develop the next-generation HPC accelerator modeling tools. ComPASS aims to develop an integrated simulation environment that will utilize existing and new accelerator physics modules with petascale capabilities, by employing modern computing and solver technologies. The ComPASS vision is to deliver to accelerator scientists a virtual accelerator and virtual prototyping modeling environment, with the necessary multiphysics, multiscale capabilities. The plan for this development includes delivering accelerator modeling applications appropriate for each stage of the ComPASS software evolution. Such applications are already being used to address challenging problems in accelerator design and optimization. The Com

  7. Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. III. Responses after labyrinthectomy

    NASA Technical Reports Server (NTRS)

    Lasker, D. M.; Hullar, T. E.; Minor, L. B.; Shelhamer, M. J. (Principal Investigator)

    2000-01-01

    The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in four squirrel monkeys after unilateral labyrinthectomy. Spontaneous nystagmus was measured at the beginning and end of each testing session. During the period that animals were kept in darkness (4 days), the nystagmus at each of these times measured approximately 20 degrees /s. Within 18-24 h after return to the light, the nystagmus (measured in darkness) decreased to 2.8 +/- 1.5 degrees /s (mean +/- SD) when recorded at the beginning but was 20.3 +/- 3.9 degrees /s at the end of the testing session. The latency of the VOR measured from responses to steps of acceleration (3,000 degrees /s(2) reaching a velocity of 150 degrees /s) was 8.4 +/- 0.3 ms for responses to ipsilesional rotations and 7.7 +/- 0.4 ms for contralesional rotations. During the period that animals were kept in darkness after the labyrinthectomy, the gain of the VOR measured during the steps of acceleration was 0.67 +/- 0.12 for contralesional rotations and 0.39 +/- 0.04 for ipsilesional rotations. Within 18-24 h after return to light, the VOR gain for contralesional rotations increased to 0.87 +/- 0.08, whereas there was only a slight increase for ipsilesional rotations to 0.41 +/- 0. 06. A symmetrical increase in the gain measured at the plateau of head velocity was noted after the animals were returned to light. The VOR evoked by sinusoidal rotations of 2-15 Hz, +/-20 degrees /s, showed a better recovery of gain at lower (2-4 Hz) than at higher (6-15 Hz) frequencies. At 0.5 Hz, gain decreased symmetrically when the peak amplitude was increased from 20 to 100 degrees /s. At 10 Hz, gain was decreased for ipsilesional half-cycles and increased for contralesional half-cycles when velocity was raised from 20 to 50 degrees /s. A model incorporating linear and nonlinear pathways was used to simulate the data. Selective increases in the gain for the linear pathway accounted for the

  8. Genetic moderation of multiple pathways linking early cumulative socioeconomic adversity and young adults' cardiometabolic disease risk.

    PubMed

    Wickrama, Kandauda A S; Lee, Tae Kyoung; O'Neal, Catherine Walker

    2018-02-01

    Recent research suggests that psychosocial resources and life stressors are mediating pathways explaining socioeconomic variation in young adults' health risks. However, less research has examined both these pathways simultaneously and their genetic moderation. A nationally representative sample of 11,030 respondents with prospective data collected over 13 years from the National Study of Adolescent to Adult Health was examined. First, the association between early cumulative socioeconomic adversity and young adults' (ages 25-34) cardiometabolic disease risk, as measured by 10 biomarkers, through psychosocial resources (educational attainment) and life stressors (accelerated transition to adulthood) was examined. Second, moderation of these pathways by the serotonin transporter linked polymorphic region gene (5-HTTLPR) was examined. There was evidence for the association between early socioeconomic adversity and young adults' cardiometabolic disease risk directly and indirectly through educational attainment and accelerated transitions. These direct and mediating pathways were amplified by the 5-HTTLPR polymorphism. These findings elucidate how early adversity can have an enduring influence on young adults' cardiometabolic disease risk directly and indirectly through psychosocial resources and life stressors and their genetic moderation. This information suggests that effective intervention and prevention programs should focus on early adversity, youth educational attainment, and their transition to young adulthood.

  9. Ion acceleration and heating by kinetic Alfvén waves associated with magnetic reconnection

    NASA Astrophysics Data System (ADS)

    Liang, Ji; Lin, Yu; Johnson, Jay R.; Wang, Zheng-Xiong; Wang, Xueyi

    2017-10-01

    Our previous study on the generation and signatures of kinetic Alfvén waves (KAWs) associated with magnetic reconnection in a current sheet revealed that KAWs are a common feature during reconnection [Liang et al. J. Geophys. Res.: Space Phys. 121, 6526 (2016)]. In this paper, ion acceleration and heating by the KAWs generated during magnetic reconnection are investigated with a three-dimensional (3-D) hybrid model. It is found that in the outflow region, a fraction of inflow ions are accelerated by the KAWs generated in the leading bulge region of reconnection, and their parallel velocities gradually increase up to slightly super-Alfvénic. As a result of wave-particle interactions, an accelerated ion beam forms in the direction of the anti-parallel magnetic field, in addition to the core ion population, leading to the development of non-Maxwellian velocity distributions, which include a trapped population with parallel velocities consistent with the wave speed. The ions are heated in both parallel and perpendicular directions. In the parallel direction, the heating results from nonlinear Landau resonance of trapped ions. In the perpendicular direction, however, evidence of stochastic heating by the KAWs is found during the acceleration stage, with an increase of magnetic moment μ. The coherence in the perpendicular ion temperature T⊥ and the perpendicular electric and magnetic fields of KAWs also provides evidence for perpendicular heating by KAWs. The parallel and perpendicular heating of the accelerated beam occur simultaneously, leading to the development of temperature anisotropy with T⊥>T∥ . The heating rate agrees with the damping rate of the KAWs, and the heating is dominated by the accelerated ion beam. In the later stage, with the increase of the fraction of the accelerated ions, interaction between the accelerated beam and the core population also contributes to the ion heating, ultimately leading to overlap of the beams and an overall

  10. Ion acceleration and heating by kinetic Alfvén waves associated with magnetic reconnection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liang, Ji; Lin, Yu; Johnson, Jay R.

    In a previous study on the generation and signatures of kinetic Alfv en waves (KAWs) associated with magnetic reconnection in a current sheet revealed that KAWs are a common feature during reconnection [Liang et al. J. Geophys. Res.: Space Phys. 121, 6526 (2016)]. In this paper, ion acceleration and heating by the KAWs generated during magnetic reconnection are investigated with a three-dimensional (3-D) hybrid model. It is found that in the outflow region, a fraction of inflow ions are accelerated by the KAWs generated in the leading bulge region of reconnection, and their parallel velocities gradually increase up to slightly super-Alfv enic. As a result of waveparticle interactions, an accelerated ion beam forms in the direction of the anti-parallel magnetic field, in addition to the core ion population, leading to the development of non-Maxwellian velocity distributions, which include a trapped population with parallel velocities consistent with the wave speed. We then heat ions in both parallel and perpendicular directions. In the parallel direction, the heating results from nonlinear Landau resonance of trapped ions. In the perpendicular direction, however, evidence of stochastic heating by the KAWs is found during the acceleration stage, with an increase of magnetic moment μ. The coherence in the T more » $$\\perp$$ ion temperature and the perpendicular electric and magnetic fields of KAWs also provides evidence for perpendicular heating by KAWs. The parallel and perpendicular heating of the accelerated beam occur simultaneously, leading to the development of temperature anisotropy with the perpendicular temperature T $$\\perp$$>T $$\\parallel$$ temperature. The heating rate agrees with the damping rate of the KAWs, and the heating is dominated by the accelerated ion beam. In the later stage, with the increase of the fraction of the accelerated ions, interaction between the accelerated beam and the core population also contributes to the ion heating

  11. Ion acceleration and heating by kinetic Alfvén waves associated with magnetic reconnection

    DOE PAGES

    Liang, Ji; Lin, Yu; Johnson, Jay R.; ...

    2017-09-19

    In a previous study on the generation and signatures of kinetic Alfv en waves (KAWs) associated with magnetic reconnection in a current sheet revealed that KAWs are a common feature during reconnection [Liang et al. J. Geophys. Res.: Space Phys. 121, 6526 (2016)]. In this paper, ion acceleration and heating by the KAWs generated during magnetic reconnection are investigated with a three-dimensional (3-D) hybrid model. It is found that in the outflow region, a fraction of inflow ions are accelerated by the KAWs generated in the leading bulge region of reconnection, and their parallel velocities gradually increase up to slightly super-Alfv enic. As a result of waveparticle interactions, an accelerated ion beam forms in the direction of the anti-parallel magnetic field, in addition to the core ion population, leading to the development of non-Maxwellian velocity distributions, which include a trapped population with parallel velocities consistent with the wave speed. We then heat ions in both parallel and perpendicular directions. In the parallel direction, the heating results from nonlinear Landau resonance of trapped ions. In the perpendicular direction, however, evidence of stochastic heating by the KAWs is found during the acceleration stage, with an increase of magnetic moment μ. The coherence in the T more » $$\\perp$$ ion temperature and the perpendicular electric and magnetic fields of KAWs also provides evidence for perpendicular heating by KAWs. The parallel and perpendicular heating of the accelerated beam occur simultaneously, leading to the development of temperature anisotropy with the perpendicular temperature T $$\\perp$$>T $$\\parallel$$ temperature. The heating rate agrees with the damping rate of the KAWs, and the heating is dominated by the accelerated ion beam. In the later stage, with the increase of the fraction of the accelerated ions, interaction between the accelerated beam and the core population also contributes to the ion heating

  12. Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. IV. Responses after spectacle-induced adaptation

    NASA Technical Reports Server (NTRS)

    Clendaniel, R. A.; Lasker, D. M.; Minor, L. B.; Shelhamer, M. J. (Principal Investigator)

    2001-01-01

    of the VOR containing linear and nonlinear pathways that describe the normal behavior and adaptive processes. Adaptation for the linear pathway is described by a transfer function that shows the dependence of adaptation on the frequency of the head movement. The adaptive process for the nonlinear pathway is a gain enhancement element that provides for the accentuated gain with rising head velocity and the increased cubic component of the responses to steps of acceleration. While this model is substantially different from earlier models of VOR adaptation, it accounts for the data in the present experiments and also predicts the findings observed in the earlier studies.

  13. Accelerators, Beams And Physical Review Special Topics - Accelerators And Beams

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Siemann, R.H.; /SLAC

    Accelerator science and technology have evolved as accelerators became larger and important to a broad range of science. Physical Review Special Topics - Accelerators and Beams was established to serve the accelerator community as a timely, widely circulated, international journal covering the full breadth of accelerators and beams. The history of the journal and the innovations associated with it are reviewed.

  14. Commnity Petascale Project for Accelerator Science And Simulation: Advancing Computational Science for Future Accelerators And Accelerator Technologies

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spentzouris, Panagiotis; /Fermilab; Cary, John

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessarymore » accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.« less

  15. The Hippo Pathway Regulates Homeostatic Growth of Stem Cell Niche Precursors in the Drosophila Ovary

    PubMed Central

    Sarikaya, Didem P.; Extavour, Cassandra G.

    2015-01-01

    The Hippo pathway regulates organ size, stem cell proliferation and tumorigenesis in adult organs. Whether the Hippo pathway influences establishment of stem cell niche size to accommodate changes in organ size, however, has received little attention. Here, we ask whether Hippo signaling influences the number of stem cell niches that are established during development of the Drosophila larval ovary, and whether it interacts with the same or different effector signaling pathways in different cell types. We demonstrate that canonical Hippo signaling regulates autonomous proliferation of the soma, while a novel hippo-independent activity of Yorkie regulates autonomous proliferation of the germ line. Moreover, we demonstrate that Hippo signaling mediates non-autonomous proliferation signals between germ cells and somatic cells, and contributes to maintaining the correct proportion of these niche precursors. Finally, we show that the Hippo pathway interacts with different growth pathways in distinct somatic cell types, and interacts with EGFR and JAK/STAT pathways to regulate non-autonomous proliferation of germ cells. We thus provide evidence for novel roles of the Hippo pathway in establishing the precise balance of soma and germ line, the appropriate number of stem cell niches, and ultimately regulating adult female reproductive capacity. PMID:25643260

  16. SIN accelerator, operational experience and improvement programs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Joho, W.; Olivo, M.; Stammbach, T.

    1977-06-01

    The SIN meson facility, in operation since 1974, consists of a 590 MeV ring cyclotron for protons and a 72 MeV injector cyclotron. The average beam current on target is presently about 50 ..mu..A, the peak being 112 ..mu..A. Extraction efficiency, once considered a severe handicap for cyclotrons, is now 99.6 to 99.9% for the ring cyclotron and about 90% for the injector. Many improvements in both accelerators allow single turn extraction in the ring cyclotron. The present current limit is given by the injector, while the ring itself could accept now a 600 ..mu..A beam, with 2 to 4more » mA as an ultimate limit. Some muon experiments require a pulsed beam with on-off times in the order of the lifetime of the muon. First trials with beam pulse frequencies of 200 and 400 kHz and a 50% duty cycle have been successful.« less

  17. Early Induction of NRF2 Antioxidant Pathway by RHBDF2 Mediates Rapid Cutaneous Wound Healing

    PubMed Central

    Hosur, Vishnu; Burzenski, Lisa M.; Stearns, Timothy M.; Farley, Michelle L.; Sundberg, John P.; Wiles, Michael V.; Shultz, Leonard D.

    2017-01-01

    Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2cub/cub) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2cub/cub mice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2cub/cub and Rhbdf2+/+ mice at 0h, 15 min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15 min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2cub/cub mice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds. PMID:28268192

  18. Early induction of NRF2 antioxidant pathway by RHBDF2 mediates rapid cutaneous wound healing.

    PubMed

    Hosur, Vishnu; Burzenski, Lisa M; Stearns, Timothy M; Farley, Michelle L; Sundberg, John P; Wiles, Michael V; Shultz, Leonard D

    2017-04-01

    Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2 cub/cub ) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2 cub/cub mice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2 cub/cub and Rhbdf2 +/+ mice at 0h, 15min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2 cub/cub mice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Adjudicating pathological criminal incapacity within a climate of ultimate issue barriers: a comparative perspective.

    PubMed

    Stevens, Geert Philip

    2015-01-01

    Mental health experts are increasingly being utilised by the criminal justice system to provide assistance to courts during the assessment of issues falling beyond the knowledge and/or experience of the courts. A particular domain where the assistance of qualified psychiatrists and psychologists is becoming essential is where the defence of pathological criminal incapacity falls to be assessed. Mental health professionals testifying during trials where the defence of pathological criminal incapacity is raised will present opinion evidence which is one of the exceptions to the rule of inadmissibility of opinion evidence. Mental health professionals providing their opinion evidence are, however, prohibited from expressing opinions on so-called "ultimate issues" upon which only the court may ultimately rule upon. The latter rule is also commonly known in practice as the "ultimate issue" rule which presents multifaceted challenges in respect of the application of the defence of pathological criminal incapacity. In this article, the author assesses the application of the ultimate issue rule with reference to the defence of pathological criminal incapacity as it operates within the South African criminal law context. A comparative analysis is also provided with reference to the rule as it operates in the United States of America and more specifically Federal Rule 704. It is concluded that the ultimate issue rule unnecessarily restricts testimony provided by mental health professionals as such placing a barrier on such evidence. As such, it is argued that the rule is superfluous as it remains within the discretion of the trier of fact to decide as to what weight to attach to such evidence. Copyright © 2015. Published by Elsevier Ltd.

  20. Necrotrophic pathogens use the salicylic acid signaling pathway to promote disease development in tomato.

    PubMed

    Rahman, Taha Abd El; Oirdi, Mohamed El; Gonzalez-Lamothe, Rocio; Bouarab, Kamal

    2012-12-01

    Plants use different immune pathways to combat pathogens. The activation of the jasmonic acid (JA)-signaling pathway is required for resistance against necrotrophic pathogens; however, to combat biotrophic pathogens, the plants activate mainly the salicylic acid (SA)-signaling pathway. SA can antagonize JA signaling and vice versa. NPR1 (noninducible pathogenesis-related 1) is considered a master regulator of SA signaling. NPR1 interacts with TGA transcription factors, ultimately leading to the activation of SA-dependent responses. SA has been shown to promote disease development caused by the necrotrophic pathogen Botrytis cinerea through NPR1, by suppressing the expression of two JA-dependent defense genes, proteinase inhibitors I and II. We show here that the transcription factor TGA1.a contributes to disease development caused by B. cinerea in tomato by suppressing the expression of proteinase inhibitors I and II. Finally, we present evidence that the SA-signaling pathway contributes to disease development caused by another necrotrophic pathogen, Alternaria solani, in tomato. Disease development promoted by SA through NPR1 requires the TGA1.a transcription factor. These data highlight how necrotrophs manipulate the SAsignaling pathway to promote their disease in tomato.

  1. The Ultimate Challenge: Prove B. F. Skinner Wrong

    PubMed Central

    Chance, Paul

    2007-01-01

    For much of his career, B. F. Skinner displayed the optimism that is often attributed to behaviorists. With time, however, he became less and less sanguine about the power of behavior science to solve the major problems facing humanity. Near the end of his life he concluded that a fair consideration of principles revealed by the scientific analysis of behavior leads to pessimism about our species. In this article I discuss the case for Skinner's pessimism and suggest that the ultimate challenge for behavior analysts today is to prove Skinner wrong. PMID:22478494

  2. Fermilab | Tevatron | Accelerator

    Science.gov Websites

    Leading accelerator technology Accelerator complex Illinois Accelerator Research Center Fermilab temperature. They were used to transfer particles from one part of the Fermilab accelerator complex to another center ring of Fermilab's accelerator complex. Before the Tevatron shut down, it had three primary

  3. Promoting Student Learning and Productive Persistence in Developmental Mathematics: Research Frameworks Informing the Carnegie Pathways

    ERIC Educational Resources Information Center

    Edwards, Ann R.; Beattie, Rachel L.

    2016-01-01

    This paper focuses on two research-based frameworks that inform the design of instruction and promote student success in accelerated, developmental mathematics pathways. These are Learning Opportunities--productive struggle on challenging and relevant tasks, deliberate practice, and explicit connections, and Productive Persistence--promoting…

  4. Clinical Pathways and the Patient Perspective in the Pursuit of Value-Based Oncology Care.

    PubMed

    Ersek, Jennifer L; Nadler, Eric; Freeman-Daily, Janet; Mazharuddin, Samir; Kim, Edward S

    2017-01-01

    The art of practicing oncology has evolved substantially in the past 5 years. As more and more diagnostic tests, biomarker-directed therapies, and immunotherapies make their way to the oncology marketplace, oncologists will find it increasingly difficult to keep up with the many therapeutic options. Additionally, the cost of cancer care seems to be increasing. Clinical pathways are a systematic way to organize and display detailed, evidence-based treatment options and assist the practitioner with best practice. When selecting which treatment regimens to include on a clinical pathway, considerations must include the efficacy and safety, as well as costs, of the therapy. Pathway treatment regimens must be continually assessed and modified to ensure that the most up-to-date, high-quality options are incorporated. Value-based models, such as the ASCO Value Framework, can assist providers in presenting economic evaluations of clinical pathway treatment options to patients, thus allowing the patient to decide the overall value of each treatment regimen. Although oncologists and pathway developers can decide which treatment regimens to include on a clinical pathway based on the efficacy of the treatment, assessment of the value of that treatment regimen ultimately lies with the patient. Patient definitions of value will be an important component to enhancing current value-based oncology care models and incorporating new, high-quality, value-based therapeutics into oncology clinical pathways.

  5. Transition to the Ultimate Regime in Two-Dimensional Rayleigh-Bénard Convection

    NASA Astrophysics Data System (ADS)

    Zhu, Xiaojue; Mathai, Varghese; Stevens, Richard J. A. M.; Verzicco, Roberto; Lohse, Detlef

    2018-04-01

    The possible transition to the so-called ultimate regime, wherein both the bulk and the boundary layers are turbulent, has been an outstanding issue in thermal convection, since the seminal work by Kraichnan [Phys. Fluids 5, 1374 (1962), 10.1063/1.1706533]. Yet, when this transition takes place and how the local flow induces it is not fully understood. Here, by performing two-dimensional simulations of Rayleigh-Bénard turbulence covering six decades in Rayleigh number Ra up to 1 014 for Prandtl number Pr =1 , for the first time in numerical simulations we find the transition to the ultimate regime, namely, at Ra*=1013 . We reveal how the emission of thermal plumes enhances the global heat transport, leading to a steeper increase of the Nusselt number than the classical Malkus scaling Nu ˜Ra1 /3 [Proc. R. Soc. A 225, 196 (1954), 10.1098/rspa.1954.0197]. Beyond the transition, the mean velocity profiles are logarithmic throughout, indicating turbulent boundary layers. In contrast, the temperature profiles are only locally logarithmic, namely, within the regions where plumes are emitted, and where the local Nusselt number has an effective scaling Nu ˜Ra0.38 , corresponding to the effective scaling in the ultimate regime.

  6. Ion Acceleration in Solar Flares

    NASA Technical Reports Server (NTRS)

    Miller, James A.; Weir, Sue B.

    1996-01-01

    Solar flares are among the most energetic and interesting phenomena in the Solar system, releasing up to 1032 ergs of energy on timescales of several tens of seconds to several tens of minutes. Much of this energy is in the form of suprathermal electrons and ions, which remain trapped at the Sun and produce a wide variety of radiations, as well as escape into interplanetary space, where they can be directly observed. The radiation from trapped particles consists in general of (1) continuum emission; (2) narrow gamma-ray nuclear deexcitation lines; and (3) high-energy neutrons observed in space or by ground-based neutron monitors. The particles that escape into space consist of both electrons and ions, which often have compositions quite different than that of the ambient solar atmosphere. Flares thus present many diagnostics of the particle acceleration mechanism(s), the identification of which is the ultimate goal of flare research. Moreover, flares in fact offer the only opportunity in astrophysics to study the simultaneous energization of both electrons and ions. Hopefully, an understanding of flares with their wealth of diagnostic data will lead to a better understanding of particle acceleration at other sites in the Universe. It is now generally accepted that flares are roughly divided into two classes: impulsive and gradual. Gradual events are large, occur high in the corona, have long-duration soft and hard X-rays and gamma rays, are electron poor, are associated with Type II radio emission and coronal mass ejections (CMEs), and produce energetic ions with coronal abundance ratios. Impulsive events are more compact, occur lower in the corona, produce short-duration radiation, and exhibit dramatic abundance enhancements in the energetic ions. Their He-3/He-4 ratio is - 1, which is a huge increase over the coronal value of about 5 x 10(exp -4), and they also posses smaller but still significant enhancements of Ne, Mg, Si, and Fe relative to He-4, C, N, and O

  7. Piezoelectric particle accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kemp, Mark A.; Jongewaard, Erik N.; Haase, Andrew A.

    2017-08-29

    A particle accelerator is provided that includes a piezoelectric accelerator element, where the piezoelectric accelerator element includes a hollow cylindrical shape, and an input transducer, where the input transducer is disposed to provide an input signal to the piezoelectric accelerator element, where the input signal induces a mechanical excitation of the piezoelectric accelerator element, where the mechanical excitation is capable of generating a piezoelectric electric field proximal to an axis of the cylindrical shape, where the piezoelectric accelerator is configured to accelerate a charged particle longitudinally along the axis of the cylindrical shape according to the piezoelectric electric field.

  8. EDITORIAL: Laser and plasma accelerators Laser and plasma accelerators

    NASA Astrophysics Data System (ADS)

    Bingham, Robert

    2009-02-01

    This special issue on laser and plasma accelerators illustrates the rapid advancement and diverse applications of laser and plasma accelerators. Plasma is an attractive medium for particle acceleration because of the high electric field it can sustain, with studies of acceleration processes remaining one of the most important areas of research in both laboratory and astrophysical plasmas. The rapid advance in laser and accelerator technology has led to the development of terawatt and petawatt laser systems with ultra-high intensities and short sub-picosecond pulses, which are used to generate wakefields in plasma. Recent successes include the demonstration by several groups in 2004 of quasi-monoenergetic electron beams by wakefields in the bubble regime with the GeV energy barrier being reached in 2006, and the energy doubling of the SLAC high-energy electron beam from 42 to 85 GeV. The electron beams generated by the laser plasma driven wakefields have good spatial quality with energies ranging from MeV to GeV. A unique feature is that they are ultra-short bunches with simulations showing that they can be as short as a few femtoseconds with low-energy spread, making these beams ideal for a variety of applications ranging from novel high-brightness radiation sources for medicine, material science and ultrafast time-resolved radiobiology or chemistry. Laser driven ion acceleration experiments have also made significant advances over the last few years with applications in laser fusion, nuclear physics and medicine. Attention is focused on the possibility of producing quasi-mono-energetic ions with energies ranging from hundreds of MeV to GeV per nucleon. New acceleration mechanisms are being studied, including ion acceleration from ultra-thin foils and direct laser acceleration. The application of wakefields or beat waves in other areas of science such as astrophysics and particle physics is beginning to take off, such as the study of cosmic accelerators considered

  9. Ultimate Success Rates on National Board Examinations: A Research Brief.

    ERIC Educational Resources Information Center

    Gross, Leon J.; Wallis, Norman E.; Present, Richard K.

    1999-01-01

    A study investigated the percentage of optometry students successfully completing the four-component National Board of Examiners in Optometry examination at graduation between 1995 to 1997. Ultimate pass rates for all four components ranged from 87.0% to 90.9%. Results are discussed in relation to the 1993 test-sequence expansion and to the number…

  10. Sunlight-driven Environmental Benign Production of Bioactive Natural Products with Focus on Diterpenoids and the Pathways Involved in their Formation.

    PubMed

    Luo, Dan; Møller, Birger Lindberg; Pateraki, Irini

    2017-12-01

    Diterpenoids are high value compounds characterized by high structural complexity. They constitute the largest class of specialized metabolites produced by plants. Diterpenoids are flexible molecules able to engage in specific binding to drug targets like receptors and transporters. In this review we provide an account on how the complex pathways for diterpenoids may be elucidated. Following plant pathway discovery, the compounds may be produced in heterologous hosts like yeasts and E. coli. Environmentally contained production in photosynthetic cells like cyanobacteria, green algae or mosses are envisioned as the ultimate future production system.

  11. An introduction to UGRS: the ultimate grading and remanufacturing system

    Treesearch

    John Moody; Charles J. Gatchell; Elizabeth S. Walker; Powsiri Klinkhachorn

    1998-01-01

    The Ultimate Grading and Remanufactming System (UGRS) is an advanced computer program for grading and remanufacturing lumber. It is an interactive program that will both grade lumber according to NHLA rules and remanufacture it for maximum value. UGRS is written to run under Microsoft Windows 3.0 or later updates and provides a sophisticated graphical user interface....

  12. Characteristics and Postsecondary Pathways of Students Who Participate in Acceleration Programs in Minnesota. REL 2017-234

    ERIC Educational Resources Information Center

    Davis, Elisabeth; Smither, Cameron; Zhu, Bo; Stephan, Jennifer

    2017-01-01

    Acceleration programs are academically challenging courses in which high school students can simultaneously earn credit toward a high school diploma and a postsecondary degree (dual credit). These programs include Advanced Placement courses, concurrent-enrollment courses, Postsecondary Enrollment Options courses (a dual-enrollment program in…

  13. Source-to-accelerator quadrupole matching section for a compact linear accelerator

    NASA Astrophysics Data System (ADS)

    Seidl, P. A.; Persaud, A.; Ghiorso, W.; Ji, Q.; Waldron, W. L.; Lal, A.; Vinayakumar, K. B.; Schenkel, T.

    2018-05-01

    Recently, we presented a new approach for a compact radio-frequency (RF) accelerator structure and demonstrated the functionality of the individual components: acceleration units and focusing elements. In this paper, we combine these units to form a working accelerator structure: a matching section between the ion source extraction grids and the RF-acceleration unit and electrostatic focusing quadrupoles between successive acceleration units. The matching section consists of six electrostatic quadrupoles (ESQs) fabricated using 3D-printing techniques. The matching section enables us to capture more beam current and to match the beam envelope to conditions for stable transport in an acceleration lattice. We present data from an integrated accelerator consisting of the source, matching section, and an ESQ doublet sandwiched between two RF-acceleration units.

  14. TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

    PubMed Central

    Cammareri, Patrizia; Vincent, David F; Hodder, Michael C; Ridgway, Rachel A; Murgia, Claudio; Nobis, Max; Campbell, Andrew D; Varga, Julia; Huels, David J; Subramani, Chithra; Prescott, Katie L H; Nixon, Colin; Hedley, Ann; Barry, Simon T; Greten, Florian R; Inman, Gareth J; Sansom, Owen J

    2017-01-01

    Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment. PMID:28622298

  15. Kinase Pathway Dependence in Primary Human Leukemias Determined by Rapid Inhibitor Screening

    PubMed Central

    Tyner, Jeffrey W.; Yang, Wayne F.; Bankhead, Armand; Fan, Guang; Fletcher, Luke B.; Bryant, Jade; Glover, Jason M.; Chang, Bill H.; Spurgeon, Stephen E.; Fleming, William H.; Kovacsovics, Tibor; Gotlib, Jason R.; Oh, Stephen T.; Deininger, Michael W.; Zwaan, C. Michel; Den Boer, Monique L.; van den Heuvel-Eibrink, Marry M.; O’Hare, Thomas; Druker, Brian J.; Loriaux, Marc M.

    2012-01-01

    Kinases are dysregulated in most cancer but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of gene targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options. PMID:23087056

  16. Ultimate biochemical oxygen demand in semi-intensively managed shrimp pond waters

    USDA-ARS?s Scientific Manuscript database

    Three independent studies were conducted to quantified ultimate biochemical oxygen demand (UBOD) and the corresponding decomposition rate constant for production pond (average 21.5 ha each) waters and effluents on six semi-intensively managed marine shrimp (Litopenaeus vannamei) farms in Honduras. S...

  17. Estimation of Ultimate Tensile Strength of dentin Using Finite Element Analysis from Endodontically Treated Tooth

    NASA Astrophysics Data System (ADS)

    Sinthaworn, S.; Puengpaiboon, U.; Warasetrattana, N.; Wanapaisarn, S.

    2018-01-01

    Endodontically treated teeth were simulated by finite element analysis in order to estimate ultimate tensile strength of dentin. Structures of the endodontically treated tooth cases are flared root canal, restored with different number of fiber posts {i.e. resin composite core without fiber post (group 1), fiber post No.3 with resin composite core (group 2) and fiber post No.3 accessory 2 fiber posts No.0 with resin composite core (group 3)}. Elastic modulus and Poisson’s ratio of materials were selected from literatures. The models were loaded by the average fracture resistances load of each groups (group 1: 361.80 N, group 2: 559.46 N, group 3: 468.48 N) at 135 degree angulation in respect to the longitudinal axis of the teeth. The stress analysis and experimental confirm that fracture zone is at dentin area. To estimate ultimate tensile strength of dentin, trial and error of ultimate tensile strength were tested to obtain factor of safety (FOS) equal to 1.00. The result reveals that ultimate tensile strength of dentin of group 1, 2, 3 are 38.89, 30.96, 37.19 MPa, respectively.

  18. Can perspective-taking reduce crime? Examining a pathway through empathic-concern and guilt-proneness.

    PubMed

    Martinez, Andres G; Stuewig, Jeffrey; Tangney, June P

    2014-12-01

    We describe and appraise a theoretical model in which individual differences in perspective-taking eventuate in crime reduction. Specifically, it is hypothesized that perspective-taking propensities influence the tendency to feel empathic-concern, thereby heightening proneness for guilt, which ultimately inhibits criminal behavior (perspective-taking → empathic-concern → guilt-proneness → crime desistance). Data from two sources were analyzed: (a) a cross-sectional college sample and (b) a longitudinal sample of jail inmates. Overall, results lend credence to this theoretical model: Perspective-taking propensities ultimately "put the brakes" on criminal behavior-via an emotional pathway of empathic-concern and then guilt-proneness. Discussion focuses on the nature of perspective-taking, its generative role for moral emotion and behavior, as well as potential applications for crime reduction. © 2014 by the Society for Personality and Social Psychology, Inc.

  19. 15 CFR Supplement No. 3 to Part 748 - BIS-711, Statement by Ultimate Consignee and Purchaser Instructions

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... this form. Block 6: Ultimate Consignee. Enter the requested information and sign the statement in ink... must be signed in ink by the Purchaser, if the Purchaser is not the same as the Ultimate Consignee...

  20. 15 CFR Supplement No. 3 to Part 748 - BIS-711, Statement by Ultimate Consignee and Purchaser Instructions

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... this form. Block 6: Ultimate Consignee. Enter the requested information and sign the statement in ink... must be signed in ink by the Purchaser, if the Purchaser is not the same as the Ultimate Consignee...

  1. 15 CFR Supplement No. 3 to Part 748 - BIS-711, Statement by Ultimate Consignee and Purchaser Instructions

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... this form. Block 6: Ultimate Consignee. Enter the requested information and sign the statement in ink... must be signed in ink by the Purchaser, if the Purchaser is not the same as the Ultimate Consignee...

  2. 15 CFR Supplement No. 3 to Part 748 - BIS-711, Statement by Ultimate Consignee and Purchaser Instructions

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... this form. Block 6: Ultimate Consignee. Enter the requested information and sign the statement in ink... must be signed in ink by the Purchaser, if the Purchaser is not the same as the Ultimate Consignee...

  3. Pathway collages: personalized multi-pathway diagrams.

    PubMed

    Paley, Suzanne; O'Maille, Paul E; Weaver, Daniel; Karp, Peter D

    2016-12-13

    Metabolic pathway diagrams are a classical way of visualizing a linked cascade of biochemical reactions. However, to understand some biochemical situations, viewing a single pathway is insufficient, whereas viewing the entire metabolic network results in information overload. How do we enable scientists to rapidly construct personalized multi-pathway diagrams that depict a desired collection of interacting pathways that emphasize particular pathway interactions? We define software for constructing personalized multi-pathway diagrams called pathway-collages using a combination of manual and automatic layouts. The user specifies a set of pathways of interest for the collage from a Pathway/Genome Database. Layouts for the individual pathways are generated by the Pathway Tools software, and are sent to a Javascript Pathway Collage application implemented using Cytoscape.js. That application allows the user to re-position pathways; define connections between pathways; change visual style parameters; and paint metabolomics, gene expression, and reaction flux data onto the collage to obtain a desired multi-pathway diagram. We demonstrate the use of pathway collages in two application areas: a metabolomics study of pathogen drug response, and an Escherichia coli metabolic model. Pathway collages enable facile construction of personalized multi-pathway diagrams.

  4. How Stuttering Develops: The Multifactorial Dynamic Pathways Theory

    PubMed Central

    Weber, Christine

    2017-01-01

    Purpose We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. Method We review evidence related to how stuttering develops, including genetic/epigenetic factors; motor, linguistic, and emotional features; and advances in neuroimaging studies. We update evidence for our earlier claim: Although stuttering ultimately reflects impairment in speech sensorimotor processes, its course over the life span is strongly conditioned by linguistic and emotional factors. Results Our current account places primary emphasis on the dynamic developmental context in which stuttering emerges and follows its course during the preschool years. Rapid changes in many neurobehavioral systems are ongoing, and critical interactions among these systems likely play a major role in determining persistence of or recovery from stuttering. Conclusion Stuttering, or childhood onset fluency disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; American Psychiatric Association [APA], 2013), is a neurodevelopmental disorder that begins when neural networks supporting speech, language, and emotional functions are rapidly developing. The multifactorial dynamic pathways theory motivates experimental and clinical work to determine the specific factors that contribute to each child's pathway to the diagnosis of stuttering and those most likely to promote recovery. PMID:28837728

  5. Crystallization Conditions at Cascade and Other Arc Volcanoes: The Role of Recharge, and Ultimate, Proximal and Immediate Causes of Eruption

    NASA Astrophysics Data System (ADS)

    Putirka, K. D.

    2016-12-01

    A number of hypotheses have been offered to explain why volcanoes erupt. These include magma mixing, mafic recharge, or partial crystallization, any of which can drive parts or all of a system to vapor saturation, and so add to a magma's buoyancy. Age dates indicate long pre-eruption storage times for felsic magmas erupted at arcs, indicating that mafic recharge magmas, which can reinvigorate such systems, is a possible eruption trigger. However, plutonic systems reveal numerous recharge events that have no obvious ties to eruption (Coint et al. 2013; Putirka et al. 2014). And crystallization conditions at some arc systems support the implicit view, that recharge might be a necessary, but not a sufficient condition for eruption. At several Cascade volcanoes, Cpx and Amp crystals record coolings of 100-300oC. The Cpx grains derive exclusively from mafic enclaves, while Amp grains derive from both host and enclave materials. These considerable coolings call for a time lag following recharge, and indicate that vapor saturation is a proximal, although not necessarily an immediate cause of eruption. But we cannot discount recharge altogether. At the Cascades and at other arcs, Cpx crystalizes throughout the middle and upper crust, mostly from the surface down to 15 km. And high Fo olivine grains provide evidence for very hot magmas that intrude the upper mantle and lower crust, and possibly the middle crust, if hydrous. Volcanic pathways thus clearly extend into the middle crust, and at times, well below the Moho. It is unclear to what extent these deep pathways are hydraulically connected to the surface, or the role of deep-seated processes in initiating or sustaining eruptions. Progress in understanding these pathways, and triggering mechanisms, requires our differentiating "ultimate", "proximal" and "immediate" causes, and determining which of various magmatic processes provide necessary or sufficient conditions for eruption.

  6. Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. II. Responses after canal plugging

    NASA Technical Reports Server (NTRS)

    Lasker, D. M.; Backous, D. D.; Lysakowski, A.; Davis, G. L.; Minor, L. B.

    1999-01-01

    The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in four squirrel monkeys after unilateral plugging of the three semicircular canals. During the period (1-4 days) that animals were kept in darkness after plugging, the gain during steps of acceleration (3, 000 degrees /s(2), peak velocity = 150 degrees /s) was 0.61 +/- 0.14 (mean +/- SD) for contralesional rotations and 0.33 +/- 0.03 for ipsilesional rotations. Within 18-24 h after animals were returned to light, the VOR gain for contralesional rotations increased to 0. 88 +/- 0.05, whereas there was only a slight increase in the gain for ipsilesional rotations to 0.37 +/- 0.07. A symmetrical increase in the gain measured at the plateau of head velocity was noted after animals were returned to light. The latency of the VOR was 8.2 +/- 0. 4 ms for ipsilesional and 7.1 +/- 0.3 ms for contralesional rotations. The VOR evoked by sinusoidal rotations of 0.5-15 Hz, +/-20 degrees /s had no significant half-cycle asymmetries. The recovery of gain for these responses after plugging was greater at lower than at higher frequencies. Responses to rotations at higher velocities for frequencies >/=4 Hz showed an increase in contralesional half-cycle gain, whereas ipsilesional half-cycle gain was unchanged. A residual response that appeared to be canal and not otolith mediated was noted after plugging of all six semicircular canals. This response increased with frequency to reach a gain of 0.23 +/- 0.03 at 15 Hz, resembling that predicted based on a reduction of the dominant time constant of the canal to 32 ms after plugging. A model incorporating linear and nonlinear pathways was used to simulate the data. The coefficients of this model were determined from data in animals with intact vestibular function. Selective increases in the gain for the linear and nonlinear pathways predicted the changes in recovery observed after canal plugging. An increase in gain of

  7. Accelerated aging, natural aging, and small punch testing of gamma-air sterilized polycarbonate urethane acetabular components.

    PubMed

    Kurtz, S M; Siskey, R; Reitman, M

    2010-05-01

    The objectives of this study were three-fold: (1) to determine the applicability of the small punch test to characterize Bionate 80A polycarbonate urethane (PCU) acetabular implants; (2) to evaluate the susceptibility of PCU acetabular implants to exhibit degradation of mechanical behavior following gamma irradiation in air and accelerated aging; and (3) to compare the oxidation of gamma-air sterilized PCU following accelerated aging and 5 years of natural shelf aging. In addition to attenuated total reflectance-Fourier transform infrared spectroscopy, we also adapted a miniature specimen mechanical test, the small punch test, for the deformable PCU cups. Accelerated aging was performed using ASTM F2003, a standard test that represents a severe oxidative challenge. The results of this study suggest that the small punch test is sufficiently sensitive and reproducible to discriminate slight differences in the large-deformation mechanical behavior of Bionate 80A following accelerated aging. The gamma-air sterilized PCU had a reduction of 9% in ultimate load after aging. Five years of shelf aging had little effect on the mechanical properties of the PCU. Overall, our findings suggest that the Bionate 80A material has greater oxidative stability than ultra-high molecular weight polyethylene following gamma irradiation in air and exposure to a severe oxidative challenge. (c) 2010 Wiley Periodicals, Inc.

  8. Mammalian O-Mannosylation Pathway: Glycan Structures, Enzymes, and Protein Substrates

    PubMed Central

    2015-01-01

    The mammalian O-mannosylation pathway for protein post-translational modification is intricately involved in modulating cell–matrix interactions in the musculature and nervous system. Defects in enzymes of this biosynthetic pathway are causative for multiple forms of congenital muscular dystophy. The application of advanced genetic and biochemical technologies has resulted in remarkable progress in this field over the past few years, culminating with the publication of three landmark papers in 2013 alone. In this review, we will highlight recent progress focusing on the dramatic expansion of the set of genes known to be involved in O-mannosylation and disease processes, the concurrent acceleration of the rate of O-mannosylation pathway protein functional assignments, the tremendous increase in the number of proteins now known to be modified by O-mannosylation, and the recent progress in protein O-mannose glycan quantification and site assignment. Also, we attempt to highlight key outstanding questions raised by this abundance of new information. PMID:24786756

  9. Wall roughness induces asymptotic ultimate turbulence

    NASA Astrophysics Data System (ADS)

    Zhu, Xiaojue; Verschoof, Ruben A.; Bakhuis, Dennis; Huisman, Sander G.; Verzicco, Roberto; Sun, Chao; Lohse, Detlef

    2018-04-01

    Turbulence governs the transport of heat, mass and momentum on multiple scales. In real-world applications, wall-bounded turbulence typically involves surfaces that are rough; however, characterizing and understanding the effects of wall roughness on turbulence remains a challenge. Here, by combining extensive experiments and numerical simulations, we examine the paradigmatic Taylor-Couette system, which describes the closed flow between two independently rotating coaxial cylinders. We show how wall roughness greatly enhances the overall transport properties and the corresponding scaling exponents associated with wall-bounded turbulence. We reveal that if only one of the walls is rough, the bulk velocity is slaved to the rough side, due to the much stronger coupling to that wall by the detaching flow structures. If both walls are rough, the viscosity dependence is eliminated, giving rise to asymptotic ultimate turbulence—the upper limit of transport—the existence of which was predicted more than 50 years ago. In this limit, the scaling laws can be extrapolated to arbitrarily large Reynolds numbers.

  10. Can Accelerators Accelerate Learning?

    NASA Astrophysics Data System (ADS)

    Santos, A. C. F.; Fonseca, P.; Coelho, L. F. S.

    2009-03-01

    The 'Young Talented' education program developed by the Brazilian State Funding Agency (FAPERJ) [1] makes it possible for high-schools students from public high schools to perform activities in scientific laboratories. In the Atomic and Molecular Physics Laboratory at Federal University of Rio de Janeiro (UFRJ), the students are confronted with modern research tools like the 1.7 MV ion accelerator. Being a user-friendly machine, the accelerator is easily manageable by the students, who can perform simple hands-on activities, stimulating interest in physics, and getting the students close to modern laboratory techniques.

  11. Pathways to extinction: beyond the error threshold.

    PubMed

    Manrubia, Susanna C; Domingo, Esteban; Lázaro, Ester

    2010-06-27

    Since the introduction of the quasispecies and the error catastrophe concepts for molecular evolution by Eigen and their subsequent application to viral populations, increased mutagenesis has become a common strategy to cause the extinction of viral infectivity. Nevertheless, the high complexity of virus populations has shown that viral extinction can occur through several other pathways apart from crossing an error threshold. Increases in the mutation rate enhance the appearance of defective forms and promote the selection of mechanisms that are able to counteract the accelerated appearance of mutations. Current models of viral evolution take into account more realistic scenarios that consider compensatory and lethal mutations, a highly redundant genotype-to-phenotype map, rough fitness landscapes relating phenotype and fitness, and where phenotype is described as a set of interdependent traits. Further, viral populations cannot be understood without specifying the characteristics of the environment where they evolve and adapt. Altogether, it turns out that the pathways through which viral quasispecies go extinct are multiple and diverse.

  12. Accelerations in Flight

    NASA Technical Reports Server (NTRS)

    Doolittle, J H

    1925-01-01

    This work on accelerometry was done at McCook Field for the purpose of continuing the work done by other investigators and obtaining the accelerations which occur when a high-speed pursuit airplane is subjected to the more common maneuvers. The accelerations obtained in suddenly pulling out of a dive with well-balanced elevators are shown to be within 3 or 4 per cent of the theoretically possible accelerations. The maximum acceleration which a pilot can withstand depends upon the length of time the acceleration is continued. It is shown that he experiences no difficulty under the instantaneous accelerations as high as 7.8 G., but when under accelerations in excess of 4.5 G., continued for several seconds, he quickly loses his faculties.

  13. The psychiatrist's guide to right and wrong: Part IV: The insanity defense and the Ultimate Issue Rule.

    PubMed

    Goldstein, R L

    1989-01-01

    In the wake of Hinckley, widespread public dissatisfaction with the role of psychiatrists in insanity defense litigation prompted Congress in 1984 to amend the Federal Rules of Evidence to prohibit psychiatric testimony on the ultimate legal issue of whether or not a defendant is insane. APA's Statement on the Insanity Defense served as the ably articulated premise for this evidentiary amendment. APA argued that in going beyond their psychiatric expertise by answering ultimate issue questions as to whether defendants are legally insane, experts are likely to confuse the jury and undermine public confidence in psychiatry. APA also asserted that there was an impermissible logical leap between scientific psychiatric inquiry and moral-legal conclusions on the ultimate issue of insanity. This article reviews the origins, history, and vicissitudes of the Ultimate Issue Rule and analyzes the Statement on the Insanity Defense from both a legal and psychiatric perspective on the issue of whether psychiatrists should answer the ultimate question in insanity cases. The analysis suggests that APA's conclusions are not supported on scientific or evidentiary grounds, but may be warranted as a policy consideration to safeguard the public image of psychiatry.

  14. Prisoner Fasting as Symbolic Speech: The Ultimate Speech-Action Test.

    ERIC Educational Resources Information Center

    Sneed, Don; Stonecipher, Harry W.

    The ultimate test of the speech-action dichotomy, as it relates to symbolic speech to be considered by the courts, may be the fasting of prison inmates who use hunger strikes to protest the conditions of their confinement or to make political statements. While hunger strikes have been utilized by prisoners for years as a means of protest, it was…

  15. Novel Dedifferentiated Liposarcoma Xenograft Models Reveal PTEN Down-Regulation as a Malignant Signature and Response to PI3K Pathway Inhibition

    PubMed Central

    Smith, Kathleen B.; Tran, Linh M.; Tam, Brenna M.; Shurell, Elizabeth M.; Li, Yunfeng; Braas, Daniel; Tap, William D.; Christofk, Heather R.; Dry, Sarah M.; Eilber, Fritz C.; Wu, Hong

    2014-01-01

    Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care. PMID:23416162

  16. Collaborative development of an accelerated graduate entry nursing programme outside of traditional funding mechanisms.

    PubMed

    Whiffin, C J; Clarke, H; Brundrett, H; Baker, D; Whitehead, B

    2018-01-01

    Financial support for students entering nurse education programmes has typically been the responsibility of Governments who make a substantial contribution to tuition and/or living costs. However, where programmes are not funded by Government bodies, students must make alternative arrangements for financial support. This paper explores how a university worked with local employers to design, recruit and deliver an accelerated graduate entry nursing programme and how this philosophy of collaboration ultimately led to local health employers providing sponsorship for students. Therefore, we offer for debate the benefits of collaborative curriculum design and future considerations of attracting employer funding for graduate entry nursing programmes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Microbially-accelerated consolidation of oil sands tailings. Pathway I: changes in porewater chemistry

    PubMed Central

    Siddique, Tariq; Kuznetsov, Petr; Kuznetsova, Alsu; Arkell, Nicholas; Young, Rozlyn; Li, Carmen; Guigard, Selma; Underwood, Eleisha; Foght, Julia M.

    2014-01-01

    Dispersed clay particles in mine tailings and soft sediments remain suspended for decades, hindering consolidation and challenging effective management of these aqueous slurries. Current geotechnical engineering models of self-weight consolidation of tailings do not consider microbial contribution to sediment behavior, however, here we show that microorganisms indigenous to oil sands tailings change the porewater chemistry and accelerate consolidation of oil sands tailings. A companion paper describes the role of microbes in alteration of clay chemistry in tailings. Microbial metabolism in mature fine tailings (MFT) amended with an organic substrate (hydrolyzed canola meal) produced methane (CH4) and carbon dioxide (CO2). Dissolution of biogenic CO2 lowered the pH of amended MFT to pH 6.4 vs. unamended MFT (pH 7.7). About 12% more porewater was recovered from amended than unamended MFT during 2 months of active microbial metabolism, concomitant with consolidation of tailings. The lower pH in amended MFT dissolved carbonate minerals, thereby releasing divalent cations including calcium (Ca2+) and magnesium (Mg2+) and increasing bicarbonate (HCO−3) in porewater. The higher concentrations increased the ionic strength of the porewater, in turn reducing the thickness of the diffuse double layer (DDL) of clay particles by reducing the surface charge potential (repulsive forces) of the clay particles. The combination of these processes accelerated consolidation of oil sands tailings. In addition, ebullition of biogenic gases created transient physical channels for release of porewater. In contrast, saturating the MFT with non-biogenic CO2 had little effect on consolidation. These results have significant implications for management and reclamation of oil sands tailings ponds and broad importance in anaerobic environments such as contaminated harbors and estuaries containing soft sediments rich in clays and organics. PMID:24711805

  18. Microbially-accelerated consolidation of oil sands tailings. Pathway I: changes in porewater chemistry.

    PubMed

    Siddique, Tariq; Kuznetsov, Petr; Kuznetsova, Alsu; Arkell, Nicholas; Young, Rozlyn; Li, Carmen; Guigard, Selma; Underwood, Eleisha; Foght, Julia M

    2014-01-01

    Dispersed clay particles in mine tailings and soft sediments remain suspended for decades, hindering consolidation and challenging effective management of these aqueous slurries. Current geotechnical engineering models of self-weight consolidation of tailings do not consider microbial contribution to sediment behavior, however, here we show that microorganisms indigenous to oil sands tailings change the porewater chemistry and accelerate consolidation of oil sands tailings. A companion paper describes the role of microbes in alteration of clay chemistry in tailings. Microbial metabolism in mature fine tailings (MFT) amended with an organic substrate (hydrolyzed canola meal) produced methane (CH4) and carbon dioxide (CO2). Dissolution of biogenic CO2 lowered the pH of amended MFT to pH 6.4 vs. unamended MFT (pH 7.7). About 12% more porewater was recovered from amended than unamended MFT during 2 months of active microbial metabolism, concomitant with consolidation of tailings. The lower pH in amended MFT dissolved carbonate minerals, thereby releasing divalent cations including calcium (Ca(2+)) and magnesium (Mg(2+)) and increasing bicarbonate (HCO(-) 3) in porewater. The higher concentrations increased the ionic strength of the porewater, in turn reducing the thickness of the diffuse double layer (DDL) of clay particles by reducing the surface charge potential (repulsive forces) of the clay particles. The combination of these processes accelerated consolidation of oil sands tailings. In addition, ebullition of biogenic gases created transient physical channels for release of porewater. In contrast, saturating the MFT with non-biogenic CO2 had little effect on consolidation. These results have significant implications for management and reclamation of oil sands tailings ponds and broad importance in anaerobic environments such as contaminated harbors and estuaries containing soft sediments rich in clays and organics.

  19. Ectodysplasin A Pathway Contributes to Human and Murine Skin Repair.

    PubMed

    Garcin, Clare L; Huttner, Kenneth M; Kirby, Neil; Schneider, Pascal; Hardman, Matthew J

    2016-05-01

    The highly conserved ectodysplasin A (EDA)/EDA receptor signaling pathway is critical during development for the formation of skin appendages. Mutations in genes encoding components of the EDA pathway disrupt normal appendage development, leading to the human disorder hypohidrotic ectodermal dysplasia. Spontaneous mutations in the murine Eda (Tabby) phenocopy human X-linked hypohidrotic ectodermal dysplasia. Little is known about the role of EDA signaling in adult skin homeostasis or repair. Because wound healing largely mimics the morphogenic events that occur during development, we propose a role for EDA signaling in adult wound repair. Here we report a pronounced delay in healing in Tabby mice, demonstrating a functional role for EDA signaling in adult skin. Moreover, pharmacological activation of the EDA pathway in both Tabby and wild-type mice significantly accelerates healing, influencing multiple processes including re-epithelialization and granulation tissue matrix deposition. Finally, we show that the healing promoting effects of EDA receptor activation are conserved in human skin repair. Thus, targeted manipulation of the EDA/EDA receptor pathway has clear therapeutic potential for the future treatment of human pathological wound healing. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. LRFD software for design and actual ultimate capacity of confined rectangular columns.

    DOT National Transportation Integrated Search

    2013-04-01

    The analysis of concrete columns using unconfined concrete models is a well established practice. On the : other hand, prediction of the actual ultimate capacity of confined concrete columns requires specialized nonlinear : analysis. Modern codes and...

  1. Compact Plasma Accelerator

    NASA Technical Reports Server (NTRS)

    Foster, John E.

    2004-01-01

    A plasma accelerator has been conceived for both material-processing and spacecraft-propulsion applications. This accelerator generates and accelerates ions within a very small volume. Because of its compactness, this accelerator could be nearly ideal for primary or station-keeping propulsion for spacecraft having masses between 1 and 20 kg. Because this accelerator is designed to generate beams of ions having energies between 50 and 200 eV, it could also be used for surface modification or activation of thin films.

  2. Agriculture and nutrition in India: mapping evidence to pathways.

    PubMed

    Kadiyala, Suneetha; Harris, Jody; Headey, Derek; Yosef, Sivan; Gillespie, Stuart

    2014-12-01

    In India, progress against undernutrition has been slow. Given its importance for income generation, improving diets, care practices, and maternal health, the agriculture sector is widely regarded as playing an important role in accelerating the reduction in undernutrition. This paper comprehensively maps existing evidence along agriculture-nutrition pathways in India and assesses both the quality and coverage of the existing literature. We present a conceptual framework delineating six key pathways between agriculture and nutrition. Three pathways pertain to the nutritional impacts of farm production, farm incomes, and food prices. The other three pertain to agriculture-gender linkages. After an extensive search, we found 78 research papers that provided evidence to populate these pathways. The literature suggests that Indian agriculture has a range of important influences on nutrition. Agriculture seems to influence diets even when controlling for income, and relative food prices could partly explain observed dietary changes in recent decades. The evidence on agriculture-gender linkages to nutrition is relatively weak. Sizeable knowledge gaps remain. The root causes of these gaps include an interdisciplinary disconnect between nutrition and economics/agriculture, a related problem of inadequate survey data, and limited policy-driven experimentation. Closing these gaps is essential to strengthening the agriculture sector's contribution to reducing undernutrition. © 2014 New York Academy of Sciences.

  3. The Interstellar Mapping and Acceleration Probe - A Mission to Discover the Origin of Particle Acceleration and its Fundamental Connection to the Global Interstellar Interaction

    NASA Astrophysics Data System (ADS)

    Schwadron, N.

    2017-12-01

    Our piece of cosmic real-estate, the heliosphere, is the domain of all human existence - an astrophysical case-history of the successful evolution of life in a habitable system. The Interstellar Boundary Explorer (IBEX) was the first mission to explore the global heliosphere and in concert with Voyager 1 and Voyager 2 is discovering a fundamentally new and uncharted physical domain of the outer heliosphere. In parallel, Cassini/INCA maps the global heliosphere at energies ( 5-55 keV) above those measured by IBEX. The enigmatic IBEX ribbon and the INCA belt were unanticipated discoveries demonstrating that much of what we know or think we understand about the outer heliosphere needs to be revised. The global structure of the heliosphere is highly complex and influenced by competing factors ranging from the local interstellar magnetic field, suprathermal populations both within and beyond the heliopause, and the detailed flow properties of the LISM. Global heliospheric structure and microphysics in turn influences the acceleration of energetic particles and creates feedbacks that modify the interstellar interaction as a whole. The next quantum leap enabled by IMAP will open new windows on the frontier of Heliophysics and probe the acceleration of suprathermal and higher energy particles at a time when the space environment is rapidly evolving. IMAP ultimately connects the acceleration processes observed directly at 1 AU with unprecedented sensitivity and temporal resolution with the global structure of our heliosphere. The remarkable synergy between IMAP, Voyager 1 and Voyager 2 will remain for at least the next decade as Voyager 1 pushes further into the interstellar domain and Voyager 2 moves through the heliosheath. IMAP, like ACE before it, will be a keystone of the Heliophysics System Observatory by providing comprehensive energetic particle, pickup ion, suprathermal ion, neutral atom, solar wind, solar wind heavy ion, and magnetic field observations to diagnose

  4. Microelectromechanical acceleration-sensing apparatus

    DOEpatents

    Lee, Robb M [Albuquerque, NM; Shul, Randy J [Albuquerque, NM; Polosky, Marc A [Albuquerque, NM; Hoke, Darren A [Albuquerque, NM; Vernon, George E [Rio Rancho, NM

    2006-12-12

    An acceleration-sensing apparatus is disclosed which includes a moveable shuttle (i.e. a suspended mass) and a latch for capturing and holding the shuttle when an acceleration event is sensed above a predetermined threshold level. The acceleration-sensing apparatus provides a switch closure upon sensing the acceleration event and remains latched in place thereafter. Examples of the acceleration-sensing apparatus are provided which are responsive to an acceleration component in a single direction (i.e. a single-sided device) or to two oppositely-directed acceleration components (i.e. a dual-sided device). A two-stage acceleration-sensing apparatus is also disclosed which can sense two acceleration events separated in time. The acceleration-sensing apparatus of the present invention has applications, for example, in an automotive airbag deployment system.

  5. SHORT ACCELERATION TIMES FROM SUPERDIFFUSIVE SHOCK ACCELERATION IN THE HELIOSPHERE

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Perri, S.; Zimbardo, G., E-mail: silvia.perri@fis.unical.it

    2015-12-10

    The analysis of time profiles of particles accelerated at interplanetary shocks allows particle transport properties to be inferred. The frequently observed power-law decay upstream, indeed, implies a superdiffusive particle transport when the level of magnetic field variance does not change as the time interval from the shock front increases. In this context, a superdiffusive shock acceleration (SSA) theory has been developed, allowing us to make predictions of the acceleration times. In this work we estimate for a number of interplanetary shocks, including the solar wind termination shock, the acceleration times for energetic protons in the framework of SSA and wemore » compare the results with the acceleration times predicted by standard diffusive shock acceleration. The acceleration times due to SSA are found to be much shorter than in the classical model, and also shorter than the interplanetary shock lifetimes. This decrease of the acceleration times is due to the scale-free nature of the particle displacements in the framework of superdiffusion. Indeed, very long displacements are possible, increasing the probability for particles far from the front of the shock to return, and short displacements have a high probability of occurrence, increasing the chances for particles close to the front to cross the shock many times.« less

  6. Pathway Distiller - multisource biological pathway consolidation.

    PubMed

    Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

    2012-01-01

    One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow

  7. Rapid population growth and environmental degradation: ultimate versus proximate factors.

    PubMed

    Shaw, R P

    1989-01-01

    This philosophical review of 2 arguments about responsibility for and solutions to environmental degradation concludes that both sides are correct: the ultimate and the proximal causes. Ultimate causes of pollution are defined as the technology responsible for a given type of pollution, such as burning fossil fuel; proximate causes are defined as situation-specific factors confounding the problem, such as population density or rate of growth. Commoner and others argue that developed countries with low or negative population growth rates are responsible for 80% of world pollution, primarily in polluting technologies such as automobiles, power generation, plastics, pesticides, toxic wastes, garbage, warfaring, and nuclear weapons wastes. Distortionary policies also contribute; examples are agricultural trade protection, land mismanagement, urban bias in expenditures, and institutional rigidity., Poor nations are responsible for very little pollution because poverty allows little waste or expenditures for polluting, synthetic technologies. The proximal causes of pollution include numbers and rate of growth of populations responsible for the pollution. Since change in the ultimate cause of pollution remains out of reach, altering the numbers of polluters can make a difference. Predictions are made for proportions of the world's total waste production, assuming current 1.6 tons/capita for developed countries and 0.17 tons/capita for developing countries. If developing countries grow at current rates and become more wealthy, they will be emitting half the world's waste by 2025. ON the other hand, unsustainable population growth goes along with inadequate investment in human capital: education, health, employment, infrastructure. The solution is to improve farming technologies in the 117 non-self-sufficient countries, fund development in the most unsustainable enclaves of growing countries, break institutionalized socio-political rigidity in these enclaves, and focus on

  8. Age and Ultimate Attainment in the Pronunciation of a Foreign Language.

    ERIC Educational Resources Information Center

    Bongaerts, Theo; van Summeren, Chantal; Planken, Brigette; Schils, Erik

    1997-01-01

    Reports on two studies addressing the issue of ultimate attainment of pronunciation by late second-language learners. Findings indicate that it is not impossible to achieve an authentic, nativelike pronunciation of a second language after a specified biological time. The article argues that certain learner characteristics and learning contexts may…

  9. MABE multibeam accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hasti, D.E.; Ramirez, J.J.; Coleman, P.D.

    1985-01-01

    The Megamp Accelerator and Beam Experiment (MABE) was the technology development testbed for the multiple beam, linear induction accelerator approach for Hermes III, a new 20 MeV, 0.8 MA, 40 ns accelerator being developed at Sandia for gamma-ray simulation. Experimental studies of a high-current, single-beam accelerator (8 MeV, 80 kA), and a nine-beam injector (1.4 MeV, 25 kA/beam) have been completed, and experiments on a nine-beam linear induction accelerator are in progress. A two-beam linear induction accelerator is designed and will be built as a gamma-ray simulator to be used in parallel with Hermes III. The MABE pulsed power systemmore » and accelerator for the multiple beam experiments is described. Results from these experiments and the two-beam design are discussed. 11 refs., 6 figs.« less

  10. Probing electron acceleration and x-ray emission in laser-plasma accelerators

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Thaury, C.; Ta Phuoc, K.; Corde, S.

    2013-06-15

    While laser-plasma accelerators have demonstrated a strong potential in the acceleration of electrons up to giga-electronvolt energies, few experimental tools for studying the acceleration physics have been developed. In this paper, we demonstrate a method for probing the acceleration process. A second laser beam, propagating perpendicular to the main beam, is focused on the gas jet few nanosecond before the main beam creates the accelerating plasma wave. This second beam is intense enough to ionize the gas and form a density depletion, which will locally inhibit the acceleration. The position of the density depletion is scanned along the interaction lengthmore » to probe the electron injection and acceleration, and the betatron X-ray emission. To illustrate the potential of the method, the variation of the injection position with the plasma density is studied.« less

  11. Long noncoding RNA HULC accelerates liver cancer by inhibiting PTEN via autophagy cooperation to miR15a.

    PubMed

    Xin, Xiaoru; Wu, Mengying; Meng, Qiuyu; Wang, Chen; Lu, Yanan; Yang, Yuxin; Li, Xiaonan; Zheng, Qidi; Pu, Hu; Gui, Xin; Li, Tianming; Li, Jiao; Jia, Song; Lu, Dongdong

    2018-06-12

    Long noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear. RT-PCR, Western blotting, Chromatin immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed. HULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, β-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin-proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells. This study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis.

  12. Phosphofructokinase and mitochondria partially explain the high ultimate pH of broiler pectoralis major muscle.

    PubMed

    Matarneh, Sulaiman K; Yen, Con-Ning; Elgin, Jennifer M; Beline, Mariane; da Luz E Silva, Saulo; Wicks, Jordan C; England, Eric M; Dalloul, Rami A; Persia, Michael E; Omara, Islam I; Shi, Hao; Gerrard, David E

    2018-05-01

    During postmortem metabolism, muscle pH gradually declines to reach an ultimate pH near 5.6 across most meat species. Yet, broiler pectoralis major (P. major) muscle generates meat with high ultimate pH (pH ∼ 5.9). For better understanding of the underlying mechanism responsible for this phenomenon, we evaluated the involvement of breast muscle chilling on the extent of postmortem metabolism. Broiler breast muscles were either subjected to chilling treatment (control) or left at room temperature (RT) for 120 min. P. major muscle from the RT treatment had lower ultimate pH, greater glycogen degradation and lactate accumulation. While these findings suggest that carcass chilling can contribute to the premature termination of postmortem metabolism, chilling did not fully explain the high ultimate pH of P. major muscle. Our results also revealed that glucose-6-phosphate (G6P) was very low at 24 h, and therefore we hypothesized that G6P was limiting. To test this hypothesis, muscle samples from P. major and porcine longissimus lumborum (LL) muscle were homogenized into a reaction buffer that mimics postmortem glycolysis with or without 0.5 mg/mL isolated mitochondria. While samples containing porcine LL muscle reached the normal level of ultimate pH, P. major muscle samples reached a value similar to that observed in vivo even in the presence of excess G6P, indicating that G6P was not limiting. Mitochondria enhanced the glycolytic flux and pH decline in systems containing muscle from both species. More importantly, however, was that in vitro system containing chicken with mitochondria reached pH value similar to that of samples containing LL muscle without mitochondria. To investigate further, phosphofructokinase (PFK) activity was compared in broiler P. major and porcine LL muscle at different pH values. PFK activity was lower in P. major muscle at pH 7, 6.5, and 6.2 than LL muscle. In conclusion, carcass chilling can partially contribute to the high ultimate p

  13. METHYLATED ASIII COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC

    EPA Science Inventory

    METHYLATED Asm COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC.

    The methylation of inorganic arsenic has typically been viewed as a detoxification process. Genotoxicity tests have generally shown that arsenite has greater mutagenic p...

  14. Reaction pathways in atomistic models of thin film growth

    NASA Astrophysics Data System (ADS)

    Lloyd, Adam L.; Zhou, Ying; Yu, Miao; Scott, Chris; Smith, Roger; Kenny, Steven D.

    2017-10-01

    The atomistic processes that form the basis of thin film growth often involve complex multi-atom movements of atoms or groups of atoms on or close to the surface of a substrate. These transitions and their pathways are often difficult to predict in advance. By using an adaptive kinetic Monte Carlo (AKMC) approach, many complex mechanisms can be identified so that the growth processes can be understood and ultimately controlled. Here the AKMC technique is briefly described along with some special adaptions that can speed up the simulations when, for example, the transition barriers are small. Examples are given of such complex processes that occur in different material systems especially for the growth of metals and metallic oxides.

  15. Pathway Distiller - multisource biological pathway consolidation

    PubMed Central

    2012-01-01

    Background One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. Methods After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. Results We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/Pathway

  16. Social-emotional characteristics of gifted accelerated and non-accelerated students in the Netherlands.

    PubMed

    Hoogeveen, Lianne; van Hell, Janet G; Verhoeven, Ludo

    2012-12-01

    In the studies of acceleration conducted so far a multidimensional perspective has largely been neglected. No attempt has been made to relate social-emotional characteristics of accelerated versus non-accelerated students in perspective of environmental factors. In this study, social-emotional characteristics of accelerated gifted students in the Netherlands were examined in relation to personal and environmental factors. Self-concept and social contacts of accelerated (n = 148) and non-accelerated (n = 55) gifted students, aged 4 to 27 (M = 11.22, SD = 4.27) were measured. Self-concept and social contacts of accelerated and non-accelerated gifted students were measured using a questionnaire and a diary, and parents of these students evaluated their behavioural characteristics. Gender and birth order were studied as personal factors and grade, classroom, teachers' gender, teaching experience, and the quality of parent-school contact as environmental factors. The results showed minimal differences in the social-emotional characteristics of accelerated and non-accelerated gifted students. The few differences we found favoured the accelerated students. We also found that multiple grade skipping does not have negative effects on social-emotional characteristics, and that long-term effects of acceleration tend to be positive. As regards the possible modulation of personal and environmental factors, we merely found an impact of such factors in the non-accelerated group. The results of this study strongly suggest that social-emotional characteristics of accelerated gifted students and non-accelerated gifted students are largely similar. These results thus do not support worries expressed by teachers about the acceleration of gifted students. Our findings parallel the outcomes of earlier studies in the United States and Germany in that we observed that acceleration does not harm gifted students, not even in the case of multiple grade skipping. On the contrary, there is a

  17. Stability limits and transformation pathways of α-quartz under high pressure

    NASA Astrophysics Data System (ADS)

    Hu, Q. Y.; Shu, J.-F.; Yang, W. G.; Park, C.; Chen, M. W.; Fujita, T.; Mao, H.-K.; Sheng, H. W.

    2017-03-01

    Ubiquitous on Earth, α-quartz plays an important role in modern science and technology. However, despite extensive research in the past, the mechanism of the polymorphic transitions of α-quartz at high pressures remains poorly understood. Here, combining in situ single-crystal x-ray diffraction experiment and advanced ab initio modeling, we report two stability limits and competing transition pathways of α-quartz under high pressure. Under near-equilibrium compression conditions at room temperature, α-quartz transits to a new P 2 /c silica phase via a structural intermediate. If the thermally activated transition is kinetically suppressed, the ultimate stability of α-quartz is controlled by its phonon instability and α-quartz collapses into a different crystalline phase. Our studies reveal that pressure-induced solid-state transformation of α-quartz undergoes a succession of structural stability limits, due to thermodynamic and mechanical catastrophes, and exhibits a hierarchy of transition pathways contingent upon kinetic conditions.

  18. Modulation of the Isoprenoid/Cholesterol Biosynthetic Pathway During Neuronal Differentiation In Vitro.

    PubMed

    Cartocci, Veronica; Segatto, Marco; Di Tunno, Ilenia; Leone, Stefano; Pfrieger, Frank W; Pallottini, Valentina

    2016-09-01

    During differentiation, neurons acquire their typical shape and functional properties. At present, it is unclear, whether this important developmental step involves metabolic changes. Here, we studied the contribution of the mevalonate (MVA) pathway to neuronal differentiation using the mouse neuroblastoma cell line N1E-115 as experimental model. Our results show that during differentiation, the activity of 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR), a key enzyme of MVA pathway, and the level of Low Density Lipoprotein receptor (LDLr) decrease, whereas the level of LDLr-related protein-1 (LRP1) and the dimerization of Scavanger Receptor B1 (SRB-1) rise. Pharmacologic inhibition of HMGR by simvastatin accelerated neuronal differentiation by modulating geranylated proteins. Collectively, our data suggest that during neuronal differentiation, the activity of the MVA pathway decreases and we postulate that any interference with this process impacts neuronal morphology and function. Therefore, the MVA pathway appears as an attractive pharmacological target to modulate neurological and metabolic symptoms of developmental neuropathologies. J. Cell. Biochem. 117: 2036-2044, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Putative adverse outcome pathways relevant to neurotoxicity

    PubMed Central

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  20. HHV Predicting Correlations for Torrefied Biomass Using Proximate and Ultimate Analyses

    PubMed Central

    Nhuchhen, Daya Ram; Afzal, Muhammad T.

    2017-01-01

    Many correlations are available in the literature to predict the higher heating value (HHV) of raw biomass using the proximate and ultimate analyses. Studies on biomass torrefaction are growing tremendously, which suggest that the fuel characteristics, such as HHV, proximate analysis and ultimate analysis, have changed significantly after torrefaction. Such changes may cause high estimation errors if the existing HHV correlations were to be used in predicting the HHV of torrefied biomass. No study has been carried out so far to verify this. Therefore, this study seeks answers to the question: “Can the existing correlations be used to determine the HHV of the torrefied biomass”? To answer this, the existing HHV predicting correlations were tested using torrefied biomass data points. Estimation errors were found to be significantly high for the existing HHV correlations, and thus, they are not suitable for predicting the HHV of the torrefied biomass. New correlations were then developed using data points of torrefied biomass. The ranges of reported data for HHV, volatile matter (VM), fixed carbon (FC), ash (ASH), carbon (C), hydrogen (H) and oxygen (O) contents were 14.90 MJ/kg–33.30 MJ/kg, 13.30%–88.57%, 11.25%–82.74%, 0.08%–47.62%, 35.08%–86.28%, 0.53%–7.46% and 4.31%–44.70%, respectively. Correlations with the minimum mean absolute errors and having all components of proximate and ultimate analyses were selected for future use. The selected new correlations have a good accuracy of prediction when they are validated using another set of data (26 samples). Thus, these new and more accurate correlations can be useful in modeling different thermochemical processes, including combustion, pyrolysis and gasification processes of torrefied biomass. PMID:28952487

  1. Systematic Analysis of Long Noncoding RNAs in the Senescence-accelerated Mouse Prone 8 Brain Using RNA Sequencing.

    PubMed

    Zhang, Shuai; Qin, Chunxia; Cao, Guoqiong; Xin, Wenfeng; Feng, Chengqiang; Zhang, Wensheng

    2016-08-02

    Long noncoding RNAs (lncRNAs) may play an important role in Alzheimer's disease (AD) pathogenesis. However, despite considerable research in this area, the comprehensive and systematic understanding of lncRNAs in AD is still limited. The emergence of RNA sequencing provides a predictor and has incomparable advantage compared with other methods, including microarray. In this study, we identified lncRNAs in a 7-month-old mouse brain through deep RNA sequencing using the senescence-accelerated mouse prone 8 (SAMP8) and senescence-accelerated mouse resistant 1 (SAMR1) models. A total of 599,985,802 clean reads and 23,334 lncRNA transcripts were obtained. Then, we identified 97 significantly upregulated and 114 significantly downregulated lncRNA transcripts from all cases in SAMP8 mice relative to SAMR1 mice. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these significantly dysregulated lncRNAs were involved in regulating the development of AD from various angles, such as nerve growth factor term (GO: 1990089), mitogen-activated protein kinase signaling pathway, and AD pathway. Furthermore, the most probable AD-associated lncRNAs were predicted and listed in detail. Our study provided the systematic dissection of lncRNA profiling in SAMP8 mouse brain and accelerated the development of lncRNA biomarkers in AD. These attracting biomarkers could provide significant insights into AD therapy in the future.

  2. The ultimate quantum limits on the accuracy of measurements

    NASA Technical Reports Server (NTRS)

    Yuen, Horace P.

    1992-01-01

    A quantum generalization of rate-distortion theory from standard communication and information theory is developed for application to determining the ultimate performance limit of measurement systems in physics. For the estimation of a real or a phase parameter, it is shown that the root-mean-square error obtained in a measurement with a single-mode photon level N cannot do better than approximately N exp -1, while approximately exp(-N) may be obtained for multi-mode fields with the same photon level N. Possible ways to achieve the remarkable exponential performance are indicated.

  3. Shortened length of stay and hospital cost reduction with implementation of an accelerated clinical care pathway after elective colon resection.

    PubMed

    Stephen, Antonia E; Berger, David L

    2003-03-01

    Patient care pathways have been developed for operative procedures with documented improvements in length of stay and cost without compromising outcome. The average hospital stay after colonic resection is 5 to 10 days. This study describes a clinical pathway for colon resections and examines patient outcome before and after institution of the pathway. One hundred thirty-eight patients underwent elective colon resections at our institution by a single surgeon before (n = 52) and after (n = 86) introduction of a clinical pathway. Length of stay, postoperative complications, readmissions, and cost per patient were compared between the 2 groups. Mean total length of stay (+/- standard deviation [SD]) was less in the postclinical pathway patients (3.7 +/- 1.5 days) compared to preclinical pathway patients (6.6 +/- 3.3 days) (P <.001). When adjusted for age, sex, diagnosis, and type of operation, the difference in length of stay remains statistically significant (P <.001). There was 1 readmission in the prepathway group and 8 readmissions in the postpathway group. When the readmissions were added to the original admissions, the mean length of stay in the postpathway patients was 4.2 +/- 2.8 days and in the prepathway patients was 6.9 +/- 4.1 days (P <.001). The average cost per patient (+/- standard error of the mean), with readmission costs added, was 9310 +/- 5170 US dollars in the prepathway group and 7070 +/- 3670 US dollars in the postpathway group (P =.002). The institution of a clinical pathway for elective, open colon resections can be done safely with improvements in cost and length of stay.

  4. Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

    PubMed Central

    Fatima, Ayesha; Abdul, Ahmad Bustamam Hj.; Abdullah, Rasedee; Karjiban, Roghayeh Abedi; Lee, Vannajan Sanghiran

    2015-01-01

    Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis. PMID:25629232

  5. Integrative pathway knowledge bases as a tool for systems molecular medicine.

    PubMed

    Liang, Mingyu

    2007-08-20

    There exists a sense of urgency to begin to generate a cohesive assembly of biomedical knowledge as the pace of knowledge accumulation accelerates. The urgency is in part driven by the emergence of systems molecular medicine that emphasizes the combination of systems analysis and molecular dissection in the future of medical practice and research. A potentially powerful approach is to build integrative pathway knowledge bases that link organ systems function with molecules.

  6. Semiconductor acceleration sensor

    NASA Astrophysics Data System (ADS)

    Ueyanagi, Katsumichi; Kobayashi, Mitsuo; Goto, Tomoaki

    1996-09-01

    This paper reports a practical semiconductor acceleration sensor especially suited for automotive air bag systems. The acceleration sensor includes four beams arranged in a swastika structure. Two piezoresistors are formed on each beam. These eight piezoresistors constitute a Wheatstone bridge. The swastika structure of the sensing elements, an upper glass plate and a lower glass plate exhibit the squeeze film effect which enhances air dumping, by which the constituent silicon is prevented from breakdown. The present acceleration sensor has the following features. The acceleration force component perpendicular to the sensing direction can be cancelled. The cross-axis sensitivity is less than 3 percent. And, the erroneous offset caused by the differences between the thermal expansion coefficients of the constituent materials can be canceled. The high aspect ratio configuration realized by plasma etching facilitates reducing the dimensions and improving the sensitivity of the acceleration sensor. The present acceleration sensor is 3.9 mm by 3.9 mm in area and 1.2 mm in thickness. The present acceleration sensor can measure from -50 to +50 G with sensitivity of 0.275 mV/G and with non-linearity of less than 1 percent. The acceleration sensor withstands shock of 3000 G.

  7. Evolution of auroral acceleration region field-aligned current systems, plasma, and potentials observed by Cluster during substorms

    NASA Astrophysics Data System (ADS)

    Hull, A. J.; Chaston, C. C.; Fillingim, M. O.; Frey, H. U.; Goldstein, M. L.; Bonnell, J. W.; Mozer, F.

    2015-12-01

    The auroral acceleration region is an integral link in the chain of events that transpire during substorms, and the currents, plasma and electric fields undergo significant changes driven by complex dynamical processes deep in the magnetotail. The acceleration processes that occur therein accelerate and heat the plasma that ultimately leads to some of the most intense global substorm auroral displays. Though this region has garnered considerable attention, the temporal evolution of field-aligned current systems, associated acceleration processes, and resultant changes in the plasma constituents that occur during key stages of substorm development remain unclear. In this study we present a survey of Cluster traversals within and just above the auroral acceleration region (≤3 Re altitude) during substorms. Particular emphasis is on the spatial morphology and developmental sequence of auroral acceleration current systems, potentials and plasma constituents, with the aim of identifying controlling factors, and assessing auroral emmission consequences. Exploiting multi-point measurements from Cluster in combination with auroral imaging, we reveal the injection powered, Alfvenic nature of both the substorm onset and expansion of auroral particle acceleration. We show evidence that indicates substorm onsets are characterized by the gross-intensification and filamentation/striation of pre-existing large-scale current systems to smaller/dispersive scale Alfven waves. Such an evolutionary sequence has been suggested in theoretical models or single spacecraft data, but has not been demonstrated or characterized in multispacecraft observations until now. It is also shown how the Alfvenic variations over time may dissipate to form large-scale inverted-V structures characteristic of the quasi-static aurora. These findings suggest that, in addition to playing active roles in driving substorm aurora, inverted-V and Alfvenic acceleration processes are causally linked. Key

  8. [Accelerated recovery program after hip fracture surgery].

    PubMed

    Rasmussen, Sten; Kristensen, Billy B; Foldager, Susanne; Myhrmann, Lis; Kehlet, Henrik

    2002-12-30

    A multimodal approach to minimise the effect of the surgical stress response can reduce complications and hospital stay after abdominal surgery and hip arthroplasty. The aim of the study was to assess the results of a well-defined rehabilitation programme after hip fracture. In an open intervention study, we entered 200 consecutive patients with hip fracture allowing full weight-bearing after operative treatment. The effect of a revised, optimised perioperative care programme with continuous epidural analgesia, early oral nutrition, oxygen supplementation, restricted volume and transfusion therapy, and intensive physiotherapy and mobilisation was assessed (n = 100) and compared with the conventional perioperative treatment programme before the intervention (n = 100). The median age was 82 (56-96) years in the control group and 82 (63-101) years in the accelerated multimodal perioperative treatment group. The median hospital stay was reduced from 21 (range 1-162, mean 32) to 11 (range 1-100, mean 17) days. The total use of days in hospital was reduced from 3211 to 1667. There were fewer complications, whereas the need for home care after discharge was unchanged. An accelerated clinical pathway with focus on pain relief, oral nutrition, and rehabilitation may reduce hospital stay and improve recovery after hip fracture.

  9. 78 FR 72972 - Application of Ultimate JETCHARTERS, LLC for Commuter Air Carrier Authority

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-04

    ... all interested persons to show cause why it should not issue an order finding Ultimate JETCHARTERS, LLC, fit, willing, and able, and awarding it commuter air carrier authority to conduct scheduled...

  10. Signature energetic analysis of accelerate electron beam after first acceleration station by accelerating stand of Joint Institute for Nuclear Research

    NASA Astrophysics Data System (ADS)

    Sledneva, A. S.; Kobets, V. V.

    2017-06-01

    The linear electron accelerator based on the LINAC - 800 accelerator imported from the Netherland is created at Joint Institute for Nuclear Research in the framework of the project on creation of the Testbed with an electron beam of a linear accelerator with an energy up to 250 MV. Currently two accelerator stations with a 60 MV energy of a beam are put in operation and the work is to put the beam through accelerating section of the third accelerator station. The electron beam with an energy of 23 MeV is used for testing the crystals (BaF2, CsI (native), and LYSO) in order to explore the opportunity to use them in particle detectors in experiments: Muon g-2, Mu2e, Comet, whose preparation requires a detailed study of the detectors properties such as their irradiation by the accelerator beams.

  11. FERMILAB ACCELERATOR R&D PROGRAM TOWARDS INTENSITY FRONTIER ACCELERATORS : STATUS AND PROGRESS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shiltsev, Vladimir

    2016-11-15

    The 2014 P5 report indicated the accelerator-based neutrino and rare decay physics research as a centrepiece of the US domestic HEP program at Fermilab. Operation, upgrade and development of the accelerators for the near- term and longer-term particle physics program at the Intensity Frontier face formidable challenges. Here we discuss key elements of the accelerator physics and technology R&D program toward future multi-MW proton accelerators and present its status and progress. INTENSITY FRONTIER ACCELERATORS

  12. Theoretical evaluation of two plausible routes for bioactivation of S-(1,1-difluoro-2,2-dihaloethyl)-L-cysteine conjugates: thiirane vs thionoacyl fluoride pathway.

    PubMed

    Shim, J Y; Richard, A M

    1997-01-01

    The selective nephrotoxicity of halogenated alkenes has been attributed to a glutathione (GSH) S-conjugate pathway involving enzymatic hydrolysis to the cysteine S-conjugate and beta-lyase bioactivation to thiolates, which are presumed to give rise to the ultimate mutagenic or cytotoxic reactive species. Studies have shown that the brominated S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are mutagenic in the Ames test, whereas the nonbrominated analogues are nonmutagenic. While careful experimentation has contributed much to current understanding, the ultimate reactive species responsible for the differing mutagenic effects remain unknown. Computational methods were applied to the investigation of two proposed metabolic pathways leading from the thiolate to either a thiirane or thionoacyl fluoride intermediate, both electrophilic species presumed capable of binding to proteins or DNA. Studied were six F-, Cl-, and Br-substituted 2,2-dihalo-1,1-difluoroethane-1-thiolates (2,2-dihalo-DFETs). Pathway preference was determined for each thiolate by comparison of reaction energy profiles and activation energies. At all but the lowest level of ab initio theory, a thionoacyl fluoride pathway was predicted for 2,2-difluoro-DFET, while a thiirane pathway was energetically preferred for the brominated 2,2-dihalo-DFETs. These results offer a clear mechanism-based rationale for distinguishing 2,2-difluoro-DFET from the brominated 2,2-dihalo-DFETs, while the results are less clear for the 2,2-dichloro and 2-chloro-2-fluoro-DFETs, which at the highest level of ab initio treatment had a relatively small energy preference (2.4 kcal/mol) for the thiirane pathway. The predicted clear preference for a thiirane pathway for the brominated 2,2-dihalo-DFETs is not consistent with a recently proposed pathway involving alpha-thiolactone formation through a thionoacyl fluoride intermediate [Finkelstein, M. B., et al. (1995) J. Am. Chem. Soc. 117, 9590-9591], but is supported by

  13. 7 CFR 4280.29 - Supplemental financing required for the Ultimate Recipient Project.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 15 2010-01-01 2010-01-01 false Supplemental financing required for the Ultimate Recipient Project. 4280.29 Section 4280.29 Agriculture Regulations of the Department of Agriculture... AND GRANTS Rural Economic Development Loan and Grant Programs § 4280.29 Supplemental financing...

  14. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    NASA Astrophysics Data System (ADS)

    Chen, Chun-Long; Qi, Jiahui; Tao, Jinhui; Zuckermann, Ronald N.; Deyoreo, James J.

    2014-09-01

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic and hydrophobic interactions, with hydrophobic interactions playing the dominant role. While either strong electrostatic or hydrophobic interactions inhibit growth and reduces expression of the {104} faces, correlations between peptoid-crystal binding energies and observed changes in calcite growth indicate moderate electrostatic interactions allow peptoids to weakly adsorb while moderate hydrophobic interactions cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of the {104} faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications.

  15. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chen, Chunlong; Qi, Jiahui; Tao, Jinhui

    2014-09-05

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic interactions (EI) and hydrophobic interactions (HI), with HI playing the dominant role. While either strong EI or HI inhibit growth and suppress (104) face expression, correlations between peptoid-crystal binding energiesmore » and observed changes in calcite growth indicate moderate EI allow peptoids to weakly adsorb while moderate HI cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of (104) faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications.« less

  16. Tuning calcite morphology and growth acceleration by a rational design of highly stable protein-mimetics

    PubMed Central

    Chen, Chun-Long; Qi, Jiahui; Tao, Jinhui; Zuckermann, Ronald N.; DeYoreo, James J.

    2014-01-01

    In nature, proteins play a significant role in biomineral formation. One of the ultimate goals of bioinspired materials science is to develop highly stable synthetic molecules that mimic the function of these natural proteins by controlling crystal formation. Here, we demonstrate that both the morphology and the degree of acceleration or inhibition observed during growth of calcite in the presence of peptoids can be rationally tuned by balancing the electrostatic and hydrophobic interactions, with hydrophobic interactions playing the dominant role. While either strong electrostatic or hydrophobic interactions inhibit growth and reduces expression of the {104} faces, correlations between peptoid-crystal binding energies and observed changes in calcite growth indicate moderate electrostatic interactions allow peptoids to weakly adsorb while moderate hydrophobic interactions cause disruption of surface-adsorbed water layers, leading to growth acceleration with retained expression of the {104} faces. This study provides fundamental principles for designing peptoids as crystallization promoters, and offers a straightforward screening method based on macroscopic crystal morphology. Because peptoids are sequence-specific, highly stable, and easily synthesized, peptoid-enhanced crystallization offers a broad range of potential applications. PMID:25189418

  17. Mechanistic pathways of recognition of a solvent-inaccessible cavity of protein by a ligand

    NASA Astrophysics Data System (ADS)

    Mondal, Jagannath; Pandit, Subhendu; Dandekar, Bhupendra; Vallurupalli, Pramodh

    One of the puzzling questions in the realm of protein-ligand recognition is how a solvent-inaccessible hydrophobic cavity of a protein gets recognized by a ligand. We address the topic by simulating, for the first time, the complete binding process of benzene from aqueous media to the well-known buried cavity of L99A T4 Lysozyme at an atomistic resolution. Our multiple unbiased microsecond-long trajectories, which were completely blind to the location of target binding site, are able to unequivocally identify the kinetic pathways along which benzene molecule meanders across the solvent and protein and ultimately spontaneously recognizes the deeply buried cavity of L99A T4 Lysozyme at an accurate precision. Our simulation, combined with analysis based on markov state model and free energy calculation, reveals that there are more than one distinct ligand binding pathways. Intriguingly, each of the identified pathways involves the transient opening of a channel of the protein prior to ligand binding. The work will also decipher rich mechanistic details on unbinding kinetics of the ligand as obtained from enhanced sampling techniques.

  18. Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches

    PubMed Central

    Demine, Stéphane; Reddy, Nagabushana; Renard, Patricia; Raes, Martine; Arnould, Thierry

    2014-01-01

    Mitochondrial dysfunction(s) (MDs) can be defined as alterations in the mitochondria, including mitochondrial uncoupling, mitochondrial depolarization, inhibition of the mitochondrial respiratory chain, mitochondrial network fragmentation, mitochondrial or nuclear DNA mutations and the mitochondrial accumulation of protein aggregates. All these MDs are known to alter the capacity of ATP production and are observed in several pathological states/diseases, including cancer, obesity, muscle and neurological disorders. The induction of MDs can also alter the secretion of several metabolites, reactive oxygen species production and modify several cell-signalling pathways to resolve the mitochondrial dysfunction or ultimately trigger cell death. Many metabolites, such as fatty acids and derived compounds, could be secreted into the blood stream by cells suffering from mitochondrial alterations. In this review, we summarize how a mitochondrial uncoupling can modify metabolites, the signalling pathways and transcription factors involved in this process. We describe how to identify the causes or consequences of mitochondrial dysfunction using metabolomics (liquid and gas chromatography associated with mass spectrometry analysis, NMR spectroscopy) in the obesity and insulin resistance thematic. PMID:25257998

  19. Analysis of EAWAG-BBD pathway prediction system for the identification of malathion degrading microbes

    PubMed Central

    Sivakumar, Subramaniam; Anitha, Palanivel; Ramesh, Balsubramanian; Suresh, Gopal

    2017-01-01

    Insecticides are the toxic substances that are used to kill insects. The use of insecticides is believed to be one of the major factors behind the increase in agricultural productivity in the 20th century. The organophosphates are now the largest and most versatile class of insecticide used and Malathion is the predominant type utilized. The accumulation of Malathion in environment is the biggest threat to the environment because of its toxicity. Malathion is lethal to beneficial insects, snails, micro crustaceans, fish, birds, amphibians, and soil microorganisms. Chronic exposure of non-diabetic farmers to organophosphorus Malathion pesticides may induce insulin resistance, which might ultimately results in diabetes mellitus. Given the potential carcinogenic risk from the pesticides there is serious need to develop remediation processes to eliminate or minimize contamination in the environment. Biodegradation could be a reliable and cost effective technique for pesticide abatement. Since today as there were no metabolic pathway predicted for the degradation of organophosphates pesticide Malathion in KEGG database or in any of the other pathway databases. Thus in the present study, an attempt has been made to predict the microbial biodegradation pathway of Malathion using bioinformatics tools. The present study predicted the degradation pathway for Malathion. The present study also identifies, Streptomyces sp. and E.coli are capable of degrading Malathion through pathway prediction system. PMID:28584447

  20. Analysis of EAWAG-BBD pathway prediction system for the identification of malathion degrading microbes.

    PubMed

    Sivakumar, Subramaniam; Anitha, Palanivel; Ramesh, Balsubramanian; Suresh, Gopal

    2017-01-01

    Insecticides are the toxic substances that are used to kill insects. The use of insecticides is believed to be one of the major factors behind the increase in agricultural productivity in the 20th century. The organophosphates are now the largest and most versatile class of insecticide used and Malathion is the predominant type utilized. The accumulation of Malathion in environment is the biggest threat to the environment because of its toxicity. Malathion is lethal to beneficial insects, snails, micro crustaceans, fish, birds, amphibians, and soil microorganisms. Chronic exposure of non-diabetic farmers to organophosphorus Malathion pesticides may induce insulin resistance, which might ultimately results in diabetes mellitus. Given the potential carcinogenic risk from the pesticides there is serious need to develop remediation processes to eliminate or minimize contamination in the environment. Biodegradation could be a reliable and cost effective technique for pesticide abatement. Since today as there were no metabolic pathway predicted for the degradation of organophosphates pesticide Malathion in KEGG database or in any of the other pathway databases. Thus in the present study, an attempt has been made to predict the microbial biodegradation pathway of Malathion using bioinformatics tools. The present study predicted the degradation pathway for Malathion. The present study also identifies, Streptomyces sp. and E.coli are capable of degrading Malathion through pathway prediction system.

  1. Demountable damped cavity for HOM-damping in ILC superconducting accelerating cavities

    NASA Astrophysics Data System (ADS)

    Konomi, T.; Yasuda, F.; Furuta, F.; Saito, K.

    2014-01-01

    We have designed a new higher-order-mode (HOM) damper called a demountable damped cavity (DDC) as part of the R&D efforts for the superconducting cavity of the International Linear Collider (ILC). The DDC has two design concepts. The first is an axially symmetrical layout to obtain high damping efficiency. The DDC has a coaxial structure along the beam axis to realize strong coupling with HOMs. HOMs are damped by an RF absorber at the end of the coaxial waveguide and the accelerating mode is reflected by a choke filter mounted at the entrance of the coaxial waveguide. The second design concept is a demountable structure to facilitate cleaning, in order to suppress the Q-slope problem in a high field. A single-cell cavity with the DDC was fabricated to test four performance parameters. The first was frequency matching between the accelerating cavity and the choke filter. Since the bandwidth of the resonance frequency in a superconducting cavity is very narrow, there is a possibility that the accelerating field will leak to the RF absorber because of thermal shrinkage. The design bandwidth of the choke filter is 25 kHz. It was demonstrated that frequency matching adjusted at room temperature could be successfully maintained at 2 K. The second parameter was the performance of the demountable structure. At the joint, the magnetic field is 1/6 of the maximum field in the accelerating cavity. Ultimately, the accelerating field reached 19 MV/m and Q0 was 1.5×1010 with a knife-edge shape. The third parameter was field emission and multipacting. Although the choke structure has numerous parallel surfaces that are susceptible to the multipacting problem, it was found that neither field emission nor multipacting presented problems in both an experiment and simulation. The final parameter was the Q values of the HOM. The RF absorber adopted in the system is a Ni-Zn ferrite type. The RF absorber shape was designed based on the measurement data of permittivity and permeability

  2. Assembly of Customized TAL Effectors Through Advanced ULtiMATE System.

    PubMed

    Yang, Junjiao; Guo, Shengjie; Yuan, Pengfei; Wei, Wensheng

    2016-01-01

    Transcription activator-like effectors (TALEs) have been widely applied in gene targeting. Here we describe an advanced ULtiMATE (USER-based Ligation-Mediated Assembly of TAL Effector) system that utilizes USER fusion technique and archive of 512 tetramer templates to achieve highly efficient construction of TALEs, which takes only half a day to accomplish the assembly of any given TALE construct. This system is also suitable for large-scale assembly of TALENs and any other TALE-based constructions.

  3. Defending the mitochondria: The pathways of mitophagy and mitochondrial-derived vesicles.

    PubMed

    Roberts, Rosalind F; Tang, Matthew Y; Fon, Edward A; Durcan, Thomas M

    2016-10-01

    Mitochondria are the powerhouses for the cell, consuming oxygen to generate sufficient energy for the maintenance of normal cellular processes. However, a deleterious consequence of this process are reactive oxygen species generated as side-products of these reactions. As a means to protect mitochondria from damage, cells and mitochondria have developed a wide-range of mitochondrial quality control mechanisms that remove damaged mitochondrial cargo, enabling the mitochondria to repair the damage and ultimately restore their normal function. If the damage is extensive and mitochondria can no longer be repaired, a process termed mitophagy is initiated in which the mitochondria are directed for autophagic clearance. Canonical mitophagy is regulated by two proteins, PINK1 and Parkin, which are mutated in familial forms of Parkinson's disease. In this review, we discuss recent work elucidating the mechanism of PINK1/Parkin-mediated mitophagy, along with recently uncovered PINK1/Parkin-independent mitophagy pathways. Moreover, we describe a novel mitochondrial quality control pathway, involving mitochondrial-derived vesicles that direct distinct and damaged mitochondrial cargo for degradation in the lysosome. Finally, we discuss the association between mitochondrial quality control, cardiac, hepatic and neurodegenerative disease and discuss the possibility of targeting these pathways for therapeutic purposes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Illinois Accelerator Research Center

    DOE PAGES

    Kroc, Thomas K.; Cooper, Charlie A.

    2017-10-26

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 heavy assembly building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, whichmore » contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. Finally, at IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.« less

  5. Illinois Accelerator Research Center

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kroc, Thomas K.; Cooper, Charlie A.

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 heavy assembly building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, whichmore » contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. Finally, at IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.« less

  6. Illinois Accelerator Research Center

    NASA Astrophysics Data System (ADS)

    Kroc, Thomas K.; Cooper, Charlie A.

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 Heavy Assembly Building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft2 Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, which contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. At IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.

  7. Accelerated test design

    NASA Technical Reports Server (NTRS)

    Mcdermott, P. P.

    1980-01-01

    The design of an accelerated life test program for electric batteries is discussed. A number of observations and suggestions on the procedures and objectives for conducting an accelerated life test program are presented. Equations based on nonlinear regression analysis for predicting the accelerated life test parameters are discussed.

  8. Plug nozzles: The ultimate customer driven propulsion system

    NASA Technical Reports Server (NTRS)

    Aukerman, Carl A.

    1991-01-01

    This paper presents the results of a study applying the plug cluster nozzle concept to the propulsion system for a typical lunar excursion vehicle. Primary attention for the design criteria is given to user defined factors such as reliability, low volume, and ease of propulsion system development. Total thrust and specific impulse are held constant in the study while other parameters are explored to minimize the design chamber pressure. A brief history of the plug nozzle concept is included to point out the advanced level of technology of the concept and the feasibility of exploiting the variables considered in this study. The plug cluster concept looks very promising as a candidate for consideration for the ultimate customer driven propulsion system.

  9. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer.

    PubMed

    Vahid, Sepideh; Thaper, Daksh; Gibson, Kate F; Bishop, Jennifer L; Zoubeidi, Amina

    2016-08-24

    Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers.

  10. Evaluating the Potential of Commercial GIS for Accelerator Configuration Management

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    T.L. Larrieu; Y.R. Roblin; K. White

    2005-10-10

    The Geographic Information System (GIS) is a tool used by industries needing to track information about spatially distributed assets. A water utility, for example, must know not only the precise location of each pipe and pump, but also the respective pressure rating and flow rate of each. In many ways, an accelerator such as CEBAF (Continuous Electron Beam Accelerator Facility) can be viewed as an ''electron utility''. Whereas the water utility uses pipes and pumps, the ''electron utility'' uses magnets and RF cavities. At Jefferson lab we are exploring the possibility of implementing ESRI's ArcGIS as the framework for buildingmore » an all-encompassing accelerator configuration database that integrates location, configuration, maintenance, and connectivity details of all hardware and software. The possibilities of doing so are intriguing. From the GIS, software such as the model server could always extract the most-up-to-date layout information maintained by the Survey & Alignment for lattice modeling. The Mechanical Engineering department could use ArcGIS tools to generate CAD drawings of machine segments from the same database. Ultimately, the greatest benefit of the GIS implementation could be to liberate operators and engineers from the limitations of the current system-by-system view of machine configuration and allow a more integrated regional approach. The commercial GIS package provides a rich set of tools for database-connectivity, versioning, distributed editing, importing and exporting, and graphical analysis and querying, and therefore obviates the need for much custom development. However, formidable challenges to implementation exist and these challenges are not only technical and manpower issues, but also organizational ones. The GIS approach would crosscut organizational boundaries and require departments, which heretofore have had free reign to manage their own data, to cede some control and agree to a centralized framework.« less

  11. Plasma inverse transition acceleration

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xie, Ming

    It can be proved fundamentally from the reciprocity theorem with which the electromagnetism is endowed that corresponding to each spontaneous process of radiation by a charged particle there is an inverse process which defines a unique acceleration mechanism, from Cherenkov radiation to inverse Cherenkov acceleration (ICA) [1], from Smith-Purcell radiation to inverse Smith-Purcell acceleration (ISPA) [2], and from undulator radiation to inverse undulator acceleration (IUA) [3]. There is no exception. Yet, for nearly 30 years after each of the aforementioned inverse processes has been clarified for laser acceleration, inverse transition acceleration (ITA), despite speculation [4], has remained the least understood,more » and above all, no practical implementation of ITA has been found, until now. Unlike all its counterparts in which phase synchronism is established one way or the other such that a particle can continuously gain energy from an acceleration wave, the ITA to be discussed here, termed plasma inverse transition acceleration (PITA), operates under fundamentally different principle. As a result, the discovery of PITA has been delayed for decades, waiting for a conceptual breakthrough in accelerator physics: the principle of alternating gradient acceleration [5, 6, 7, 8, 9, 10]. In fact, PITA was invented [7, 8] as one of several realizations of the new principle.« less

  12. The mevalonate pathway in neurons: It's not just about cholesterol.

    PubMed

    Moutinho, Miguel; Nunes, Maria João; Rodrigues, Elsa

    2017-11-01

    Cholesterol homeostasis greatly impacts neuronal function due to the essential role of this sterol in the brain. The mevalonate (MVA) pathway leads to the synthesis of cholesterol, but also supplies cells with many other intermediary molecules crucial for neuronal function. Compelling evidence point to a model in which neurons shutdown cholesterol synthesis, and rely on a shuttle derived from astrocytes to meet their cholesterol needs. Nevertheless, several reports suggest that neurons maintain the MVA pathway active, even with sustained cholesterol supply by astrocytes. Hence, in this review we focus not on cholesterol production, but rather on the role of the MVA pathway in the synthesis of particular intermediaries, namely isoprenoids, and on their role on neuronal function. Isoprenoids act as anchors for membrane association, after being covalently bound to proteins, such as most of the small guanosine triphosphate-binding proteins, which are critical to neuronal cell function. Based on literature, on our own results, and on the analysis of public transcriptomics databases, we raise the idea that in neurons there is a shift of the MVA pathway towards the non-sterol branch, responsible for isoprenoid synthesis, in detriment to post-squalene branch, and that this is ultimately essential for synaptic activity. Nevertheless new tools that facilitate imaging and the biochemical characterization and quantification of the prenylome in neurons and astrocytes are needed to understand the regulation of isoprenoid production and protein prenylation in the brain, and to analyze its differences on diverse physiological or pathological conditions, such as aging and neurodegenerative states. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Multipactor Physics, Acceleration, and Breakdown in Dielectric-Loaded Accelerating Structures

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fischer, Richard P.; Gold, Steven H.

    2016-07-01

    The objective of this 3-year program is to study the physics issues associated with rf acceleration in dielectric-loaded accelerating (DLA) structures, with a focus on the key issue of multipactor loading, which has been found to cause very significant rf power loss in DLA structures whenever the rf pulsewidth exceeds the multipactor risetime (~10 ns). The experiments are carried out in the X-band magnicon laboratory at the Naval Research Laboratory (NRL) in collaboration with Argonne National Laboratory (ANL) and Euclid Techlabs LLC, who develop the test structures with support from the DoE SBIR program. There are two main elements inmore » the research program: (1) high-power tests of DLA structures using the magnicon output (20 MW @11.4 GHz), and (2) tests of electron acceleration in DLA structures using relativistic electrons from a compact X-band accelerator. The work during this period has focused on a study of the use of an axial magnetic field to suppress multipactor in DLA structures, with several new high power tests carried out at NRL, and on preparation of the accelerator for the electron acceleration experiments.« less

  14. Induction linear accelerators

    NASA Astrophysics Data System (ADS)

    Birx, Daniel

    1992-03-01

    Among the family of particle accelerators, the Induction Linear Accelerator is the best suited for the acceleration of high current electron beams. Because the electromagnetic radiation used to accelerate the electron beam is not stored in the cavities but is supplied by transmission lines during the beam pulse it is possible to utilize very low Q (typically<10) structures and very large beam pipes. This combination increases the beam breakup limited maximum currents to of order kiloamperes. The micropulse lengths of these machines are measured in 10's of nanoseconds and duty factors as high as 10-4 have been achieved. Until recently the major problem with these machines has been associated with the pulse power drive. Beam currents of kiloamperes and accelerating potentials of megavolts require peak power drives of gigawatts since no energy is stored in the structure. The marriage of liner accelerator technology and nonlinear magnetic compressors has produced some unique capabilities. It now appears possible to produce electron beams with average currents measured in amperes, peak currents in kiloamperes and gradients exceeding 1 MeV/meter, with power efficiencies approaching 50%. The nonlinear magnetic compression technology has replaced the spark gap drivers used on earlier accelerators with state-of-the-art all-solid-state SCR commutated compression chains. The reliability of these machines is now approaching 1010 shot MTBF. In the following paper we will briefly review the historical development of induction linear accelerators and then discuss the design considerations.

  15. ION ACCELERATOR

    DOEpatents

    Bell, J.S.

    1959-09-15

    An arrangement for the drift tubes in a linear accelerator is described whereby each drift tube acts to shield the particles from the influence of the accelerating field and focuses the particles passing through the tube. In one embodiment the drift tube is splii longitudinally into quadrants supported along the axis of the accelerator by webs from a yoke, the quadrants. webs, and yoke being of magnetic material. A magnetic focusing action is produced by energizing a winding on each web to set up a magnetic field between adjacent quadrants. In the other embodiment the quadrants are electrically insulated from each other and have opposite polarity voltages on adjacent quadrants to provide an electric focusing fleld for the particles, with the quadrants spaced sufficienily close enough to shield the particles within the tube from the accelerating electric field.

  16. Schooling in Times of Acceleration

    ERIC Educational Resources Information Center

    Buddeberg, Magdalena; Hornberg, Sabine

    2017-01-01

    Modern societies are characterised by forms of acceleration, which influence social processes. Sociologist Hartmut Rosa has systematised temporal structures by focusing on three categories of social acceleration: technical acceleration, acceleration of social change, and acceleration of the pace of life. All three processes of acceleration are…

  17. Osthole improves an accelerated focal segmental glomerulosclerosis model in the early stage by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated COX-2 expression and apoptosis.

    PubMed

    Yang, Shun-Min; Chan, Yi-Lin; Hua, Kuo-Feng; Chang, Jia-Ming; Chen, Hui-Ling; Tsai, Yung-Jen; Hsu, Yu-Juei; Chao, Louis Kuoping; Feng-Ling, Yang; Tsai, Yu-Ling; Wu, Shih-Hsiung; Wang, Yih-Fuh; Tsai, Change-Ling; Chen, Ann; Ka, Shuk-Man

    2014-08-01

    Inflammatory reactions and oxidative stress are implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common chronic kidney disease with relatively poor prognosis and unsatisfactory treatment regimens. Previously, we showed that osthole, a coumarin compound isolated from the seeds of Cnidium monnieri, can inhibit reactive oxygen species generation, NF-κB activation, and cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages. In this study, we further evaluated its renoprotective effect in a mouse model of accelerated FSGS (acFSGS), featuring early development of proteinuria, followed by impaired renal function, glomerular epithelial cell hyperplasia lesions (a sensitive sign that precedes the development of glomerular sclerosis), periglomerular inflammation, and glomerular hyalinosis/sclerosis. The results show that osthole significantly prevented the development of the acFSGS model in the treated group of mice. The mechanisms involved in the renoprotective effects of osthole on the acFSGS model were mainly a result of an activated Nrf2-mediated antioxidant pathway in the early stage (proteinuria and ischemic collapse of the glomeruli) of acFSGS, followed by a decrease in: (1) NF-κB activation and COX-2 expression as well as PGE2 production, (2) podocyte injury, and (3) apoptosis. Our data support that targeting the Nrf2 antioxidant pathway may justify osthole being established as a candidate renoprotective compound for FSGS. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Ultimate strength performance of tankers associated with industry corrosion addition practices

    NASA Astrophysics Data System (ADS)

    Kim, Do Kyun; Kim, Han Byul; Zhang, Xiaoming; Li, Chen Guang; Paik, Jeom Kee

    2014-09-01

    In the ship and offshore structure design, age-related problems such as corrosion damage, local denting, and fatigue damage are important factors to be considered in building a reliable structure as they have a significant influence on the residual structural capacity. In shipping, corrosion addition methods are widely adopted in structural design to prevent structural capacity degradation. The present study focuses on the historical trend of corrosion addition rules for ship structural design and investigates their effects on the ultimate strength performance such as hull girder and stiffened panel of double hull oil tankers. Three types of rules based on corrosion addition models, namely historic corrosion rules (pre-CSR), Common Structural Rules (CSR), and harmonised Common Structural Rules (CSRH) are considered and compared with two other corrosion models namely UGS model, suggested by the Union of Greek Shipowners (UGS), and Time-Dependent Corrosion Wastage Model (TDCWM). To identify the general trend in the effects of corrosion damage on the ultimate longitudinal strength performance, the corrosion addition rules are applied to four representative sizes of double hull oil tankers namely Panamax, Aframax, Suezmax, and VLCC. The results are helpful in understanding the trend of corrosion additions for tanker structures

  19. Biotransformation pathways of fluorotelomer-based polyfluoroalkyl substances: a review.

    PubMed

    Butt, Craig M; Muir, Derek C G; Mabury, Scott A

    2014-02-01

    The study reviews the current state of knowledge regarding the biotransformation of fluorotelomer-based compounds, with a focus on compounds that ultimately degrade to form perfluoroalkyl carboxylates (PFCAs). Most metabolism studies have been performed with either microbial systems or rats and mice, and comparatively few studies have used fish models. Furthermore, biotransformation studies thus far have predominately used the 8:2 fluorotelomer alcohol (FTOH) as the substrate. However, there have been an increasing number of studies investigating 6:2 FTOH biotransformation as a result of industry's transition to shorter-chain fluorotelomer chemistry. Studies with the 8:2 FTOH metabolism universally show the formation of perfluorooctanoate (PFOA) and, to a smaller fraction, perfluorononanoate (PFNA) and lower-chain-length PFCAs. In general, the overall yield of PFOA is low, presumably because of the multiple branches in the biotransformation pathways, including conjugation reactions in animal systems. There have been a few studies of non-FTOH biotransformation, which include polyfluoroalkyl phosphates (PAPs), 8:2 fluorotelomer acrylate (8:2 FTAC), and fluorotelomer carboxylates (FTCAs, FTUCAs). The PAPs compounds and 8:2 FTAC were shown to be direct precursors to FTOHs and thus follow similar degradation pathways. © 2013 SETAC.

  20. Understanding disease mechanisms with models of signaling pathway activities.

    PubMed

    Sebastian-Leon, Patricia; Vidal, Enrique; Minguez, Pablo; Conesa, Ana; Tarazona, Sonia; Amadoz, Alicia; Armero, Carmen; Salavert, Francisco; Vidal-Puig, Antonio; Montaner, David; Dopazo, Joaquín

    2014-10-25

    Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine. Here we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets. The proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.

  1. ACCELERATION AND THE GIFTED.

    ERIC Educational Resources Information Center

    GIBSON, ARTHUR R.; STEPHANS, THOMAS M.

    ACCELERATION OF PUPILS AND SUBJECTS IS CONSIDERED A MEANS OF EDUCATING THE ACADEMICALLY GIFTED STUDENT. FIVE INTRODUCTORY ARTICLES PROVIDE A FRAMEWORK FOR THINKING ABOUT ACCELERATION. FIVE PROJECT REPORTS OF ACCELERATED PROGRAMS IN OHIO ARE INCLUDED. ACCELERATION IS NOW BEING REGARDED MORE FAVORABLY THAN FORMERLY, BECAUSE METHODS HAVE BEEN…

  2. Activation of the PI3K/Akt pathway mediates bone morphogenetic protein 2-induced invasion of pancreatic cancer cells Panc-1.

    PubMed

    Chen, Xiong; Liao, Jie; Lu, YeBin; Duan, XiaoHui; Sun, WeiJia

    2011-06-01

    Bone morphogenetic proteins (BMPs) signaling has an emerging role in pancreatic cancer. However, because of the multiple effects of different BMPs, no final conclusions have been made as to the role of BMPs in pancreatic cancer. In our studies, we have focused on bone morphogenetic protein 2(BMP-2) because it induces an epithelial to mesenchymal transition (EMT) and accelerates invasion in the human pancreatic cancer cell line Panc-1. It has been reported that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediates invasion of gastric and colon cancer cells, which is unrevealed in pancreatic cancer cells. The objective of our study was to investigate whether BMP-2 mediated invasion might pass through the PI3K/Akt pathway. Our results show that expression of phosphorylation of Akt was increased by treatment with BMP-2, but not Noggin, a BMP-2 antagonist. Then pretreatment of Panc-1 cells with LY294002, an inhibitor of the PI3K/AKT pathway, significantly inhibited BMP-2-induced EMT and invasiveness. The data suggest that BMP-2 accelerates invasion of panc-1 cells via the PI3K/AKT pathway in panc-1 cells, which gives clues to searching new therapy targets in advanced pancreatic cancer.

  3. The Assessment of the Ultimate Hull Girder Strength of RO-RO Ship after Damages

    NASA Astrophysics Data System (ADS)

    Zubair Muis Alie, Muhammad; Sitepu, Ganding; Izaak Latumahin, Samuel

    2018-03-01

    Many accidents of Ro-Ro ships happen in Indonesia such as collision and grounding. When the collision or grounding takes place on the Ro-Ro ship, the ultimate strength of hull structure after damage becomes decrease. Car and passenger decks are critical location since collision and/or grounding occur. In the present study, the assessment of the ultimate hull girder strength is conducted. The cross section of Ro-Ro ship is taken to be analyzed. The collision and grounding damages are assumed to be palced on the side and bottom area, respectively. The damages are created by removing the element from the side shell and bottom part. Finally, the result obtained is compared with one another.

  4. Development of Acceleration Sensor and Acceleration Evaluation System for Super-Low-Range Frequencies

    NASA Astrophysics Data System (ADS)

    Asano, Shogo; Matsumoto, Hideki

    2001-05-01

    This paper describes the development process for acceleration sensors used on automobiles and an acceleration evaluation system designed specifically for acceleration at super-low-range frequencies. The features of the newly developed sensor are as follows. 1) Original piezo-bimorph design based on a disc-center-fixed structure achieves pyroeffect cancelling and stabilization of sensor characteristics and enables the detection of the acceleration of 0.0009 G at the super-low-range-frequency of 0.03 Hz. 2) The addition of a self-diagnostic function utilizing the characteristics of piezoceramics enables constant monitoring of sensor failure. The frequency range of acceleration for accurate vehicle motion control is considered to be from DC to about 50 Hz. However, the measurement of acceleration in the super-low-range frequency near DC has been difficult because of mechanical and electrical noise interruption. This has delayed the development of the acceleration sensor for automotive use. We have succeeded in the development of an acceleration evaluation system for super-low-range frequencies from 0.015 Hz to 2 Hz with detection of the acceleration range from 0.0002 G (0.2 gal) to 1 G, as well as the development of a piezoelectric-type acceleration sensor for automotive use.

  5. Acceleration: It's Elementary

    ERIC Educational Resources Information Center

    Willis, Mariam

    2012-01-01

    Acceleration is one tool for providing high-ability students the opportunity to learn something new every day. Some people talk about acceleration as taking a student out of step. In actuality, what one is doing is putting a student in step with the right curriculum. Whole-grade acceleration, also called grade-skipping, usually happens between…

  6. Overlapping gene expression profiles indicative of antigen processing and the interferon pathway characterize inflammatory fibrotic skin diseases.

    PubMed

    Limpers, Annelies; van Royen-Kerkhof, Annet; van Roon, Joel A G; Radstake, Timothy R D J; Broen, Jasper C A

    2014-02-01

    Inflammatory fibrotic disorders have been of high interest both for dermatologists and rheumatologists. Although the phenotypic end stage of this group of diseases is ultimately the same, namely fibrosis, patients present with different clinical features and are often treated with distinct therapeutic modalities. This review addresses whether there is evidence for different underlying molecular pathways in the various inflammatory fibrotic diseases such as localized scleroderma, pediatric lichen sclerosus, adult lichen sclerosus, eosinophilic fasciitis and systemic sclerosis. To investigate this, a large number of gene expression microarray studies performed on skin or fibroblasts from patients with these aforementioned diseases were described, (re-)analysed, and compared. As suspected by the heterogeneous phenotype, most diseases showed unique gene expression features. Intriguingly, a clear overlap was observed between adult and pediatric lichen sclerosus and localized scleroderma, in antigen processing and the interferon pathway. Delineating the cause and consequence of these pathways may generate novel tools to better characterize and more effectively treat these patients.

  7. Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations.

    PubMed

    Iliakis, George; Murmann, Tamara; Soni, Aashish

    2015-11-01

    DNA double strand breaks (DSB) are the most deleterious lesions for the integrity of the genome, as their misrepair can lead to the formation of chromosome translocations. Cells have evolved two main repair pathways to suppress the formation of these genotoxic lesions: homology-dependent, error-free homologous recombination repair (HRR), and potentially error-prone, classical, DNA-PK-dependent non-homologous end-joining (c-NHEJ). The most salient feature of c-NHEJ, speed, will largely suppress chromosome translocation formation, while sequence alterations at the junction remain possible. It is now widely accepted that when c-NHEJ is inactivated, globally or locally, an alternative form of end-joining (alt-EJ) removes DSBs. Alt-EJ operates with speed and fidelity markedly lower than c-NHEJ, causing thus with higher probability chromosome translocations, and generating more extensive sequence alterations at the junction. Our working hypothesis is that alt-EJ operates as a backup to c-NHEJ. Recent results show that alt-EJ can also backup abrogated HRR in G2 phase cells, again at the cost of elevated formation of chromosome translocations. These observations raise alt-EJ to a global rescuing mechanism operating on ends that have lost their chromatin context in ways that compromise processing by HRR or c-NHEJ. While responsible for eliminating from the genome highly cytotoxic DNA ends, alt-EJ provides this function at the price of increased translocation formation. Here, we analyze recent literature on the mechanisms of chromosome translocation formation and propose a functional hierarchy among DSB processing pathways that makes alt-EJ the global backup pathway. We discuss possible ramifications of this model in cellular DSB management and pathway choice, and analyze its implications in radiation carcinogenesis and the design of novel therapeutic approaches. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Biological pathways, candidate genes and molecular markers associated with quality-of-life domains: an update

    PubMed Central

    Sprangers, Mirjam A.G.; Thong, Melissa S.Y.; Bartels, Meike; Barsevick, Andrea; Ordoñana, Juan; Shi, Qiuling; Wang, Xin Shelley; Klepstad, Pål; Wierenga, Eddy A.; Singh, Jasvinder A.; Sloan, Jeff A.

    2014-01-01

    Background There is compelling evidence of a genetic foundation of patient-reported QOL. Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010. Objectives The objective is to provide an updated overview of the biological pathways, candidate genes and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL. Methods We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains. Results Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception and the COMT gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL. Conclusions Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients’ QOL. PMID:24604075

  9. Biological pathways, candidate genes, and molecular markers associated with quality-of-life domains: an update.

    PubMed

    Sprangers, Mirjam A G; Thong, Melissa S Y; Bartels, Meike; Barsevick, Andrea; Ordoñana, Juan; Shi, Qiuling; Wang, Xin Shelley; Klepstad, Pål; Wierenga, Eddy A; Singh, Jasvinder A; Sloan, Jeff A

    2014-09-01

    There is compelling evidence of a genetic foundation of patient-reported quality of life (QOL). Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010. The objective was to provide an updated overview of the biological pathways, candidate genes, and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL. We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains. Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception, and the catechol-O-methyltransferase (COMT) gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL. Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients' QOL.

  10. Terahertz-driven linear electron acceleration

    PubMed Central

    Nanni, Emilio A.; Huang, Wenqian R.; Hong, Kyung-Han; Ravi, Koustuban; Fallahi, Arya; Moriena, Gustavo; Dwayne Miller, R. J.; Kärtner, Franz X.

    2015-01-01

    The cost, size and availability of electron accelerators are dominated by the achievable accelerating gradient. Conventional high-brightness radio-frequency accelerating structures operate with 30–50 MeV m−1 gradients. Electron accelerators driven with optical or infrared sources have demonstrated accelerating gradients orders of magnitude above that achievable with conventional radio-frequency structures. However, laser-driven wakefield accelerators require intense femtosecond sources and direct laser-driven accelerators suffer from low bunch charge, sub-micron tolerances and sub-femtosecond timing requirements due to the short wavelength of operation. Here we demonstrate linear acceleration of electrons with keV energy gain using optically generated terahertz pulses. Terahertz-driven accelerating structures enable high-gradient electron/proton accelerators with simple accelerating structures, high repetition rates and significant charge per bunch. These ultra-compact terahertz accelerators with extremely short electron bunches hold great potential to have a transformative impact for free electron lasers, linear colliders, ultrafast electron diffraction, X-ray science and medical therapy with X-rays and electron beams. PMID:26439410

  11. Terahertz-driven linear electron acceleration

    DOE PAGES

    Nanni, Emilio A.; Huang, Wenqian R.; Hong, Kyung-Han; ...

    2015-10-06

    The cost, size and availability of electron accelerators are dominated by the achievable accelerating gradient. Conventional high-brightness radio-frequency accelerating structures operate with 30–50 MeVm -1 gradients. Electron accelerators driven with optical or infrared sources have demonstrated accelerating gradients orders of magnitude above that achievable with conventional radio-frequency structures. However, laser-driven wakefield accelerators require intense femtosecond sources and direct laser-driven accelerators suffer from low bunch charge, sub-micron tolerances and sub-femtosecond timing requirements due to the short wavelength of operation. Here we demonstrate linear acceleration of electrons with keV energy gain using optically generated terahertz pulses. Terahertz-driven accelerating structures enable high-gradient electron/protonmore » accelerators with simple accelerating structures, high repetition rates and significant charge per bunch. As a result, these ultra-compact terahertz accelerators with extremely short electron bunches hold great potential to have a transformative impact for free electron lasers, linear colliders, ultrafast electron diffraction, X-ray science and medical therapy with X-rays and electron beams.« less

  12. The Pathway Coexpression Network: Revealing pathway relationships

    PubMed Central

    Tanzi, Rudolph E.

    2018-01-01

    A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer’s Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of

  13. Laser driven ion accelerator

    DOEpatents

    Tajima, Toshiki

    2006-04-18

    A system and method of accelerating ions in an accelerator to optimize the energy produced by a light source. Several parameters may be controlled in constructing a target used in the accelerator system to adjust performance of the accelerator system. These parameters include the material, thickness, geometry and surface of the target.

  14. High brightness electron accelerator

    DOEpatents

    Sheffield, Richard L.; Carlsten, Bruce E.; Young, Lloyd M.

    1994-01-01

    A compact high brightness linear accelerator is provided for use, e.g., in a free electron laser. The accelerator has a first plurality of acclerating cavities having end walls with four coupling slots for accelerating electrons to high velocities in the absence of quadrupole fields. A second plurality of cavities receives the high velocity electrons for further acceleration, where each of the second cavities has end walls with two coupling slots for acceleration in the absence of dipole fields. The accelerator also includes a first cavity with an extended length to provide for phase matching the electron beam along the accelerating cavities. A solenoid is provided about the photocathode that emits the electons, where the solenoid is configured to provide a substantially uniform magnetic field over the photocathode surface to minimize emittance of the electons as the electrons enter the first cavity.

  15. Acceleration of a trailing positron bunch in a plasma wakefield accelerator

    DOE PAGES

    Doche, A.; Beekman, C.; Corde, S.; ...

    2017-10-27

    High gradients of energy gain and high energy efficiency are necessary parameters for compact, cost-efficient and high-energy particle colliders. Plasma Wakefield Accelerators (PWFA) offer both, making them attractive candidates for next-generation colliders. Here in these devices, a charge-density plasma wave is excited by an ultra-relativistic bunch of charged particles (the drive bunch). The energy in the wave can be extracted by a second bunch (the trailing bunch), as this bunch propagates in the wake of the drive bunch. While a trailing electron bunch was accelerated in a plasma with more than a gigaelectronvolt of energy gain, accelerating a trailing positronmore » bunch in a plasma is much more challenging as the plasma response can be asymmetric for positrons and electrons. We report the demonstration of the energy gain by a distinct trailing positron bunch in a plasma wakefield accelerator, spanning nonlinear to quasi-linear regimes, and unveil the beam loading process underlying the accelerator energy efficiency. A positron bunch is used to drive the plasma wake in the experiment, though the quasi-linear wake structure could as easily be formed by an electron bunch or a laser driver. Finally, the results thus mark the first acceleration of a distinct positron bunch in plasma-based particle accelerators.« less

  16. Acceleration of a trailing positron bunch in a plasma wakefield accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Doche, A.; Beekman, C.; Corde, S.

    High gradients of energy gain and high energy efficiency are necessary parameters for compact, cost-efficient and high-energy particle colliders. Plasma Wakefield Accelerators (PWFA) offer both, making them attractive candidates for next-generation colliders. Here in these devices, a charge-density plasma wave is excited by an ultra-relativistic bunch of charged particles (the drive bunch). The energy in the wave can be extracted by a second bunch (the trailing bunch), as this bunch propagates in the wake of the drive bunch. While a trailing electron bunch was accelerated in a plasma with more than a gigaelectronvolt of energy gain, accelerating a trailing positronmore » bunch in a plasma is much more challenging as the plasma response can be asymmetric for positrons and electrons. We report the demonstration of the energy gain by a distinct trailing positron bunch in a plasma wakefield accelerator, spanning nonlinear to quasi-linear regimes, and unveil the beam loading process underlying the accelerator energy efficiency. A positron bunch is used to drive the plasma wake in the experiment, though the quasi-linear wake structure could as easily be formed by an electron bunch or a laser driver. Finally, the results thus mark the first acceleration of a distinct positron bunch in plasma-based particle accelerators.« less

  17. Commissioning of the helium cryogenic system for the HIE- ISOLDE accelerator upgrade at CERN

    NASA Astrophysics Data System (ADS)

    Delruelle, N.; Inglese, V.; Leclercq, Y.; Pirotte, O.; Williams, L.

    2015-12-01

    The High Intensity and Energy ISOLDE (HIE-ISOLDE) project is a major upgrade of the existing ISOLDE and REX-ISOLDE facilities at CERN. The most significant improvement will come from replacing the existing REX accelerating structure by a superconducting linear accelerator (SC linac) composed ultimately of six cryo-modules installed in series, each containing superconducting RF cavities and solenoids operated at 4.5 K. In order to provide the cooling capacity at all temperature levels between 300 K and 4.5 K for the six cryo-modules, an existing helium refrigerator, manufactured in 1986 and previously used to cool the ALEPH magnet during LEP operation from 1989 to 2000, has been refurbished, reinstalled and recommissioned in a dedicated building located next to the HIE-ISOLDE experimental hall. This helium refrigerator has been connected to a new cryogenic distribution line, consisting of a 30-meter long vacuum-insulated transfer line, a 2000-liter storage dewar and six interconnecting valve boxes, one for each cryo-module. This paper describes the whole cryogenic system and presents the commissioning results including the preliminary operation at 4.5 K of the first cryo- module in the experimental hall.

  18. Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition.

    PubMed

    Smith, Kathleen B; Tran, Linh M; Tam, Brenna M; Shurell, Elizabeth M; Li, Yunfeng; Braas, Daniel; Tap, William D; Christofk, Heather R; Dry, Sarah M; Eilber, Fritz C; Wu, Hong

    2013-04-01

    Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  19. Accelerator-based BNCT.

    PubMed

    Kreiner, A J; Baldo, M; Bergueiro, J R; Cartelli, D; Castell, W; Thatar Vento, V; Gomez Asoia, J; Mercuri, D; Padulo, J; Suarez Sandin, J C; Erhardt, J; Kesque, J M; Valda, A A; Debray, M E; Somacal, H R; Igarzabal, M; Minsky, D M; Herrera, M S; Capoulat, M E; Gonzalez, S J; del Grosso, M F; Gagetti, L; Suarez Anzorena, M; Gun, M; Carranza, O

    2014-06-01

    The activity in accelerator development for accelerator-based BNCT (AB-BNCT) both worldwide and in Argentina is described. Projects in Russia, UK, Italy, Japan, Israel, and Argentina to develop AB-BNCT around different types of accelerators are briefly presented. In particular, the present status and recent progress of the Argentine project will be reviewed. The topics will cover: intense ion sources, accelerator tubes, transport of intense beams, beam diagnostics, the (9)Be(d,n) reaction as a possible neutron source, Beam Shaping Assemblies (BSA), a treatment room, and treatment planning in realistic cases. © 2013 Elsevier Ltd. All rights reserved.

  20. Middle School Math Acceleration and Equitable Access to Eighth-Grade Algebra: Evidence from the Wake County Public School System

    ERIC Educational Resources Information Center

    Dougherty, Shaun M.; Goodman, Joshua S.; Hill, Darryl V.; Litke, Erica G.; Page, Lindsay C.

    2015-01-01

    Taking algebra by eighth grade is considered an important milestone on the pathway to college readiness. We highlight a collaboration to investigate one district's effort to increase middle school algebra course-taking. In 2010, the Wake County Public Schools began assigning middle school students to accelerated math and eighth-grade algebra based…

  1. The Accelerated Schools Movement: Expansion and Support through Accelerated Schools Centers.

    ERIC Educational Resources Information Center

    Brunner, Ilse; And Others

    From 1987 to 1995, the Accelerated Schools Project moved from a two-school pilot project to a national movement of over 700 schools in 35 states. This paper examines how the Accelerated Schools Centers have helped the expansion of the accelerated schools movement by recruiting and supporting schools in their regions, and how their institutional…

  2. Standard Modular Hydropower Technology Acceleration Workshop: Summary Report

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, Brennan T.; DeNeale, Scott T.; Witt, Adam M.

    In support of the Department of Energy (DOE) funded Standard Modular Hydropower (SMH) Technology Acceleration project, Oak Ridge National Laboratory (ORNL) staff convened with five small hydropower technology entrepreneurs on June 14 and 15, 2017 to discuss gaps, challenges, and opportunities for small modular hydropower development. The workshop was designed to walk through SMH concepts, discuss the SMH research vision, assess how each participant’s technology aligns with SMH concepts and research, and identify future pathways for mutually beneficial collaboration that leverages ORNL expertise and entrepreneurial industry experience. The goal coming out of the workshop is to advance standardized, scalable, modularmore » hydropower technologies and development approaches with sustained and open dialogue among diverse stakeholder groups.« less

  3. Accelerator mass spectrometry in biomedical research

    NASA Astrophysics Data System (ADS)

    Vogel, J. S.; Turteltaub, K. W.

    1994-06-01

    Biological effects occur in natural systems at chemical concentrations of parts per billion (1:10 9) or less. Affected biomolecules may be separable in only milligram or microgram quantities. Quantification at attomole sensitivity is needed to study these interactions. AMS measures isotope concentrations to parts per 10 13-15 on milligram-sized samples and is ideal for quantifying long-lived radioisotopic labels for tracing biochemical pathways in natural systems. 14C-AMS has now been coupled to a variety of organic separation and definition technologies. Our primary research investigates pharmacokinetics and genotoxicities of toxins and drugs at very low doses. Human subjects research using AMS includes nutrition, toxicity and elemental balance studies. 3H, 41Ca and 26Al are also traced by AMS for fundamental biochemical kinetic research. Expansion of biomedical AMS awaits further development of biochemical and accelerator technologies designed specifically for these applications.

  4. Accelerating the Development of 21st-Century Toxicology: Outcome of a Human Toxicology Project Consortium Workshop

    PubMed Central

    Stephens, Martin L.; Barrow, Craig; Andersen, Melvin E.; Boekelheide, Kim; Carmichael, Paul L.; Holsapple, Michael P.; Lafranconi, Mark

    2012-01-01

    The U.S. National Research Council (NRC) report on “Toxicity Testing in the 21st century” calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments. The new approach would move toward in vitro methods, typically using human cells in a high-throughput context. The in vitro methods would be designed to detect significant perturbations to “toxicity pathways,” i.e., key biological pathways that, when sufficiently perturbed, lead to adverse health outcomes. To explore progress on the report’s implementation, the Human Toxicology Project Consortium hosted a workshop on 9–10 November 2010 in Washington, DC. The Consortium is a coalition of several corporations, a research institute, and a non-governmental organization dedicated to accelerating the implementation of 21st-century Toxicology as aligned with the NRC vision. The goal of the workshop was to identify practical and scientific ways to accelerate implementation of the NRC vision. The workshop format consisted of plenary presentations, breakout group discussions, and concluding commentaries. The program faculty was drawn from industry, academia, government, and public interest organizations. Most presentations summarized ongoing efforts to modernize toxicology testing and approaches, each with some overlap with the NRC vision. In light of these efforts, the workshop identified recommendations for accelerating implementation of the NRC vision, including greater strategic coordination and planning across projects (facilitated by a steering group), the development of projects that test the proof of concept for implementation of the NRC vision, and greater outreach and communication across stakeholder communities. PMID:21948868

  5. Clinical outcomes and cost effectiveness of accelerated diagnostic protocol in a chest pain center compared with routine care of patients with chest pain.

    PubMed

    Asher, Elad; Reuveni, Haim; Shlomo, Nir; Gerber, Yariv; Beigel, Roy; Narodetski, Michael; Eldar, Michael; Or, Jacob; Hod, Hanoch; Shamiss, Arie; Matetzky, Shlomi

    2015-01-01

    The aim of this study was to compare in patients presenting with acute chest pain the clinical outcomes and cost-effectiveness of an accelerated diagnostic protocol utilizing contemporary technology in a chest pain unit versus routine care in an internal medicine department. Hospital and 90-day course were prospectively studied in 585 consecutive low-moderate risk acute chest pain patients, of whom 304 were investigated in a designated chest pain center using a pre-specified accelerated diagnostic protocol, while 281 underwent routine care in an internal medicine ward. Hospitalization was longer in the routine care compared with the accelerated diagnostic protocol group (p<0.001). During hospitalization, 298 accelerated diagnostic protocol patients (98%) vs. 57 (20%) routine care patients underwent non-invasive testing, (p<0.001). Throughout the 90-day follow-up, diagnostic imaging testing was performed in 125 (44%) and 26 (9%) patients in the routine care and accelerated diagnostic protocol patients, respectively (p<0.001). Ultimately, most patients in both groups had non-invasive imaging testing. Accelerated diagnostic protocol patients compared with those receiving routine care was associated with a lower incidence of readmissions for chest pain [8 (3%) vs. 24 (9%), p<0.01], and acute coronary syndromes [1 (0.3%) vs. 9 (3.2%), p<0.01], during the follow-up period. The accelerated diagnostic protocol remained a predictor of lower acute coronary syndromes and readmissions after propensity score analysis [OR = 0.28 (CI 95% 0.14-0.59)]. Cost per patient was similar in both groups [($2510 vs. $2703 for the accelerated diagnostic protocol and routine care group, respectively, (p = 0.9)]. An accelerated diagnostic protocol is clinically superior and as cost effective as routine in acute chest pain patients, and may save time and resources.

  6. Clinical Outcomes and Cost Effectiveness of Accelerated Diagnostic Protocol in a Chest Pain Center Compared with Routine Care of Patients with Chest Pain

    PubMed Central

    Asher, Elad; Reuveni, Haim; Shlomo, Nir; Gerber, Yariv; Beigel, Roy; Narodetski, Michael; Eldar, Michael; Or, Jacob; Hod, Hanoch; Shamiss, Arie; Matetzky, Shlomi

    2015-01-01

    Aims The aim of this study was to compare in patients presenting with acute chest pain the clinical outcomes and cost-effectiveness of an accelerated diagnostic protocol utilizing contemporary technology in a chest pain unit versus routine care in an internal medicine department. Methods and Results Hospital and 90-day course were prospectively studied in 585 consecutive low-moderate risk acute chest pain patients, of whom 304 were investigated in a designated chest pain center using a pre-specified accelerated diagnostic protocol, while 281 underwent routine care in an internal medicine ward. Hospitalization was longer in the routine care compared with the accelerated diagnostic protocol group (p<0.001). During hospitalization, 298 accelerated diagnostic protocol patients (98%) vs. 57 (20%) routine care patients underwent non-invasive testing, (p<0.001). Throughout the 90-day follow-up, diagnostic imaging testing was performed in 125 (44%) and 26 (9%) patients in the routine care and accelerated diagnostic protocol patients, respectively (p<0.001). Ultimately, most patients in both groups had non-invasive imaging testing. Accelerated diagnostic protocol patients compared with those receiving routine care was associated with a lower incidence of readmissions for chest pain [8 (3%) vs. 24 (9%), p<0.01], and acute coronary syndromes [1 (0.3%) vs. 9 (3.2%), p<0.01], during the follow-up period. The accelerated diagnostic protocol remained a predictor of lower acute coronary syndromes and readmissions after propensity score analysis [OR = 0.28 (CI 95% 0.14–0.59)]. Cost per patient was similar in both groups [($2510 vs. $2703 for the accelerated diagnostic protocol and routine care group, respectively, (p = 0.9)]. Conclusion An accelerated diagnostic protocol is clinically superior and as cost effective as routine in acute chest pain patients, and may save time and resources. PMID:25622029

  7. PathwayAccess: CellDesigner plugins for pathway databases.

    PubMed

    Van Hemert, John L; Dickerson, Julie A

    2010-09-15

    CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

  8. Systems and methods for the magnetic insulation of accelerator electrodes in electrostatic accelerators

    DOEpatents

    Grisham, Larry R

    2013-12-17

    The present invention provides systems and methods for the magnetic insulation of accelerator electrodes in electrostatic accelerators. Advantageously, the systems and methods of the present invention improve the practically obtainable performance of these electrostatic accelerators by addressing, among other things, voltage holding problems and conditioning issues. The problems and issues are addressed by flowing electric currents along these accelerator electrodes to produce magnetic fields that envelope the accelerator electrodes and their support structures, so as to prevent very low energy electrons from leaving the surfaces of the accelerator electrodes and subsequently picking up energy from the surrounding electric field. In various applications, this magnetic insulation must only produce modest gains in voltage holding capability to represent a significant achievement.

  9. A TE-mode accelerator

    NASA Astrophysics Data System (ADS)

    Takeuchi, S.; Sakai, K.; Matsumoto, M.; Sugihara, R.

    1987-04-01

    An accelerator is proposed in which a TE-mode wave is used to drive charged particles in contrast to the usual linear accelerators in which longitudinal electric fields or TM-mode waves are supposed to be utilized. The principle of the acceleration is based on the V(p) x B acceleration of a dynamo force acceleration, in which a charged particle trapped in a transverse wave feels a constant electric field (Faraday induction field) and subsequently is accelerated when an appropriate magnetic field is externally applied in the direction perpendicular to the wave propagation. A pair of dielectric plates is used to produce a slow TE mode. The conditions of the particle trapping the stabilization of the particle orbit are discussed.

  10. Uniformly accelerated black holes

    NASA Astrophysics Data System (ADS)

    Letelier, Patricio S.; Oliveira, Samuel R.

    2001-09-01

    The static and stationary C metric are examined in a generic framework and their interpretations studied in some detail, especially those with two event horizons, one for the black hole and another for the acceleration. We find that (i) the spacetime of an accelerated static black hole is plagued by either conical singularities or a lack of smoothness and compactness of the black hole horizon, (ii) by using standard black hole thermodynamics we show that accelerated black holes have a higher Hawking temperature than Unruh temperature of the accelerated frame, and (iii) the usual upper bound on the product of the mass and acceleration parameters (<1/27) is just a coordinate artifact. The main results are extended to accelerated rotating black holes with no significant changes.

  11. Using student satisfaction data to evaluate a new online accelerated nursing education program.

    PubMed

    Gazza, Elizabeth A; Matthias, April

    2016-10-01

    As increasing numbers of students enroll in online education, institutions of higher education are responsible for delivering quality online courses and programs. Agencies that accredit institutions and programs require evidence of program quality, including student satisfaction. A large state university in the Southeastern United States transitioned an online nursing education degree completion, or Registered Nurse-to-Bachelor of Science in Nursing, program to an online accelerated format in order to meet the needs of working nurses and ultimately, increase the number of nurses prepared at the baccalaureate level. This article describes a descriptive, cross-sectional study that evaluated the effectiveness of the new online accelerated program using the quality indicator of student satisfaction. Ninety-one (32%) of the 284 students who were enrolled or had been enrolled in a course within the online accelerated degree completion program between fall 2013 session 1 and summer 2014 session participated in the study. The electronic Noel-Levitz Priorities Survey for Online Learners™ was used to measure student satisfaction with the program and associated services. Results provided insight into the students' satisfaction with the new program format and served as the basis for an interdepartmental program enhancement plan aimed at maintaining and enhancing student satisfaction and overall program quality. Findings indicated that measuring and evaluating student satisfaction can provide valuable information about the effectiveness of an online program. Recommendations for using the measurement tool in online program planning and studying student satisfaction in relation to retention and program completion were identified. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Trypanosoma cruzi Exploits Wnt Signaling Pathway to Promote Its Intracellular Replication in Macrophages.

    PubMed

    Volpini, Ximena; Ambrosio, Laura F; Fozzatti, Laura; Insfran, Constanza; Stempin, Cinthia C; Cervi, Laura; Motran, Claudia Cristina

    2018-01-01

    During the acute phase of Trypanosoma cruzi infection, macrophages can act as host cells for the parasites as well as effector cells in the early anti-parasitic immune response. Thus, the targeting of specific signaling pathways could modulate macrophages response to restrict parasite replication and instruct an appropriate adaptive response. Recently, it has become evident that Wnt signaling has immunomodulatory functions during inflammation and infection. Here, we tested the hypothesis that during T. cruzi infection, the activation of Wnt signaling pathway in macrophages plays a role in modulating the inflammatory/tolerogenic response and therefore regulating the control of parasite replication. In this report, we show that early after T. cruzi infection of bone marrow-derived macrophages (BMM), β-catenin was activated and Wnt3a, Wnt5a, and some Frizzled receptors as well as Wnt/β-catenin pathway's target genes were upregulated, with Wnt proteins signaling sustaining the activation of Wnt/β-catenin pathway and then activating the Wnt/Ca +2 pathway. Wnt signaling pathway activation was critical to sustain the parasite's replication in BMM; since the treatments with specific inhibitors of β-catenin transcriptional activation or Wnt proteins secretion limited the parasite replication. Mechanistically, inhibition of Wnt signaling pathway armed BMM to fight against T. cruzi by inducing the production of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase activity and by downregulating arginase activity. Likewise, in vivo pharmacological inhibition of the Wnts' interaction with its receptors controlled the parasite replication and improved the survival of lethally infected mice. It is well established that T. cruzi infection activates a plethora of signaling pathways that ultimately regulate immune mediators to determine the modulation of a defined set of effector functions in macrophages. In this study, we have revealed a new signaling pathway that is

  13. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

    PubMed Central

    McLelland, Gian-Luca; Soubannier, Vincent; Chen, Carol X; McBride, Heidi M; Fon, Edward A

    2014-01-01

    Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD. PMID:24446486

  14. Ultimate Osmosis Engineered by the Pore Geometry and Functionalization of Carbon Nanostructures

    PubMed Central

    Song, Zhigong; Xu, Zhiping

    2015-01-01

    Osmosis is the key process in establishing versatile functions of cellular systems and enabling clean-water harvesting technologies. Membranes with single-atom thickness not only hold great promises in approaching the ultimate limit of these functions, but also offer an ideal test-bed to explore the underlying physical mechanisms. In this work, we explore diffusive and osmotic transport of water and ions through carbon nanotube and porous graphene based membranes by performing molecular dynamics simulations. Our comparative study shows that the cylindrical confinement in carbon nanotubes offers much higher salt rejection at similar permeability in osmosis compared to porous graphene. Moreover, chemical functionalization of the pores modulates the membrane performance by its steric and electrostatic nature, especially at small-size pores due to the fact that the optimal transport is achieved by ordered water transport near pore edges. These findings lay the ground for the ultimate design of forward osmosis membranes with optimized performance trade-off, given the capability of nano-engineering nanostructures by their geometry and chemistry. PMID:26037602

  15. Accelerated Reader.

    ERIC Educational Resources Information Center

    Education Commission of the States, Denver, CO.

    This paper provides an overview of Accelerated Reader, a system of computerized testing and record-keeping that supplements the regular classroom reading program. Accelerated Reader's primary goal is to increase literature-based reading practice. The program offers a computer-aided reading comprehension and management program intended to motivate…

  16. The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease.

    PubMed

    Amaral, Marta; Outeiro, Tiago F; Scrutton, Nigel S; Giorgini, Flaviano

    2013-06-01

    Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds.

  17. The prospects of transition metal dichalcogenides for ultimately scaled CMOS

    NASA Astrophysics Data System (ADS)

    Thiele, S.; Kinberger, W.; Granzner, R.; Fiori, G.; Schwierz, F.

    2018-05-01

    MOSFET gate length scaling has been a main source of progress in digital electronics for decades. Today, researchers still spend considerable efforts on reducing the gate length and on developing ultimately scaled MOSFETs, thereby exploring both new device architectures and alternative channel materials beyond Silicon such as two-dimensional TMDs (transition metal dichalcogenide). On the other hand, the envisaged scaling scenario for the next 15 years has undergone a significant change recently. While the 2013 ITRS edition required a continuation of aggressive gate length scaling for at least another 15 years, the 2015 edition of the ITRS suggests a deceleration and eventually a levelling off of gate length scaling and puts more emphasis on alternative options such as pitch scaling to keep Moore's Law alive. In the present paper, future CMOS scaling is discussed in the light of emerging two-dimensional MOSFET channel, in particular two-dimensional TMDs. To this end, the scaling scenarios of the 2013 and 2015 ITRS editions are considered and the scaling potential of TMD MOSFETs is investigated by means of quantum-mechanical device simulations. It is shown that for ultimately scaled MOSFETs as required in the 2013 ITRS, the heavy carrier effective masses of the Mo- and W-based TMDs are beneficial for the suppression of direct source-drain tunneling, while to meet the significantly relaxed scaling targets of the 2016 ITRS heavy-effective-mass channels are not needed.

  18. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway

    PubMed Central

    Williams, Andrea; Sarkar, Sovan; Cuddon, Paul; Ttofi, Evangelia K.; Saiki, Shinji; Siddiqi, Farah H.; Jahreiss, Luca; Fleming, Angeleen; Pask, Dean; Goldsmith, Paul; O’Kane, Cahir J.; Floto, R. Andres; Rubinsztein, David C.

    2009-01-01

    Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases like Huntington’s disease. Autophagy induction with the mTOR inhibitor, rapamycin, accelerates clearance of these toxic substrates. As rapamycin has non-trivial side effects, we screened FDA-approved drugs to identify novel autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the Gi signaling activator clonidine, induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, where cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating Gsα, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced and we provide proof-of-principle for therapeutic relevance in Huntington’s disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+, like excitotoxicity, will inhibit autophagy, thus retarding clearance of aggregate-prone proteins. PMID:18391949

  19. Amps particle accelerator definition study

    NASA Technical Reports Server (NTRS)

    Sellen, J. M., Jr.

    1975-01-01

    The Particle Accelerator System of the AMPS (Atmospheric, Magnetospheric, and Plasmas in Space) payload is a series of charged particle accelerators to be flown with the Space Transportation System Shuttle on Spacelab missions. In the configuration presented, the total particle accelerator system consists of an energetic electron beam, an energetic ion accelerator, and both low voltage and high voltage plasma acceleration devices. The Orbiter is illustrated with such a particle accelerator system.

  20. Radical Acceleration

    ERIC Educational Resources Information Center

    Gross, Miraca U. M.; Van Vliet, Helen E.

    2005-01-01

    Research has found that teachers' objections to accelerating gifted students are mainly based on a fear that acceleration will lead to social or emotional damage. Ironically, it is the academic and emotional maturity which characterizes intellectually gifted students, coupled with their high levels of academic achievement, which makes them such…

  1. Observation of acceleration and deceleration in gigaelectron-volt-per-metre gradient dielectric wakefield accelerators

    DOE PAGES

    O’Shea, B. D.; Andonian, G.; Barber, S. K.; ...

    2016-09-14

    There is urgent need to develop new acceleration techniques capable of exceeding gigaelectron-volt-per-metre (GeV m –1) gradients in order to enable future generations of both light sources and high-energy physics experiments. To address this need, short wavelength accelerators based on wakefields, where an intense relativistic electron beam radiates the demanded fields directly into the accelerator structure or medium, are currently under intense investigation. One such wakefield based accelerator, the dielectric wakefield accelerator, uses a dielectric lined-waveguide to support a wakefield used for acceleration. Here we show gradients of 1.347±0.020 GeV m –1 using a dielectric wakefield accelerator of 15 cmmore » length, with sub-millimetre transverse aperture, by measuring changes of the kinetic state of relativistic electron beams. We follow this measurement by demonstrating accelerating gradients of 320±17 MeV m –1. As a result, both measurements improve on previous measurements by and order of magnitude and show promise for dielectric wakefield accelerators as sources of high-energy electrons.« less

  2. Observation of acceleration and deceleration in gigaelectron-volt-per-metre gradient dielectric wakefield accelerators

    PubMed Central

    O'Shea, B. D.; Andonian, G.; Barber, S. K.; Fitzmorris, K. L.; Hakimi, S.; Harrison, J.; Hoang, P. D.; Hogan, M. J.; Naranjo, B.; Williams, O. B.; Yakimenko, V.; Rosenzweig, J. B.

    2016-01-01

    There is urgent need to develop new acceleration techniques capable of exceeding gigaelectron-volt-per-metre (GeV m−1) gradients in order to enable future generations of both light sources and high-energy physics experiments. To address this need, short wavelength accelerators based on wakefields, where an intense relativistic electron beam radiates the demanded fields directly into the accelerator structure or medium, are currently under intense investigation. One such wakefield based accelerator, the dielectric wakefield accelerator, uses a dielectric lined-waveguide to support a wakefield used for acceleration. Here we show gradients of 1.347±0.020 GeV m−1 using a dielectric wakefield accelerator of 15 cm length, with sub-millimetre transverse aperture, by measuring changes of the kinetic state of relativistic electron beams. We follow this measurement by demonstrating accelerating gradients of 320±17 MeV m−1. Both measurements improve on previous measurements by and order of magnitude and show promise for dielectric wakefield accelerators as sources of high-energy electrons. PMID:27624348

  3. Staging of RF-accelerating Units in a MEMS-based Ion Accelerator

    NASA Astrophysics Data System (ADS)

    Persaud, A.; Seidl, P. A.; Ji, Q.; Feinberg, E.; Waldron, W. L.; Schenkel, T.; Ardanuc, S.; Vinayakumar, K. B.; Lal, A.

    Multiple Electrostatic Quadrupole Array Linear Accelerators (MEQALACs) provide an opportunity to realize compact radio- frequency (RF) accelerator structures that can deliver very high beam currents. MEQALACs have been previously realized with acceleration gap distances and beam aperture sizes of the order of centimeters. Through advances in Micro-Electro-Mechanical Systems (MEMS) fabrication, MEQALACs can now be scaled down to the sub-millimeter regime and batch processed on wafer substrates. In this paper we show first results from using three RF stages in a compact MEMS-based ion accelerator. The results presented show proof-of-concept with accelerator structures formed from printed circuit boards using a 3 × 3 beamlet arrangement and noble gas ions at 10 keV. We present a simple model to describe the measured results. We also discuss some of the scaling behaviour of a compact MEQALAC. The MEMS-based approach enables a low-cost, highly versatile accelerator covering a wide range of currents (10 μA to 100 mA) and beam energies (100 keV to several MeV). Applications include ion-beam analysis, mass spectrometry, materials processing, and at very high beam powers, plasma heating.

  4. Staging of RF-accelerating Units in a MEMS-based Ion Accelerator

    DOE PAGES

    Persaud, A.; Seidl, P. A.; Ji, Q.; ...

    2017-10-26

    Multiple Electrostatic Quadrupole Array Linear Accelerators (MEQALACs) provide an opportunity to realize compact radio- frequency (RF) accelerator structures that can deliver very high beam currents. MEQALACs have been previously realized with acceleration gap distances and beam aperture sizes of the order of centimeters. Through advances in Micro-Electro-Mechanical Systems (MEMS) fabrication, MEQALACs can now be scaled down to the sub-millimeter regime and batch processed on wafer substrates. In this paper we show first results from using three RF stages in a compact MEMS-based ion accelerator. The results presented show proof-of-concept with accelerator structures formed from printed circuit boards using a 3more » × 3 beamlet arrangement and noble gas ions at 10 keV. We present a simple model to describe the measured results. We also discuss some of the scaling behaviour of a compact MEQALAC. The MEMS-based approach enables a low-cost, highly versatile accelerator covering a wide range of currents (10 μA to 100 mA) and beam energies (100 keV to several MeV). Applications include ion-beam analysis, mass spectrometry, materials processing, and at very high beam powers, plasma heating.« less

  5. Staging of RF-accelerating Units in a MEMS-based Ion Accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Persaud, A.; Seidl, P. A.; Ji, Q.

    Multiple Electrostatic Quadrupole Array Linear Accelerators (MEQALACs) provide an opportunity to realize compact radio- frequency (RF) accelerator structures that can deliver very high beam currents. MEQALACs have been previously realized with acceleration gap distances and beam aperture sizes of the order of centimeters. Through advances in Micro-Electro-Mechanical Systems (MEMS) fabrication, MEQALACs can now be scaled down to the sub-millimeter regime and batch processed on wafer substrates. In this paper we show first results from using three RF stages in a compact MEMS-based ion accelerator. The results presented show proof-of-concept with accelerator structures formed from printed circuit boards using a 3more » × 3 beamlet arrangement and noble gas ions at 10 keV. We present a simple model to describe the measured results. We also discuss some of the scaling behaviour of a compact MEQALAC. The MEMS-based approach enables a low-cost, highly versatile accelerator covering a wide range of currents (10 μA to 100 mA) and beam energies (100 keV to several MeV). Applications include ion-beam analysis, mass spectrometry, materials processing, and at very high beam powers, plasma heating.« less

  6. Proposal for an Accelerator R&D User Facility at Fermilab's Advanced Superconducting Test Accelerator (ASTA)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Church, M.; Edwards, H.; Harms, E.

    2013-10-01

    Fermilab is the nation’s particle physics laboratory, supported by the DOE Office of High Energy Physics (OHEP). Fermilab is a world leader in accelerators, with a demonstrated track-record— spanning four decades—of excellence in accelerator science and technology. We describe the significant opportunity to complete, in a highly leveraged manner, a unique accelerator research facility that supports the broad strategic goals in accelerator science and technology within the OHEP. While the US accelerator-based HEP program is oriented toward the Intensity Frontier, which requires modern superconducting linear accelerators and advanced highintensity storage rings, there are no accelerator test facilities that support themore » accelerator science of the Intensity Frontier. Further, nearly all proposed future accelerators for Discovery Science will rely on superconducting radiofrequency (SRF) acceleration, yet there are no dedicated test facilities to study SRF capabilities for beam acceleration and manipulation in prototypic conditions. Finally, there are a wide range of experiments and research programs beyond particle physics that require the unique beam parameters that will only be available at Fermilab’s Advanced Superconducting Test Accelerator (ASTA). To address these needs we submit this proposal for an Accelerator R&D User Facility at ASTA. The ASTA program is based on the capability provided by an SRF linac (which provides electron beams from 50 MeV to nearly 1 GeV) and a small storage ring (with the ability to store either electrons or protons) to enable a broad range of beam-based experiments to study fundamental limitations to beam intensity and to develop transformative approaches to particle-beam generation, acceleration and manipulation which cannot be done elsewhere. It will also establish a unique resource for R&D towards Energy Frontier facilities and a test-bed for SRF accelerators and high brightness beam applications in support of the

  7. Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

    PubMed Central

    Menendez, Javier A.; Folguera-Blasco, Núria; Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Joven, Jorge; Alarcón, Tomás

    2016-01-01

    The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger “accelerated geroncogenesis” in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes “permissive” with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the “install phase” that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the “geroncogenic risk” of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited “one-hit” metabolic “field effect” might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome. PMID:26943589

  8. Diffusive shock acceleration - Acceleration rate, magnetic-field direction and the diffusion limit

    NASA Technical Reports Server (NTRS)

    Jokipii, J. R.

    1992-01-01

    This paper reviews the concept of diffusive shock acceleration, showing that the acceleration of charged particles at a collisionless shock is a straightforward consequence of the standard cosmic-ray transport equation, provided that one treats the discontinuity at the shock correctly. This is true for arbitrary direction of the upstream magnetic field. Within this framework, it is shown that acceleration at perpendicular or quasi-perpendicular shocks is generally much faster than for parallel shocks. Paradoxically, it follows also that, for a simple scattering law, the acceleration is faster for less scattering or larger mean free path. Obviously, the mean free path can not become too large or the diffusion limit becomes inapplicable. Gradient and curvature drifts caused by the magnetic-field change at the shock play a major role in the acceleration process in most cases. Recent observations of the charge state of the anomalous component are shown to require the faster acceleration at the quasi-perpendicular solar-wind termination shock.

  9. Rapid Evolution of piRNA Pathway in the Teleost Fish: Implication for an Adaptation to Transposon Diversity

    PubMed Central

    Yi, Minhan; Chen, Feng; Luo, Majing; Cheng, Yibin; Zhao, Huabin; Cheng, Hanhua; Zhou, Rongjia

    2014-01-01

    The Piwi-interacting RNA (piRNA) pathway is responsible for germline specification, gametogenesis, transposon silencing, and genome integrity. Transposable elements can disrupt genome and its functions. However, piRNA pathway evolution and its adaptation to transposon diversity in the teleost fish remain unknown. This article unveils evolutionary scene of piRNA pathway and its association with diverse transposons by systematically comparative analysis on diverse teleost fish genomes. Selective pressure analysis on piRNA pathway and miRNA/siRNA (microRNA/small interfering RNA) pathway genes between teleosts and mammals showed an accelerated evolution of piRNA pathway genes in the teleost lineages, and positive selection on functional PAZ (Piwi/Ago/Zwille) and Tudor domains involved in the Piwi–piRNA/Tudor interaction, suggesting that the amino acid substitutions are adaptive to their functions in piRNA pathway in the teleost fish species. Notably five piRNA pathway genes evolved faster in the swamp eel, a kind of protogynous hermaphrodite fish, than the other teleosts, indicating a differential evolution of piRNA pathway between the swamp eel and other gonochoristic fishes. In addition, genome-wide analysis showed higher diversity of transposons in the teleost fish species compared with mammals. Our results suggest that rapidly evolved piRNA pathway in the teleost fish is likely to be involved in the adaption to transposon diversity. PMID:24846630

  10. Multi-pathway Kinase Signatures of Multipotent Stromal Cells are Predictive for Osteogenic Differentiation

    PubMed Central

    Platt, Manu O.; Wilder, Catera L.; Wells, Alan; Griffith, Linda G.; Lauffenburger, Douglas A.

    2010-01-01

    Bone marrow-derived multi-potent stromal cells (MSCs) offer great promise for regenerating tissue. While certain transcription factors have been identified in association with tendency toward particular MSC differentiation phenotypes, the regulatory network of key receptor-mediated signaling pathways activated by extracellular ligands that induce various differentiation responses remain poorly understood. Attempts to predict differentiation fate tendencies from individual pathways in isolation are problematic due to the complex pathway interactions inherent in signaling networks. Accordingly, we have undertaken a multi-variate systems approach integrating experimental measurement of multiple kinase pathway activities and osteogenic differentiation in MSCs, together with computational analysis to elucidate quantitative combinations of kinase signals predictive of cell behavior across diverse contexts. In particular, for culture on polymeric biomaterials surfaces presenting tethered epidermal growth factor (tEGF), type-I collagen, neither, or both, we have found that a partial least-squares regression model yields successful prediction of phenotypic behavior on the basis of two principal components comprising the weighted sums of 8 intracellular phosphoproteins: p-EGFR, p-Akt, p-ERK1/2, p-Hsp27, p-c-jun, p-GSK3α/β, p-p38, and p-STAT3. This combination provides strongest predictive capability for 21-day differentiated phenotype status when calculated from day-7 signal measurements (99%); day-4 (88%) and day-14 (89%) signal measurements are also significantly predictive, indicating a broad time-frame during MSC osteogenesis wherein multiple pathways and states of the kinase signaling network are quantitatively integrated to regulate gene expression, cell processes, and ultimately, cell fate. PMID:19750537

  11. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

    PubMed Central

    Vahid, Sepideh; Thaper, Daksh; Gibson, Kate F.; Bishop, Jennifer L.; Zoubeidi, Amina

    2016-01-01

    Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers. PMID:27555231

  12. Plasma Wakefield Acceleration and FACET - Facilities for Accelerator Science and Experimental Test Beams at SLAC

    ScienceCinema

    Seryi, Andrei

    2017-12-22

    Plasma wakefield acceleration is one of the most promising approaches to advancing accelerator technology. This approach offers a potential 1,000-fold or more increase in acceleration over a given distance, compared to existing accelerators.  FACET, enabled by the Recovery Act funds, will study plasma acceleration, using short, intense pulses of electrons and positrons. In this lecture, the physics of plasma acceleration and features of FACET will be presented.  

  13. Bilateral crosstalk of rho- and extracellular-signal-regulated-kinase (ERK) pathways is confined to an unidirectional mode in spinal muscular atrophy (SMA).

    PubMed

    Hensel, Niko; Stockbrügger, Inga; Rademacher, Sebastian; Broughton, Natasha; Brinkmann, Hella; Grothe, Claudia; Claus, Peter

    2014-03-01

    Rho-kinase (ROCK) as well as extracellular signal regulated kinase (ERK) control actin cytoskeletal organization thereby regulating dynamic changes of cellular morphology. In neurons, motility processes such as axonal guidance and neurite outgrowth demand a fine regulation of upstream pathways. Here we demonstrate a bilateral ROCK-ERK information flow in neurons. This process is shifted towards an unidirectional crosstalk in a model of the neurodegenerative disease Spinal Muscular Atrophy (SMA), ultimately leading to neurite outgrowth dysregulations. As both pathways are of therapeutic relevance for SMA, our results argue for a combinatorial ROCK/ERK-targeting as a future treatment strategy. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Ultimate boundedness stability and controllability of hereditary systems

    NASA Technical Reports Server (NTRS)

    Chukwu, E. N.

    1979-01-01

    By generalizing the Liapunov-Yoshizawa techniques, necessary and sufficient conditions are given for uniform boundedness and uniform ultimate boundedness of a rather general class of nonlinear differential equations of neutral type. Among the applications treated by the methods are the Lienard equation of neutral type and hereditary systems of Lurie type. The absolute stability of this later equation is also investigated. A certain existence result of a solution of a neutral functional differential inclusion with two point boundary values is applied to study the exact function space controllability of a nonlinear neutral functional differential control system. A geometric growth condition is used to characterize both the function space and Euclidean controllability of another nonlinear delay system which has a compact and convex control set. This yields conditions under which perturbed nonlinear delay controllable systems are controllable.

  15. Genetic Ablation of Apolipoprotein A-IV Accelerates Alzheimer's Disease Pathogenesis in a Mouse Model

    PubMed Central

    Cui, Yujie; Huang, Mingwei; He, Yingbo; Zhang, Shuyan; Luo, Yongzhang

    2011-01-01

    The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been suggested to play an important role in brain metabolism. Although there are clinical debates on the function of its polymorphism in AD, the pathologic role of apoA-IV in AD is still unknown. Here, we report that genetic ablation of apoA-IV is able to accelerate AD pathogenesis in mice. In a mouse model that overexpresses human amyloid precursor protein (APP) and presenilin 1, genetic reduction of apoA-IV augments extracellular amyloid-β peptide (Aβ) burden and aggravates neuron loss in the brain. In addition, genetic ablation of apoA-IV also accelerates spatial learning deficits and increases the mortality of mice. We have found that apoA-IV colocalizes within Aβ plaques in APP/presenilin 1 transgenic mice and binds to Aβ in vitro. Subsequent studies show that apoA-IV in this model facilitates Aβ uptake in the Aβ clearance pathway mediated by astrocytes rather than the amyloidogenic pathway of APP processing. Taken together, we conclude that apoA-IV deficiency increases Aβ deposition and results in cognitive damage in the mouse model. Enhancing levels of apoA-IV may have therapeutic potential in AD treatment. PMID:21356380

  16. Electron beam accelerator with magnetic pulse compression and accelerator switching

    DOEpatents

    Birx, Daniel L.; Reginato, Louis L.

    1988-01-01

    An electron beam accelerator comprising an electron beam generator-injector to produce a focused beam of .gtoreq.0.1 MeV energy electrons; a plurality of substantially identical, aligned accelerator modules to sequentially receive and increase the kinetic energies of the beam electrons by about 0.1-1 MeV per module. Each accelerator module includes a pulse-forming network that delivers a voltage pulse to the module of substantially .gtoreq.0.1-1 MeV maximum energy over a time duration of .ltoreq.1 .mu.sec.

  17. Electron beam accelerator with magnetic pulse compression and accelerator switching

    DOEpatents

    Birx, Daniel L.; Reginato, Louis L.

    1987-01-01

    An electron beam accelerator comprising an electron beam generator-injector to produce a focused beam of .gtoreq.0.1 MeV energy electrons; a plurality of substantially identical, aligned accelerator modules to sequentially receive and increase the kinetic energies of the beam electrons by about 0.1-1 MeV per module. Each accelerator module includes a pulse-forming network that delivers a voltage pulse to the module of substantially 0.1-1 MeV maximum energy over a time duration of .ltoreq.1 .mu.sec.

  18. Particle acceleration

    NASA Technical Reports Server (NTRS)

    Vlahos, L.; Machado, M. E.; Ramaty, R.; Murphy, R. J.; Alissandrakis, C.; Bai, T.; Batchelor, D.; Benz, A. O.; Chupp, E.; Ellison, D.

    1986-01-01

    Data is compiled from Solar Maximum Mission and Hinothori satellites, particle detectors in several satellites, ground based instruments, and balloon flights in order to answer fundamental questions relating to: (1) the requirements for the coronal magnetic field structure in the vicinity of the energization source; (2) the height (above the photosphere) of the energization source; (3) the time of energization; (4) transistion between coronal heating and flares; (5) evidence for purely thermal, purely nonthermal and hybrid type flares; (6) the time characteristics of the energization source; (7) whether every flare accelerates protons; (8) the location of the interaction site of the ions and relativistic electrons; (9) the energy spectra for ions and relativistic electrons; (10) the relationship between particles at the Sun and interplanetary space; (11) evidence for more than one acceleration mechanism; (12) whether there is single mechanism that will accelerate particles to all energies and also heat the plasma; and (13) how fast the existing mechanisms accelerate electrons up to several MeV and ions to 1 GeV.

  19. ACCELERATION INTEGRATOR

    DOEpatents

    Pope, K.E.

    1958-01-01

    This patent relates to an improved acceleration integrator and more particularly to apparatus of this nature which is gyrostabilized. The device may be used to sense the attainment by an airborne vehicle of a predetermined velocitv or distance along a given vector path. In its broad aspects, the acceleration integrator utilizes a magnetized element rotatable driven by a synchronous motor and having a cylin drical flux gap and a restrained eddy- current drag cap deposed to move into the gap. The angular velocity imparted to the rotatable cap shaft is transmitted in a positive manner to the magnetized element through a servo feedback loop. The resultant angular velocity of tae cap is proportional to the acceleration of the housing in this manner and means may be used to measure the velocity and operate switches at a pre-set magnitude. To make the above-described dcvice sensitive to acceleration in only one direction the magnetized element forms the spinning inertia element of a free gyroscope, and the outer housing functions as a gimbal of a gyroscope.

  20. Joint kinematics and kinetics of overground accelerated running versus running on an accelerated treadmill

    PubMed Central

    Van Caekenberghe, Ine; Segers, Veerle; Aerts, Peter; Willems, Patrick; De Clercq, Dirk

    2013-01-01

    Literature shows that running on an accelerated motorized treadmill is mechanically different from accelerated running overground. Overground, the subject has to enlarge the net anterior–posterior force impulse proportional to acceleration in order to overcome linear whole body inertia, whereas on a treadmill, this force impulse remains zero, regardless of belt acceleration. Therefore, it can be expected that changes in kinematics and joint kinetics of the human body also are proportional to acceleration overground, whereas no changes according to belt acceleration are expected on a treadmill. This study documents kinematics and joint kinetics of accelerated running overground and running on an accelerated motorized treadmill belt for 10 young healthy subjects. When accelerating overground, ground reaction forces are characterized by less braking and more propulsion, generating a more forward-oriented ground reaction force vector and a more forwardly inclined body compared with steady-state running. This change in body orientation as such is partly responsible for the changed force direction. Besides this, more pronounced hip and knee flexion at initial contact, a larger hip extension velocity, smaller knee flexion velocity and smaller initial plantarflexion velocity are associated with less braking. A larger knee extension and plantarflexion velocity result in larger propulsion. Altogether, during stance, joint moments are not significantly influenced by acceleration overground. Therefore, we suggest that the overall behaviour of the musculoskeletal system (in terms of kinematics and joint moments) during acceleration at a certain speed remains essentially identical to steady-state running at the same speed, yet acting in a different orientation. However, because acceleration implies extra mechanical work to increase the running speed, muscular effort done (in terms of power output) must be larger. This is confirmed by larger joint power generation at the level

  1. Ultimate force and stiffness of 2-piece zirconium dioxide implants with screw-retained monolithic lithium-disilicate reconstructions.

    PubMed

    Joda, Tim; Voumard, Benjamin; Zysset, Philippe K; Brägger, Urs; Ferrari, Marco

    2018-04-01

    The aims were to analyze stiffness, ultimate force, and failure modes of a 2-piece zirconium dioxide (ZrO 2 ) implant system. Eleven 2-piece ZrO 2 implants, each mounted with ZrO 2 abutments plus bonded monolithic lithium disilicate (LS 2 ) restorations, were grouped for 3.3mm (A) and 4.1mm (B) diameter samples. Quasi-static load was monotonically applied under a standardized test set-up (loading configuration according to DIN ISO 14801). The ultimate force was defined as the maximum force that implants are able to carry out until fracture; stiffness was measured as the maximum slope during loading. An unpaired t-test was performed between group A and B for ultimate force and stiffness (p<0.05). Force-displacement curves revealed statistically homogenous inner-group results for all samples. Failure modes showed characteristic fractures at the neck configuration of the implants independent of the diameter. Mean stiffness was 1099N/mm (±192) for group A, and significantly lower compared to group B with 1630N/mm (±274) (p<0.01); whereas mean ultimate force was 348N (±53) for group A, and significantly increased for group B with 684N (±29) (p<0.0001). The examined 2-piece ZrO 2 implant system mounted to LS 2 -restorations seems to be a stable unit under in-vitro conditions with mechanical properties compared to loading capacity of physiological force. The metal-free implant reconstructions demonstrated high stiffness and ultimate force under quasi-static load for single tooth replacement under consideration of the dental indication of narrow and standard diameter implants. Copyright © 2017 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

  2. Electron beam accelerator with magnetic pulse compression and accelerator switching

    DOEpatents

    Birx, D.L.; Reginato, L.L.

    1984-03-22

    An electron beam accelerator is described comprising an electron beam generator-injector to produce a focused beam of greater than or equal to .1 MeV energy electrons; a plurality of substantially identical, aligned accelerator modules to sequentially receive and increase the kinetic energies of the beam electron by about .1-1 MeV per module. Each accelerator module includes a pulse-forming network that delivers a voltage pulse to the module of substantially .1-1 MeV maximum energy over a time duration of less than or equal to 1 ..mu..sec.

  3. Traveling wave linear accelerator with RF power flow outside of accelerating cavities

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dolgashev, Valery A.

    A high power RF traveling wave accelerator structure includes a symmetric RF feed, an input matching cell coupled to the symmetric RF feed, a sequence of regular accelerating cavities coupled to the input matching cell at an input beam pipe end of the sequence, one or more waveguides parallel to and coupled to the sequence of regular accelerating cavities, an output matching cell coupled to the sequence of regular accelerating cavities at an output beam pipe end of the sequence, and output waveguide circuit or RF loads coupled to the output matching cell. Each of the regular accelerating cavities hasmore » a nose cone that cuts off field propagating into the beam pipe and therefore all power flows in a traveling wave along the structure in the waveguide.« less

  4. L2 and L3 Ultimate Attainment: An Investigation of Two Parameters

    ERIC Educational Resources Information Center

    Hermas, Abdelkader

    2014-01-01

    This study considers the upper limit of ultimate attainment in the L2 French and L3 English of trilingual learners. The learners are native speakers of Moroccan Arabic who started learning L2 French at eight and L3 English at 16. They are advanced in both languages. Four constructions representing the verb movement and null subject parameter were…

  5. Development of bipolar-pulse accelerator for intense pulsed ion beam acceleration

    NASA Astrophysics Data System (ADS)

    Masugata, Katsumi; Shimizu, Yuichro; Fujioka, Yuhki; Kitamura, Iwao; Tanoue, Hisao; Arai, Kazuo

    2004-12-01

    To improve the purity of intense pulsed ion beams, a new type of pulsed ion beam accelerator named "bipolar pulse accelerator" was proposed. To confirm the principle of the accelerator a prototype of the experimental system was developed. The system utilizes By type magnetically insulated acceleration gap and operated with single polar negative pulse. A coaxial gas puff plasma gun was used as an ion source, which was placed inside the grounded anode. Source plasma (nitrogen) of current density ≈25 A/cm2, duration ≈1.5 μs was injected into the acceleration gap by the plasma gun. The ions were successfully accelerated from the grounded anode to the drift tube by applying negative pulse of voltage 240 kV, duration 100 ns to the drift tube. Pulsed ion beam of current density ≈40 A/cm2, duration ≈50 ns was obtained at 41 mm downstream from the anode surface. To evaluate the irradiation effect of the ion beam to solid material, an amorphous silicon thin film of thickness ≈500 nm was used as the target, which was deposited on the glass substrate. The film was found to be poly-crystallized after 4-shots of the pulsed nitrogen ion beam irradiation.

  6. Compact particle accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Elizondo-Decanini, Juan M.

    2017-08-29

    A compact particle accelerator having an input portion configured to receive power to produce particles for acceleration, where the input portion includes a switch, is provided. In a general embodiment, a vacuum tube receives particles produced from the input portion at a first end, and a plurality of wafer stacks are positioned serially along the vacuum tube. Each of the plurality of wafer stacks include a dielectric and metal-oxide pair, wherein each of the plurality of wafer stacks further accelerate the particles in the vacuum tube. A beam shaper coupled to a second end of the vacuum tube shapes themore » particles accelerated by the plurality of wafer stacks into a beam and an output portion outputs the beam.« less

  7. Accelerating gradient improvement using shape-tailor laser front in radiation pressure acceleration progress

    NASA Astrophysics Data System (ADS)

    Wang, W. P.; Shen, B. F.; Xu, Z. Z.

    2017-05-01

    The accelerating gradient of a proton beam is crucial for stable radiation pressure acceleration (RPA) because the multi-dimensional instabilities increase γ times slower in the relativistic region. In this paper, a shape-tailored laser is proposed to significantly accelerate the ions in a controllable high accelerating gradient. In this method, the fastest ions initially rest in the middle of the foil are controlled to catch the compressed electron layer at the end of the hole-boring stage, thus the light-sail stage can start as soon as possible. Then the compressed electron layer is accelerated tightly together with the fastest ions by the shaped laser intensity, which further increases the accelerating gradient in the light-sail stage. Such tailored pulse may be beneficial for the RPA driven by the 10-fs 10 petawatt laser in the future.

  8. Human T-lymphotropic virus proteins and post-translational modification pathways

    PubMed Central

    Bidoia, Carlo

    2012-01-01

    Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications (PTMs). PTMs alter the conformation, the stability, the localization, and hence the pattern of interactions of the targeted protein. Cell pathways involve the activation of enzymes, like kinases, ligases and transferases, that, once activated, act on many proteins simultaneously, altering the state of the cell and triggering the processes they are involved in. Viruses enter a balanced system and hijack the cell, exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways, with the ultimate consequence to perpetuate through their replication. Human T-lymphotropic virus type 1 (HTLV-1) is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions. HTLV-1 protein activity is controlled by PTMs and, in turn, viral activity is associated with the modulation of cellular pathways based on PTMs. More knowledge is acquired about the PTMs involved in the activation of its proteins, like Tax, Rex, p12, p13, p30, HTLV-I basic leucine zipper factor and Gag. However, more has to be understood at the biochemical level in order to counteract the associated fatal outcomes. This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins. PMID:24175216

  9. ACCELERATION RESPONSIVE SWITCH

    DOEpatents

    Chabrek, A.F.; Maxwell, R.L.

    1963-07-01

    An acceleration-responsive device with dual channel capabilities whereby a first circuit is actuated upon attainment of a predetermined maximum acceleration level and when the acceleration drops to a predetermined minimum acceleriltion level another circuit is actuated is described. A fluid-damped sensing mass slidably mounted in a relatively frictionless manner on a shaft through the intermediation of a ball bushing and biased by an adjustable compression spring provides inertially operated means for actuating the circuits. (AEC)

  10. High Gradient Accelerator Research

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Temkin, Richard

    The goal of the MIT program of research on high gradient acceleration is the development of advanced acceleration concepts that lead to a practical and affordable next generation linear collider at the TeV energy level. Other applications, which are more near-term, include accelerators for materials processing; medicine; defense; mining; security; and inspection. The specific goals of the MIT program are: • Pioneering theoretical research on advanced structures for high gradient acceleration, including photonic structures and metamaterial structures; evaluation of the wakefields in these advanced structures • Experimental research to demonstrate the properties of advanced structures both in low-power microwave coldmore » test and high-power, high-gradient test at megawatt power levels • Experimental research on microwave breakdown at high gradient including studies of breakdown phenomena induced by RF electric fields and RF magnetic fields; development of new diagnostics of the breakdown process • Theoretical research on the physics and engineering features of RF vacuum breakdown • Maintaining and improving the Haimson / MIT 17 GHz accelerator, the highest frequency operational accelerator in the world, a unique facility for accelerator research • Providing the Haimson / MIT 17 GHz accelerator facility as a facility for outside users • Active participation in the US DOE program of High Gradient Collaboration, including joint work with SLAC and with Los Alamos National Laboratory; participation of MIT students in research at the national laboratories • Training the next generation of Ph. D. students in the field of accelerator physics.« less

  11. Experimental and finite element study of ultimate strength of continuous composite concrete slabs with steel decking

    NASA Astrophysics Data System (ADS)

    Gholamhoseini, Alireza

    2018-03-01

    Composite one-way concrete slabs with profiled steel decking as permanent formwork are commonly used in the construction industry. The steel decking supports the wet concrete of a cast in situ reinforced or post-tensioned concrete slab and, after the concrete sets, acts as external reinforcement. In this type of slab, longitudinal shear failure between the concrete and the steel decking is the most common type of failure at the ultimate load stage. Design codes require the experimental evaluation of the ultimate load capacity and longitudinal shear strength of each type of steel decking using full-scale tests on simple-span slabs. There is also no procedure in current design codes to evaluate the ultimate load capacity and longitudinal shear strength of continuous composite slabs and this is often assessed experimentally by full-scale tests. This paper presents the results of three full-scale tests up to failure on continuous composite concrete slabs cast with trapezoidal steel decking profile (KF70) that is widely used in Australia. Slab specimens were tested in four-point bending at each span with shear spans of span/4. The longitudinal shear failure of each slab is evaluated and the measured mid-span deflection, the end slip and the mid-span steel and concrete strains are also presented and discussed. Redistribution of bending moment in each slab is presented and discussed. A finite element model is proposed and verified by experimental data using interface element to model the bond properties between steel decking and concrete slab and investigate the ultimate strength of continuous composite concrete slabs.

  12. Understanding How Kurtosis Is Transferred from Input Acceleration to Stress Response and Its Influence on Fatigue Llife

    NASA Technical Reports Server (NTRS)

    Kihm, Frederic; Rizzi, Stephen A.; Ferguson, Neil S.; Halfpenny, Andrew

    2013-01-01

    High cycle fatigue of metals typically occurs through long term exposure to time varying loads which, although modest in amplitude, give rise to microscopic cracks that can ultimately propagate to failure. The fatigue life of a component is primarily dependent on the stress amplitude response at critical failure locations. For most vibration tests, it is common to assume a Gaussian distribution of both the input acceleration and stress response. In real life, however, it is common to experience non-Gaussian acceleration input, and this can cause the response to be non-Gaussian. Examples of non-Gaussian loads include road irregularities such as potholes in the automotive world or turbulent boundary layer pressure fluctuations for the aerospace sector or more generally wind, wave or high amplitude acoustic loads. The paper first reviews some of the methods used to generate non-Gaussian excitation signals with a given power spectral density and kurtosis. The kurtosis of the response is examined once the signal is passed through a linear time invariant system. Finally an algorithm is presented that determines the output kurtosis based upon the input kurtosis, the input power spectral density and the frequency response function of the system. The algorithm is validated using numerical simulations. Direct applications of these results include improved fatigue life estimations and a method to accelerate shaker tests by generating high kurtosis, non-Gaussian drive signals.

  13. Transverse phase space diagnostics for ionization injection in laser plasma acceleration using permanent magnetic quadrupoles

    NASA Astrophysics Data System (ADS)

    Li, F.; Nie, Z.; Wu, Y. P.; Guo, B.; Zhang, X. H.; Huang, S.; Zhang, J.; Cheng, Z.; Ma, Y.; Fang, Y.; Zhang, C. J.; Wan, Y.; Xu, X. L.; Hua, J. F.; Pai, C. H.; Lu, W.; Mori, W. B.

    2018-04-01

    We report the transverse phase space diagnostics for electron beams generated through ionization injection in a laser-plasma accelerator. Single-shot measurements of both ultimate emittance and Twiss parameters are achieved by means of permanent magnetic quadrupole. Beams with emittance of μm rad level are obtained in a typical ionization injection scheme, and the dependence on nitrogen concentration and charge density is studied experimentally and confirmed by simulations. A key feature of the transverse phase space, matched beams with Twiss parameter α T ≃ 0, is identified according to the measurement. Numerical simulations that are in qualitative agreement with the experimental results reveal that a sufficient phase mixing induced by an overlong injection length leads to the matched phase space distribution.

  14. The Ultimate Strength of Double Hull Oil Tanker Due to Grounding and Collision

    NASA Astrophysics Data System (ADS)

    Izaak Latumahina, Samuel; Zubair Muis Alie, Muhammad; Sitepu, Ganding

    2018-02-01

    The damaged tanker by grounding and collision may totally collapse if loss its buoyancy, stability and suffer structural failure. The objective of the present study is to investigate the ultimate strength of double hull oil tanker under vertical bending moments due to grounding and collision. The damages are modelled by removing the elements consist of stiffened and unstiffened plates from the damages part. One-frame space of the double hull oil tanker is taken to be analysed. Two damages cases are considered in the analyses those are grounding and collision. The transversal damage extent for grounding are 10%, 25%, 40% and 55%. The groundings are placed at symmetric position on the outer bottom part. For the case of collision, the vertical damage extent are taken as 10%, 20%, 40% and 60%. The transversal damages extent is taken to be B/16 and it is constant for all collision damages. The investigation of the ultimate strength is performed by the Non-Linear Finite Element Analysis method under moment control. The boundary condition is applied with fully constrained on all nodes at the aft-end, while the rigid linked on all nodes is attached at the fore-end with respect to the reference point on the neutral axis. The initial imperfection, welding residual stress and crack are not considered in the analyses. The results obtained by Non-Linear Finite Element Analyses for the ultimate strength are compared with the in-house program using Smith’s method implemented in HULLST. The stress distribution and deformation for every case of damages including intact are also discussed in the present study.

  15. Space simulation ultimate pressure lowered two decades by removal of diffusion pump oil contaminants during operation

    NASA Technical Reports Server (NTRS)

    Buggele, A. E.

    1973-01-01

    The complex problem why large space simulation chambers do not realize the true ultimate vacuum was investigated. Some contaminating factors affecting diffusion pump performance have been identified and some advances in vacuum/distillation/fractionation technology have been achieved which resulted in a two decade or more lower ultimate pressure. Data are presented to show the overall or individual contaminating effect of commonly used phthalate ester plasticizers of 390 to 530 molecular weight on diffusion pump performance. Methods for removing contaminants from diffusion pump silicone oil during operation and reclaiming contaminated oil by high vacuum molecular distillation are described.

  16. PKM2-dependent metabolic reprogramming in CD4+ T cells is crucial for hyperhomocysteinemia-accelerated atherosclerosis.

    PubMed

    Lü, Silin; Deng, Jiacheng; Liu, Huiying; Liu, Bo; Yang, Juan; Miao, Yutong; Li, Jing; Wang, Nan; Jiang, Changtao; Xu, Qingbo; Wang, Xian; Feng, Juan

    2018-06-01

    Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE -/- mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling. In this study, we further explored the important role of glycolysis-mediated metabolic reprogramming in Hcy-activated CD4 + T cells. Mechanistically, Hcy-activated CD4 + T cell increased the protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 by small interfering RNA reduced Hcy-induced CD4 + T cell IFN-γ secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2 fl/fl mice and observed that Hcy-induced glycolysis and oxidative phosphorylation were both diminished in PKM2-deficient CD4 + T cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-γ secretion. T cell-depleted apolipoprotein E-deficient (ApoE -/- ) mice adoptively transferred with PKM2-deficient CD4 + T cells, compared to mice transferred with control cells, showed significantly decreased HHcy-accelerated early atherosclerotic lesion formation. In conclusion, this work indicates that the PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic regulation, is crucial for HHcy-induced CD4 + T cell activation to accelerate early atherosclerosis in ApoE -/- mice. Metabolic reprogramming is crucial for Hcy-induced CD4 + T cell inflammatory activation. Hcy activates

  17. Ultimate Tensile Strength as a Function of Test Rate for Various Ceramic Matrix Composites at Elevated Temperatures

    NASA Technical Reports Server (NTRS)

    Choi, Sung R.; Bansal, Narottam P.; Gyekenyesi, John P.

    2002-01-01

    Ultimate tensile strength of five different continuous fiber-reinforced ceramic composites, including SiC/BSAS (2D 2 types), SiC/MAS-5 (2D), SiC/SiC (2D enhanced), and C/SiC(2D) was determined as a function of test rate at I 100 to 1200 'C in air. All five composite materials exhibited a significant dependency of ultimate strength on test rate such that the ultimate strength decreased with decreasing test rate, similar to the behavior observed in many advanced monolithic ceramics at elevated temperatures. The application of the preloading technique as well as the prediction of life from one loading configuration (constant stress rate) to another (constant stress loading) for SiC/BSAS suggested that the overall macroscopic failure mechanism of the composites would be the one governed by a power-law type of damage evolution/accumulation, analogous to slow crack growth commonly observed in advanced monolithic ceramics.

  18. Linear Accelerator (LINAC)

    MedlinePlus

    ... equipment? How is safety ensured? What is this equipment used for? A linear accelerator (LINAC) is the ... Therapy (SBRT) . top of page How does the equipment work? The linear accelerator uses microwave technology (similar ...

  19. Virtual Institute of Microbial Stress and Survival: Deduction of Stress Response Pathways in Metal and Radionuclide Reducing Microorganisms

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    None

    2004-04-17

    The projects application goals are to: (1) To understand bacterial stress-response to the unique stressors in metal/radionuclide contamination sites; (2) To turn this understanding into a quantitative, data-driven model for exploring policies for natural and biostimulatory bioremediation; (3) To implement proposed policies in the field and compare results to model predictions; and (4) Close the experimental/computation cycle by using discrepancies between models and predictions to drive new measurements and construction of new models. The projects science goals are to: (1) Compare physiological and molecular response of three target microorganisms to environmental perturbation; (2) Deduce the underlying regulatory pathways that controlmore » these responses through analysis of phenotype, functional genomic, and molecular interaction data; (3) Use differences in the cellular responses among the target organisms to understand niche specific adaptations of the stress and metal reduction pathways; (4) From this analysis derive an understanding of the mechanisms of pathway evolution in the environment; and (5) Ultimately, derive dynamical models for the control of these pathways to predict how natural stimulation can optimize growth and metal reduction efficiency at field sites.« less

  20. [Development and implementation of an integrated care pathway at the POLIKUM health centers using the example of anemia].

    PubMed

    Bierbaum, M; Grad, M O; Wulff, H; Kewenig, S; Schöffski, O

    2014-04-01

    Integrated treatment pathways are an appropriate means for increasing the quality of treatment and outcome via process optimization. Taking the POLIKUM Health Centers as an example, we intend to demonstrate how the implementation can be effected for the indication of anemia. The development and implementation were executed by an interdisciplinary workgroup in several workshops. In addition, the diagnoses and hemoglobin values of all patients with requests for hemograms were obtained and analyzed at two locations. Developing the pathway required significantly greater efforts than initially planned. The biggest challenge was to adequately map the complexity of the different forms of anemia and, concomitantly, to design a pathway that can actually be realized in everyday life. Moreover, evaluation of the patient data demonstrated that there are a large number of cases where existing anemias are not reflected in the respective diagnoses. While the ultimate effects of the new pathway cannot yet be assessed conclusively, it was possible to obtain valuable findings for practical use even at this point. Despite the limitations of the sample, the surprisingly high number of undetected anemias should give physicians cause for taking diagnostic measures even in patients with mild anemia.

  1. 78 FR 55117 - Ultimate Heat Sink for Nuclear Power Plants; Draft Regulatory Guide

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-09

    ... applicants may use to implement general design criteria (GDC) that are applicable to the ultimate heat sink... only for comments received on or before this date. Although a time limit is given, comments and... published guides are encouraged at any time. ADDRESSES: You may submit comment by any of the following...

  2. Evidence for two distinct phosphorylation pathways activated by high affinity immunoglobulin E receptors.

    PubMed

    Adamczewski, M; Paolini, R; Kinet, J P

    1992-09-05

    The high affinity receptor for immunoglobulin (Ig) E on mast cells, along with the antigen receptors on T and B cells and Fc receptors for IgG, belongs to a class of receptors which lack intrinsic kinase activity, but activate non-receptor tyrosine and serine/threonine kinases. Receptor engagement triggers a chain of signaling events leading from protein phosphorylation to activation of phosphatidylinositol-specific phospholipase C, an increase in intracellular calcium levels, and ultimately the activation of more specialized functions. IgE receptor disengagement leads to reversal of phosphorylation by undefined phosphatases and to inhibition of activation pathways. Here we show that phenylarsine oxide, a chemical which reacts with thiol groups and has been reported to inhibit tyrosine phosphatases, uncouples the IgE receptor-mediated phosphorylation signal from activation of phosphatidyl inositol metabolism, the increase in intracellular calcium levels, and serotonin release. Phenylarsine oxide inhibits neither the kinases (tyrosine and serine/threonine) phosphorylating the receptor and various cellular substrates nor, unexpectedly, the phosphatases responsible for the dephosphorylation following receptor disengagement. By contrast, it abolishes the receptor-mediated phosphorylation of phospholipase C-gamma 1, but not phospholipase C activity in vitro. Therefore the phosphorylation and activation of phospholipase C likely requires a phenylarsine oxide-sensitive element. Receptor aggregation thus activates at least two distinct phosphorylation pathways: a phenylarsine oxide-insensitive pathway leading to phosphorylation/dephosphorylation of the receptor and of various substrates and a sensitive pathway leading to phospholipase C-gamma 1 phosphorylation.

  3. USPAS | U.S. Particle Accelerator School

    Science.gov Websites

    U.S. Particle Accelerator School U.S. Particle Accelerator School U.S. Particle Accelerator School U.S. Particle Accelerator School Education in Beam Physics and Accelerator Technology Home About About University Credits Joint International Accelerator School University-Style Programs Symposium-Style Programs

  4. The spinning disc: studying radial acceleration and its damping process with smartphone acceleration sensors

    NASA Astrophysics Data System (ADS)

    Hochberg, K.; Gröber, S.; Kuhn, J.; Müller, A.

    2014-03-01

    Here, we show the possibility of analysing circular motion and acceleration using the acceleration sensors of smartphones. For instance, the known linear dependence of the radial acceleration on the distance to the centre (a constant angular frequency) can be shown using multiple smartphones attached to a revolving disc. As a second example, the decrease of the radial acceleration and the rotation frequency due to friction can be measured and fitted with a quadratic function, in accordance with theory. Finally, because the disc is not set up exactly horizontal, each smartphone measures a component of the gravitational acceleration that adds to the radial acceleration during one half of the period and subtracts from the radial acceleration during the other half. Hence, every graph shows a small modulation, which can be used to determine the rotation frequency, thus converting a ‘nuisance effect’ into a source of useful information, making additional measurements with stopwatches or the like unnecessary.

  5. Social-Emotional Characteristics of Gifted Accelerated and Non-Accelerated Students in the Netherlands

    ERIC Educational Resources Information Center

    Hoogeveen, Lianne; van Hell, Janet G.; Verhoeven, Ludo

    2012-01-01

    Background: In the studies of acceleration conducted so far a multidimensional perspective has largely been neglected. No attempt has been made to relate social-emotional characteristics of accelerated versus non-accelerated students in perspective of environmental factors. Aims: In this study, social-emotional characteristics of accelerated…

  6. Anomalous acceleration of ions in a plasma accelerator with an anodic layer

    NASA Astrophysics Data System (ADS)

    V, M. BARDAKOV; S, D. IVANOV; A, V. KAZANTSEV; N, A. STROKIN; A, N. STUPIN; Binhao, JIANG; Zhenyu, WANG

    2018-03-01

    In a plasma accelerator with an anodic layer (PAAL), we discovered experimentally the effect of ‘super-acceleration’ of the bulk of the ions to energies W exceeding the energy equivalent to the discharge voltage V d. The E × B discharge was ignited in an environment of atomic argon and helium and molecular nitrogen. Singly charged argon ions were accelerated most effectively in the case of the largest discharge currents and pressure P of the working gas. Helium ions with W > eV d (e being the electron charge) were only recorded at maximum pressures. Molecular nitrogen was not accelerated to energies W > eV d. Anomalous acceleration is realized in the range of radial magnetic fields on the anode 2.8 × 10 -2 ≤ B rA ≤ 4 × 10 -2 T. It was also found analytically that the cathode of the accelerator can receive anomalously accelerated ions. In this case, the value of the potential in the anodic layer becomes higher than the anode potential, and the anode current exceeds some critical value. Numerical modeling in terms of the developed theory showed qualitative agreement between modeling data and measurements.

  7. Epidermal E-Cadherin Dependent β-Catenin Pathway Is Phytochemical Inducible and Accelerates Anagen Hair Cycling.

    PubMed

    Ahmed, Noha S; Ghatak, Subhadip; El Masry, Mohamed S; Gnyawali, Surya C; Roy, Sashwati; Amer, Mohamed; Everts, Helen; Sen, Chandan K; Khanna, Savita

    2017-11-01

    Unlike the epidermis, which regenerates continually, hair follicles anchored in the subcutis periodically regenerate by spontaneous repetitive cycles of growth (anagen), degeneration (catagen), and rest (telogen). The loss of hair follicles in response to injuries or pathologies such as alopecia endangers certain inherent functions of the skin. Thus, it is of interest to understand mechanisms underlying follicular regeneration in adults. In this work, a phytochemical rich in the natural vitamin E tocotrienol (TRF) served as a productive tool to unveil a novel epidermal pathway of hair follicular regeneration. Topical TRF application markedly induced epidermal hair follicle development akin to that during fetal skin development. This was observed in the skin of healthy as well as diabetic mice, which are known to be resistant to anagen hair cycling. TRF suppressed epidermal E-cadherin followed by 4-fold induction of β-catenin and its nuclear translocation. Nuclear β-catenin interacted with Tcf3. Such sequestration of Tcf3 from its otherwise known function to repress pluripotent factors induced the plasticity factors Oct4, Sox9, Klf4, c-Myc, and Nanog. Pharmacological inhibition of β-catenin arrested anagen hair cycling by TRF. This work reports epidermal E-cadherin/β-catenin as a novel pathway capable of inducing developmental folliculogenesis in the adult skin. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  8. Ultimate pier and contraction scour prediction in cohesive soils at selected bridges in Illinois.

    DOT National Transportation Integrated Search

    2013-09-01

    The Scour Rate In COhesive Soils-Erosion Function Apparatus (SRICOS-EFA) method includes an ultimate scour prediction that is : the equilibrium maximum pier and contraction scour of cohesive soils over time. The purpose of this report is to present t...

  9. Rapid evolution of piRNA pathway in the teleost fish: implication for an adaptation to transposon diversity.

    PubMed

    Yi, Minhan; Chen, Feng; Luo, Majing; Cheng, Yibin; Zhao, Huabin; Cheng, Hanhua; Zhou, Rongjia

    2014-05-19

    The Piwi-interacting RNA (piRNA) pathway is responsible for germline specification, gametogenesis, transposon silencing, and genome integrity. Transposable elements can disrupt genome and its functions. However, piRNA pathway evolution and its adaptation to transposon diversity in the teleost fish remain unknown. This article unveils evolutionary scene of piRNA pathway and its association with diverse transposons by systematically comparative analysis on diverse teleost fish genomes. Selective pressure analysis on piRNA pathway and miRNA/siRNA (microRNA/small interfering RNA) pathway genes between teleosts and mammals showed an accelerated evolution of piRNA pathway genes in the teleost lineages, and positive selection on functional PAZ (Piwi/Ago/Zwille) and Tudor domains involved in the Piwi-piRNA/Tudor interaction, suggesting that the amino acid substitutions are adaptive to their functions in piRNA pathway in the teleost fish species. Notably five piRNA pathway genes evolved faster in the swamp eel, a kind of protogynous hermaphrodite fish, than the other teleosts, indicating a differential evolution of piRNA pathway between the swamp eel and other gonochoristic fishes. In addition, genome-wide analysis showed higher diversity of transposons in the teleost fish species compared with mammals. Our results suggest that rapidly evolved piRNA pathway in the teleost fish is likely to be involved in the adaption to transposon diversity. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  10. Acceleration characteristics of human ocular accommodation.

    PubMed

    Bharadwaj, Shrikant R; Schor, Clifton M

    2005-01-01

    Position and velocity of accommodation are known to increase with stimulus magnitude, however, little is known about acceleration properties. We investigated three acceleration properties: peak acceleration, time-to-peak acceleration and total duration of acceleration to step changes in defocus. Peak velocity and total duration of acceleration increased with response magnitude. Peak acceleration and time-to-peak acceleration remained independent of response magnitude. Independent first-order and second-order dynamic components of accommodation demonstrate that neural control of accommodation has an initial open-loop component that is independent of response magnitude and a closed-loop component that increases with response magnitude.

  11. Bio-Spectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Ageing Mouse Model.

    PubMed

    Fimognari, Nicholas; Hollings, Ashley; Lam, Virginie; Tidy, Rebecca J; Kewish, Cameron M; Albrecht, Matthew A; Takechi, Ryu; Mamo, John C L; Hackett, Mark J

    2018-06-14

    Western society is facing a health epidemic due to the increasing incidence of dementia in ageing populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Ageing is the greatest risk factor for memory loss that occurs during the natural ageing process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Therefore, greater understanding of the biochemical pathways that drive a healthy ageing brain towards dementia (pathological ageing or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein over-expression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural ageing process. A promising animal model reported to model mechanisms of accelerated natural ageing and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain ageing. A limitation to traditional methods of biochemical characterisation is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or micro-spatial resolution. Therefore, in this investigation we report the first multi-modal biospectroscopic characterisation of the SAMP8 model, and have identified important biochemical and elemental alterations, and co-localisations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of altered metabolism and disturbed lipid homeostasis within corpus callosum white matter, in addition to localised hippocampal metal deficiencies, in the accelerated ageing phenotype. Such findings have important implication for future research aimed at

  12. Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters

    PubMed Central

    Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong

    2016-01-01

    ABSTRACT The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. IMPORTANCE Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. PMID:27068592

  13. Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters.

    PubMed

    Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong; Alexandre, Gladys

    2016-06-15

    The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  14. Angular Acceleration without Torque?

    ERIC Educational Resources Information Center

    Kaufman, Richard D.

    2012-01-01

    Hardly. Just as Robert Johns qualitatively describes angular acceleration by an internal force in his article "Acceleration Without Force?" here we will extend the discussion to consider angular acceleration by an internal torque. As we will see, this internal torque is due to an internal force acting at a distance from an instantaneous center.

  15. 1985 Particle Accelerator Conference: Accelerator Engineering and Technology, 11th, Vancouver, Canada, May 13-16, 1985, Proceedings

    NASA Astrophysics Data System (ADS)

    Strathdee, A.

    1985-10-01

    The topics discussed are related to high-energy accelerators and colliders, particle sources and electrostatic accelerators, controls, instrumentation and feedback, beam dynamics, low- and intermediate-energy circular accelerators and rings, RF and other acceleration systems, beam injection, extraction and transport, operations and safety, linear accelerators, applications of accelerators, radiation sources, superconducting supercolliders, new acceleration techniques, superconducting components, cryogenics, and vacuum. Accelerator and storage ring control systems are considered along with linear and nonlinear orbit theory, transverse and longitudinal instabilities and cures, beam cooling, injection and extraction orbit theory, high current dynamics, general beam dynamics, and medical and radioisotope applications. Attention is given to superconducting RF structures, magnet technology, superconducting magnets, and physics opportunities with relativistic heavy ion accelerators.

  16. Accelerators for America's Future

    NASA Astrophysics Data System (ADS)

    Bai, Mei

    2016-03-01

    Particle accelerator, a powerful tool to energize beams of charged particles to a desired speed and energy, has been the working horse for investigating the fundamental structure of matter and fundermental laws of nature. Most known examples are the 2-mile long Stanford Linear Accelerator at SLAC, the high energy proton and anti-proton collider Tevatron at FermiLab, and Large Hadron Collider that is currently under operation at CERN. During the less than a century development of accelerator science and technology that led to a dazzling list of discoveries, particle accelerators have also found various applications beyond particle and nuclear physics research, and become an indispensible part of the economy. Today, one can find a particle accelerator at almost every corner of our lives, ranging from the x-ray machine at the airport security to radiation diagnostic and therapy in hospitals. This presentation will give a brief introduction of the applications of this powerful tool in fundermental research as well as in industry. Challenges in accelerator science and technology will also be briefly presented

  17. Medulloblastoma initiation and spread: Where neurodevelopment, microenvironment and cancer cross pathways.

    PubMed

    Martirosian, Vahan; Chen, Thomas C; Lin, Michelle; Neman, Josh

    2016-12-01

    Medulloblastomas are the most common malignant pediatric brain tumors. Over the past several decades, a wide range of tumor-centric studies have identified genes and their regulators within signaling pathways that promote medulloblastoma growth. This review aims to raise awareness that transdisciplinary research between developmental neurobiology and cancer foundations can advance our current understanding of how the nervous system contributes to medulloblastomas. By leveraging current advances in neurodevelopment, microenvironment (including secreted neuropeptides), neurotransmitters, and axon guidance cues, we can uncover novel mechanisms used by the nervous system to promote medulloblastoma growth and spread. This will ultimately result in development of improved strategies for cancer prevention and treatment of pediatric patients with this devastating disease. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics.

    PubMed

    Kantarci, Sibel; Donahoe, Patricia K

    2007-05-15

    Congenital diaphragmatic hernia (CDH) is a common birth defect with high mortality and morbidity. Two hundred seventy CDH patients were ascertained, carefully phenotyped, and classified as isolated (diaphragm defects alone) or complex (with additional anomalies) cases. We established different strategies to reveal CDH-critical chromosome loci and genes in humans. Candidate genes for sequencing analyses were selected from CDH animal models, genetic intervals of recurrent chromosomal aberration in humans, such as 15q26.1-q26.2 or 1q41-q42.12, as well as genes in the retinoic acid and related pathways and those known to be involved in embryonic lung development. For instance, FOG2, GATA4, and COUP-TFII are all needed for both normal diaphragm and lung development and are likely all in the same genetic and molecular pathway. Linkage analysis was applied first in a large inbred family and then in four multiplex families with Donnai-Barrow syndrome (DBS) associated with CDH. 10K SNP chip and microsatellite markers revealed a DBS locus on chromosome 2q23.3-q31.1. We applied array-based comparative genomic hybridization (aCGH) techniques to over 30, mostly complex, CDH patients and found a de novo microdeletion in a patient with Fryns syndrome related to CDH. Fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) techniques allowed us to further define the deletion interval. Our aim is to identify genetic intervals and, in those, to prioritize genes that might reveal molecular pathways, mutations in any step of which, might contribute to the same phenotype. More important, the elucidation of pathways may ultimately provide clues to treatment strategies. (c) 2007 Wiley-Liss, Inc.

  19. Improved plasma accelerator

    NASA Technical Reports Server (NTRS)

    Cheng, D. Y.

    1971-01-01

    Converging, coaxial accelerator electrode configuration operates in vacuum as plasma gun. Plasma forms by periodic injections of high pressure gas that is ionized by electrical discharges. Deflagration mode of discharge provides acceleration, and converging contours of plasma gun provide focusing.

  20. Beam acceleration through proton radio frequency quadrupole accelerator in BARC

    NASA Astrophysics Data System (ADS)

    Bhagwat, P. V.; Krishnagopal, S.; Mathew, J. V.; Singh, S. K.; Jain, P.; Rao, S. V. L. S.; Pande, M.; Kumar, R.; Roychowdhury, P.; Kelwani, H.; Rama Rao, B. V.; Gupta, S. K.; Agarwal, A.; Kukreti, B. M.; Singh, P.

    2016-05-01

    A 3 MeV proton Radio Frequency Quadrupole (RFQ) accelerator has been designed at the Bhabha Atomic Research Centre, Mumbai, India, for the Low Energy High Intensity Proton Accelerator (LEHIPA) programme. The 352 MHz RFQ is built in 4 segments and in the first phase two segments of the LEHIPA RFQ were commissioned, accelerating a 50 keV, 1 mA pulsed proton beam from the ion source, to an energy of 1.24 MeV. The successful operation of the RFQ gave confidence in the physics understanding and technology development that have been achieved, and indicate that the road forward can now be traversed rather more quickly.

  1. Coupling and decoupling of the accelerating units for pulsed synchronous linear accelerator

    NASA Astrophysics Data System (ADS)

    Shen, Yi; Liu, Yi; Ye, Mao; Zhang, Huang; Wang, Wei; Xia, Liansheng; Wang, Zhiwen; Yang, Chao; Shi, Jinshui; Zhang, Linwen; Deng, Jianjun

    2017-12-01

    A pulsed synchronous linear accelerator (PSLA), based on the solid-state pulse forming line, photoconductive semiconductor switch, and high gradient insulator technologies, is a novel linear accelerator. During the prototype PSLA commissioning, the energy gain of proton beams was found to be much lower than expected. In this paper, the degradation of the energy gain is explained by the circuit and cavity coupling effect of the accelerating units. The coupling effects of accelerating units are studied, and the circuit topologies of these two kinds of coupling effects are presented. Two methods utilizing inductance and membrane isolations, respectively, are proposed to reduce the circuit coupling effects. The effectiveness of the membrane isolation method is also supported by simulations. The decoupling efficiency of the metal drift tube is also researched. We carried out the experiments on circuit decoupling of the multiple accelerating cavity. The result shows that both circuit decoupling methods could increase the normalized voltage.

  2. Refining the aggregate exposure pathway.

    PubMed

    Tan, Yu-Mei; Leonard, Jeremy A; Edwards, Stephen; Teeguarden, Justin; Egeghy, Peter

    2018-03-01

    Advancements in measurement technologies and modeling capabilities continue to result in an abundance of exposure information, adding to that currently in existence. However, fragmentation within the exposure science community acts as an obstacle for realizing the vision set forth in the National Research Council's report on Exposure Science in the 21 st century to consider exposures from source to dose, on multiple levels of integration, and to multiple stressors. The concept of an Aggregate Exposure Pathway (AEP) was proposed as a framework for organizing and integrating diverse exposure information that exists across numerous repositories and among multiple scientific fields. A workshop held in May 2016 followed introduction of the AEP concept, allowing members of the exposure science community to provide extensive evaluation and feedback regarding the framework's structure, key components, and applications. The current work briefly introduces topics discussed at the workshop and attempts to address key challenges involved in refining this framework. The resulting evolution in the AEP framework's features allows for facilitating acquisition, integration, organization, and transparent application and communication of exposure knowledge in a manner that is independent of its ultimate use, thereby enabling reuse of such information in many applications.

  3. Exploring Ultimate Water Capillary Evaporation in Nanoscale Conduits.

    PubMed

    Li, Yinxiao; Alibakhshi, Mohammad Amin; Zhao, Yihong; Duan, Chuanhua

    2017-08-09

    Capillary evaporation in nanoscale conduits is an efficient heat/mass transfer strategy that has been widely utilized by both nature and mankind. Despite its broad impact, the ultimate transport limits of capillary evaporation in nanoscale conduits, governed by the evaporation/condensation kinetics at the liquid-vapor interface, have remained poorly understood. Here we report experimental study of the kinetic limits of water capillary evaporation in two dimensional nanochannels using a novel hybrid channel design. Our results show that the kinetic-limited evaporation fluxes break down the limits predicated by the classical Hertz-Knudsen equation by an order of magnitude, reaching values up to 37.5 mm/s with corresponding heat fluxes up to 8500 W/cm 2 . The measured evaporation flux increases with decreasing channel height and relative humidity but decreases as the channel temperature decreases. Our findings have implications for further understanding evaporation at the nanoscale and developing capillary evaporation-based technologies for both energy- and bio-related applications.

  4. Testing relativistic electron acceleration mechanisms

    NASA Astrophysics Data System (ADS)

    Green, Janet Carol

    2002-09-01

    This dissertation tests models of relativistic electron acceleration in the earth's outer radiation belt. The models fall into two categories: external and internal. External acceleration models transport and accelerate electrons from a source region in the outer magnetosphere to the inner magnetosphere. Internal acceleration models accelerate a population of electrons already present in the inner magnetosphere. In this dissertation, we test one specific external acceleration mechanism, perform a general test that differentiates between internal and external acceleration models, and test one promising internal acceleration model. We test the models using Polar-HIST data that we transform into electron phase space density (PSD) as a function of adiabatic invariants. We test the ultra low frequency (ULF) wave enhanced radial diffusion external acceleration mechanism by looking for a causal relationship between increased wave power and increased electron PSD at three L* values. One event with increased wave power at two L* values and no subsequent PSD increase does not support the model suggesting that ULF wave power alone is not sufficient to cause an electron response. Excessive loss of electrons and the duration of wave power do not explain the lack of a PSD enhancement at low L*. We differentiate between internal and external acceleration mechanisms by examining the radial profile of electron PSD. We observe PSD profiles that depend on local time. Nightside profiles are highly dependent on the magnetic field model used to calculate PSD as a function of adiabatic invariants and are not reliable. Dayside PSD profiles are more robust and consistent with internal acceleration of electrons. We test one internal acceleration model, the whistler/electromagnetic ion cyclotron wave model, by comparing observed pitch angle distributions to those predicted by the model using a superposed epoch analysis. The observations show pitch angle distributions corresponding to

  5. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy?

    PubMed

    Jagoe, R T; Goldberg, A L

    2001-05-01

    Studies of many different rodent models of muscle wasting have indicated that accelerated proteolysis via the ubiquitin-proteasome pathway is the principal cause of muscle atrophy induced by fasting, cancer cachexia, metabolic acidosis, denervation, disuse, diabetes, sepsis, burns, hyperthyroidism and excess glucocorticoids. However, our understanding about how muscle proteins are degraded, and how the ubiquitin-proteasome pathway is activated in muscle under these conditions, is still very limited. The identities of the important ubiquitin-protein ligases in skeletal muscle, and the ways in which they recognize substrates are still largely unknown. Recent in-vitro studies have suggested that one set of ubquitination enzymes, E2(14K) and E3(alpha), which are responsible for the 'N-end rule' system of ubiquitination, plays an important role in muscle, especially in catabolic states. However, their functional significance in degrading different muscle proteins is still unclear. This review focuses on the many gaps in our understanding of the functioning of the ubiquitin-proteasome pathway in muscle atrophy, and highlights the strengths and limitations of the different experimental approaches used in such studies.

  6. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy?

    NASA Technical Reports Server (NTRS)

    Jagoe, R. T.; Goldberg, A. L.

    2001-01-01

    Studies of many different rodent models of muscle wasting have indicated that accelerated proteolysis via the ubiquitin-proteasome pathway is the principal cause of muscle atrophy induced by fasting, cancer cachexia, metabolic acidosis, denervation, disuse, diabetes, sepsis, burns, hyperthyroidism and excess glucocorticoids. However, our understanding about how muscle proteins are degraded, and how the ubiquitin-proteasome pathway is activated in muscle under these conditions, is still very limited. The identities of the important ubiquitin-protein ligases in skeletal muscle, and the ways in which they recognize substrates are still largely unknown. Recent in-vitro studies have suggested that one set of ubquitination enzymes, E2(14K) and E3(alpha), which are responsible for the 'N-end rule' system of ubiquitination, plays an important role in muscle, especially in catabolic states. However, their functional significance in degrading different muscle proteins is still unclear. This review focuses on the many gaps in our understanding of the functioning of the ubiquitin-proteasome pathway in muscle atrophy, and highlights the strengths and limitations of the different experimental approaches used in such studies.

  7. Aloesin from Aloe vera accelerates skin wound healing by modulating MAPK/Rho and Smad signaling pathways in vitro and in vivo.

    PubMed

    Wahedi, Hussain Mustatab; Jeong, Minsun; Chae, Jae Kyoung; Do, Seon Gil; Yoon, Hyeokjun; Kim, Sun Yeou

    2017-05-15

    Cutaneous wound healing is a complex process involving various regulatory factors at the molecular level. Aloe vera is widely used for cell rejuvenation, wound healing, and skin moisturizing. This study aimed to investigate the effects of aloesin from Aloe vera on cutaneous wound healing and mechanisms involved therein. This study consisted of both in vitro and in vivo experiments involving skin cell lines and mouse model to demonstrate the wound healing effects of aloesin by taking into account several parameters ranging from cultured cell migration to wound healing in mice. The activities of Smad signaling molecules (Smad2 and Smad3), MAPKs (ERK and JNK), and migration-related proteins (Cdc42, Rac1, and α-Pak) were assessed after aloesin treatment in cultured cells (1, 5 and 10µM) and mouse skin (0.1% and 0.5%). We also monitored macrophage recruitment, secretion of cytokines and growth factors, tissue development, and angiogenesis after aloesin treatment using IHC analysis and ELISAs. Aloesin increased cell migration via phosphorylation of Cdc42 and Rac1. Aloesin positively regulated the release of cytokines and growth factors (IL-1β, IL-6, TGF-β1 and TNF-α) from macrophages (RAW264.7) and enhanced angiogenesis in endothelial cells (HUVECs). Aloesin treatment accelerated wound closure rates in hairless mice by inducing angiogenesis, collagen deposition and granulation tissue formation. More importantly, aloesin treatment resulted in the activation of Smad and MAPK signaling proteins that are key players in cell migration, angiogenesis and tissue development. Aloesin ameliorates each phase of the wound healing process including inflammation, proliferation and remodeling through MAPK/Rho and Smad signaling pathways. These findings indicate that aloesin has the therapeutic potential for treating cutaneous wounds. Copyright © 2017 Elsevier GmbH. All rights reserved.

  8. TGF-β1 accelerates the DNA damage response in epithelial cells via Smad signaling

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Jeeyong; Kim, Mi-Ra; Kim, Hyun-Ji

    The evidence suggests that transforming growth factor-beta (TGF-β) regulates the DNA-damage response (DDR) upon irradiation, and we previously reported that TGF-β1 induced DNA ligase IV (Lig4) expression and enhanced the nonhomologous end-joining repair pathway in irradiated cells. In the present study, we investigated the effects of TGF-β1 on the irradiation-induced DDRs of A431 and HaCaT cells. Cells were pretreated with or without TGF-β1 and irradiated. At 30 min post-irradiation, DDRs were detected by immunoblotting of phospho-ATM, phospho-Chk2, and the presence of histone foci (γH2AX). The levels of all three factors were similar right after irradiation regardless of TGF-β1 pretreatment. However, theymore » soon thereafter exhibited downregulation in TGF-β1-pretreated cells, indicating the acceleration of the DDR. Treatment with a TGF-β type I receptor inhibitor (SB431542) or transfections with siRNAs against Smad2/3 or DNA ligase IV (Lig4) reversed this acceleration of the DDR. Furthermore, the frequency of irradiation-induced apoptosis was decreased by TGF-β1 pretreatment in vivo, but this effect was abrogated by SB431542. These results collectively suggest that TGF-β1 could enhance cell survival by accelerating the DDR via Smad signaling and Lig4 expression. -- Highlights: •TGF-β1 pretreatment accelerates γ-radiation-induced DNA damage response. •TGF-β1-accelerated DNA damage response is dependent on Smad signaling and DNA Ligase IV. •TGF-β1 pretreatment protects epithelial cells from γ-radiation in vivo.« less

  9. User's guide to UGRS: the Ultimate Grading and Remanufacturing System (version 5.0).

    Treesearch

    John Moody; Charles J. Gatchell; Elizabeth S. Walker; Powsiri Klinkhachorn

    1998-01-01

    The Ultimate Grading and Remanufacturing System (UGRS) is the latest generation of advanced computer programs for lumber grading. It is designed to be a training and research tool that allows grading of lumber according to 1998 NHLA rules and remanufacturing for maximum dollar value. A 32-bit application that runs under all Microsoft Windows operating systems, UGRS...

  10. Multi-beam linear accelerator EVT

    NASA Astrophysics Data System (ADS)

    Teryaev, Vladimir E.; Kazakov, Sergey Yu.; Hirshfield, Jay L.

    2016-09-01

    A novel electron multi-beam accelerator is presented. The accelerator, short-named EVT (Electron Voltage Transformer) belongs to the class of two-beam accelerators. It combines an RF generator and essentially an accelerator within the same vacuum envelope. Drive beam-lets and an accelerated beam are modulated in RF modulators and then bunches pass into an accelerating structure, comprising uncoupled with each other and inductive tuned cavities, where the energy transfer from the drive beams to the accelerated beam occurs. A phasing of bunches is solved by choice correspond distances between gaps of the adjacent cavities. Preliminary results of numerical simulations and the initial specification of EVT operating in S-band, with a 60 kV gun and generating a 2.7 A, 1.1 MV beam at its output is presented. A relatively high efficiency of 67% and high design average power suggest that EVT can find its use in industrial applications.

  11. Multi-beam linear accelerator EVT

    DOE PAGES

    Teryaev, Vladimir E.; Kazakov, Sergey Yu.; Hirshfield, Jay L.

    2016-03-29

    A novel electron multi-beam accelerator is presented. The accelerator, short-named EVT (Electron Voltage Transformer) belongs to the class of two-beam accelerators. It combines an RF generator and essentially an accelerator within the same vacuum envelope. Drive beam-lets and an accelerated beam are modulated in RF modulators and then bunches pass into an accelerating structure, comprising uncoupled with each other and inductive tuned cavities, where the energy transfer from the drive beams to the accelerated beam occurs. A phasing of bunches is solved by choice correspond distances between gaps of the adjacent cavities. Preliminary results of numerical simulations and the initialmore » specification of EVT operating in S-band, with a 60 kV gun and generating a 2.7 A, 1.1 MV beam at its output is presented. Furthermore, a relatively high efficiency of 67% and high design average power suggest that EVT can find its use in industrial applications.« less

  12. The theoretical ultimate magnetoelectric coefficients of magnetoelectric composites by optimization design

    NASA Astrophysics Data System (ADS)

    Wang, H.-L.; Liu, B.

    2014-03-01

    This paper investigates what is the largest magnetoelectric (ME) coefficient of ME composites, and how to realize it. From the standpoint of energy conservation, a theoretical analysis is carried out on an imaginary lever structure consisting of a magnetostrictive phase, a piezoelectric phase, and a rigid lever. This structure is a generalization of various composite layouts for optimization on ME effect. The predicted theoretical ultimate ME coefficient plays a similar role as the efficiency of ideal heat engine in thermodynamics, and is used to evaluate the existing typical ME layouts, such as the parallel sandwiched layout and the serial layout. These two typical layouts exhibit ME coefficient much lower than the theoretical largest values, because in the general analysis the stress amplification ratio and the volume ratio can be optimized independently and freely, but in typical layouts they are dependent or fixed. To overcome this shortcoming and achieve the theoretical largest ME coefficient, a new design is presented. In addition, it is found that the most commonly used electric field ME coefficient can be designed to be infinitely large. We doubt the validity of this coefficient as a reasonable ME effect index and consider three more ME coefficients, namely the electric charge ME coefficient, the voltage ME coefficient, and the static electric energy ME coefficient. We note that the theoretical ultimate value of the static electric energy ME coefficient is finite and might be a more proper measure of ME effect.

  13. The theoretical ultimate magnetoelectric coefficients of magnetoelectric composites by optimization design

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, H.-L.; Liu, B., E-mail: liubin@tsinghua.edu.cn

    2014-03-21

    This paper investigates what is the largest magnetoelectric (ME) coefficient of ME composites, and how to realize it. From the standpoint of energy conservation, a theoretical analysis is carried out on an imaginary lever structure consisting of a magnetostrictive phase, a piezoelectric phase, and a rigid lever. This structure is a generalization of various composite layouts for optimization on ME effect. The predicted theoretical ultimate ME coefficient plays a similar role as the efficiency of ideal heat engine in thermodynamics, and is used to evaluate the existing typical ME layouts, such as the parallel sandwiched layout and the serial layout.more » These two typical layouts exhibit ME coefficient much lower than the theoretical largest values, because in the general analysis the stress amplification ratio and the volume ratio can be optimized independently and freely, but in typical layouts they are dependent or fixed. To overcome this shortcoming and achieve the theoretical largest ME coefficient, a new design is presented. In addition, it is found that the most commonly used electric field ME coefficient can be designed to be infinitely large. We doubt the validity of this coefficient as a reasonable ME effect index and consider three more ME coefficients, namely the electric charge ME coefficient, the voltage ME coefficient, and the static electric energy ME coefficient. We note that the theoretical ultimate value of the static electric energy ME coefficient is finite and might be a more proper measure of ME effect.« less

  14. Laser Accelerator

    DTIC Science & Technology

    2014-09-01

    hollow metal sphere. Voltages of over 10 MV can be reached if used with an insulating gas. Corona discharge limits all electrostatic accelerators to...laser field. Lasers can have strong electric fields with frequencies high enough to avoid corona formation and break- down. The key is to couple the...leading to a spark discharge in the accelerator and thus a breakdown of the electrostatic field [6], [7]. Figure 1.1: Cockroft-Walton cascade generator

  15. Ultra-high vacuum photoelectron linear accelerator

    DOEpatents

    Yu, David U.L.; Luo, Yan

    2013-07-16

    An rf linear accelerator for producing an electron beam. The outer wall of the rf cavity of said linear accelerator being perforated to allow gas inside said rf cavity to flow to a pressure chamber surrounding said rf cavity and having means of ultra high vacuum pumping of the cathode of said rf linear accelerator. Said rf linear accelerator is used to accelerate polarized or unpolarized electrons produced by a photocathode, or to accelerate thermally heated electrons produced by a thermionic cathode, or to accelerate rf heated field emission electrons produced by a field emission cathode.

  16. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

    PubMed

    Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

    2014-08-15

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

  17. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

    PubMed Central

    Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

    2014-01-01

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

  18. Engineering Ultimate Self-Protection in Autonomic Agents for Space Exploration Missions

    NASA Technical Reports Server (NTRS)

    Sterritt, Roy; Hinchey, Mike

    2005-01-01

    NASA's Exploration Initiative (EI) will push space exploration missions to the limit. Future missions will be required to be self-managing as well as self-directed, in order to meet the challenges of human and robotic space exploration. We discuss security and self protection in autonomic agent based-systems, and propose the ultimate self-protection mechanism for such systems-self-destruction. Like other metaphors in Autonomic Computing, this is inspired by biological systems, and is the analog of biological apoptosis. Finally, we discus the role it might play in future NASA space exploration missions.

  19. Ultimate journey of the terminally ill: Ways and pathways of hope.

    PubMed

    Daneault, Serge; Lussier, Véronique; Mongeau, Suzanne; Yelle, Louise; Côté, Andréanne; Sicotte, Claude; Paillé, Pierre; Dion, Dominique; Coulombe, Manon

    2016-08-01

    To better understand the role of hope among terminally ill cancer patients. Qualitative analysis. A tertiary specialized cancer centre in Canada. Cancer patients in palliative care with an estimated remaining life expectancy of 12 months or less (N = 12) and their loved ones (N = 12) and treating physicians (N = 12). Each patient underwent up to 3 interviews and identified a loved one who participated in 1 interview. Treating physicians were also interviewed. All interviews were fully transcribed and analyzed by at least 2 investigators. Interviews were collected until saturation occurred. Seven attributes describe the experiences of palliative cancer patients and their caregivers: hope as an irrational phenomenon that is a deeply rooted, affect-based response to adversity; initial hope for miraculous healing; hope as a phenomenon that changes over time, evolving in different ways depending on circumstances; hope for prolonged life when there is no further hope for cure; hope for a good quality of life when the possibility of prolonging life becomes limited; a lack of hope for some when treatments are no longer effective in curbing illness progression; and for others hope as enjoying the present moment and preparing for the end of life. Approaches aimed at sustaining hope need to reflect that patients' reactions might fluctuate between despair and a form of acceptance that leads to a certain serenity. Clinicians need to maintain some degree of hope while remaining as realistic as possible. The findings also raise questions about how hope influences patients' perceptions and acceptance of their treatments. Copyright© the College of Family Physicians of Canada.

  20. Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom.

    PubMed

    Huminiecki, Lukasz; Goldovsky, Leon; Freilich, Shiri; Moustakas, Aristidis; Ouzounis, Christos; Heldin, Carl-Henrik

    2009-02-03

    The question of how genomic processes, such as gene duplication, give rise to co-ordinated organismal properties, such as emergence of new body plans, organs and lifestyles, is of importance in developmental and evolutionary biology. Herein, we focus on the diversification of the transforming growth factor-beta (TGF-beta) pathway -- one of the fundamental and versatile metazoan signal transduction engines. After an investigation of 33 genomes, we show that the emergence of the TGF-beta pathway coincided with appearance of the first known animal species. The primordial pathway repertoire consisted of four Smads and four receptors, similar to those observed in the extant genome of the early diverging tablet animal (Trichoplax adhaerens). We subsequently retrace duplications in ancestral genomes on the lineage leading to humans, as well as lineage-specific duplications, such as those which gave rise to novel Smads and receptors in teleost fishes. We conclude that the diversification of the TGF-beta pathway can be parsimoniously explained according to the 2R model, with additional rounds of duplications in teleost fishes. Finally, we investigate duplications followed by accelerated evolution which gave rise to an atypical TGF-beta pathway in free-living bacterial feeding nematodes of the genus Rhabditis. Our results challenge the view of well-conserved developmental pathways. The TGF-beta signal transduction engine has expanded through gene duplication, continually adopting new functions, as animals grew in anatomical complexity, colonized new environments, and developed an active immune system.

  1. Space Acceleration Measurement System (SAMS)/Orbital Acceleration Research Experiment (OARE)

    NASA Technical Reports Server (NTRS)

    Hakimzadeh, Roshanak

    1998-01-01

    The Life and Microgravity Spacelab (LMS) payload flew on the Orbiter Columbia on mission STS-78 from June 20th to July 7th, 1996. The LMS payload on STS-78 was dedicated to life sciences and microgravity experiments. Two accelerometer systems managed by the NASA Lewis Research Center (LERC) flew to support these experiments, namely the Orbital Acceleration Research Experiment (OARE) and the Space Acceleration Measurements System (SAMS). In addition, the Microgravity Measurement Assembly (NOAA), managed by the European Space Research and Technology Center (ESA/ESTEC), and sponsored by NASA, collected acceleration data in support of the experiments on-board the LMS mission. OARE downlinked real-time quasi-steady acceleration data, which was provided to the investigators. The SAMS recorded higher frequency data on-board for post-mission analysis. The MMA downlinked real-time quasi-steady as well as higher frequency acceleration data, which was provided to the investigators. The Principal Investigator Microgravity Services (PIMS) project at NASA LERC supports principal investigators of microgravity experiments as they evaluate the effects of varying acceleration levels on their experiments. A summary report was prepared by PIMS to furnish interested experiment investigators with a guide to evaluate the acceleration environment during STS-78, and as a means of identifying areas which require further study. The summary report provides an overview of the STS-78 mission, describes the accelerometer systems flown on this mission, discusses some specific analyses of the accelerometer data in relation to the various activities which occurred during the mission, and presents plots resulting from these analyses as a snapshot of the environment during the mission. Numerous activities occurred during the STS-78 mission that are of interest to the low-gravity community. Specific activities of interest during this mission were crew exercise, radiator deployment, Vernier Reaction

  2. Benchmarking pathway interaction network for colorectal cancer to identify dysregulated pathways.

    PubMed

    Wang, Q; Shi, C-J; Lv, S-H

    2017-03-30

    Different pathways act synergistically to participate in many biological processes. Thus, the purpose of our study was to extract dysregulated pathways to investigate the pathogenesis of colorectal cancer (CRC) based on the functional dependency among pathways. Protein-protein interaction (PPI) information and pathway data were retrieved from STRING and Reactome databases, respectively. After genes were aligned to the pathways, each pathway activity was calculated using the principal component analysis (PCA) method, and the seed pathway was discovered. Subsequently, we constructed the pathway interaction network (PIN), where each node represented a biological pathway based on gene expression profile, PPI data, as well as pathways. Dysregulated pathways were then selected from the PIN according to classification performance and seed pathway. A PIN including 11,960 interactions was constructed to identify dysregulated pathways. Interestingly, the interaction of mRNA splicing and mRNA splicing-major pathway had the highest score of 719.8167. Maximum change of the activity score between CRC and normal samples appeared in the pathway of DNA replication, which was selected as the seed pathway. Starting with this seed pathway, a pathway set containing 30 dysregulated pathways was obtained with an area under the curve score of 0.8598. The pathway of mRNA splicing, mRNA splicing-major pathway, and RNA polymerase I had the maximum genes of 107. Moreover, we found that these 30 pathways had crosstalks with each other. The results suggest that these dysregulated pathways might be used as biomarkers to diagnose CRC.

  3. Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ting, L; Shi, W; Lewandowicz, A

    Plasmodium falciparum is unable to synthesize purine bases and relies upon purine salvage and purine recycling to meet its purine needs. We report that purines formed as products of the polyamine pathway are recycled in a novel pathway in which 5'-methylthioinosine is generated by adenosine deaminase. The action of P. falciparum purine nucleoside phosphorylase is a convergent step of purine salvage, converting both 5'-methylthioinosine and inosine to hypoxanthine. We used accelerator mass spectrometry to verify that 5'-methylthioinosine is an active nucleic acid precursor in P. falciparum. Prior studies have shown that inhibitors of purine salvage enzymes kill malaria, but potentmore » malaria-specific inhibitors of these enzymes have not previously been described. 5'-methylthio-Immucillin-H, a transition state analogue inhibitor that is selective for malarial over human purine nucleoside phosphorylase, kills P. falciparum in culture. Immucillins are currently in clinical trials for other indications and may have application as antimalarials.« less

  4. Stress transgenerationally programs metabolic pathways linked to altered mental health.

    PubMed

    Kiss, Douglas; Ambeskovic, Mirela; Montina, Tony; Metz, Gerlinde A S

    2016-12-01

    Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Down-stream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-great-grandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1 H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

  5. Advanced Accelerators for Medical Applications

    NASA Astrophysics Data System (ADS)

    Uesaka, Mitsuru; Koyama, Kazuyoshi

    We review advanced accelerators for medical applications with respect to the following key technologies: (i) higher RF electron linear accelerator (hereafter “linac”); (ii) optimization of alignment for the proton linac, cyclotron and synchrotron; (iii) superconducting magnet; (iv) laser technology. Advanced accelerators for medical applications are categorized into two groups. The first group consists of compact medical linacs with high RF, cyclotrons and synchrotrons downsized by optimization of alignment and superconducting magnets. The second group comprises laser-based acceleration systems aimed of medical applications in the future. Laser plasma electron/ion accelerating systems for cancer therapy and laser dielectric accelerating systems for radiation biology are mentioned. Since the second group has important potential for a compact system, the current status of the established energy and intensity and of the required stability are given.

  6. Advanced Accelerators for Medical Applications

    NASA Astrophysics Data System (ADS)

    Uesaka, Mitsuru; Koyama, Kazuyoshi

    We review advanced accelerators for medical applications with respect to the following key technologies: (i) higher RF electron linear accelerator (hereafter "linac"); (ii) optimization of alignment for the proton linac, cyclotron and synchrotron; (iii) superconducting magnet; (iv) laser technology. Advanced accelerators for medical applications are categorized into two groups. The first group consists of compact medical linacs with high RF, cyclotrons and synchrotrons downsized by optimization of alignment and superconducting magnets. The second group comprises laserbased acceleration systems aimed of medical applications in the future. Laser plasma electron/ion accelerating systems for cancer therapy and laser dielectric accelerating systems for radiation biology are mentioned. Since the second group has important potential for a compact system, the current status of the established energy and intensity and of the required stability are given.

  7. 22 CFR 123.9 - Country of ultimate destination and approval of reexports or retransfers.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ARMS REGULATIONS LICENSES FOR THE EXPORT OF DEFENSE ARTICLES § 123.9 Country of ultimate destination... the Directorate of Defense Trade Controls must be obtained before reselling, transferring, reexporting, retransferring, transshipping, or disposing of a defense article to any end-user, end-use, or destination other...

  8. Transverse phase space diagnostics for ionization injection in laser plasma acceleration using permanent magnetic quadrupoles

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, F.; Nie, Z.; Wu, Y. P.

    We report the transverse phase space diagnostics for electron beams generated through ionization injection in a laser-plasma accelerator. Single-shot measurements of both ultimate emittance and Twiss parameters are achieved by means of permanent magnetic quadrupole. Beams with emittance of μm rad level are obtained in a typical ionization injection scheme, and the dependence on nitrogen concentration and charge density is studied experimentally and confirmed by simulations. A key feature of the transverse phase space, matched beams with Twiss parameter α T ≃ 0, is identified according to the measurement. Lastly, numerical simulations that are in qualitative agreement with the experimentalmore » results reveal that a sufficient phase mixing induced by an overlong injection length leads to the matched phase space distribution.« less

  9. Transverse phase space diagnostics for ionization injection in laser plasma acceleration using permanent magnetic quadrupoles

    DOE PAGES

    Li, F.; Nie, Z.; Wu, Y. P.; ...

    2018-02-22

    We report the transverse phase space diagnostics for electron beams generated through ionization injection in a laser-plasma accelerator. Single-shot measurements of both ultimate emittance and Twiss parameters are achieved by means of permanent magnetic quadrupole. Beams with emittance of μm rad level are obtained in a typical ionization injection scheme, and the dependence on nitrogen concentration and charge density is studied experimentally and confirmed by simulations. A key feature of the transverse phase space, matched beams with Twiss parameter α T ≃ 0, is identified according to the measurement. Lastly, numerical simulations that are in qualitative agreement with the experimentalmore » results reveal that a sufficient phase mixing induced by an overlong injection length leads to the matched phase space distribution.« less

  10. The ultimate state of polymeric materials and laminated and fibrous composites under asymmetric high-cycle loading

    NASA Astrophysics Data System (ADS)

    Golub, V. P.; Pogrebniak, A. D.; Kochetkova, E. S.

    2008-01-01

    The prediction of the high-cycle fatigue strength of polymeric and composite materials in asymmetric loading is considered. The problem is solved on the basis of a nonlinear model of ultimate state allowing us to describe all typical forms of the diagrams of ultimate stresses. The material constants of the model are determined from the results of fatigue tests in symmetric reversed cycling, in a single fatigue test with the minimum stress equal to zero, and in a short-term strength test. The fatigue strength characteristics of some polymers, glass-fiber laminates, glass-fiber-reinforced plastics, organic-fiber-reinforced plastics, and wood laminates in asymmetric tension-compression, bending, and torsion have been calculated and approved experimentally.

  11. LINEAR ACCELERATOR

    DOEpatents

    Christofilos, N.C.; Polk, I.J.

    1959-02-17

    Improvements in linear particle accelerators are described. A drift tube system for a linear ion accelerator reduces gap capacity between adjacent drift tube ends. This is accomplished by reducing the ratio of the diameter of the drift tube to the diameter of the resonant cavity. Concentration of magnetic field intensity at the longitudinal midpoint of the external sunface of each drift tube is reduced by increasing the external drift tube diameter at the longitudinal center region.

  12. Gaussian Accelerated Molecular Dynamics in NAMD

    PubMed Central

    2016-01-01

    Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for “unconstrained” enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules. PMID:28034310

  13. Gaussian Accelerated Molecular Dynamics in NAMD.

    PubMed

    Pang, Yui Tik; Miao, Yinglong; Wang, Yi; McCammon, J Andrew

    2017-01-10

    Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for "unconstrained" enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M 3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M 3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules.

  14. Accelerators (4/5)

    ScienceCinema

    Metral, Elias

    2017-12-09

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  15. Accelerators (5/5)

    ScienceCinema

    None

    2018-05-16

    1a) Introduction and motivation; 1b) History and accelerator types; 2) Transverse beam dynamics; 3a) Longitudinal beam dynamics; 3b) Figure of merit of a synchrotron/collider; 3c) Beam control; 4) Main limiting factors; 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  16. Biochemical evidence for Ku-independent backup pathways of NHEJ.

    PubMed

    Wang, Huichen; Perrault, Ange Ronel; Takeda, Yoshihiko; Qin, Wei; Wang, Hongyan; Iliakis, George

    2003-09-15

    Cells of higher eukaryotes process within minutes double strand breaks (DSBs) in their genome using a non-homologous end joining (NHEJ) apparatus that engages DNA-PKcs, Ku, DNA ligase IV, XRCC4 and other as of yet unidentified factors. Although chemical inhibition, or mutation, in any of these factors delays processing, cells ultimately remove the majority of DNA DSBs using an alternative pathway operating with an order of magnitude slower kinetics. This alternative pathway is active in mutants deficient in genes of the RAD52 epistasis group and frequently joins incorrect ends. We proposed, therefore, that it reflects an alternative form of NHEJ that operates as a backup (B-NHEJ) to the DNA-PK-dependent (D-NHEJ) pathway, rather than homology directed repair of DSBs. The present study investigates the role of Ku in the coordination of these pathways using as a model end joining of restriction endonuclease linearized plasmid DNA in whole cell extracts. Efficient, error-free, end joining observed in such in vitro reactions is strongly inhibited by anti-Ku antibodies. The inhibition requires DNA-PKcs, despite the fact that Ku efficiently binds DNA ends in the presence of antibodies, or in the absence of DNA-PKcs. Strong inhibition of DNA end joining is also mediated by wortmannin, an inhibitor of DNA-PKcs, in the presence but not in the absence of Ku, and this inhibition can be rescued by pre-incubating the reaction with double stranded oligonucleotides. The results are compatible with a role of Ku in directing end joining to a DNA-PK dependent pathway, mediated by efficient end binding and productive interactions with DNA-PKcs. On the other hand, efficient end joining is observed in extracts of cells lacking DNA-PKcs, as well as in Ku-depleted extracts in line with the operation of alternative pathways. Extracts depleted of Ku and DNA-PKcs rejoin blunt ends, as well as homologous ends with 3' or 5' protruding single strands with similar efficiency, but addition of Ku

  17. Biochemical evidence for Ku-independent backup pathways of NHEJ

    PubMed Central

    Wang, Huichen; Perrault, Ange Ronel; Takeda, Yoshihiko; Qin, Wei; Wang, Hongyan; Iliakis, George

    2003-01-01

    Cells of higher eukaryotes process within minutes double strand breaks (DSBs) in their genome using a non-homologous end joining (NHEJ) apparatus that engages DNA-PKcs, Ku, DNA ligase IV, XRCC4 and other as of yet unidentified factors. Although chemical inhibition, or mutation, in any of these factors delays processing, cells ultimately remove the majority of DNA DSBs using an alternative pathway operating with an order of magnitude slower kinetics. This alternative pathway is active in mutants deficient in genes of the RAD52 epistasis group and frequently joins incorrect ends. We proposed, therefore, that it reflects an alternative form of NHEJ that operates as a backup (B-NHEJ) to the DNA-PK-dependent (D-NHEJ) pathway, rather than homology directed repair of DSBs. The present study investigates the role of Ku in the coordination of these pathways using as a model end joining of restriction endonuclease linearized plasmid DNA in whole cell extracts. Efficient, error-free, end joining observed in such in vitro reactions is strongly inhibited by anti-Ku antibodies. The inhibition requires DNA-PKcs, despite the fact that Ku efficiently binds DNA ends in the presence of antibodies, or in the absence of DNA-PKcs. Strong inhibition of DNA end joining is also mediated by wortmannin, an inhibitor of DNA-PKcs, in the presence but not in the absence of Ku, and this inhibition can be rescued by pre-incubating the reaction with double stranded oligonucleotides. The results are compatible with a role of Ku in directing end joining to a DNA-PK dependent pathway, mediated by efficient end binding and productive interactions with DNA-PKcs. On the other hand, efficient end joining is observed in extracts of cells lacking DNA-PKcs, as well as in Ku-depleted extracts in line with the operation of alternative pathways. Extracts depleted of Ku and DNA-PKcs rejoin blunt ends, as well as homologous ends with 3′ or 5′ protruding single strands with similar efficiency, but addition of

  18. MiYA, an efficient machine-learning workflow in conjunction with the YeastFab assembly strategy for combinatorial optimization of heterologous metabolic pathways in Saccharomyces cerevisiae.

    PubMed

    Zhou, Yikang; Li, Gang; Dong, Junkai; Xing, Xin-Hui; Dai, Junbiao; Zhang, Chong

    2018-05-01

    Facing boosting ability to construct combinatorial metabolic pathways, how to search the metabolic sweet spot has become the rate-limiting step. We here reported an efficient Machine-learning workflow in conjunction with YeastFab Assembly strategy (MiYA) for combinatorial optimizing the large biosynthetic genotypic space of heterologous metabolic pathways in Saccharomyces cerevisiae. Using β-carotene biosynthetic pathway as example, we first demonstrated that MiYA has the power to search only a small fraction (2-5%) of combinatorial space to precisely tune the expression level of each gene with a machine-learning algorithm of an artificial neural network (ANN) ensemble to avoid over-fitting problem when dealing with a small number of training samples. We then applied MiYA to improve the biosynthesis of violacein. Feed with initial data from a colorimetric plate-based, pre-screened pool of 24 strains producing violacein, MiYA successfully predicted, and verified experimentally, the existence of a strain that showed a 2.42-fold titer improvement in violacein production among 3125 possible designs. Furthermore, MiYA was able to largely avoid the branch pathway of violacein biosynthesis that makes deoxyviolacein, and produces very pure violacein. Together, MiYA combines the advantages of standardized building blocks and machine learning to accelerate the Design-Build-Test-Learn (DBTL) cycle for combinatorial optimization of metabolic pathways, which could significantly accelerate the development of microbial cell factories. Copyright © 2018 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  19. Shade avoidance components and pathways in adult plants revealed by phenotypic profiling.

    PubMed

    Nozue, Kazunari; Tat, An V; Kumar Devisetty, Upendra; Robinson, Matthew; Mumbach, Maxwell R; Ichihashi, Yasunori; Lekkala, Saradadevi; Maloof, Julin N

    2015-04-01

    Shade from neighboring plants limits light for photosynthesis; as a consequence, plants have a variety of strategies to avoid canopy shade and compete with their neighbors for light. Collectively the response to foliar shade is called the shade avoidance syndrome (SAS). The SAS includes elongation of a variety of organs, acceleration of flowering time, and additional physiological responses, which are seen throughout the plant life cycle. However, current mechanistic knowledge is mainly limited to shade-induced elongation of seedlings. Here we use phenotypic profiling of seedling, leaf, and flowering time traits to untangle complex SAS networks. We used over-representation analysis (ORA) of shade-responsive genes, combined with previous annotation, to logically select 59 known and candidate novel mutants for phenotyping. Our analysis reveals shared and separate pathways for each shade avoidance response. In particular, auxin pathway components were required for shade avoidance responses in hypocotyl, petiole, and flowering time, whereas jasmonic acid pathway components were only required for petiole and flowering time responses. Our phenotypic profiling allowed discovery of seventeen novel shade avoidance mutants. Our results demonstrate that logical selection of mutants increased success of phenotypic profiling to dissect complex traits and discover novel components.

  20. Regulation of Inflammatory Pathways in Cancer and Infectious Disease of the Cervix

    PubMed Central

    Adefuye, Anthonio; Sales, Kurt

    2012-01-01

    Cervical cancer is one of the leading gynaecological malignancies worldwide. It is an infectious disease of the cervix, associated with human papillomavirus infection (HPV), infection with bacterial agents such as Chlamydia trachomatis and Neisseria gonorrhoea as well as human immunodeficiency virus (HIV). Furthermore, it is an AIDS-defining disease with an accelerated mortality in HIV-infected women with cervical cancer. With the introduction of robust vaccination strategies against HPV in the developed world, it is anticipated that the incidence of cervical cancer will decrease in the coming years. However, vaccination has limited benefit for women already infected with high-risk HPV, and alternative therapeutic intervention strategies are needed for these women. Many pathological disorders, including cervical cancer, are characterised by the exacerbated activation and maintenance of inflammatory pathways which are considered to be regulated by infectious agents. In cervical cancer, hyperactivation of these inflammatory pathways and regulation of immune infiltrate into tissues can potentially play a role not only in tumorigenesis but also in HIV infection. In this paper we will discuss the contribution of inflammatory pathways to cervical cancer progression and HIV infection and the role of HIV in cervical cancer progression. PMID:24278714

  1. Do adverse pregnancy outcomes contribute to accelerated cardiovascular events seen in young women with systemic lupus erythematosus?

    PubMed

    Soh, M C; Nelson-Piercy, C; Westgren, M; McCowan, L; Pasupathy, D

    2017-11-01

    Cardiovascular events (CVEs) are prevalent in patients with systemic lupus erythematosus (SLE), and it is the young women who are disproportionately at risk. The risk factors for accelerated cardiovascular disease remain unclear, with multiple studies producing conflicting results. In this paper, we aim to address both traditional and SLE-specific risk factors postulated to drive the accelerated vascular disease in this cohort. We also discuss the more recent hypothesis that adverse pregnancy outcomes in the form of maternal-placental syndrome and resultant preterm delivery could potentially contribute to the CVEs seen in young women with SLE who have fewer traditional cardiovascular risk factors. The pathophysiology of how placental-mediated vascular insufficiency and hypoxia (with the secretion of placenta-like growth factor (PlGF) and soluble fms-tyrosine-like kinase-1 (sFlt-1), soluble endoglin (sEng) and other placental factors) work synergistically to damage the vascular endothelium is discussed. Adverse pregnancy outcomes ultimately are a small contributing factor to the complex pathophysiological process of cardiovascular disease in patients with SLE. Future collaborative studies between cardiologists, obstetricians, obstetric physicians and rheumatologists may pave the way for a better understanding of a likely multifactorial aetiological process.

  2. Influence of the ambient acceleration field upon acute acceleration tolerance in chickens

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Spangler, W. L.; Rhode, E. A.; Burton, R. R.

    1979-01-01

    The paper measured the acceleration tolerance of domestic fowl (Rhode Island Red cocks), acutely exposed to a 6 Gz field, as the time over which a normal heart rate can be maintained. This period of circulatory adjustment ends abruptly with pronounced bradycardia. For chickens which previously have been physiologically adapted to 2.5 -G field, the acute acceleration tolerance is greatly increased. The influence of the ambient acceleration field on the adjustment of the circulatory system appears to be a general phenomenon.

  3. Intervention of Phytohormone Pathways by Pathogen Effectors[OPEN

    PubMed Central

    Kazan, Kemal; Lyons, Rebecca

    2014-01-01

    The constant struggle between plants and microbes has driven the evolution of multiple defense strategies in the host as well as offense strategies in the pathogen. To defend themselves from pathogen attack, plants often rely on elaborate signaling networks regulated by phytohormones. In turn, pathogens have adopted innovative strategies to manipulate phytohormone-regulated defenses. Tactics frequently employed by plant pathogens involve hijacking, evading, or disrupting hormone signaling pathways and/or crosstalk. As reviewed here, this is achieved mechanistically via pathogen-derived molecules known as effectors, which target phytohormone receptors, transcriptional activators and repressors, and other components of phytohormone signaling in the host plant. Herbivores and sap-sucking insects employ obligate pathogens such as viruses, phytoplasma, or symbiotic bacteria to intervene with phytohormone-regulated defenses. Overall, an improved understanding of phytohormone intervention strategies employed by pests and pathogens during their interactions with plants will ultimately lead to the development of new crop protection strategies. PMID:24920334

  4. Ultimate Drivers and Proximate Correlates of Polyandry in Predatory Mites

    PubMed Central

    Schausberger, Peter; Patiño-Ruiz, J. David; Osakabe, Masahiro; Murata, Yasumasa; Sugimoto, Naoya; Uesugi, Ryuji; Walzer, Andreas

    2016-01-01

    Polyandry is more widespread than anticipated from Bateman’s principle but its ultimate (evolutionary) causes and proximate (mechanistic) correlates are more difficult to pinpoint than those of polygyny. Here, we combined mating experiments, quantification of reproductive traits and microsatellite genotyping to determine the fitness implications of polyandry in two predatory mite species, where males are highly polygynous (up to 45 fertilized females during life), whereas females range from monandry to various polyandry levels. The medium-level polyandrous (up to eight male mates possible) Neoseiulus californicus received clear direct and indirect benefits: multiply mated females produced more offspring with higher survival chances over longer times than singly mated females. In contrast, singly and multiply mated females of the low-level polyandrous (commonly two male mates at maximum) Phytoseiulus persimilis produced similar numbers of offspring having similar survival chances. In both species, multiple mating resulted in mixed offspring paternities, opening the chance for indirect fitness benefits such as enhanced genetic compatibility, complementarity and/or variability. However, the female re-mating likelihood and the paternity chance of non-first male mates were lower in P. persimilis than in N. californicus. Regarding proximate factors, in both species first mating duration and female re-mating likelihood were negatively correlated. Based on occasional fertilization failure of first male mates in P. persimilis, and mixed offspring paternities in both species, we argue that fertilization assurance and the chance to gain indirect fitness benefits are the ultimate drivers of polyandry in P. persimilis, whereas those of N. californicus are higher offspring numbers coupled with enhanced offspring viability and possibly other indirect fitness benefits. Overall, the adaptive significance and proximate events well reflected the polyandry levels. Our study provides

  5. Ultimate Drivers and Proximate Correlates of Polyandry in Predatory Mites.

    PubMed

    Schausberger, Peter; Patiño-Ruiz, J David; Osakabe, Masahiro; Murata, Yasumasa; Sugimoto, Naoya; Uesugi, Ryuji; Walzer, Andreas

    2016-01-01

    Polyandry is more widespread than anticipated from Bateman's principle but its ultimate (evolutionary) causes and proximate (mechanistic) correlates are more difficult to pinpoint than those of polygyny. Here, we combined mating experiments, quantification of reproductive traits and microsatellite genotyping to determine the fitness implications of polyandry in two predatory mite species, where males are highly polygynous (up to 45 fertilized females during life), whereas females range from monandry to various polyandry levels. The medium-level polyandrous (up to eight male mates possible) Neoseiulus californicus received clear direct and indirect benefits: multiply mated females produced more offspring with higher survival chances over longer times than singly mated females. In contrast, singly and multiply mated females of the low-level polyandrous (commonly two male mates at maximum) Phytoseiulus persimilis produced similar numbers of offspring having similar survival chances. In both species, multiple mating resulted in mixed offspring paternities, opening the chance for indirect fitness benefits such as enhanced genetic compatibility, complementarity and/or variability. However, the female re-mating likelihood and the paternity chance of non-first male mates were lower in P. persimilis than in N. californicus. Regarding proximate factors, in both species first mating duration and female re-mating likelihood were negatively correlated. Based on occasional fertilization failure of first male mates in P. persimilis, and mixed offspring paternities in both species, we argue that fertilization assurance and the chance to gain indirect fitness benefits are the ultimate drivers of polyandry in P. persimilis, whereas those of N. californicus are higher offspring numbers coupled with enhanced offspring viability and possibly other indirect fitness benefits. Overall, the adaptive significance and proximate events well reflected the polyandry levels. Our study provides a

  6. Particle acceleration in pulsar magnetospheres

    NASA Technical Reports Server (NTRS)

    Baker, K. B.

    1978-01-01

    The structure of pulsar magnetospheres and the acceleration mechanism for charged particles in the magnetosphere was studied using a pulsar model which required large acceleration of the particles near the surface of the star. A theorem was developed which showed that particle acceleration cannot be expected when the angle between the magnetic field lines and the rotation axis is constant (e.g. radial field lines). If this angle is not constant, however, acceleration must occur. The more realistic model of an axisymmetric neutron star with a strong dipole magnetic field aligned with the rotation axis was investigated. In this case, acceleration occurred at large distances from the surface of the star. The magnitude of the current can be determined using the model presented. In the case of nonaxisymmetric systems, the acceleration is expected to occur nearer to the surface of the star.

  7. A traveling-wave forward coupler design for a new accelerating mode in a silicon woodpile accelerator

    DOE PAGES

    Wu, Ziran; Lee, Chunghun H.; Wootton, Kent P.; ...

    2016-03-01

    Silicon woodpile photonic crystals provide a base structure that can be used to build a three-dimensional dielectric waveguide system for high-gradient laser driven acceleration. A new woodpile waveguide design that hosts a phase synchronous, centrally confined accelerating mode is proposed. Comparing with previously discovered silicon woodpile accelerating modes, this mode shows advantages in terms of better electron beam loading and higher achievable acceleration gradient. Several traveling-wave coupler design schemes developed for multi-cell RF cavity accelerators are adapted to the woodpile power coupler design for this new accelerating mode. Design of a forward coupled, highly efficient silicon woodpile accelerator is achieved.more » Simulation shows high efficiency of over 75% of the drive laser power coupled to this fundamental accelerating mode, with less than 15% backward wave scattering. The estimated acceleration gradient, when the coupler structure is driven at the damage threshold fluence of silicon at its operating 1.506 μm wavelength, can reach 185 MV/m. Lastly, a 17-layer woodpile waveguide structure was successfully fabricated, and the measured bandgap is in excellent agreement with simulation.« less

  8. A traveling-wave forward coupler design for a new accelerating mode in a silicon woodpile accelerator

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, Ziran; Lee, Chunghun H.; Wootton, Kent P.

    Silicon woodpile photonic crystals provide a base structure that can be used to build a three-dimensional dielectric waveguide system for high-gradient laser driven acceleration. A new woodpile waveguide design that hosts a phase synchronous, centrally confined accelerating mode is proposed. Comparing with previously discovered silicon woodpile accelerating modes, this mode shows advantages in terms of better electron beam loading and higher achievable acceleration gradient. Several traveling-wave coupler design schemes developed for multi-cell RF cavity accelerators are adapted to the woodpile power coupler design for this new accelerating mode. Design of a forward coupled, highly efficient silicon woodpile accelerator is achieved.more » Simulation shows high efficiency of over 75% of the drive laser power coupled to this fundamental accelerating mode, with less than 15% backward wave scattering. The estimated acceleration gradient, when the coupler structure is driven at the damage threshold fluence of silicon at its operating 1.506 μm wavelength, can reach 185 MV/m. Lastly, a 17-layer woodpile waveguide structure was successfully fabricated, and the measured bandgap is in excellent agreement with simulation.« less

  9. 22 CFR 123.9 - Country of ultimate destination and approval of reexports or retransfers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... ARMS REGULATIONS LICENSES FOR THE EXPORT OF DEFENSE ARTICLES § 123.9 Country of ultimate destination... the Directorate of Defense Trade Controls must be obtained before reselling, transferring, transshipping, or disposing of a defense article to any end user, end use or destination other than as stated on...

  10. Transport, Acceleration and Spatial Access of Solar Energetic Particles

    NASA Astrophysics Data System (ADS)

    Borovikov, D.; Sokolov, I.; Effenberger, F.; Jin, M.; Gombosi, T. I.

    2017-12-01

    Solar Energetic Particles (SEPs) are a major branch of space weather. Often driven by Coronal Mass Ejections (CMEs), SEPs have a very high destructive potential, which includes but is not limited to disrupting communication systems on Earth, inflicting harmful and potentially fatal radiation doses to crew members onboard spacecraft and, in extreme cases, to people aboard high altitude flights. However, currently the research community lacks efficient tools to predict such hazardous SEP events. Such a tool would serve as the first step towards improving humanity's preparedness for SEP events and ultimately its ability to mitigate their effects. The main goal of the presented research is to develop a computational tool that provides the said capabilities and meets the community's demand. Our model has the forecasting capability and can be the basis for operational system that will provide live information on the current potential threats posed by SEPs based on observations of the Sun. The tool comprises several numerical models, which are designed to simulate different physical aspects of SEPs. The background conditions in the interplanetary medium, in particular, the Coronal Mass Ejection driving the particle acceleration, play a defining role and are simulated with the state-of-the-art MHD solver, Block-Adaptive-Tree Solar-wind Roe-type Upwind Scheme (BATS-R-US). The newly developed particle code, Multiple-Field-Line-Advection Model for Particle Acceleration (M-FLAMPA), simulates the actual transport and acceleration of SEPs and is coupled to the MHD code. The special property of SEPs, the tendency to follow magnetic lines of force, is fully taken advantage of in the computational model, which substitutes a complicated 3-D model with a multitude of 1-D models. This approach significantly simplifies computations and improves the time performance of the overall model. Also, it plays an important role of mapping the affected region by connecting it with the origin of

  11. Charged particle accelerator grating

    DOEpatents

    Palmer, Robert B.

    1986-01-01

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams into the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  12. Charged particle accelerator grating

    DOEpatents

    Palmer, R.B.

    1985-09-09

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator is described. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams onto the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  13. Charged particle accelerator grating

    DOEpatents

    Palmer, Robert B.

    1986-09-02

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams into the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  14. HEAVY ION LINEAR ACCELERATOR

    DOEpatents

    Van Atta, C.M.; Beringer, R.; Smith, L.

    1959-01-01

    A linear accelerator of heavy ions is described. The basic contributions of the invention consist of a method and apparatus for obtaining high energy particles of an element with an increased charge-to-mass ratio. The method comprises the steps of ionizing the atoms of an element, accelerating the resultant ions to an energy substantially equal to one Mev per nucleon, stripping orbital electrons from the accelerated ions by passing the ions through a curtain of elemental vapor disposed transversely of the path of the ions to provide a second charge-to-mass ratio, and finally accelerating the resultant stripped ions to a final energy of at least ten Mev per nucleon.

  15. CLASHING BEAM PARTICLE ACCELERATOR

    DOEpatents

    Burleigh, R.J.

    1961-04-11

    A charged-particle accelerator of the proton synchrotron class having means for simultaneously accelerating two separate contra-rotating particle beams within a single annular magnet structure is reported. The magnet provides two concentric circular field regions of opposite magnetic polarity with one field region being of slightly less diameter than the other. The accelerator includes a deflector means straddling the two particle orbits and acting to collide the two particle beams after each has been accelerated to a desired energy. The deflector has the further property of returning particles which do not undergo collision to the regular orbits whereby the particles recirculate with the possibility of colliding upon subsequent passages through the deflector.

  16. Some Physics Constraints on Ultimate Achievement in Track and Field

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Frohlich, Cliff

    2009-02-06

    World records in track and field have improved remarkably throughout the last 100 years; however, in several events physics places quite strict limitations on ultimate performance. For example, analysis suggests that records in broad jump and pole vault have approached their optimum possible values. Physical constraints are more subtle for events such as javelin, high jump, and the distance races, and thus there may be opportunities for “breakthroughs” in current records. Considering that there is enormous cultural interest and economic expenditure on sports, for most events the level of scientific analysis isn’t very high. This presents a research opportunity formore » fans who are engineers or physicists.« less

  17. Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

    PubMed

    Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

    2017-06-01

    Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RP<0.01 were defined as critical pathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RP<0.01, and the top 10 pathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing

  18. Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation.

    PubMed

    Miao, Yinglong; Feher, Victoria A; McCammon, J Andrew

    2015-08-11

    A Gaussian accelerated molecular dynamics (GaMD) approach for simultaneous enhanced sampling and free energy calculation of biomolecules is presented. By constructing a boost potential that follows Gaussian distribution, accurate reweighting of the GaMD simulations is achieved using cumulant expansion to the second order. Here, GaMD is demonstrated on three biomolecular model systems: alanine dipeptide, chignolin folding, and ligand binding to the T4-lysozyme. Without the need to set predefined reaction coordinates, GaMD enables unconstrained enhanced sampling of these biomolecules. Furthermore, the free energy profiles obtained from reweighting of the GaMD simulations allow us to identify distinct low-energy states of the biomolecules and characterize the protein-folding and ligand-binding pathways quantitatively.

  19. β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

    PubMed Central

    Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

    2010-01-01

    Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

  20. Milky Way's Super-efficient Particle Accelerators Caught in The Act

    NASA Astrophysics Data System (ADS)

    2009-06-01

    Thanks to a unique "ballistic study" that combines data from ESO's Very Large Telescope and NASA's Chandra X-ray Observatory, astronomers have now solved a long-standing mystery of the Milky Way's particle accelerators. They show in a paper published today on Science Express that cosmic rays from our galaxy are very efficiently accelerated in the remnants of exploded stars. During the Apollo flights astronauts reported seeing odd flashes of light, visible even with their eyes closed. We have since learnt that the cause was cosmic rays - extremely energetic particles from outside the Solar System arriving at the Earth, and constantly bombarding its atmosphere. Once they reach Earth, they still have sufficient energy to cause glitches in electronic components. Galactic cosmic rays come from sources inside our home galaxy, the Milky Way, and consist mostly of protons moving at close to the speed of light, the "ultimate speed limit" in the Universe. These protons have been accelerated to energies exceeding by far the energies that even CERN's Large Hadron Collider will be able to achieve. "It has long been thought that the super-accelerators that produce these cosmic rays in the Milky Way are the expanding envelopes created by exploded stars, but our observations reveal the smoking gun that proves it", says Eveline Helder from the Astronomical Institute Utrecht of Utrecht University in the Netherlands, the first author of the new study. "You could even say that we have now confirmed the calibre of the gun used to accelerate cosmic rays to their tremendous energies", adds collaborator Jacco Vink, also from the Astronomical Institute Utrecht. For the first time Helder, Vink and colleagues have come up with a measurement that solves the long-standing astronomical quandary of whether or not stellar explosions produce enough accelerated particles to explain the number of cosmic rays that hit the Earth's atmosphere. The team's study indicates that they indeed do and it