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Sample records for optimizes functional inhibition

  1. Optimal Decision Making in Neural Inhibition Models

    ERIC Educational Resources Information Center

    van Ravenzwaaij, Don; van der Maas, Han L. J.; Wagenmakers, Eric-Jan

    2012-01-01

    In their influential "Psychological Review" article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the…

  2. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials.

    PubMed

    Angiolillo, Dominick J; Schneider, David J; Bhatt, Deepak L; French, William J; Price, Matthew J; Saucedo, Jorge F; Shaburishvili, Tamaz; Huber, Kurt; Prats, Jayne; Liu, Tiepu; Harrington, Robert A; Becker, Richard C

    2012-07-01

    Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower

  3. Optimality Functions and Lopsided Convergence

    DTIC Science & Technology

    2015-03-16

    Problems involving functions defined in terms of integrals or optimization problems (as the maxi - mization in Example 3), functions defined on infinite...optimization methods in finite time. The key technical challenge associate with the above scheme is to establish ( weak ) consistency. In the next...Theorem 4.3. In view of this result, it is clear that ( weak ) consistency will be ensured by epi-convergence of the approximating objective functions and

  4. Optimal inverse functions created via population-based optimization.

    PubMed

    Jennings, Alan L; Ordóñez, Raúl

    2014-06-01

    Finding optimal inputs for a multiple-input, single-output system is taxing for a system operator. Population-based optimization is used to create sets of functions that produce a locally optimal input based on a desired output. An operator or higher level planner could use one of the functions in real time. For the optimization, each agent in the population uses the cost and output gradients to take steps lowering the cost while maintaining their current output. When an agent reaches an optimal input for its current output, additional agents are generated in the output gradient directions. The new agents then settle to the local optima for the new output values. The set of associated optimal points forms an inverse function, via spline interpolation, from a desired output to an optimal input. In this manner, multiple locally optimal functions can be created. These functions are naturally clustered in input and output spaces allowing for a continuous inverse function. The operator selects the best cluster over the anticipated range of desired outputs and adjusts the set point (desired output) while maintaining optimality. This reduces the demand from controlling multiple inputs, to controlling a single set point with no loss in performance. Results are demonstrated on a sample set of functions and on a robot control problem.

  5. Optimality Functions in Stochastic Programming

    DTIC Science & Technology

    2009-12-02

    nonconvex. Non - convex stochastic optimization problems arise in such diverse applications as estimation of mixed logit models [2], engineering design...first- order necessary optimality conditions ; see for example Propositions 3.3.1 and 3.3.5 in [7] or Theorem 2.2.4 in [25]. If the evaluation of f j...procedures for validation analysis of a candidate point x ∈ IRn. Since P may be nonconvex, we focus on first-order necessary optimality conditions as

  6. Antibiotic inhibition of group I ribozyme function.

    PubMed

    von Ahsen, U; Davies, J; Schroeder, R

    1991-09-26

    The discovery of catalytically active RNA has provided the basis for the evolutionary concept of an RNA world. It has been proposed that during evolution the functions of ancient catalytic RNA were modulated by low molecular weight effectors, related to antibiotics, present in the primordial soup. Antibiotics and RNA may have coevolved in the formation of the modern ribosome. Here we report that a set of aminoglycoside antibiotics, which are known to interact with the decoding region of the 16S ribosomal RNA of Escherichia coli, inhibit the second step of splicing of the T4 phage-derived td intron. Thus catalytic RNA seems to interact not only with a mononucleotide and an amino acid, but also with another class of biomolecules, the sugars. Splicing of other group I introns but not group II introns was inhibited. The similarity in affinity and specificity of these antibiotics for group I introns and rRNAs may result from recognition of evolutionarily conserved structures.

  7. Partial inhibition and bilevel optimization in flux balance analysis

    PubMed Central

    2013-01-01

    Motivation Within Flux Balance Analysis, the investigation of complex subtasks, such as finding the optimal perturbation of the network or finding an optimal combination of drugs, often requires to set up a bilevel optimization problem. In order to keep the linearity and convexity of these nested optimization problems, an ON/OFF description of the effect of the perturbation (i.e. Boolean variable) is normally used. This restriction may not be realistic when one wants, for instance, to describe the partial inhibition of a reaction induced by a drug. Results In this paper we present a formulation of the bilevel optimization which overcomes the oversimplified ON/OFF modeling while preserving the linear nature of the problem. A case study is considered: the search of the best multi-drug treatment which modulates an objective reaction and has the minimal perturbation on the whole network. The drug inhibition is described and modulated through a convex combination of a fixed number of Boolean variables. The results obtained from the application of the algorithm to the core metabolism of E.coli highlight the possibility of finding a broader spectrum of drug combinations compared to a simple ON/OFF modeling. Conclusions The method we have presented is capable of treating partial inhibition inside a bilevel optimization, without loosing the linearity property, and with reasonable computational performances also on large metabolic networks. The more fine-graded representation of the perturbation allows to enlarge the repertoire of synergistic combination of drugs for tasks such as selective perturbation of cellular metabolism. This may encourage the use of the approach also for other cases in which a more realistic modeling is required. PMID:24286232

  8. Directed evolution: new parts and optimized function.

    PubMed

    Dougherty, Michael J; Arnold, Frances H

    2009-08-01

    Constructing novel biological systems that function in a robust and predictable manner requires better methods for discovering new functional molecules and for optimizing their assembly in novel biological contexts. By enabling functional diversification and optimization in the absence of detailed mechanistic understanding, directed evolution is a powerful complement to 'rational' engineering approaches. Aided by clever selection schemes, directed evolution has generated new parts for genetic circuits, cell-cell communication systems, and non-natural metabolic pathways in bacteria.

  9. Do optimism and pessimism predict physical functioning?

    PubMed

    Brenes, Gretchen A; Rapp, Stephen R; Rejeski, W Jack; Miller, Michael E

    2002-06-01

    Dispositional optimism has been shown to be related to self-report measures of health and well-being, yet little research has examined the relationship between optimism and more objective measures of functioning. The purpose of this study was to examine the relationship between optimism and pessimism and objective physical functioning. Four hundred eighty community-dwelling older adults with knee pain completed a measure of optimism and pessimism and were observed performing four daily activities (walking, lifting an object, climbing stairs, and getting into and out of a car). Results indicated that pessimism was significantly related to performance on all four tasks (p < .001), while optimism was related to performance only on the walking task (p < .05), after controlling for demographic and health variables.

  10. Nitric oxide synthases: structure, function and inhibition.

    PubMed Central

    Alderton, W K; Cooper, C E; Knowles, R G

    2001-01-01

    This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated. PMID:11463332

  11. Bromodomains: Structure, function and pharmacology of inhibition.

    PubMed

    Ferri, Elena; Petosa, Carlo; McKenna, Charles E

    2016-04-15

    Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. The human proteome comprises 46 bromodomain-containing proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Over the past five years, bromodomains have attracted great interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, and cardiovascular disease. The demonstration in 2010 that two small molecule compounds, JQ1 and I-BET762, potently inhibit proteins of the bromodomain and extra-terminal (BET) family with translational potential for cancer and inflammatory disease sparked intense efforts in academia and pharmaceutical industry to develop novel bromodomain antagonists for therapeutic applications. Several BET inhibitors are already in clinical trials for hematological malignancies, solid tumors and cardiovascular disease. Currently, the field faces the challenge of single-target selectivity, especially within the BET family, and of overcoming problems related to the development of drug resistance. At the same time, new trends in bromodomain inhibitor research are emerging, including an increased interest in non-BET bromodomains and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of bromodomains, traces the development of bromodomain inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this vibrant new field in drug discovery.

  12. Genetic learning automata for function optimization.

    PubMed

    Howell, M N; Gordon, T J; Brandao, F V

    2002-01-01

    Stochastic learning automata and genetic algorithms (GAs) have previously been shown to have valuable global optimization properties. Learning automata have, however, been criticized for having a relatively slow rate of convergence. In this paper, these two techniques are combined to provide an increase in the rate of convergence for the learning automata and also to improve the chances of escaping local optima. The technique separates the genotype and phenotype properties of the GA and has the advantage that the degree of convergence can be quickly ascertained. It also provides the GA with a stopping rule. If the technique is applied to real-valued function optimization problems, then bounds on the range of the values within which the global optima is expected can be determined throughout the search process. The technique is demonstrated through a number of bit-based and real-valued function optimization examples.

  13. A novel bee swarm optimization algorithm for numerical function optimization

    NASA Astrophysics Data System (ADS)

    Akbari, Reza; Mohammadi, Alireza; Ziarati, Koorush

    2010-10-01

    The optimization algorithms which are inspired from intelligent behavior of honey bees are among the most recently introduced population based techniques. In this paper, a novel algorithm called bee swarm optimization, or BSO, and its two extensions for improving its performance are presented. The BSO is a population based optimization technique which is inspired from foraging behavior of honey bees. The proposed approach provides different patterns which are used by the bees to adjust their flying trajectories. As the first extension, the BSO algorithm introduces different approaches such as repulsion factor and penalizing fitness (RP) to mitigate the stagnation problem. Second, to maintain efficiently the balance between exploration and exploitation, time-varying weights (TVW) are introduced into the BSO algorithm. The proposed algorithm (BSO) and its two extensions (BSO-RP and BSO-RPTVW) are compared with existing algorithms which are based on intelligent behavior of honey bees, on a set of well known numerical test functions. The experimental results show that the BSO algorithms are effective and robust; produce excellent results, and outperform other algorithms investigated in this consideration.

  14. Inhibiting the Function of an Enzyme

    SciTech Connect

    2015-06-17

    In order to stop bacteria from reproducing and causing a disease like tuberculosis, researchers must first block its enzymes' ability to bind with certain molecules. A research team from Brandeis University worked with the Advanced Protein Characterization Facility at Argonne National Laboratory to define 13 different bacterial structures and uncover the mechanism by which their enzymes form and break bonds with molecules. This animation depicts how an enzyme may be inhibited using this knowledge.

  15. Optimization of constrained density functional theory

    NASA Astrophysics Data System (ADS)

    O'Regan, David D.; Teobaldi, Gilberto

    2016-07-01

    Constrained density functional theory (cDFT) is a versatile electronic structure method that enables ground-state calculations to be performed subject to physical constraints. It thereby broadens their applicability and utility. Automated Lagrange multiplier optimization is necessary for multiple constraints to be applied efficiently in cDFT, for it to be used in tandem with geometry optimization, or with molecular dynamics. In order to facilitate this, we comprehensively develop the connection between cDFT energy derivatives and response functions, providing a rigorous assessment of the uniqueness and character of cDFT stationary points while accounting for electronic interactions and screening. In particular, we provide a nonperturbative proof that stable stationary points of linear density constraints occur only at energy maxima with respect to their Lagrange multipliers. We show that multiple solutions, hysteresis, and energy discontinuities may occur in cDFT. Expressions are derived, in terms of convenient by-products of cDFT optimization, for quantities such as the dielectric function and a condition number quantifying ill definition in multiple constraint cDFT.

  16. Optimizing nondecomposable loss functions in structured prediction.

    PubMed

    Ranjbar, Mani; Lan, Tian; Wang, Yang; Robinovitch, Steven N; Li, Ze-Nian; Mori, Greg

    2013-04-01

    We develop an algorithm for structured prediction with nondecomposable performance measures. The algorithm learns parameters of Markov Random Fields (MRFs) and can be applied to multivariate performance measures. Examples include performance measures such as Fβ score (natural language processing), intersection over union (object category segmentation), Precision/Recall at k (search engines), and ROC area (binary classifiers). We attack this optimization problem by approximating the loss function with a piecewise linear function. The loss augmented inference forms a Quadratic Program (QP), which we solve using LP relaxation. We apply this approach to two tasks: object class-specific segmentation and human action retrieval from videos. We show significant improvement over baseline approaches that either use simple loss functions or simple scoring functions on the PASCAL VOC and H3D Segmentation datasets, and a nursing home action recognition dataset.

  17. Maximizing Academic Success: Introducing the Concept of Optimized Functioning

    ERIC Educational Resources Information Center

    Phan, Huy P.

    2015-01-01

    This research article reports on two correlational studies that examined the notion of "optimized functioning." Optimized functioning, introduced in a recent published study, offers an alternative approach into the understanding of optimization. Optimized functioning is proposed to consist of four distinctive components: personal…

  18. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    SciTech Connect

    Cho, Yoon Sun; Jung, Hye Jin; Seok, Seung Hyeok; Payumo, Alexander Y.; Chen, James K.; Kwon, Ho Jeong

    2013-04-19

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.

  19. Optimization with quadratic support functions in nonconvex smooth optimization

    NASA Astrophysics Data System (ADS)

    Khamisov, O. V.

    2016-10-01

    Problem of global minimization of twice continuously differentiable function with Lipschitz second derivatives over a polytope is considered. We suggest a branch and bound method with polytopes as partition elements. Due to the Lipschitz property of the objective function we can construct a quadratic support minorant at each point of the feasible set. Global minimum of of this minorant provides a lower bound of the objective over given partition subset. The main advantage of the suggested method consists in the following. First quadratic minorants usually are nonconvex and we have to solve auxiliary global optimization problem. This problem is reduced to a mixed 0-1 linear programming problem and can be solved by an advanced 0-1 solver. Then we show that the quadratic minorants are getting convex as soon as partition elements are getting smaller in diameter. Hence, at the final steps of the branch and bound method we solve convex auxiliary quadratic problems. Therefore, the method accelerates when we are close to the global minimum of the initial problem.

  20. Optimal Reward Functions in Distributed Reinforcement Learning

    NASA Technical Reports Server (NTRS)

    Wolpert, David H.; Tumer, Kagan

    2000-01-01

    We consider the design of multi-agent systems so as to optimize an overall world utility function when (1) those systems lack centralized communication and control, and (2) each agents runs a distinct Reinforcement Learning (RL) algorithm. A crucial issue in such design problems is to initialize/update each agent's private utility function, so as to induce best possible world utility. Traditional 'team game' solutions to this problem sidestep this issue and simply assign to each agent the world utility as its private utility function. In previous work we used the 'Collective Intelligence' framework to derive a better choice of private utility functions, one that results in world utility performance up to orders of magnitude superior to that ensuing from use of the team game utility. In this paper we extend these results. We derive the general class of private utility functions that both are easy for the individual agents to learn and that, if learned well, result in high world utility. We demonstrate experimentally that using these new utility functions can result in significantly improved performance over that of our previously proposed utility, over and above that previous utility's superiority to the conventional team game utility.

  1. Caspase activation inhibits proteasome function during apoptosis.

    PubMed

    Sun, Xiao-Ming; Butterworth, Michael; MacFarlane, Marion; Dubiel, Wolfgang; Ciechanover, Aaron; Cohen, Gerald M

    2004-04-09

    The ubiquitin/proteasome system regulates protein turnover by degrading polyubiquitinated proteins. To date, all studies on the relationship of apoptosis and the proteasome have emphasized the key role of the proteasome in the regulation of apoptosis, by virtue of its ability to degrade regulatory molecules involved in apoptosis. We now demonstrate how induction of apoptosis may regulate the activity of the proteasome. During apoptosis, caspase activation results in the cleavage of three specific subunits of the 19S regulatory complex of the proteasome: S6' (Rpt5) and S5a (Rpn10), whose role is to recognize polyubiquitinated substrates of the proteasome, and S1 (Rpn2), which with S5a and S2 (Rpn1) holds together the lid and base of the 19S regulatory complex. This caspase-mediated cleavage inhibits the proteasomal degradation of ubiquitin-dependent and -independent cellular substrates, including proapoptotic molecules such as Smac, so facilitating the execution of the apoptotic program by providing a feed-forward amplification loop.

  2. Phosphatidylinositol 4-kinases: Function, structure, and inhibition

    SciTech Connect

    Boura, Evzen Nencka, Radim

    2015-10-01

    The phosphatidylinositol 4-kinases (PI4Ks) synthesize phosphatidylinositol 4-phosphate (PI4P), a key member of the phosphoinositide family. PI4P defines the membranes of Golgi and trans-Golgi network (TGN) and regulates trafficking to and from the Golgi. Humans have two type II PI4Ks (α and β) and two type III enzymes (α and β). Recently, the crystal structures were solved for both type II and type III kinase revealing atomic details of their function. Importantly, the type III PI4Ks are hijacked by +RNA viruses to create so-called membranous web, an extensively phosphorylated and modified membrane system dedicated to their replication. Therefore, selective and potent inhibitors of PI4Ks have been developed as potential antiviral agents. Here we focus on the structure and function of PI4Ks and their potential in human medicine.

  3. Sampling design optimization for spatial functions

    USGS Publications Warehouse

    Olea, R.A.

    1984-01-01

    A new procedure is presented for minimizing the sampling requirements necessary to estimate a mappable spatial function at a specified level of accuracy. The technique is based on universal kriging, an estimation method within the theory of regionalized variables. Neither actual implementation of the sampling nor universal kriging estimations are necessary to make an optimal design. The average standard error and maximum standard error of estimation over the sampling domain are used as global indices of sampling efficiency. The procedure optimally selects those parameters controlling the magnitude of the indices, including the density and spatial pattern of the sample elements and the number of nearest sample elements used in the estimation. As an illustration, the network of observation wells used to monitor the water table in the Equus Beds of Kansas is analyzed and an improved sampling pattern suggested. This example demonstrates the practical utility of the procedure, which can be applied equally well to other spatial sampling problems, as the procedure is not limited by the nature of the spatial function. ?? 1984 Plenum Publishing Corporation.

  4. Effect of glycolysis inhibition on mitochondrial function in rat brain.

    PubMed

    Cano-Ramírez, D; Torres-Vargas, C E; Guerrero-Castillo, S; Uribe-Carvajal, S; Hernández-Pando, R; Pedraza-Chaverri, J; Orozco-Ibarra, M

    2012-05-01

    Inhibition of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase enhances the neural vulnerability to excitotoxicity both in vivo and in vitro through an unknown mechanism possibly related to mitochondrial failure. However, as the effect of glycolysis inhibition on mitochondrial function in brain has not been studied, the aim of the present work was to evaluate the effect of glycolysis inhibition induced by iodoacetate on mitochondrial function and oxidative stress in brain. Mitochondria were isolated from brain cortex, striatum and cerebellum of rats treated systemically with iodoacetate (25 mg/kg/day for 3 days). Oxygen consumption, ATP synthesis, transmembrane potential, reactive oxygen species production, lipoperoxidation, glutathione levels, and aconitase activity were assessed. Oxygen consumption and aconitase activity decreased in the brain cortex and striatum, showing that glycolysis inhibition did not trigger severe mitochondrial impairment, but a slight mitochondrial malfunction and oxidative stress were present.

  5. Inhibiting ice recrystallization and optimization of cell viability after cryopreservation.

    PubMed

    Chaytor, Jennifer L; Tokarew, Jacqueline M; Wu, Luke K; Leclère, Mathieu; Tam, Roger Y; Capicciotti, Chantelle J; Guolla, Louise; von Moos, Elisabeth; Findlay, C Scott; Allan, David S; Ben, Robert N

    2012-01-01

    The ice recrystallization inhibition activity of various mono- and disaccharides has been correlated with their ability to cryopreserve human cell lines at various concentrations. Cell viabilities after cryopreservation were compared with control experiments where cells were cryopreserved with dimethylsulfoxide (DMSO). The most potent inhibitors of ice recrystallization were 220 mM solutions of disaccharides; however, the best cell viability was obtained when a 200 mM d-galactose solution was utilized. This solution was minimally cytotoxic at physiological temperature and effectively preserved cells during freeze-thaw. In fact, this carbohydrate was just as effective as a 5% DMSO solution. Further studies indicated that the cryoprotective benefit of d-galactose was a result of its internalization and its ability to mitigate osmotic stress, prevent intracellular ice formation and/or inhibit ice recrystallization. This study supports the hypothesis that the ability of a cryoprotectant to inhibit ice recrystallization is an important property to enhance cell viability post-freeze-thaw. This cryoprotective benefit is observed in three different human cell lines. Furthermore, we demonstrated that the ability of a potential cryoprotectant to inhibit ice recrystallation may be used as a predictor of its ability to preserve cells at subzero temperatures.

  6. Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

    PubMed Central

    Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

    2013-01-01

    Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

  7. Optimization of irinotecan chronotherapy with P-glycoprotein inhibition

    SciTech Connect

    Filipski, Elisabeth; Berland, Elodie; Ozturk, Narin; Guettier, Catherine; Horst, Gijsbertus T.J. van der; Lévi, Francis; and others

    2014-02-01

    The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F{sub 1} mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50 mg/kg/day i.v. × 4 days) as a single agent or combined with P-gp inhibitor PSC833 (6.25 mg/kg/day i.p. × 4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40 mg/kg/day × 4 days) and +/− PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p < 0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p < 0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to ∼ 60%. In tumor-bearing mice, body weight loss was ∼ halved in the mice on irinotecan or irinotecan–PSC833 combination at ZT15 as compared to ZT3 (p < 0.001). PSC833–irinotecan at ZT15 increased tumor inhibition by ∼ 40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan. - Highlights: • Irinotecan chronotolerance and chronoefficacy change as drug was applied with PSC833. • P-glycoprotein is an important player of the toxicity and efficacy of irinotecan. • Timing should be considered if chemotherapy is performed with a MDR1 inhibitor.

  8. Optimal control design of pulse shapes as analytic functions.

    PubMed

    Skinner, Thomas E; Gershenzon, Naum I

    2010-06-01

    Representing NMR pulse shapes by analytic functions is widely employed in procedures for optimizing performance. Insights concerning pulse dynamics can be applied to the choice of appropriate functions that target specific performance criteria, focusing the solution search and reducing the space of possible pulse shapes that must be considered to a manageable level. Optimal control theory can accommodate significantly larger parameter spaces and has been able to tackle problems of much larger scope than more traditional optimization methods. However, its numerically generated pulses, as currently constructed, do not readily incorporate the capabilities of particular functional forms, and the pulses are not guaranteed to vary smoothly in time, which can be a problem for faithful implementation on older hardware. An optimal control methodology is derived for generating pulse shapes as simple parameterized functions. It combines the benefits of analytic and numerical protocols in a single powerful algorithm that both complements and enhances existing optimization strategies.

  9. Optimization of Milling Parameters Employing Desirability Functions

    NASA Astrophysics Data System (ADS)

    Ribeiro, J. L. S.; Rubio, J. C. Campos; Abrão, A. M.

    2011-01-01

    The principal aim of this paper is to investigate the influence of tool material (one cermet and two coated carbide grades), cutting speed and feed rate on the machinability of hardened AISI H13 hot work steel, in order to identify the cutting conditions which lead to optimal performance. A multiple response optimization procedure based on tool life, surface roughness, milling forces and the machining time (required to produce a sample cavity) was employed. The results indicated that the TiCN-TiN coated carbide and cermet presented similar results concerning the global optimum values for cutting speed and feed rate per tooth, outperforming the TiN-TiCN-Al2O3 coated carbide tool.

  10. Arginase inhibition restores endothelial function in diet-induced obesity.

    PubMed

    Chung, Ji Hyung; Moon, Jiyoung; Lee, Youn Sue; Chung, Hye-Kyung; Lee, Seung-Min; Shin, Min-Jeong

    2014-08-22

    Arginase may play a major role in the regulation of vascular function in various cardiovascular disorders by impairing nitric oxide (NO) production. In the current study, we investigated whether supplementation of the arginase inhibitor N(ω)-hydroxy-nor-l-arginine (nor-NOHA) could restore endothelial function in an animal model of diet-induced obesity. Arginase 1 expression was significantly lower in the aorta of C57BL/6J mice fed a high-fat diet (HFD) supplemented with nor-NOHA (40mgkg(-1)/day) than in mice fed HFD without nor-NOHA. Arginase inhibition led to considerable increases in eNOS expression and NO levels and significant decreases in the levels of circulating ICAM-1. These findings were further confirmed by the results of siRNA-mediated knockdown of Arg in human umbilical vein endothelial cells. In conclusion, arginase inhibition can help restore dysregulated endothelial function by increasing the eNOS-dependent NO production in the endothelium, indicating that arginase could be a therapeutic target for correcting obesity-induced vascular endothelial dysfunction.

  11. Zap70 Inhibits Syk-mediated Osteoclast Function

    PubMed Central

    Zou, Wei; Croke, Monica; Fukunaga, Tomohiro; Broekelmann, Thomas J.; Mecham, Robert P.; Teitelbaum, Steven L.

    2014-01-01

    The αvβ3 integrin stimulates the resorptive capacity of the differentiated osteoclast (OC) by organizing its cytoskeleton via the tyrosine kinase, Syk. Thus, Syk-deficient OCs fail to spread or form actin rings, in vitro and in vivo. The Syk family of tyrosine kinases consists of Syk itself and Zap70 which are expressed by different cell types. Because of their structural similarity, and its compensatory properties in other cells, we asked if Zap70 can substitute for absence of Syk in OCs. While expression of Syk, as expected, normalizes the cytoskeletal abnormalities of Syk-/- OCs, Zap70 fails do so. In keeping with this observation, Syk, but not Zap70, rescues αvβ3 integrin-induced SLP76 phosphorylation in Syk-/- OCs. Furthermore the kinase sequence of Syk partially rescues the Syk-/- phenotype but full normalization also requires its SH2 domains. Surprisingly, expression of Zap70 inhibits WT OC spreading, actin ring formation and bone resorptive activity, but not differentiation. In keeping with arrested cytoskeletal organization, Zap70 blocks integrin-activated endogenous Syk and Vav3, SLP76 phosphorylation. Such inhibition requires Zap70 kinase activity, as it is abolished by mutation of the Zap70 kinase domain. Thus, while the kinase domain of Syk is uniquely required for OC function, that of Zap70 inhibits it. PMID:23494777

  12. Optimization of an exchange-correlation density functional for water

    NASA Astrophysics Data System (ADS)

    Fritz, Michelle; Fernández-Serra, Marivi; Soler, José M.

    2016-06-01

    We describe a method, that we call data projection onto parameter space (DPPS), to optimize an energy functional of the electron density, so that it reproduces a dataset of experimental magnitudes. Our scheme, based on Bayes theorem, constrains the optimized functional not to depart unphysically from existing ab initio functionals. The resulting functional maximizes the probability of being the "correct" parameterization of a given functional form, in the sense of Bayes theory. The application of DPPS to water sheds new light on why density functional theory has performed rather poorly for liquid water, on what improvements are needed, and on the intrinsic limitations of the generalized gradient approximation to electron exchange and correlation. Finally, we present tests of our water-optimized functional, that we call vdW-DF-w, showing that it performs very well for a variety of condensed water systems.

  13. Bafetinib inhibits functional responses of human eosinophils in vitro.

    PubMed

    Milara, Javier; Martinez-Losa, Maleles; Sanz, Celia; Almudéver, Patricia; Peiró, Teresa; Serrano, Adela; Morcillo, Esteban Jesus; Zaragozá, Cristóbal; Cortijo, Julio

    2013-09-05

    Eosinophils play a prominent role in the process of allergic inflammation. Non-receptor associated Lyn tyrosine kinases generate key initial signals in eosinophils. Bafetinib, a specific Abl/Lyn tyrosine kinase inhibitor has shown a potent antiproliferative activity in leukemic cells, but its effects on eosinophils have not been reported. Therefore, we studied the effects of bafetinib on functional and mechanistic responses of isolated human eosinophils. Bafetinib was more potent than non-specific tyrosin kinase comparators genistein and tyrphostin inhibiting superoxide anion triggered by N-formyl-Met-Leu-Phe (fMLF; 100 nM) (-log IC50=7.25 ± 0.04 M; 6.1 ± 0.04 M; and 6.55 ± 0.03 M, respectively). Bafetinib, genistein and tyrphostin did not modify the [Ca(2+)]i responses to fMLF. Bafetinib inhibited the release of EPO induced by fMLF with higher potency than genistein and tyrphostin (-log IC50=7.24 ± 0.09 M; 5.36 ± 0.28 M; and 5.37 ± 0.19 M, respectively), and nearly suppressed LTC4, ECP and chemotaxis. Bafetinib, genistein and tyrphostin did not change constitutive apoptosis. However bafetinib inhibited the ability of granulocyte-monocyte colony-stimulating factor to prevent apoptosis. The activation of Lyn tyrosine kinase, p-ERK1/2 and p-38 induced by fMLF was suppressed by bafetinib and attenuated by genistein and tyrphostin. In conclusion, bafetinib inhibits oxidative burst and generation of inflammatory mediators, and reverses the eosinophil survival. Therefore, future anti-allergic therapies based on bafetinib, could help to suppress excessive inflammatory response of eosinophils at inflammatory sites.

  14. Optimization of removal function in computer controlled optical surfacing

    NASA Astrophysics Data System (ADS)

    Chen, Xi; Guo, Peiji; Ren, Jianfeng

    2010-10-01

    The technical principle of computer controlled optical surfacing (CCOS) and the common method of optimizing removal function that is used in CCOS are introduced in this paper. A new optimizing method time-sharing synthesis of removal function is proposed to solve problems of the removal function being far away from Gaussian type and slow approaching of the removal function error that encountered in the mode of planet motion or translation-rotation. Detailed time-sharing synthesis of using six removal functions is discussed. For a given region on the workpiece, six positions are selected as the centers of the removal function; polishing tool controlled by the executive system of CCOS revolves around each centre to complete a cycle in proper order. The overall removal function obtained by the time-sharing process is the ratio of total material removal in six cycles to time duration of the six cycles, which depends on the arrangement and distribution of the six removal functions. Simulations on the synthesized overall removal functions under two different modes of motion, i.e., planet motion and translation-rotation are performed from which the optimized combination of tool parameters and distribution of time-sharing synthesis removal functions are obtained. The evaluation function when optimizing is determined by an approaching factor which is defined as the ratio of the material removal within the area of half of the polishing tool coverage from the polishing center to the total material removal within the full polishing tool coverage area. After optimization, it is found that the optimized removal function obtained by time-sharing synthesis is closer to the ideal Gaussian type removal function than those by the traditional methods. The time-sharing synthesis method of the removal function provides an efficient way to increase the convergence speed of the surface error in CCOS for the fabrication of aspheric optical surfaces, and to reduce the intermediate- and high

  15. Optical transfer function optimization based on linear expansions

    NASA Astrophysics Data System (ADS)

    Schwiegerling, Jim

    2015-09-01

    The Optical Transfer Function (OTF) and its modulus the Modulation Transfer Function (MTF) are metrics of optical system performance. However in system optimization, calculation times for the OTF are often substantially longer than more traditional optimization targets such as wavefront error or transverse ray error. The OTF is typically calculated as either the autocorrelation of the complex pupil function or as the Fourier transform of the Point Spread Function. We recently demonstrated that the on-axis OTF can be represented as a linear combination of analytical functions where the weighting terms are directly related to the wavefront error coefficients and apodization of the complex pupil function. Here, we extend this technique to the off-axis case. The expansion technique offers a potential for accelerating OTF optimization in lens design, as well as insight into the interaction of aberrations with components of the OTF.

  16. Optimizing an emperical scoring function for transmembrane protein structure determination.

    SciTech Connect

    Young, Malin M.; Sale, Kenneth L.; Gray, Genetha Anne; Kolda, Tamara Gibson

    2003-10-01

    We examine the problem of transmembrane protein structure determination. Like many other questions that arise in biological research, this problem cannot be addressed by traditional laboratory experimentation alone. An approach that integrates experiment and computation is required. We investigate a procedure which states the transmembrane protein structure determination problem as a bound constrained optimization problem using a special empirical scoring function, called Bundler, as the objective function. In this paper, we describe the optimization problem and some of its mathematical properties. We compare and contrast results obtained using two different derivative free optimization algorithms.

  17. Functional Characterization of Pseudomonas Contact Dependent Growth Inhibition (CDI) Systems.

    PubMed

    Mercy, Chryslène; Ize, Bérengère; Salcedo, Suzana P; de Bentzmann, Sophie; Bigot, Sarah

    2016-01-01

    Contact-dependent inhibition (CDI) toxins, delivered into the cytoplasm of target bacterial cells, confer to host strain a significant competitive advantage. Upon cell contact, the toxic C-terminal region of surface-exposed CdiA protein (CdiA-CT) inhibits the growth of CDI- bacteria. CDI+ cells express a specific immunity protein, CdiI, which protects from autoinhibition by blocking the activity of cognate CdiA-CT. CdiA-CT are separated from the rest of the protein by conserved peptide motifs falling into two distinct classes, the "E. coli"- and "Burkholderia-type". CDI systems have been described in numerous species except in Pseudomonadaceae. In this study, we identified functional toxin/immunity genes linked to CDI systems in the Pseudomonas genus, which extend beyond the conventional CDI classes by the variability of the peptide motif that delimits the polymorphic CdiA-CT domain. Using P. aeruginosa PAO1 as a model, we identified the translational repressor RsmA as a negative regulator of CDI systems. Our data further suggest that under conditions of expression, P. aeruginosa CDI systems are implicated in adhesion and biofilm formation and provide an advantage in competition assays. All together our data imply that CDI systems could play an important role in niche adaptation of Pseudomonadaceae.

  18. Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia

    PubMed Central

    Desjardins, Danielle; Liu, Yueying; Crosson, Craig E.; Ablonczy, Zsolt

    2016-01-01

    In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE) is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE). Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb) or vascular endothelial growth factor (VEGF), increased histone deacetylase (HDAC) activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA), suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro) and fluid transport (in vivo). Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina. PMID:27617745

  19. Functional Characterization of Pseudomonas Contact Dependent Growth Inhibition (CDI) Systems

    PubMed Central

    Mercy, Chryslène; Ize, Bérengère; Salcedo, Suzana P.; de Bentzmann, Sophie; Bigot, Sarah

    2016-01-01

    Contact-dependent inhibition (CDI) toxins, delivered into the cytoplasm of target bacterial cells, confer to host strain a significant competitive advantage. Upon cell contact, the toxic C-terminal region of surface-exposed CdiA protein (CdiA-CT) inhibits the growth of CDI- bacteria. CDI+ cells express a specific immunity protein, CdiI, which protects from autoinhibition by blocking the activity of cognate CdiA-CT. CdiA-CT are separated from the rest of the protein by conserved peptide motifs falling into two distinct classes, the “E. coli”- and “Burkholderia-type”. CDI systems have been described in numerous species except in Pseudomonadaceae. In this study, we identified functional toxin/immunity genes linked to CDI systems in the Pseudomonas genus, which extend beyond the conventional CDI classes by the variability of the peptide motif that delimits the polymorphic CdiA-CT domain. Using P. aeruginosa PAO1 as a model, we identified the translational repressor RsmA as a negative regulator of CDI systems. Our data further suggest that under conditions of expression, P. aeruginosa CDI systems are implicated in adhesion and biofilm formation and provide an advantage in competition assays. All together our data imply that CDI systems could play an important role in niche adaptation of Pseudomonadaceae. PMID:26808644

  20. Kaempferol inhibits Entamoeba histolytica growth by altering cytoskeletal functions.

    PubMed

    Bolaños, Verónica; Díaz-Martínez, Alfredo; Soto, Jacqueline; Marchat, Laurence A; Sanchez-Monroy, Virginia; Ramírez-Moreno, Esther

    2015-11-01

    The flavonoid kaempferol obtained from Helianthemum glomeratum, an endemic Mexican medicinal herb used to treat gastrointestinal disorders, has been shown to inhibit growth of Entamoeba histolytica trophozoites in vitro; however, the mechanisms associated with this activity have not been documented. Several works reported that kaempferol affects cytoskeleton in mammalian cells. In order to gain insights into the action mechanisms involved in the anti-amoebic effect of kaempferol, here we evaluated the effect of this compound on the pathogenic events driven by the cytoskeleton during E. histolytica infection. We also carried out a two dimensional gel-based proteomic analysis to evidence modulated proteins that could explain the phenotypical changes observed in trophozoites. Our results showed that kaempferol produces a dose-dependent effect on trophozoites growth and viability with optimal concentration being 27.7 μM. Kaempferol also decreased adhesion, it increased migration and phagocytic activity, but it did not affect erythrocyte binding nor cytolytic capacity of E. histolytica. Congruently, proteomic analysis revealed that the cytoskeleton proteins actin, myosin II heavy chain and cortexillin II were up-regulated in response to kaempferol treatment. In conclusion, kaempferol anti-amoebic effects were associated with deregulation of proteins related with cytoskeleton, which altered invasion mechanisms.

  1. Improved Particle Swarm Optimization for Global Optimization of Unimodal and Multimodal Functions

    NASA Astrophysics Data System (ADS)

    Basu, Mousumi

    2016-12-01

    Particle swarm optimization (PSO) performs well for small dimensional and less complicated problems but fails to locate global minima for complex multi-minima functions. This paper proposes an improved particle swarm optimization (IPSO) which introduces Gaussian random variables in velocity term. This improves search efficiency and guarantees a high probability of obtaining the global optimum without significantly impairing the speed of convergence and the simplicity of the structure of particle swarm optimization. The algorithm is experimentally validated on 17 benchmark functions and the results demonstrate good performance of the IPSO in solving unimodal and multimodal problems. Its high performance is verified by comparing with two popular PSO variants.

  2. FXR and its ligands inhibit the function of platelets

    PubMed Central

    Vaiyapuri, Sakthivel; Ali, Marfoua S.; Sasikumar, Parvathy; Sage, Tanya; Flora, Gagan D; Bye, Alex P; Kriek, Neline; Dorchies, Emilie; Molendi-Coste, Olivier; Dombrowicz, David; Staels, Bart; Bishop-Bailey, David

    2016-01-01

    Objective While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of transcription factors that regulate their function through DNA-independent mechanisms. These include the Farnesoid X Receptor (FXR), a member of the superfamily of ligand-activated transcription factors that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6-ECDCA, modulate platelet activation nongenomically. Approach and Results FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cGMP levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the non-genomic actions of these ligands to the FXR receptor. Conclusion This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease. PMID:27758768

  3. Methylene blue inhibits function of the 5-HT transporter

    PubMed Central

    Oz, Murat; Isaev, Dmytro; Lorke, Dietrich E; Hasan, Muhammed; Petroianu, Georg; Shippenberg, Toni S

    2012-01-01

    BACKGROUND AND PURPOSE Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT. EXPERIMENTAL APPROACH Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP+), [3H]5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function. KEY RESULTS In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP+ accumulation (IC50: 1.4 ± 0.3 µM). A similar effect was observed in N2A cells. Uptake of [3H]5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca2+ levels remained unchanged during MB application. Further experiments revealed that ASP+ binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 µM; 10 min) did not alter surface binding of the SERT ligand [125I]RTI-55. CONCLUSIONS AND IMPLICATIONS MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5-HT toxicity. PMID:21542830

  4. Theory of optimal balance predicts and explains the amplitude and decay time of synaptic inhibition

    NASA Astrophysics Data System (ADS)

    Kim, Jaekyung K.; Fiorillo, Christopher D.

    2017-03-01

    Synaptic inhibition counterbalances excitation, but it is not known what constitutes optimal inhibition. We previously proposed that perfect balance is achieved when the peak of an excitatory postsynaptic potential (EPSP) is exactly at spike threshold, so that the slightest variation in excitation determines whether a spike is generated. Using simulations, we show that the optimal inhibitory postsynaptic conductance (IPSG) increases in amplitude and decay rate as synaptic excitation increases from 1 to 800 Hz. As further proposed by theory, we show that optimal IPSG parameters can be learned through anti-Hebbian rules. Finally, we compare our theoretical optima to published experimental data from 21 types of neurons, in which rates of synaptic excitation and IPSG decay times vary by factors of about 100 (5-600 Hz) and 50 (1-50 ms), respectively. From an infinite range of possible decay times, theory predicted experimental decay times within less than a factor of 2. Across a distinct set of 15 types of neuron recorded in vivo, theory predicted the amplitude of synaptic inhibition within a factor of 1.7. Thus, the theory can explain biophysical quantities from first principles.

  5. Theory of optimal balance predicts and explains the amplitude and decay time of synaptic inhibition

    PubMed Central

    Kim, Jaekyung K.; Fiorillo, Christopher D.

    2017-01-01

    Synaptic inhibition counterbalances excitation, but it is not known what constitutes optimal inhibition. We previously proposed that perfect balance is achieved when the peak of an excitatory postsynaptic potential (EPSP) is exactly at spike threshold, so that the slightest variation in excitation determines whether a spike is generated. Using simulations, we show that the optimal inhibitory postsynaptic conductance (IPSG) increases in amplitude and decay rate as synaptic excitation increases from 1 to 800 Hz. As further proposed by theory, we show that optimal IPSG parameters can be learned through anti-Hebbian rules. Finally, we compare our theoretical optima to published experimental data from 21 types of neurons, in which rates of synaptic excitation and IPSG decay times vary by factors of about 100 (5–600 Hz) and 50 (1–50 ms), respectively. From an infinite range of possible decay times, theory predicted experimental decay times within less than a factor of 2. Across a distinct set of 15 types of neuron recorded in vivo, theory predicted the amplitude of synaptic inhibition within a factor of 1.7. Thus, the theory can explain biophysical quantities from first principles. PMID:28281523

  6. A Rigorous Framework for Optimization of Expensive Functions by Surrogates

    NASA Technical Reports Server (NTRS)

    Booker, Andrew J.; Dennis, J. E., Jr.; Frank, Paul D.; Serafini, David B.; Torczon, Virginia; Trosset, Michael W.

    1998-01-01

    The goal of the research reported here is to develop rigorous optimization algorithms to apply to some engineering design problems for which design application of traditional optimization approaches is not practical. This paper presents and analyzes a framework for generating a sequence of approximations to the objective function and managing the use of these approximations as surrogates for optimization. The result is to obtain convergence to a minimizer of an expensive objective function subject to simple constraints. The approach is widely applicable because it does not require, or even explicitly approximate, derivatives of the objective. Numerical results are presented for a 31-variable helicopter rotor blade design example and for a standard optimization test example.

  7. Optimal Piecewise Linear Basis Functions in Two Dimensions

    SciTech Connect

    Brooks III, E D; Szoke, A

    2009-01-26

    We use a variational approach to optimize the center point coefficients associated with the piecewise linear basis functions introduced by Stone and Adams [1], for polygonal zones in two Cartesian dimensions. Our strategy provides optimal center point coefficients, as a function of the location of the center point, by minimizing the error induced when the basis function interpolation is used for the solution of the time independent diffusion equation within the polygonal zone. By using optimal center point coefficients, one expects to minimize the errors that occur when these basis functions are used to discretize diffusion equations, or transport equations in optically thick zones (where they approach the solution of the diffusion equation). Our optimal center point coefficients satisfy the requirements placed upon the basis functions for any location of the center point. We also find that the location of the center point can be optimized, but this requires numerical calculations. Curiously, the optimum center point location is independent of the values of the dependent variable on the corners only for quadrilaterals.

  8. RSUME inhibits VHL and regulates its tumor suppressor function.

    PubMed

    Gerez, J; Tedesco, L; Bonfiglio, J J; Fuertes, M; Barontini, M; Silberstein, S; Wu, Y; Renner, U; Páez-Pereda, M; Holsboer, F; Stalla, G K; Arzt, E

    2015-09-10

    Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.

  9. Strategy based on information entropy for optimizing stochastic functions.

    PubMed

    Schmidt, Tobias Christian; Ries, Harald; Spirkl, Wolfgang

    2007-02-01

    We propose a method for the global optimization of stochastic functions. During the course of the optimization, a probability distribution is built up for the location and the value of the global optimum. The concept of information entropy is used to make the optimization as efficient as possible. The entropy measures the information content of a probability distribution, and thus gives a criterion for decisions: From several possibilities we choose the one which yields the most information concerning location and value of the global maximum sought.

  10. Inhibition of oxytocin receptor function by direct binding of progesterone.

    PubMed

    Grazzini, E; Guillon, G; Mouillac, B; Zingg, H H

    1998-04-02

    The steroid hormone progesterone (P4) is essential for establishing and maintaining pregnancy in mammals. One of its functions includes maintenance of uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide hormone oxytocin. Although it is generally held that steroid hormones such as P4 act at a genomic level by binding to nuclear receptors and modulating the expression of specific target genes, we show here that the effect of P4 on uterine sensitivity to oxytocin involves direct, non-genomic action of P4 on the uterine oxytocin receptor (OTR), a member of the G-protein-coupled receptor family. P4 inhibits oxytocin binding to OTR-containing membranes in vitro, binds with high affinity to recombinant rat OTR expressed in CHO cells, and suppresses oxytocin-induced inositol phosphate production and calcium mobilization. These effects are highly steroid- and receptor-specific, because binding and signalling functions of the closely related human OTR are not affected by P4 itself but by the P4 metabolite 5beta-dihydroprogesterone. Our findings provide the first evidence for a direct interaction between a steroid hormone and a G-protein-coupled receptor and define a new level of crosstalk between the peptide- and steroid-hormone signalling pathways.

  11. Inhibition of filamentous fungi by ketoconazole-functionalized electrospun nanofibers.

    PubMed

    Veras, Flávio Fonseca; Roggia, Isabel; Pranke, Patricia; Pereira, Cláudio Nunes; Brandelli, Adriano

    2016-03-10

    Nanotechnology strategies have been used for delivery and controlled release of antimicrobial drugs. Electrospun nanofibers can be versatile vehicles to incorporate antimicrobials. In this work, poly-ε-caprolactone nanofibers functionalized with ketoconazole were produced by electrospinning and tested against filamentous fungi. Ketoconazole-free nanofibers were produced as controls. Functionalized nanofibers showed antifungal activity against Aspergillus flavus, A. carbonarius, A. niger, Aspergillus sp. A29, Fusarium oxysporum and Penicillium citrinum by agar diffusion test. Inhibitory zones ranging from 6 to 44mm were observed, this larger inhibition was against A. flavus. The nanofibers were incubated in different simulant solutions to evaluate the ketoconazole release, which was only detected in the solution containing 5% (v/v) Tween 20. Electron microscopy images showed the nanofibers with ketoconazole presented mean diameters of 526nm, and the degradation of the nanofiber structures could be observed by electron microscopy after incubation in simulant solution. Infrared and thermal analyses indicated that ketoconazole was dispersed without chemical interactions with the polycaprolactone matrix. These results suggest that polycaprolactone nanofibers incorporating ketoconazole may be an interesting alternative to control pathogenic fungi.

  12. Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice

    PubMed Central

    Van Bogaert, Tom; Vandevyver, Sofie; Dejager, Lien; Van Hauwermeiren, Filip; Pinheiro, Iris; Petta, Ioanna; Engblom, David; Kleyman, Anna; Schütz, Günther; Tuckermann, Jan; Libert, Claude

    2011-01-01

    As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNFα, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNFα-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNFα lethality was completely abolished when it was administered after TNFα stimulation, indicating compromised GR function upon TNFα challenge. TNFα-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNFα down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNFα also resulted in down-regulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNFα-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNFα inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNFα is intimately involved. PMID:21646349

  13. Obesity, Cardiovascular Fitness, and Inhibition Function: An Electrophysiological Study.

    PubMed

    Song, Tai-Fen; Chi, Lin; Chu, Chien-Heng; Chen, Feng-Tzu; Zhou, Chenglin; Chang, Yu-Kai

    2016-01-01

    The purpose of the present study was to examine how obesity and cardiovascular fitness are associated with the inhibition aspect of executive function from behavioral and electrophysiological perspectives. One hundred college students, aged 18-25 years, were categorized into four groups of equal size on the basis of body mass index and cardiovascular fitness: a normal-weight and high-fitness (NH) group, an obese-weight and high-fitness (OH) group, a normal-weight and low-fitness (NL) group, and an obese-weight and low-fitness (OL) group. Behavioral measures of response time and number of errors, as well as event-related potential measures of P3 and N1, were assessed during the Stroop Task. The results revealed that, in general, the NH group exhibited shorter response times and larger P3 amplitudes relative to the NL and OL groups, wherein the OL group exhibited the longest response time in the incongruent condition. No group differences in N1 indices were also revealed. These findings suggest that the status of being both normal weight and having high cardiovascular fitness is associated with better behavioral and later stages of electrophysiological indices of cognitive function.

  14. Obesity, Cardiovascular Fitness, and Inhibition Function: An Electrophysiological Study

    PubMed Central

    Song, Tai-Fen; Chi, Lin; Chu, Chien-Heng; Chen, Feng-Tzu; Zhou, Chenglin; Chang, Yu-Kai

    2016-01-01

    The purpose of the present study was to examine how obesity and cardiovascular fitness are associated with the inhibition aspect of executive function from behavioral and electrophysiological perspectives. One hundred college students, aged 18–25 years, were categorized into four groups of equal size on the basis of body mass index and cardiovascular fitness: a normal-weight and high-fitness (NH) group, an obese-weight and high-fitness (OH) group, a normal-weight and low-fitness (NL) group, and an obese-weight and low-fitness (OL) group. Behavioral measures of response time and number of errors, as well as event-related potential measures of P3 and N1, were assessed during the Stroop Task. The results revealed that, in general, the NH group exhibited shorter response times and larger P3 amplitudes relative to the NL and OL groups, wherein the OL group exhibited the longest response time in the incongruent condition. No group differences in N1 indices were also revealed. These findings suggest that the status of being both normal weight and having high cardiovascular fitness is associated with better behavioral and later stages of electrophysiological indices of cognitive function. PMID:27512383

  15. Menthol inhibiting parasympathetic function of tracheal smooth muscle

    PubMed Central

    Wang, Hsing-Won; Liu, Shao-Cheng; Chao, Pin-Zhir; Lee, Fei-Peng

    2016-01-01

    Menthol is used as a constituent of food and drink, tobacco and cosmetics nowadays. This cold receptor agonist has been used as a nasal inhalation solution in the daily life. The effect of menthol on nasal mucosa in vivo is well known; however, the effect of the drug on tracheal smooth muscle has been rarely explored. Therefore, during administration of the drug for nasal symptoms, it might also affect the trachea via oral intake or inhalation. We used our preparation to test the effectiveness of menthol on isolated rat tracheal smooth muscle. A 5 mm long portion of rat trachea was submersed in 30 ml Krebs solution in a muscle bath at 37ºC. Changes in tracheal contractility in response to the application of a parasympathetic mimetic agent were measured using a transducer connected to a Pentium III computer equipped with polygraph software. The following assessments of menthol were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10-6 M methacholine as a parasympathetic mimetic; (3) effect of the drug on electrically induced tracheal smooth muscle contractions. Results indicated that addition of a parasympathetic mimetic to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of menthol at doses of 10-5 M or above elicited a relaxation response to 10-6 M methacholine-induced contraction. Menthol could also inhibit electrical field stimulation (EFS) induced spike contraction. However, it alone had a minimal effect on the basal tension of trachea as the concentration increased. We concluded that the degree of drug-induced tracheal contraction or relaxation was dose-dependent. In addition, this study indicated that high concentrations of menthol might actually inhibit parasympathetic function of the trachea. PMID:27994497

  16. Optimized replica gas estimation of absolute integrals and partition functions

    NASA Astrophysics Data System (ADS)

    Minh, David D. L.

    2010-09-01

    In contrast with most Monte Carlo integration algorithms, which are used to estimate ratios, the replica gas identities recently introduced by Adib enable the estimation of absolute integrals and partition functions using multiple copies of a system and normalized transition functions. Here, an optimized form is presented. After generalizing a replica gas identity with an arbitrary weighting function, we obtain a functional form that has the minimal asymptotic variance for samples from two replicas and is provably good for a larger number. This equation is demonstrated to improve the convergence of partition function estimates in a two-dimensional Ising model.

  17. Optimized replica gas estimation of absolute integrals and partition functions.

    SciTech Connect

    Minh, D.

    2010-01-01

    In contrast with most Monte Carlo integration algorithms, which are used to estimate ratios, the replica gas identities recently introduced by Adib enable the estimation of absolute integrals and partition functions using multiple copies of a system and normalized transition functions. Here, an optimized form is presented. After generalizing a replica gas identity with an arbitrary weighting function, we obtain a functional form that has the minimal asymptotic variance for samples from two replicas and is provably good for a larger number. This equation is demonstrated to improve the convergence of partition function estimates in a two-dimensional Ising model.

  18. Study of genetic direct search algorithms for function optimization

    NASA Technical Reports Server (NTRS)

    Zeigler, B. P.

    1974-01-01

    The results are presented of a study to determine the performance of genetic direct search algorithms in solving function optimization problems arising in the optimal and adaptive control areas. The findings indicate that: (1) genetic algorithms can outperform standard algorithms in multimodal and/or noisy optimization situations, but suffer from lack of gradient exploitation facilities when gradient information can be utilized to guide the search. (2) For large populations, or low dimensional function spaces, mutation is a sufficient operator. However for small populations or high dimensional functions, crossover applied in about equal frequency with mutation is an optimum combination. (3) Complexity, in terms of storage space and running time, is significantly increased when population size is increased or the inversion operator, or the second level adaptation routine is added to the basic structure.

  19. Optimization of adiponectin-derived peptides for inhibition of cancer cell growth and signaling.

    PubMed

    Otvos, Laszlo; Kovalszky, Ilona; Olah, Julia; Coroniti, Roberta; Knappe, Daniel; Nollmann, Friederike I; Hoffmann, Ralf; Wade, John D; Lovas, Sandor; Surmacz, Eva

    2015-05-01

    Adiponectin, an adipose tissue-excreted adipokine plays protective roles in metabolic and cardiovascular diseases and exerts anti-cancer activities, partially by interfering with leptin-induced signaling. Previously we identified the active site in the adiponectin protein, and generated both a nanomolar monomeric agonist of the adiponectin receptor (10-mer ADP355) and an antagonist (8-mer ADP400) to modulate various adiponectin receptor-mediated cellular functions. As physiologically circulating adiponectin forms multimeric complexes, we also generated an agonist dimer with improved biodistribution and in vitro efficacy. In the current report, we attempted to optimize the monomeric agonist structure. Neither extension of the peptide up to 14-mer analogs nor reinstallation of native residues in permissible positions enhanced significantly the activity profile. The only substitutions that resulted in 5-10-fold improved agonistic activity were the replacement of turn-forming Gly4 and Tyr7 residues with Pro and Hyp, respectively, yielding the more active native β-sheet structure. All peptides retained good stability in human serum exhibiting half-lives >2 h. The cellular efficacy and stability rankings among the peptides followed expected structure-activity relationship trends. To investigate whether simultaneous activation of adiponectin pathways and inhibition of leptin-induced signals can result in cytostatic and anti-oncogenic signal transduction processes, we developed a chimera of the leptin receptor antagonist peptide Allo-aca (placed to the N-terminus) and ADP355 (at the C-terminus). The in vitro anti-tumor activity and intracellular signaling of the chimera were dominated by the more active Allo-aca component. The ADP355 part, however, reversed unfavorable in vivo metabolic effects of the leptin receptor antagonist.

  20. Optimal design for nonlinear estimation of the hemodynamic response function.

    PubMed

    Maus, Bärbel; van Breukelen, Gerard J P; Goebel, Rainer; Berger, Martijn P F

    2012-06-01

    Subject-specific hemodynamic response functions (HRFs) have been recommended to capture variation in the form of the hemodynamic response between subjects (Aguirre et al., [ 1998]: Neuroimage 8:360-369). The purpose of this article is to find optimal designs for estimation of subject-specific parameters for the double gamma HRF. As the double gamma function is a nonlinear function of its parameters, optimal design theory for nonlinear models is employed in this article. The double gamma function is linearized by a Taylor approximation and the maximin criterion is used to handle dependency of the D-optimal design on the expansion point of the Taylor approximation. A realistic range of double gamma HRF parameters is used for the expansion point of the Taylor approximation. Furthermore, a genetic algorithm (GA) (Kao et al., [ 2009]: Neuroimage 44:849-856) is applied to find locally optimal designs for the different expansion points and the maximin design chosen from the locally optimal designs is compared to maximin designs obtained by m-sequences, blocked designs, designs with constant interstimulus interval (ISI) and random event-related designs. The maximin design obtained by the GA is most efficient. Random event-related designs chosen from several generated designs and m-sequences have a high efficiency, while blocked designs and designs with a constant ISI have a low efficiency compared to the maximin GA design.

  1. Do community-weighted mean functional traits reflect optimal strategies?

    PubMed

    Muscarella, Robert; Uriarte, María

    2016-03-30

    The notion that relationships between community-weighted mean (CWM) traits (i.e. plot-level trait values weighted by species abundances) and environmental conditions reflect selection towards locally optimal phenotypes is challenged by the large amount of interspecific trait variation typically found within ecological communities. Reconciling these contrasting patterns is a key to advancing predictive theories of functional community ecology. We combined data on geographical distributions and three traits (wood density, leaf mass per area and maximum height) of 173 tree species in Puerto Rico. We tested the hypothesis that species are more likely to occur where their trait values are more similar to the local CWM trait values (the'CWM-optimality' hypothesis) by comparing species occurrence patterns (as a proxy for fitness) with the functional composition of forest plots across a precipitation gradient. While 70% of the species supported CWM-optimality for at least one trait, nearly 25% significantly opposed it for at least one trait, thereby contributing to local functional diversity. The majority (85%) of species that opposed CWM-optimality did so only for one trait and few species opposed CWM-optimality in multivariate trait space. Our study suggests that constraints to local functional variation act more strongly on multivariate phenotypes than on univariate traits.

  2. Optimization of a van der Waals Density Functional for water

    NASA Astrophysics Data System (ADS)

    Fritz, Michelle; Fernandez-Serra, Marivi; Soler, Jose M.

    2015-03-01

    In particularly delicate systems, like liquid water, ab initio exchange and correlation functionals are simply not accurate enough for many practical applications. In these cases, fitting the functional to reference data is a sensible alternative to empirical interatomic potentials. However, a global optimization requires functional forms that depend on many parameters and the usual trial and error strategy becomes cumbersome and suboptimal. We present a general and powerful optimization scheme called data projection onto parameter space (DPPS). In an arbitrarily large parameter space, DPPS expands the vector of unknown parameters in vectors of known data. Poorly sampled subspaces are determined by the physically-motivated functional shape of ab initio functionals, using Bayes' theory to combine this prior information with reference energies and electron densities of monomers, clusters, and condensed phases of water. We aknowledge support from FIS2012-37549 (MF and JMS) and DOE Early Career Award No. DE-SC0003871 (M.-V.F.-S.)

  3. Random search optimization based on genetic algorithm and discriminant function

    NASA Technical Reports Server (NTRS)

    Kiciman, M. O.; Akgul, M.; Erarslanoglu, G.

    1990-01-01

    The general problem of optimization with arbitrary merit and constraint functions, which could be convex, concave, monotonic, or non-monotonic, is treated using stochastic methods. To improve the efficiency of the random search methods, a genetic algorithm for the search phase and a discriminant function for the constraint-control phase were utilized. The validity of the technique is demonstrated by comparing the results to published test problem results. Numerical experimentation indicated that for cases where a quick near optimum solution is desired, a general, user-friendly optimization code can be developed without serious penalties in both total computer time and accuracy.

  4. Vaccine-enhanced artificial immune system for multimodal function optimization.

    PubMed

    Woldemariam, Kumlachew M; Yen, Gary G

    2010-02-01

    This paper emulates a biological notion in vaccines to promote exploration in the search space for solving multimodal function optimization problems using artificial immune systems (AISs). In this method, we first divide the decision space into equal subspaces. The vaccine is then randomly extracted from each subspace. A few of these vaccines, in the form of weakened antigens, are then injected into the algorithm to enhance the exploration of global and local optima. The goal of this process is to lead the antibodies to unexplored areas. Using this biologically motivated notion, we design the vaccine-enhanced AIS for multimodal function optimization, achieving promising performance.

  5. Do community-weighted mean functional traits reflect optimal strategies?

    PubMed Central

    Muscarella, Robert; Uriarte, María

    2016-01-01

    The notion that relationships between community-weighted mean (CWM) traits (i.e. plot-level trait values weighted by species abundances) and environmental conditions reflect selection towards locally optimal phenotypes is challenged by the large amount of interspecific trait variation typically found within ecological communities. Reconciling these contrasting patterns is a key to advancing predictive theories of functional community ecology. We combined data on geographical distributions and three traits (wood density, leaf mass per area and maximum height) of 173 tree species in Puerto Rico. We tested the hypothesis that species are more likely to occur where their trait values are more similar to the local CWM trait values (the ‘CWM-optimality’ hypothesis) by comparing species occurrence patterns (as a proxy for fitness) with the functional composition of forest plots across a precipitation gradient. While 70% of the species supported CWM-optimality for at least one trait, nearly 25% significantly opposed it for at least one trait, thereby contributing to local functional diversity. The majority (85%) of species that opposed CWM-optimality did so only for one trait and few species opposed CWM-optimality in multivariate trait space. Our study suggests that constraints to local functional variation act more strongly on multivariate phenotypes than on univariate traits. PMID:27030412

  6. Feminist Social Justice Orientation: An Indicator of Optimal Functioning?

    ERIC Educational Resources Information Center

    Moradi, Bonnie

    2012-01-01

    This article underscores several themes evident in Yoder, Snell, and Tobias's research; these include the conceptualization of feminism and social justice as inextricably linked, the conceptualization and operationalization of optimal functioning at intrapersonal, interpersonal, and collective levels, and potential connections and disconnections…

  7. Ciprofloxacin does not inhibit mitochondrial functions but other antibiotics do.

    PubMed Central

    Riesbeck, K; Bredberg, A; Forsgren, A

    1990-01-01

    At clinical concentrations, ciprofloxacin did not inhibit mitochondrial DNA replication, oxidative phosphorylation, protein synthesis, or mitochondrial mass (transmembrane potential). No difference in supercoiled forms of DNA was observed. The tetracyclines and chloramphenicol inhibited protein synthesis at clinically achievable concentrations, while rifampin, fusidic acid, and clindamycin did not. PMID:2327755

  8. Density functional theory optimized basis sets for gradient corrected functionals: 3d transition metal systems.

    PubMed

    Calaminici, Patrizia; Janetzko, Florian; Köster, Andreas M; Mejia-Olvera, Roberto; Zuniga-Gutierrez, Bernardo

    2007-01-28

    Density functional theory optimized basis sets for gradient corrected functionals for 3d transition metal atoms are presented. Double zeta valence polarization and triple zeta valence polarization basis sets are optimized with the PW86 functional. The performance of the newly optimized basis sets is tested in atomic and molecular calculations. Excitation energies of 3d transition metal atoms, as well as electronic configurations, structural parameters, dissociation energies, and harmonic vibrational frequencies of a large number of molecules containing 3d transition metal elements, are presented. The obtained results are compared with available experimental data as well as with other theoretical data from the literature.

  9. Optimizing global liver function in radiation therapy treatment planning

    NASA Astrophysics Data System (ADS)

    Wu, Victor W.; Epelman, Marina A.; Wang, Hesheng; Romeijn, H. Edwin; Feng, Mary; Cao, Yue; Ten Haken, Randall K.; Matuszak, Martha M.

    2016-09-01

    Liver stereotactic body radiation therapy (SBRT) patients differ in both pre-treatment liver function (e.g. due to degree of cirrhosis and/or prior treatment) and radiosensitivity, leading to high variability in potential liver toxicity with similar doses. This work investigates three treatment planning optimization models that minimize risk of toxicity: two consider both voxel-based pre-treatment liver function and local-function-based radiosensitivity with dose; one considers only dose. Each model optimizes different objective functions (varying in complexity of capturing the influence of dose on liver function) subject to the same dose constraints and are tested on 2D synthesized and 3D clinical cases. The normal-liver-based objective functions are the linearized equivalent uniform dose (\\ell \\text{EUD} ) (conventional ‘\\ell \\text{EUD} model’), the so-called perfusion-weighted \\ell \\text{EUD} (\\text{fEUD} ) (proposed ‘fEUD model’), and post-treatment global liver function (GLF) (proposed ‘GLF model’), predicted by a new liver-perfusion-based dose-response model. The resulting \\ell \\text{EUD} , fEUD, and GLF plans delivering the same target \\ell \\text{EUD} are compared with respect to their post-treatment function and various dose-based metrics. Voxel-based portal venous liver perfusion, used as a measure of local function, is computed using DCE-MRI. In cases used in our experiments, the GLF plan preserves up to 4.6 % ≤ft(7.5 % \\right) more liver function than the fEUD (\\ell \\text{EUD} ) plan does in 2D cases, and up to 4.5 % ≤ft(5.6 % \\right) in 3D cases. The GLF and fEUD plans worsen in \\ell \\text{EUD} of functional liver on average by 1.0 Gy and 0.5 Gy in 2D and 3D cases, respectively. Liver perfusion information can be used during treatment planning to minimize the risk of toxicity by improving expected GLF; the degree of benefit varies with perfusion pattern. Although fEUD model optimization is computationally inexpensive and

  10. Direct and Evolutionary Approaches for Optimal Receiver Function Inversion

    NASA Astrophysics Data System (ADS)

    Dugda, Mulugeta Tuji

    Receiver functions are time series obtained by deconvolving vertical component seismograms from radial component seismograms. Receiver functions represent the impulse response of the earth structure beneath a seismic station. Generally, receiver functions consist of a number of seismic phases related to discontinuities in the crust and upper mantle. The relative arrival times of these phases are correlated with the locations of discontinuities as well as the media of seismic wave propagation. The Moho (Mohorovicic discontinuity) is a major interface or discontinuity that separates the crust and the mantle. In this research, automatic techniques to determine the depth of the Moho from the earth's surface (the crustal thickness H) and the ratio of crustal seismic P-wave velocity (Vp) to S-wave velocity (Vs) (kappa= Vp/Vs) were developed. In this dissertation, an optimization problem of inverting receiver functions has been developed to determine crustal parameters and the three associated weights using evolutionary and direct optimization techniques. The first technique developed makes use of the evolutionary Genetic Algorithms (GA) optimization technique. The second technique developed combines the direct Generalized Pattern Search (GPS) and evolutionary Fitness Proportionate Niching (FPN) techniques by employing their strengths. In a previous study, Monte Carlo technique has been utilized for determining variable weights in the H-kappa stacking of receiver functions. Compared to that previously introduced variable weights approach, the current GA and GPS-FPN techniques have tremendous advantages of saving time and these new techniques are suitable for automatic and simultaneous determination of crustal parameters and appropriate weights. The GA implementation provides optimal or near optimal weights necessary in stacking receiver functions as well as optimal H and kappa values simultaneously. Generally, the objective function of the H-kappa stacking problem

  11. How optimization of potential functions affects protein folding.

    PubMed Central

    Hao, M H; Scheraga, H A

    1996-01-01

    The relationship between the optimization of the potential function and the foldability of theoretical protein models is studied based on investigations of a 27-mer cubic-lattice protein model and a more realistic lattice model for the protein crambin. In both the simple and the more complicated systems, optimization of the energy parameters achieves significant improvements in the statistical-mechanical characteristics of the systems and leads to foldable protein models in simulation experiments. The foldability of the protein models is characterized by their statistical-mechanical properties--e.g., by the density of states and by Monte Carlo folding simulations of the models. With optimized energy parameters, a high level of consistency exists among different interactions in the native structures of the protein models, as revealed by a correlation function between the optimized energy parameters and the native structure of the model proteins. The results of this work are relevant to the design of a general potential function for folding proteins by theoretical simulations. PMID:8643516

  12. Ramiprilate inhibits functional matrix metalloproteinase activity in Crohn's disease fistulas.

    PubMed

    Efsen, Eva; Saermark, Torben; Hansen, Alastair; Bruun, Eywin; Brynskov, Jørn

    2011-09-01

    effect on MMP activity. Increased functional MMP activity, notably MMP-3 and -9, is present in Crohn's fistulas and may be inhibited by ramiprilate, a widely available ACE inhibitor.

  13. Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling

    PubMed Central

    Mc Alpine, Tristan; Wei, Heng; Martínez, Víctor G.; Entrena, Ana; Melen, Gustavo J; MacDonald, Andrew S.; Phythian-Adams, Alexander; Sacedón, Rosa; Maraskovsky, Eugene; Cebon, Jonathan; Ramírez, Manuel

    2014-01-01

    Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions which are inhibited by the prototypic Th-2 cytokine IL-4 and the TGF-β superfamily members TGF-β1 and activin-A. Interestingly, the largest subgroup of the TGF-β superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling to NK cell effector functions have not been evaluated. Here we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8 which mediate BMP family member signaling. In opposition to the inhibitory effects of TGF-β1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L activated NK cells revealed that BMP signaling optimized IFN-γ and global cytokine and chemokine production; phenotypic activation and proliferation; autologous DC activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one which might be therapeutically manipulated to help eradicate tumors. PMID:25038228

  14. Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling.

    PubMed

    Robson, Neil C; Hidalgo, Laura; McAlpine, Tristan; Wei, Heng; Martínez, Víctor G; Entrena, Ana; Melen, Gustavo J; MacDonald, Andrew S; Phythian-Adams, Alexander; Sacedón, Rosa; Maraskovsky, Eugene; Cebon, Jonathan; Ramírez, Manuel; Vicente, Angeles; Varas, Alberto

    2014-09-15

    Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions that are inhibited by the prototypic Th2 cytokine IL4 and the TGFβ superfamily members TGFβ1 and activin-A. Interestingly, the largest subgroup of the TGFβ superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling on NK cell effector functions have not been evaluated. Here, we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8, which mediate BMP family member signaling. In opposition to the inhibitory effects of TGFβ1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L-activated NK cells revealed that BMP signaling optimized IFNγ and global cytokine and chemokine production, phenotypic activation and proliferation, and autologous dendritic cell activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one that might be therapeutically manipulated to help eradicate tumors. Cancer Res; 74(18); 5019-31. ©2014 AACR.

  15. MCMV-mediated Inhibition of the Pro-apoptotic Bak Protein Is Required for Optimal In Vivo Replication

    PubMed Central

    Fleming, Peter; Kvansakul, Marc; Voigt, Valentina; Kile, Benjamin T.; Kluck, Ruth M.; Huang, David C. S.; Degli-Esposti, Mariapia A.; Andoniou, Christopher E.

    2013-01-01

    Successful replication and transmission of large DNA viruses such as the cytomegaloviruses (CMV) family of viruses depends on the ability to interfere with multiple aspects of the host immune response. Apoptosis functions as a host innate defence mechanism against viral infection, and the capacity to interfere with this process is essential for the replication of many viruses. The Bcl-2 family of proteins are the principle regulators of apoptosis, with two pro-apoptotic members, Bax and Bak, essential for apoptosis to proceed. The m38.5 protein encoded by murine CMV (MCMV) has been identified as Bax-specific inhibitor of apoptosis. Recently, m41.1, a protein product encoded by the m41 open reading frame (ORF) of MCMV, has been shown to inhibit Bak activity in vitro. Here we show that m41.1 is critical for optimal MCMV replication in vivo. Growth of a m41.1 mutant was attenuated in multiple organs, a defect that was not apparent in Bak−/− mice. Thus, m41.1 promotes MCMV replication by inhibiting Bak-dependent apoptosis during in vivo infection. The results show that Bax and Bak mediate non-redundant functions during MCMV infection and that the virus produces distinct inhibitors for each protein to counter the activity of these proteins. PMID:23468630

  16. Construction of a directed hammerhead ribozyme library: towards the identification of optimal target sites for antisense-mediated gene inhibition.

    PubMed Central

    Pierce, M L; Ruffner, D E

    1998-01-01

    Antisense-mediated gene inhibition uses short complementary DNA or RNA oligonucleotides to block expression of any mRNA of interest. A key parameter in the success or failure of an antisense therapy is the identification of a suitable target site on the chosen mRNA. Ultimately, the accessibility of the target to the antisense agent determines target suitability. Since accessibility is a function of many complex factors, it is currently beyond our ability to predict. Consequently, identification of the most effective target(s) requires examination of every site. Towards this goal, we describe a method to construct directed ribozyme libraries against any chosen mRNA. The library contains nearly equal amounts of ribozymes targeting every site on the chosen transcript and the library only contains ribozymes capable of binding to that transcript. Expression of the ribozyme library in cultured cells should allow identification of optimal target sites under natural conditions, subject to the complexities of a fully functional cell. Optimal target sites identified in this manner should be the most effective sites for therapeutic intervention. PMID:9801305

  17. Optimizing electricity consumption: A case of function learning.

    PubMed

    Guath, Mona; Millroth, Philip; Juslin, Peter; Elwin, Ebba

    2015-12-01

    A popular way to improve consumers' control over their electricity consumption is by providing outcome feedback on the cost with in-home displays. Research on function learning, however, suggests that outcome feedback may not always be ideal for learning, especially if the feedback signal is noisy. In this study, we relate research on function learning to in-home displays and use a laboratory task simulating a household to investigate the role of outcome feedback and function learning on electricity optimization. Three function training schemes (FTSs) are presented that convey specific properties of the functions that relate the electricity consumption to the utility and cost. In Experiment 1, we compared learning from outcome feedback with 3 FTSs, 1 of which allowed maximization of the utility while keeping the budget, despite no feedback about the total monthly cost. In Experiment 2, we explored the combination of this FTS and outcome feedback. The results suggested that electricity optimization may be facilitated if feedback learning is preceded by a brief period of function training.

  18. Behaviorally inhibited individuals demonstrate significantly enhanced conditioned response acquisition under non-optimal learning conditions.

    PubMed

    Holloway, J L; Allen, M T; Myers, C E; Servatius, R J

    2014-03-15

    Behavioral inhibition (BI) is an anxiety vulnerability factor associated with hypervigilance to novel stimuli, threat, and ambiguous cues. The progression from anxiety risk to a clinical disorder is unknown, although the acquisition of defensive learning and avoidance may be a critical feature. As the expression of avoidance is also central to anxiety development, the present study examined avoidance acquisition as a function of inhibited temperament using classical eyeblink conditioning. Individuals were classified as behaviorally inhibited (BI) or non-inhibited (NI) based on combined scores from the Adult and Retrospective Measures of Behavioural Inhibition (AMBI and RMBI, respectively). Acquisition was assessed using delay, omission, or yoked conditioning schedules of reinforcement. Omission training was identical to delay, except that the emission of an eyeblink conditioned response (CR) resulted in omission of the unconditioned airpuff stimulus (US) on that trial. Each subject in the yoked group was matched on total BI score to a subject in the omission group, and received the same schedule of CS and US delivery, resulting in a partial reinforcement training schedule. Delay conditioning elicited significantly more CRs compared to the omission and yoked contingencies, the latter two of which did not differ from each other. Thus, acquisition of an avoidance response was not apparent. BI individuals demonstrated enhanced acquisition overall, while partial reinforcement training significantly distinguished between BI and NI groups. Enhanced learning in BI may be a function of an increased defensive learning capacity, or sensitivity to uncertainty. Further work examining the influence of BI on learning acquisition is important for understanding individual differences in disorder etiology in anxiety vulnerable cohorts.

  19. Galaxy Redshifts from Discrete Optimization of Correlation Functions

    NASA Astrophysics Data System (ADS)

    Lee, Benjamin C. G.; Budavári, Tamás; Basu, Amitabh; Rahman, Mubdi

    2016-12-01

    We propose a new method of constraining the redshifts of individual extragalactic sources based on celestial coordinates and their ensemble statistics. Techniques from integer linear programming (ILP) are utilized to optimize simultaneously for the angular two-point cross- and autocorrelation functions. Our novel formalism introduced here not only transforms the otherwise hopelessly expensive, brute-force combinatorial search into a linear system with integer constraints but also is readily implementable in off-the-shelf solvers. We adopt Gurobi, a commercial optimization solver, and use Python to build the cost function dynamically. The preliminary results on simulated data show potential for future applications to sky surveys by complementing and enhancing photometric redshift estimators. Our approach is the first application of ILP to astronomical analysis.

  20. Functional nanomaterials can optimize the efficacy of vaccines.

    PubMed

    Liu, Ye; Xu, Yingying; Tian, Yue; Chen, Chunying; Wang, Chen; Jiang, Xingyu

    2014-11-01

    Nanoscale materials can improve the efficacy of vaccines. Herein we review latest developments that use nanomaterials for vaccines. By highlighting the relationships between the nanoscale physicochemical characteristics and working mechanisms of nanomaterials, this paper shows the current status of the developments where researchers employ functional nanomaterials as vector and/or immunoregulators for vaccines. It also provides us some clues for improving the design and application of nanomaterials to optimize the efficacy of vaccines.

  1. Subdifferential of Optimal Value Functions in Nonlinear Infinite Programming

    SciTech Connect

    Huy, N. Q. Giang, N. D.; Yao, J.-C.

    2012-02-15

    This paper presents an exact formula for computing the normal cones of the constraint set mapping including the Clarke normal cone and the Mordukhovich normal cone in infinite programming under the extended Mangasarian-Fromovitz constraint qualification condition. Then, we derive an upper estimate as well as an exact formula for the limiting subdifferential of the marginal/optimal value function in a general Banach space setting.

  2. Optimal Wonderful Life Utility Functions in Multi-Agent Systems

    NASA Technical Reports Server (NTRS)

    Wolpert, David H.; Tumer, Kagan; Swanson, Keith (Technical Monitor)

    2000-01-01

    The mathematics of Collective Intelligence (COINs) is concerned with the design of multi-agent systems so as to optimize an overall global utility function when those systems lack centralized communication and control. Typically in COINs each agent runs a distinct Reinforcement Learning (RL) algorithm, so that much of the design problem reduces to how best to initialize/update each agent's private utility function, as far as the ensuing value of the global utility is concerned. Traditional team game solutions to this problem assign to each agent the global utility as its private utility function. In previous work we used the COIN framework to derive the alternative Wonderful Life Utility (WLU), and experimentally established that having the agents use it induces global utility performance up to orders of magnitude superior to that induced by use of the team game utility. The WLU has a free parameter (the clamping parameter) which we simply set to zero in that previous work. Here we derive the optimal value of the clamping parameter, and demonstrate experimentally that using that optimal value can result in significantly improved performance over that of clamping to zero, over and above the improvement beyond traditional approaches.

  3. A cubic extended interior penalty function for structural optimization

    NASA Technical Reports Server (NTRS)

    Prasad, B.; Haftka, R. T.

    1979-01-01

    This paper describes an optimization procedure for the minimum weight design of complex structures. The procedure is based on a new cubic extended interior penalty function (CEIPF) used with the sequence of unconstrained minimization technique (SUMT) and Newton's method. The Hessian matrix of the penalty function is approximated using only constraints and their derivatives. The CEIPF is designed to minimize the error in the approximation of the Hessian matrix, and as a result the number of structural analyses required is small and independent of the number of design variables. Three example problems are reported. The number of structural analyses is reduced by as much as 50 per cent below previously reported results.

  4. Optimizing Non-Decomposable Loss Functions in Structured Prediction

    PubMed Central

    Ranjbar, Mani; Lan, Tian; Wang, Yang; Robinovitch, Steven N.; Li, Ze-Nian; Mori, Greg

    2012-01-01

    We develop an algorithm for structured prediction with non-decomposable performance measures. The algorithm learns parameters of Markov random fields and can be applied to multivariate performance measures. Examples include performance measures such as Fβ score (natural language processing), intersection over union (object category segmentation), Precision/Recall at k (search engines) and ROC area (binary classifiers). We attack this optimization problem by approximating the loss function with a piecewise linear function. The loss augmented inference forms a quadratic program (QP), which we solve using LP relaxation. We apply this approach to two tasks: object class-specific segmentation and human action retrieval from videos. We show significant improvement over baseline approaches that either use simple loss functions or simple scoring functions on the PASCAL VOC and H3D Segmentation datasets, and a nursing home action recognition dataset. PMID:22868650

  5. On the functional optimization of a certain class of nonstationary spatial functions

    USGS Publications Warehouse

    Christakos, G.; Paraskevopoulos, P.N.

    1987-01-01

    Procedures are developed in order to obtain optimal estimates of linear functionals for a wide class of nonstationary spatial functions. These procedures rely on well-established constrained minimum-norm criteria, and are applicable to multidimensional phenomena which are characterized by the so-called hypothesis of inherentity. The latter requires elimination of the polynomial, trend-related components of the spatial function leading to stationary quantities, and also it generates some interesting mathematics within the context of modelling and optimization in several dimensions. The arguments are illustrated using various examples, and a case study computed in detail. ?? 1987 Plenum Publishing Corporation.

  6. Human cytomegalovirus function inhibits replication of herpes simplex virus

    SciTech Connect

    Cockley, K.D.; Shiraki, K.; Rapp, F.

    1988-01-01

    Human embryonic lung (HEL) cells infected with human cytomegalovirus (HCMV) restricted the replication of herpes simplex virus type 1 (HSV-1). A delay in HSV replication of 15 h as well as a consistent, almost 3 log inhibition of HSV replication in HCMV-infected cell cultures harvested 24 to 72 h after superinfection were observed compared with controls infected with HSV alone. Treatment of HCMV-infected HEL cells with cycloheximide (100 ..mu..g/ml) for 3 or 24 h was demonstrated effective in blocking HCMV protein synthesis, as shown by immunoprecipitation with HCMV antibody-positive polyvalent serum. Cycloheximide treatment of HCMV-infected HEL cells and removal of the cycloheximide block before superinfection inhibited HSV-1 replication more efficiently than non-drug-treated superinfected controls. HCMV DNA-negative temperature-sensitive mutants restricted HSV as efficiently as wild-type HCMV suggesting that immediate-early and/or early events which occur before viral DNA synthesis are sufficient for inhibition of HSV. Inhibition of HSV-1 in HCMV-infected HEL cells was unaffected by elevated temperature (40.5/sup 0/C). However, prior UV irradiation of HCMV removed the block to HSV replication, demonstrating the requirement for an active HCMV genome. HSV-2 replication was similarly inhibited in HCMV-infected HEL cells. Superinfection of HCMV-infected HEL cells with HSV-1 labeled with (/sup 3/H)thymidine provided evidence that the labeled virus could penetrate to the nucleus of cells after superinfection. Evidence for penetration of superinfecting HSV into HCMV-infected cells was also provided by blot hybridization of HSV DNA synthesized in cells infected with HSV alone versus superinfected cell cultures at 0 and 48 h after superinfection.

  7. Optimal Design for Informative Protocols in Xenograft Tumor Growth Inhibition Experiments in Mice.

    PubMed

    Lestini, Giulia; Mentré, France; Magni, Paolo

    2016-09-01

    Tumor growth inhibition (TGI) models are increasingly used during preclinical drug development in oncology for the in vivo evaluation of antitumor effect. Tumor sizes are measured in xenografted mice, often only during and shortly after treatment, thus preventing correct identification of some TGI model parameters. Our aims were (i) to evaluate the importance of including measurements during tumor regrowth and (ii) to investigate the proportions of mice included in each arm. For these purposes, optimal design theory based on the Fisher information matrix implemented in PFIM4.0 was applied. Published xenograft experiments, involving different drugs, schedules, and cell lines, were used to help optimize experimental settings and parameters using the Simeoni TGI model. For each experiment, a two-arm design, i.e., control versus treatment, was optimized with or without the constraint of not sampling during tumor regrowth, i.e., "short" and "long" studies, respectively. In long studies, measurements could be taken up to 6 g of tumor weight, whereas in short studies the experiment was stopped 3 days after the end of treatment. Predicted relative standard errors were smaller in long studies than in corresponding short studies. Some optimal measurement times were located in the regrowth phase, highlighting the importance of continuing the experiment after the end of treatment. In the four-arm designs, the results showed that the proportions of control and treated mice can differ. To conclude, making measurements during tumor regrowth should become a general rule for informative preclinical studies in oncology, especially when a delayed drug effect is suspected.

  8. Defining Conditions for Optimal Inhibition of Food Intake in Rats by a Grape-Seed Derived Proanthocyanidin Extract

    PubMed Central

    Serrano, Joan; Casanova-Martí, Àngela; Blay, Mayte; Terra, Ximena; Ardévol, Anna; Pinent, Montserrat

    2016-01-01

    Food intake depends on homeostatic and non-homeostatic factors. In order to use grape seed proanthocyanidins (GSPE) as food intake limiting agents, it is important to define the key characteristics of their bioactivity within this complex function. We treated rats with acute and chronic treatments of GSPE at different doses to identify the importance of eating patterns and GSPE dose and the mechanistic aspects of GSPE. GSPE-induced food intake inhibition must be reproduced under non-stressful conditions and with a stable and synchronized feeding pattern. A minimum dose of around 350 mg GSPE/kg body weight (BW) is needed. GSPE components act by activating the Glucagon-like peptide-1 (GLP-1) receptor because their effect is blocked by Exendin 9-39. GSPE in turn acts on the hypothalamic center of food intake control probably because of increased GLP-1 production in the intestine. To conclude, GSPE inhibits food intake through GLP-1 signaling, but it needs to be dosed under optimal conditions to exert this effect. PMID:27775601

  9. Translational Geroscience: Emphasizing function to achieve optimal longevity

    PubMed Central

    Seals, Douglas R.; Melov, Simon

    2014-01-01

    Among individuals, biological aging leads to cellular and organismal dysfunction and an increased risk of chronic degenerative diseases and disability. This sequence of events in combination with the projected increases in the number of older adults will result in a worldwide healthcare burden with dire consequences. Superimposed on this setting are the adults now reaching traditional retirement ages--the baby boomers--a group that wishes to remain active, productive and physically and cognitively fit as they grow older. Together, these conditions are producing an unprecedented demand for increased healthspan or what might be termed “optimal longevity”—to live long, but well. To meet this demand, investigators with interests in the biological aspects of aging from model organisms to human epidemiology (population aging) must work together within an interactive process that we describe as translational geroscience. An essential goal of this new investigational platform should be the optimization and preservation of physiological function throughout the lifespan, including integrative physical and cognitive function, which would serve to increase healthspan, compress morbidity and disability into a shorter period of late-life, and help achieve optimal longevity. To most effectively utilize this new approach, we must rethink how investigators and administrators working at different levels of the translational research continuum communicate and collaborate with each other, how best to train the next generation of scientists in this new field, and how contemporary biological-biomedical aging research should be organized and funded. PMID:25324468

  10. In-Core Fuel Management with Biased Multiobjective Function Optimization

    SciTech Connect

    Shatilla, Youssef A.; Little, David C.; Penkrot, Jack A.; Holland, Richard Andrew

    2000-06-15

    The capability of biased multiobjective function optimization has been added to the Westinghouse Electric Company's (Westinghouse's) Advanced Loading Pattern Search code (ALPS). The search process, given a user-defined set of design constraints, proceeds to minimize a global parameter called the total value associated with constraints compliance (VACC), an importance-weighted measure of the deviation from limit and/or margin target. The search process takes into consideration two equally important user-defined factors while minimizing the VACC, namely, the relative importance of each constraint with respect to the others and the optimization of each constraint according to its own objective function. Hence, trading off margin-to-design limits from where it is abundantly available to where it is badly needed can now be accomplished. Two practical methods are provided to the user for input of constraints and associated objective functions. One consists of establishing design limits based on traditional core design parameters such as assembly/pin burnup, power, or reactivity. The second method allows the user to write a program, or script, to define a logic not possible through ordinary means. This method of script writing was made possible through the application resident compiler feature of the technical user language integration processor (tulip), developed at Westinghouse. For the optimization problems studied, ALPS not only produced candidate loading patterns (LPs) that met all of the conflicting design constraints, but in cases where the design appeared to be over constrained gave a wide range of LPs that came very close to meeting all the constraints based on the associated objective functions.

  11. MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

    PubMed Central

    Bobustuc, George C; Smith, Joshua S; Maddipatla, Sreeram; Jeudy, Sheila; Limaye, Arati; Isley, Beth; Caparas, Maria-Lourdes M; Constantino, Susan M; Shah, Nikita; Baker, Cheryl H; Srivenugopal, Kalkunte S; Baidas, Said; Konduri, Santhi D

    2012-01-01

    Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O6-benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. In tamoxifen-resistant breast cancer cells, BG alone or in combination with antiestrogen (tamoxifen [TAM]/ICI 182,780 [fulvestrant, Faslodex]) therapy enhances p53 upregulated modulator of apoptosis (PUMA) expression, cytochrome C release and poly (ADP-ribose) polymerase (PARP) cleavage, all indicative of apoptosis. In addition, BG increases the expression of p21cip1/waf1. We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance. PMID:22549111

  12. Optimizing functional network representation of multivariate time series.

    PubMed

    Zanin, Massimiliano; Sousa, Pedro; Papo, David; Bajo, Ricardo; García-Prieto, Juan; del Pozo, Francisco; Menasalvas, Ernestina; Boccaletti, Stefano

    2012-01-01

    By combining complex network theory and data mining techniques, we provide objective criteria for optimization of the functional network representation of generic multivariate time series. In particular, we propose a method for the principled selection of the threshold value for functional network reconstruction from raw data, and for proper identification of the network's indicators that unveil the most discriminative information on the system for classification purposes. We illustrate our method by analysing networks of functional brain activity of healthy subjects, and patients suffering from Mild Cognitive Impairment, an intermediate stage between the expected cognitive decline of normal aging and the more pronounced decline of dementia. We discuss extensions of the scope of the proposed methodology to network engineering purposes, and to other data mining tasks.

  13. Optimizing Functional Network Representation of Multivariate Time Series

    NASA Astrophysics Data System (ADS)

    Zanin, Massimiliano; Sousa, Pedro; Papo, David; Bajo, Ricardo; García-Prieto, Juan; Pozo, Francisco Del; Menasalvas, Ernestina; Boccaletti, Stefano

    2012-09-01

    By combining complex network theory and data mining techniques, we provide objective criteria for optimization of the functional network representation of generic multivariate time series. In particular, we propose a method for the principled selection of the threshold value for functional network reconstruction from raw data, and for proper identification of the network's indicators that unveil the most discriminative information on the system for classification purposes. We illustrate our method by analysing networks of functional brain activity of healthy subjects, and patients suffering from Mild Cognitive Impairment, an intermediate stage between the expected cognitive decline of normal aging and the more pronounced decline of dementia. We discuss extensions of the scope of the proposed methodology to network engineering purposes, and to other data mining tasks.

  14. Ketoconazole inhibits Malassezia furfur morphogenesis in vitro under filamentation optimized conditions.

    PubMed

    Youngchim, Sirida; Nosanchuk, Joshua D; Chongkae, Siriporn; Vanittanokom, Nongnuch

    2017-01-01

    Malassezia furfur, a constituent of the normal human skin flora, is an etiological agent of pityriasis versicolor, which represents one of the most common human skin diseases. Under certain conditions, both exogenous and endogenous, the fungus can transition from a yeast form to a pathogenic mycelial form. To develop a standardized medium for reproducible production of the mycelial form of M. furfur to develop and optimize susceptibility testing for this pathogen, we examined and characterized variables, including kojic acid and glycine concentration, agar percentage, and pH, to generate a chemically defined minimal medium on which specific inoculums of M. furfur generated the most robust filamentation. Next, we examined the capacity of ketoconazole to inhibit the formation of M. furfur mycelial form. Both low and high, 0.01, 0.05 and 0.1 µg/ml concentrations of ketoconazole significantly inhibited filamentation at 11.9, 54.5 and 86.7%, respectively. Although ketoconazole can have a direct antifungal effect on both M. furfur yeast and mycelial cells, ketoconazole also has a dramatic impact on suppressing morphogenesis. Since mycelia typified the pathogenic form of Malassezia infection, the capacity of ketoconazole to block morphogenesis may represent an additional important effect of the antifungal.

  15. Investigation of using a power function as a cost function in inverse planning optimization.

    PubMed

    Xia, Ping; Yu, Naichang; Xing, Lei; Sun, Xuepeng; Verhey, Lynn J

    2005-04-01

    The purpose of this paper is to investigate the use of a power function as a cost function in inverse planning optimization. The cost function for each structure is implemented as an exponential power function of the deviation between the resultant dose and prescribed or constrained dose. The total cost function for all structures is a summation of the cost function of every structure. When the exponents of all terms in the cost function are set to 2, the cost function becomes a classical quadratic cost function. An independent optimization module was developed and interfaced with a research treatment planning system from the University of North Carolina for dose calculation and display of results. Three clinical cases were tested for this study with various exponents set for tumor targets and sensitive structures. Treatment plans with these exponent settings were compared, using dose volume histograms. The results of our study demonstrated that using an exponent higher than 2 in the cost function for the target achieved better dose homogeneity than using an exponent of 2. An exponent higher than 2 for serial sensitive structures can effectively reduce the maximum dose. Varying the exponent from 2 to 4 resulted in the most effective changes in dose volume histograms while the change from 4 to 8 is less drastic, indicating a situation of saturation. In conclusion, using a power function with exponent greater than 2 as a cost function can effectively achieve homogeneous dose inside the target and/or minimize maximum dose to the critical structures.

  16. The vigilance decrement in executive function is attenuated when individual chronotypes perform at their optimal time of day.

    PubMed

    Lara, Tania; Madrid, Juan Antonio; Correa, Ángel

    2014-01-01

    Time of day modulates our cognitive functions, especially those related to executive control, such as the ability to inhibit inappropriate responses. However, the impact of individual differences in time of day preferences (i.e. morning vs. evening chronotype) had not been considered by most studies. It was also unclear whether the vigilance decrement (impaired performance with time on task) depends on both time of day and chronotype. In this study, morning-type and evening-type participants performed a task measuring vigilance and response inhibition (the Sustained Attention to Response Task, SART) in morning and evening sessions. The results showed that the vigilance decrement in inhibitory performance was accentuated at non-optimal as compared to optimal times of day. In the morning-type group, inhibition performance decreased linearly with time on task only in the evening session, whereas in the morning session it remained more accurate and stable over time. In contrast, inhibition performance in the evening-type group showed a linear vigilance decrement in the morning session, whereas in the evening session the vigilance decrement was attenuated, following a quadratic trend. Our findings imply that the negative effects of time on task in executive control can be prevented by scheduling cognitive tasks at the optimal time of day according to specific circadian profiles of individuals. Therefore, time of day and chronotype influences should be considered in research and clinical studies as well as real-word situations demanding executive control for response inhibition.

  17. The Vigilance Decrement in Executive Function Is Attenuated When Individual Chronotypes Perform at Their Optimal Time of Day

    PubMed Central

    Lara, Tania; Madrid, Juan Antonio; Correa, Ángel

    2014-01-01

    Time of day modulates our cognitive functions, especially those related to executive control, such as the ability to inhibit inappropriate responses. However, the impact of individual differences in time of day preferences (i.e. morning vs. evening chronotype) had not been considered by most studies. It was also unclear whether the vigilance decrement (impaired performance with time on task) depends on both time of day and chronotype. In this study, morning-type and evening-type participants performed a task measuring vigilance and response inhibition (the Sustained Attention to Response Task, SART) in morning and evening sessions. The results showed that the vigilance decrement in inhibitory performance was accentuated at non-optimal as compared to optimal times of day. In the morning-type group, inhibition performance decreased linearly with time on task only in the evening session, whereas in the morning session it remained more accurate and stable over time. In contrast, inhibition performance in the evening-type group showed a linear vigilance decrement in the morning session, whereas in the evening session the vigilance decrement was attenuated, following a quadratic trend. Our findings imply that the negative effects of time on task in executive control can be prevented by scheduling cognitive tasks at the optimal time of day according to specific circadian profiles of individuals. Therefore, time of day and chronotype influences should be considered in research and clinical studies as well as real-word situations demanding executive control for response inhibition. PMID:24586404

  18. Functional modules, structural topology, and optimal activity in metabolic networks.

    PubMed

    Resendis-Antonio, Osbaldo; Hernández, Magdalena; Mora, Yolanda; Encarnación, Sergio

    2012-01-01

    Modular organization in biological networks has been suggested as a natural mechanism by which a cell coordinates its metabolic strategies for evolving and responding to environmental perturbations. To understand how this occurs, there is a need for developing computational schemes that contribute to integration of genomic-scale information and assist investigators in formulating biological hypotheses in a quantitative and systematic fashion. In this work, we combined metabolome data and constraint-based modeling to elucidate the relationships among structural modules, functional organization, and the optimal metabolic phenotype of Rhizobium etli, a bacterium that fixes nitrogen in symbiosis with Phaseolus vulgaris. To experimentally characterize the metabolic phenotype of this microorganism, we obtained the metabolic profile of 220 metabolites at two physiological stages: under free-living conditions, and during nitrogen fixation with P. vulgaris. By integrating these data into a constraint-based model, we built a refined computational platform with the capability to survey the metabolic activity underlying nitrogen fixation in R. etli. Topological analysis of the metabolic reconstruction led us to identify modular structures with functional activities. Consistent with modular activity in metabolism, we found that most of the metabolites experimentally detected in each module simultaneously increased their relative abundances during nitrogen fixation. In this work, we explore the relationships among topology, biological function, and optimal activity in the metabolism of R. etli through an integrative analysis based on modeling and metabolome data. Our findings suggest that the metabolic activity during nitrogen fixation is supported by interacting structural modules that correlate with three functional classifications: nucleic acids, peptides, and lipids. More fundamentally, we supply evidence that such modular organization during functional nitrogen fixation is

  19. A hybrid artificial bee colony algorithm for numerical function optimization

    NASA Astrophysics Data System (ADS)

    Alqattan, Zakaria N.; Abdullah, Rosni

    2015-02-01

    Artificial Bee Colony (ABC) algorithm is one of the swarm intelligence algorithms; it has been introduced by Karaboga in 2005. It is a meta-heuristic optimization search algorithm inspired from the intelligent foraging behavior of the honey bees in nature. Its unique search process made it as one of the most competitive algorithm with some other search algorithms in the area of optimization, such as Genetic algorithm (GA) and Particle Swarm Optimization (PSO). However, the ABC performance of the local search process and the bee movement or the solution improvement equation still has some weaknesses. The ABC is good in avoiding trapping at the local optimum but it spends its time searching around unpromising random selected solutions. Inspired by the PSO, we propose a Hybrid Particle-movement ABC algorithm called HPABC, which adapts the particle movement process to improve the exploration of the original ABC algorithm. Numerical benchmark functions were used in order to experimentally test the HPABC algorithm. The results illustrate that the HPABC algorithm can outperform the ABC algorithm in most of the experiments (75% better in accuracy and over 3 times faster).

  20. Cerebellar on-beam and lateral inhibition: two functionally distinct circuits.

    PubMed

    Cohen, D; Yarom, Y

    2000-04-01

    Optical imaging of voltage-sensitive dyes in an isolated cerebellum preparation was used to study the spatiotemporal functional organization of the inhibitory systems in the cerebellar cortex. Responses to surface stimulation of the cortex reveal two physiologically distinct inhibitory systems, which we refer to as lateral and on-beam inhibition following classical terminology. Lateral inhibition occurs throughout the area responding to a stimulus, whereas on-beam inhibition is confined to the area directly excited by parallel fibers. The time course of the lateral inhibition is twice as long as that of the on-beam inhibition. Both inhibitory responses increase with stimulus intensity, but the lateral inhibition has a lower threshold, and it saturates at lower stimulus intensity. The amplitude of the on-beam inhibition is linearly related to the excitation at the same location, whereas that of the lateral inhibition is linearly related to the excitation at the center of the beam. Repetitive stimulation is required to activate on-beam inhibition, whereas the same stimulus paradigm reveals prolonged depression of the lateral inhibition. We conclude that lateral inhibition reflects the activation of molecular layer interneurons, and its major role is to increase the excitability of the activated area by disinhibition. The on-beam inhibition most likely reflects Golgi cell inhibition of granule cells. However, Purkinje cell collateral inhibition of Golgi cells cannot be excluded. Both possibilities suggest that the role of the on-beam inhibition is to efficiently modulate, in time and space, the mossy fiber input to the cerebellar cortex.

  1. The Relations Among Inhibition and Interference Control Functions: A Latent-Variable Analysis

    ERIC Educational Resources Information Center

    Friedman, Naomi P.; Miyake, Akira

    2004-01-01

    This study used data from 220 adults to examine the relations among 3 inhibition-related functions. Confirmatory factor analysis suggested that Prepotent Response Inhibition and Resistance to Distractor Interference were closely related, but both were unrelated to Resistance to Proactive Interference. Structural equation modeling, which combined…

  2. Functional Developmental Changes Underlying Response Inhibition and Error-Detection Processes

    ERIC Educational Resources Information Center

    Braet, Wouter; Johnson, Katherine A.; Tobin, Claire T.; Acheson, Ruth; Bellgrove, Mark A.; Robertson, Ian H.; Garavan, Hugh

    2009-01-01

    This study examined the developmental trajectories associated with response inhibition and error processing as exemplar executive processes. We present fMRI data showing developmental changes to the functional networks underlying response inhibition and error-monitoring, comparing activation between adults and young adolescents performing the…

  3. Optimal gene partition into operons correlates with gene functional order

    NASA Astrophysics Data System (ADS)

    Zaslaver, Alon; Mayo, Avi; Ronen, Michal; Alon, Uri

    2006-09-01

    Gene arrangement into operons varies between bacterial species. Genes in a given system can be on one operon in some organisms and on several operons in other organisms. Existing theories explain why genes that work together should be on the same operon, since this allows for advantageous lateral gene transfer and accurate stoichiometry. But what causes the frequent separation into multiple operons of co-regulated genes that act together in a pathway? Here we suggest that separation is due to benefits made possible by differential regulation of each operon. We present a simple mathematical model for the optimal distribution of genes into operons based on a balance of the cost of operons and the benefit of regulation that provides 'just-when-needed' temporal order. The analysis predicts that genes are arranged such that genes on the same operon do not skip functional steps in the pathway. This prediction is supported by genomic data from 137 bacterial genomes. Our work suggests that gene arrangement is not only the result of random historical drift, genome re-arrangement and gene transfer, but has elements that are solutions of an evolutionary optimization problem. Thus gene functional order may be inferred by analyzing the operon structure across different genomes.

  4. Scope of Gradient and Genetic Algorithms in Multivariable Function Optimization

    NASA Technical Reports Server (NTRS)

    Shaykhian, Gholam Ali; Sen, S. K.

    2007-01-01

    Global optimization of a multivariable function - constrained by bounds specified on each variable and also unconstrained - is an important problem with several real world applications. Deterministic methods such as the gradient algorithms as well as the randomized methods such as the genetic algorithms may be employed to solve these problems. In fact, there are optimization problems where a genetic algorithm/an evolutionary approach is preferable at least from the quality (accuracy) of the results point of view. From cost (complexity) point of view, both gradient and genetic approaches are usually polynomial-time; there are no serious differences in this regard, i.e., the computational complexity point of view. However, for certain types of problems, such as those with unacceptably erroneous numerical partial derivatives and those with physically amplified analytical partial derivatives whose numerical evaluation involves undesirable errors and/or is messy, a genetic (stochastic) approach should be a better choice. We have presented here the pros and cons of both the approaches so that the concerned reader/user can decide which approach is most suited for the problem at hand. Also for the function which is known in a tabular form, instead of an analytical form, as is often the case in an experimental environment, we attempt to provide an insight into the approaches focusing our attention toward accuracy. Such an insight will help one to decide which method, out of several available methods, should be employed to obtain the best (least error) output. *

  5. Neutralizing nanobodies targeting diverse chemokines effectively inhibit chemokine function.

    PubMed

    Blanchetot, Christophe; Verzijl, Dennis; Mujić-Delić, Azra; Bosch, Leontien; Rem, Louise; Leurs, Rob; Verrips, C Theo; Saunders, Michael; de Haard, Hans; Smit, Martine J

    2013-08-30

    Chemokine receptors and their ligands play a prominent role in immune regulation but many have also been implicated in inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, allograft rejection after transplantation, and also in cancer metastasis. Most approaches to therapeutically target the chemokine system involve targeting of chemokine receptors with low molecular weight antagonists. Here we describe the selection and characterization of an unprecedented large and diverse panel of neutralizing Nanobodies (single domain camelid antibodies fragment) directed against several chemokines. We show that the Nanobodies directed against CCL2 (MCP-1), CCL5 (RANTES), CXCL11 (I-TAC), and CXCL12 (SDF-1α) bind the chemokines with high affinity (at nanomolar concentration), thereby blocking receptor binding, inhibiting chemokine-induced receptor activation as well as chemotaxis. Together, we show that neutralizing Nanobodies can be selected efficiently for effective and specific therapeutic treatment against a wide range of immune and inflammatory diseases.

  6. Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria.

    PubMed

    Agrawal, Anurag; Mabalirajan, Ulaganathan

    2016-01-15

    Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model--repair, reprogramming, and replacement--for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases.

  7. Gray Matter Volume of the Lingual Gyrus Mediates the Relationship between Inhibition Function and Divergent Thinking

    PubMed Central

    Zhang, Lijie; Qiao, Lei; Chen, Qunlin; Yang, Wenjing; Xu, Mengsi; Yao, Xiaonan; Qiu, Jiang; Yang, Dong

    2016-01-01

    Although previous research provides converging evidence for the role of posterior regions of the brain (including temporal, occipital, and parietal regions) involved in inhibition on creative thinking, it remains unclear as to how these regions influence individual differences in creative thinking. Thus, we explored the relationship between posterior regions (i.e., hippocampal, parahippocampal, lingual gyrus, precuneus, and cuneus), inhibition function, and divergent thinking (DT) in 128 healthy college students. The results revealed that lower inhibition was associated with larger gray matter volume (GMV) in the lingual gyrus, which in turn was associated with higher DT. In addition, GMV in the lingual gyrus mediated the association between inhibition and DT. These results provide new evidence for the role of inhibition in creative thinking. Inhibition may affect the amount of information stored in long-term memory, which, in turn influences DT. PMID:27752250

  8. Gray Matter Volume of the Lingual Gyrus Mediates the Relationship between Inhibition Function and Divergent Thinking.

    PubMed

    Zhang, Lijie; Qiao, Lei; Chen, Qunlin; Yang, Wenjing; Xu, Mengsi; Yao, Xiaonan; Qiu, Jiang; Yang, Dong

    2016-01-01

    Although previous research provides converging evidence for the role of posterior regions of the brain (including temporal, occipital, and parietal regions) involved in inhibition on creative thinking, it remains unclear as to how these regions influence individual differences in creative thinking. Thus, we explored the relationship between posterior regions (i.e., hippocampal, parahippocampal, lingual gyrus, precuneus, and cuneus), inhibition function, and divergent thinking (DT) in 128 healthy college students. The results revealed that lower inhibition was associated with larger gray matter volume (GMV) in the lingual gyrus, which in turn was associated with higher DT. In addition, GMV in the lingual gyrus mediated the association between inhibition and DT. These results provide new evidence for the role of inhibition in creative thinking. Inhibition may affect the amount of information stored in long-term memory, which, in turn influences DT.

  9. Optimal Design of Functionally Graded Metallic Foam Insulations

    NASA Technical Reports Server (NTRS)

    Haftka, Raphael T.; Sankar, Bhavani; Venkataraman, Satchi; Zhu, Huadong

    2002-01-01

    The focus of our work has been on developing an insight into the physics that govern the optimum design of thermal insulation for use in thermal protection systems of launch vehicle. Of particular interest was to obtain optimality criteria for designing foam insulations that have density (or porosity) distributions through the thickness for optimum thermal performance. We investigate the optimum design of functionally graded thermal insulation for steady state heat transfer through the foam. We showed that the heat transfer in the foam has competing modes, of radiation and conduction. The problem assumed a fixed inside temperature of 400 K and varied the aerodynamic surface heating on the outside surface from 0.2 to 1.0 MW/sq m. The thermal insulation develops a high temperature gradient through the thickness. Investigation of the model developed for heat conduction in foams showed that at high temperatures (as on outside wall) intracellular radiation dominates the heat transfer in the foam. Minimizing radiation requires reducing the pore size, which increases the density of the foam. At low temperatures (as on the inside wall), intracellular conduction (of the metal and air) dominates the heat transfer. Minimizing conduction requires increasing the pore size. This indicated that for every temperature there was an optimum value of density that minimized the heat transfer coefficient. Two optimization studies were performed. One was to minimize the heat transmitted though a fixed thickness insulation by varying density profiles. The second was to obtain the minimum mass insulation for specified thickness. Analytical optimality criteria were derived for the cases considered. The optimality condition for minimum heat transfer required that at each temperature we find the density that minimizes the heat transfer coefficient. Once a relationship between the optimum heat transfer coefficient and the temperature was found, the design problem reduced to the solution of a

  10. High functional load inhibits phonological contrast loss: a corpus study.

    PubMed

    Wedel, Andrew; Kaplan, Abby; Jackson, Scott

    2013-08-01

    For nearly a century, linguists have suggested that diachronic merger is less likely between phonemes with a high functional load--that is, phonemes that distinguish many words in the language in question. However, limitations in data and computational power have made assessing this hypothesis difficult. Here we present the first larger-scale study of the functional load hypothesis, using data from sound changes in a diverse set of languages. Our results support the functional load hypothesis: phoneme pairs undergoing merger distinguish significantly fewer minimal pairs in the lexicon than unmerged phoneme pairs. Furthermore, we show that higher phoneme probability is positively correlated with merger, but that this effect is stronger for phonemes that distinguish no minimal pairs. Finally, within our dataset we find that minimal pair count and phoneme probability better predict merger than change in system entropy at the lexical or phoneme level.

  11. Apelin: an antithrombotic factor that inhibits platelet function.

    PubMed

    Adam, Frédéric; Khatib, Abdel-Majid; Lopez, Jose Javier; Vatier, Camille; Turpin, Sabrina; Muscat, Adeline; Soulet, Fabienne; Aries, Anne; Jardin, Isaac; Bobe, Régis; Stepanian, Alain; de Prost, Dominique; Dray, Cédric; Rosado, Juan Antonio; Valet, Philippe; Feve, Bruno; Siegfried, Geraldine

    2016-02-18

    Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin- and collagen-mediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile. Their platelets exhibited increased adhesion and a reduced occlusion time in venules, and displayed a higher aggregation rate after their activation by thrombin compared with wild-type platelets. Consequently, human and mouse platelets express apelin and its receptor APJ. Apelin directly interferes with thrombin-mediated signaling pathways and platelet activation, secretion, and aggregation, but not with ADP and thromboxane A2-mediated pathways. IV apelin administration induced excessive bleeding and prevented thrombosis in mice. Taken together, these findings suggest that apelin and/or APJ agonists could potentially be useful adducts in antiplatelet therapies and may provide a promising perspective for patients who continue to display adverse thrombotic events with current antiplatelet therapies.

  12. Orbital-dependent functionals in FLAPW: hybrid functionals and optimized effective potentials

    NASA Astrophysics Data System (ADS)

    Blügel, Stefan

    2011-03-01

    Orbital-dependent functionals are a new class of exchange-correlation (xc) functionals for density-functional theory. Hybrid functionals combine a local or semi-local xc functional with a nonlocal orbital-dependent exchange functional and improve the band gaps of semiconductors and insulators as well as the description of localized states. As an alternative to nonlocal hybrid potentials, one can also construct local optimized effective potentials (OEP) from the exact exchange (EXX) functional. So far, most implementations for periodic systems use a pseudopotential plane-wave approach. We present an efficient all-electron, full-potential implementation of the PBE0 and HSE hybrid functionals as well as the OEP-EXX functional within the FLAPW method (Fleur code: www.flapw.de). Results for prototype semiconductors and insulators are in very good agreement with other implementations. We will demonstrate the improvement over conventional local or semilocal functionals for oxide materials and focus in particular on systems where standard functionals yield qualitatively wrong results. In particular, we will discuss the geometric and magnetic structures of EuO and GdN. Additionally, we will address the possibility of using the hybrid-functional ground state as starting point for a GW quasiparticle correction and show results for complex perovskite systems. Financial support from the DFG through the Priority Program 1145 and the Helmholtz association through the Young Investigators Group Program, contract VH-NG-409, is gratefully acknowledged.

  13. The gastric HK-ATPase: structure, function, and inhibition

    PubMed Central

    Shin, Jai Moo; Munson, Keith; Vagin, Olga

    2011-01-01

    The gastric H,K-ATPase, a member of the P2-type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven N-linked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E1 (ion site in) to an E2 (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E2P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E2P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases. PMID:18536934

  14. Optimal hemodynamic response model for functional near-infrared spectroscopy

    PubMed Central

    Kamran, Muhammad A.; Jeong, Myung Yung; Mannan, Malik M. N.

    2015-01-01

    Functional near-infrared spectroscopy (fNIRS) is an emerging non-invasive brain imaging technique and measures brain activities by means of near-infrared light of 650–950 nm wavelengths. The cortical hemodynamic response (HR) differs in attributes at different brain regions and on repetition of trials, even if the experimental paradigm is kept exactly the same. Therefore, an HR model that can estimate such variations in the response is the objective of this research. The canonical hemodynamic response function (cHRF) is modeled by two Gamma functions with six unknown parameters (four of them to model the shape and other two to scale and baseline respectively). The HRF model is supposed to be a linear combination of HRF, baseline, and physiological noises (amplitudes and frequencies of physiological noises are supposed to be unknown). An objective function is developed as a square of the residuals with constraints on 12 free parameters. The formulated problem is solved by using an iterative optimization algorithm to estimate the unknown parameters in the model. Inter-subject variations in HRF and physiological noises have been estimated for better cortical functional maps. The accuracy of the algorithm has been verified using 10 real and 15 simulated data sets. Ten healthy subjects participated in the experiment and their HRF for finger-tapping tasks have been estimated and analyzed. The statistical significance of the estimated activity strength parameters has been verified by employing statistical analysis (i.e., t-value > tcritical and p-value < 0.05). PMID:26136668

  15. Function-valued adaptive dynamics and optimal control theory.

    PubMed

    Parvinen, Kalle; Heino, Mikko; Dieckmann, Ulf

    2013-09-01

    In this article we further develop the theory of adaptive dynamics of function-valued traits. Previous work has concentrated on models for which invasion fitness can be written as an integral in which the integrand for each argument value is a function of the strategy value at that argument value only. For this type of models of direct effect, singular strategies can be found using the calculus of variations, with singular strategies needing to satisfy Euler's equation with environmental feedback. In a broader, more mechanistically oriented class of models, the function-valued strategy affects a process described by differential equations, and fitness can be expressed as an integral in which the integrand for each argument value depends both on the strategy and on process variables at that argument value. In general, the calculus of variations cannot help analyzing this much broader class of models. Here we explain how to find singular strategies in this class of process-mediated models using optimal control theory. In particular, we show that singular strategies need to satisfy Pontryagin's maximum principle with environmental feedback. We demonstrate the utility of this approach by studying the evolution of strategies determining seasonal flowering schedules.

  16. Measles Virus Fusion Protein: Structure, Function and Inhibition

    PubMed Central

    Plattet, Philippe; Alves, Lisa; Herren, Michael; Aguilar, Hector C.

    2016-01-01

    Measles virus (MeV), a highly contagious member of the Paramyxoviridae family, causes measles in humans. The Paramyxoviridae family of negative single-stranded enveloped viruses includes several important human and animal pathogens, with MeV causing approximately 120,000 deaths annually. MeV and canine distemper virus (CDV)-mediated diseases can be prevented by vaccination. However, sub-optimal vaccine delivery continues to foster MeV outbreaks. Post-exposure prophylaxis with antivirals has been proposed as a novel strategy to complement vaccination programs by filling herd immunity gaps. Recent research has shown that membrane fusion induced by the morbillivirus glycoproteins is the first critical step for viral entry and infection, and determines cell pathology and disease outcome. Our molecular understanding of morbillivirus-associated membrane fusion has greatly progressed towards the feasibility to control this process by treating the fusion glycoprotein with inhibitory molecules. Current approaches to develop anti-membrane fusion drugs and our knowledge on drug resistance mechanisms strongly suggest that combined therapies will be a prerequisite. Thus, discovery of additional anti-fusion and/or anti-attachment protein small-molecule compounds may eventually translate into realistic therapeutic options. PMID:27110811

  17. Bcl-2 engineered MSCs inhibited apoptosis and improved heart function.

    PubMed

    Li, Wenzhong; Ma, Nan; Ong, Lee-Lee; Nesselmann, Catharina; Klopsch, Christian; Ladilov, Yury; Furlani, Dario; Piechaczek, Christoph; Moebius, Jeannette M; Lützow, Karola; Lendlein, Andreas; Stamm, Christof; Li, Ren-Ke; Steinhoff, Gustav

    2007-08-01

    Engraftment of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for postinfarction left ventricular dysfunction. However, limited cell viability after transplantation into the myocardium has restricted its regenerative capacity. In this study, we genetically modified MSCs with an antiapoptotic Bcl-2 gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a rat left anterior descending ligation model via intracardiac injection. Rat MSCs were manipulated to overexpress the Bcl-2 gene. In vitro, the antiapoptotic and paracrine effects were assessed under hypoxic conditions. In vivo, the Bcl-2 gene-modified MSCs (Bcl-2-MSCs) were injected after myocardial infarction. The surviving cells were tracked after transplantation. Capillary density was quantified after 3 weeks. The left ventricular function was evaluated by pressure-volume loops. The Bcl-2 gene protected MSCs against apoptosis. In vitro, Bcl-2 overexpression reduced MSC apoptosis by 32% and enhanced vascular endothelial growth factor secretion by more than 60% under hypoxic conditions. Transplantation with Bcl-2-MSCs increased 2.2-fold, 1.9-fold, and 1.2-fold of the cellular survival at 4 days, 3 weeks, and 6 weeks, respectively, compared with the vector-MSC group. Capillary density in the infarct border zone was 15% higher in Bcl-2-MSC transplanted animals than in vector-MSC treated animals. Furthermore, Bcl-2-MSC transplanted animals had 17% smaller infarct size than vector-MSC treated animals and exhibited functional recovery remarkably. Our current findings support the premise that transplantation of antiapoptotic gene-modified MSCs may have values for mediating substantial functional recovery after acute myocardial infarction.

  18. A Little Goes a Long Way: Low Working Memory Load Is Associated with Optimal Distractor Inhibition and Increased Vagal Control under Anxiety

    PubMed Central

    Spangler, Derek P.; Friedman, Bruce H.

    2017-01-01

    Anxiety impairs both inhibition of distraction and attentional focus. It is unclear whether these impairments are reduced or exacerbated when loading working memory with non-affective information. Cardiac vagal control has been related to top–down regulation of anxiety; therefore, vagal control may reflect load-related inhibition of distraction under anxiety. The present study examined whether: (1) the enhancing and impairing effects of load on inhibition exist together in a non-linear function, (2) there is a similar association between inhibition and concurrent vagal control under anxiety. During anxiogenic threat-of-noise, 116 subjects maintained a digit series of varying lengths (0, 2, 4, and 6 digits) while completing a visual flanker task. The task was broken into four blocks, with a baseline period preceding each. Electrocardiography was acquired throughout to quantify vagal control as high-frequency heart rate variability (HRV). There were significant quadratic relations of working memory load to flanker performance and to HRV, but no associations between HRV and performance. Results indicate that low load was associated with relatively better inhibition and increased HRV. These findings suggest that attentional performance under anxiety depends on the availability of working memory resources, which might be reflected by vagal control. These results have implications for treating anxiety disorders, in which regulation of anxiety can be optimized for attentional focus. PMID:28217091

  19. Chemical functionalization of graphene to augment stem cell osteogenesis and inhibit biofilm formation on polymer composites for orthopedic applications.

    PubMed

    Kumar, Sachin; Raj, Shammy; Kolanthai, Elayaraja; Sood, A K; Sampath, S; Chatterjee, Kaushik

    2015-02-11

    Toward designing the next generation of resorbable biomaterials for orthopedic applications, we studied poly(ε-caprolactone) (PCL) composites containing graphene. The role, if any, of the functionalization of graphene on mechanical properties, stem cell response, and biofilm formation was systematically evaluated. PCL composites of graphene oxide (GO), reduced GO (RGO), and amine-functionalized GO (AGO) were prepared at different filler contents (1%, 3%, and 5%). Although the addition of the nanoparticles to PCL markedly increased the storage modulus, this increase was largest for GO followed by AGO and RGO. In vitro cell studies revealed that the AGO and GO particles significantly increased human mesenchymal stem cell proliferation. AGO was most effective in augmenting stem cell osteogenesis leading to mineralization. Bacterial studies revealed that interaction with functionalized GO induced bacterial cell death because of membrane damage, which was further accentuated by amine groups in AGO. As a result, AGO composites were best at inhibiting biofilm formation. The synergistic effect of oxygen containing functional groups and amine groups on AGO imparts the optimal combination of improved modulus, favorable stem cell response, and biofilm inhibition in AGO-reinforced composites desired for orthopedic applications. This work elucidates the importance of chemical functionalization of graphene in polymer composites for biomedical applications.

  20. Lysosomal cysteine proteases: structure, function and inhibition of cathepsins.

    PubMed

    Roberts, Rebecca

    2005-12-01

    Lysosomal cysteine proteases, a subgroup of the cathepsin family, are critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. In the past decade, the number of identified human cathepsins has more than doubled and their known role in several pathologies has expanded rapidly. Increased understanding of the structure and mechanism of this class of enzymes has brought on a new fervor in the design of small molecule inhibitors with the hope of producing specific, therapeutic drugs for diseases such as arthritis, allergy, multiple sclerosis, atherosclerosis, Alzheimer's disease and cancer.

  1. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.

    PubMed

    Serini, Guido; Valdembri, Donatella; Zanivan, Sara; Morterra, Giulia; Burkhardt, Constanze; Caccavari, Francesca; Zammataro, Luca; Primo, Luca; Tamagnone, Luca; Logan, Malcolm; Tessier-Lavigne, Marc; Taniguchi, Masahiko; Püschel, Andreas W; Bussolino, Federico

    2003-07-24

    The motility and morphogenesis of endothelial cells is controlled by spatio-temporally regulated activation of integrin adhesion receptors, and integrin activation is stimulated by major determinants of vascular remodelling. In order for endothelial cells to be responsive to changes in activator gradients, the adhesiveness of these cells to the extracellular matrix must be dynamic, and negative regulators of integrins could be required. Here we show that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulates integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonize integrin activation. Misexpression of dominant negative SEMA3 receptors in chick embryo endothelial cells locks integrins in an active conformation, and severely impairs vascular remodelling. Sema3a null mice show vascular defects as well. Thus during angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function.

  2. Ethanol inhibits human bone cell proliferation and function in vitro

    SciTech Connect

    Friday, K.E.; Howard, G.A. )

    1991-06-01

    The direct effects of ethanol on human bone cell proliferation and function were studied in vitro. Normal human osteoblasts from trabecular bone chips were prepared by collagenase digestion. Exposure of these osteoblasts to ethanol in concentrations of 0.05% to 1% for 22 hours induced a dose-dependent reduction in bone cell DNA synthesis as assessed by incorporation of 3H-thymidine. After 72 hours of ethanol exposure in concentrations of 0.01% to 1%, protein synthesis as measured by 3H-proline incorporation into trichbroacetic acid (TCA)-precipitable material was reduced in a dose-dependent manner. Human bone cell protein concentrations and alkaline phosphatase total activity were significantly reduced after exposure to 1% ethanol for 72 hours, but not with lower concentrations of ethanol. This reduction in osteoblast proliferation and activity may partially explain the development of osteopenia in humans consuming excessive amounts of ethanol.

  3. Diterpenoids from Tetraclinis articulata that inhibit various human leukocyte functions.

    PubMed

    Barrero, Alejandro F; Quílez del Moral, José F; Lucas, Rut; Payá, Miguel; Akssira, Mohamed; Akaad, Said; Mellouki, Fouad

    2003-06-01

    Ten new compounds, eight of them pimarane derivatives (1-8), together with a menthane dimer (9) and a totarane diterpenoid (10), were isolated from the leaves and wood of Tetraclinis articulata. The structures of 1-10 were established by using spectroscopic techniques, including 2D NMR spectra. Pimaranes 1-5 were found to possess an unusual cis interannular union of the B and C rings, which, from a biogenetic perspective, could be derived from the hydration of a carbocation at C-8. Compounds 4-6 and a mixture of 7 and 11 modulated different human leukocyte functions at a concentration of 10 microM, mainly the degranulation process measured as myeloperoxidase release and, to a lesser extent, the superoxide production measured by chemiluminescence.

  4. Fibroblast growth factor-2 inhibits mineralization of osteoblast-like Saos-2 cells by inhibiting the functioning of matrix vesicles.

    PubMed

    Liu, Chao; Cui, Yazhou; Luan, Jing; Zhou, Xiaoyan; Liu, Zhenxing; Han, Jinxiang

    2014-02-01

    Fibroblast growth factor-2 (FGF2) inhibits osteoblast mineralization, but the mechanism by which it does so is not fully understood. Matrix vesicles (MVs) play an essential role in the initiation of mineralization, so the current study examined the effect of FGF2 on the functioning of MVs to investigate this mechanism. This study found that FGF2 significantly inhibited differentiation and mineralization of osteoblast-like Saos-2 cells, as indicated by down-regulation of mRNA expression of the osteogenic master regulator runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and collagen 1 alpha 1 (Colla1), and by decreasing the formation of bone nodules. MVs were isolated from Saos-2 cells cultured in osteogenic medium supplemented with and without FGF2 and their presence was verified using electron microscopy and Western blotting. FGF2 markedly reduced the ALP activity of and in vitro mineralization by MVs. These findings suggest that FGF2 inhibits osteoblast mineralization by limiting the capacity of MVs.

  5. Impact of Chaos Functions on Modern Swarm Optimizers

    PubMed Central

    Emary, E.

    2016-01-01

    Exploration and exploitation are two essential components for any optimization algorithm. Much exploration leads to oscillation and premature convergence while too much exploitation slows down the optimization algorithm and the optimizer may be stuck in local minima. Therefore, balancing the rates of exploration and exploitation at the optimization lifetime is a challenge. This study evaluates the impact of using chaos-based control of exploration/exploitation rates against using the systematic native control. Three modern algorithms were used in the study namely grey wolf optimizer (GWO), antlion optimizer (ALO) and moth-flame optimizer (MFO) in the domain of machine learning for feature selection. Results on a set of standard machine learning data using a set of assessment indicators prove advance in optimization algorithm performance when using variational repeated periods of declined exploration rates over using systematically decreased exploration rates. PMID:27410691

  6. Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis.

    PubMed

    Aye, Irving L M H; Gao, Xiaoli; Weintraub, Susan T; Jansson, Thomas; Powell, Theresa L

    2014-04-01

    Maternal adiponectin (ADN) levels are inversely correlated with birth weight, and ADN infusion in pregnant mice down-regulates placental nutrient transporters and decreases fetal growth. In contrast to the insulin-sensitizing effects in adipose tissue and muscle, ADN inhibits insulin signaling in the placenta. However, the molecular mechanisms involved are unknown. We hypothesized that ADN inhibits insulin signaling and insulin-stimulated amino acid transport in primary human trophoblasts by peroxisome proliferator-activated receptor-α (PPARα)-mediated ceramide synthesis. Primary human term trophoblast cells were treated with ADN and/or insulin. ADN increased the phosphorylation of p38 MAPK and PPARα. ADN inhibited insulin signaling and insulin-stimulated amino acid transport. This effect was dependent on PPARα, because activation of PPARα with an agonist (GW7647) inhibited insulin signaling and function, whereas PPARα-small interfering RNA reversed the effects of ADN on the insulin response. ADN increased ceramide synthase expression and stimulated ceramide production. C2-ceramide inhibited insulin signaling and function, whereas inhibition of ceramide synthase (with Fumonisin B1) reversed the effects of ADN on insulin signaling and amino acid transport. These findings are consistent with the model that maternal ADN limits fetal growth mediated by activation of placental PPARα and ceramide synthesis, which inhibits placental insulin signaling and amino acid transport, resulting in reduced fetal nutrient availability.

  7. A Gene Optimization Strategy that Enhances Production of Fully Functional P-Glycoprotein in Pichia pastoris

    PubMed Central

    Protasevich, Irina I.; Brouillette, Christie G.; Harrell, Patina M.; Hildebrandt, Ellen; Gasser, Brigitte; Mattanovich, Diethard; Ward, Andrew; Chang, Geoffrey; Urbatsch, Ina L.

    2011-01-01

    Background Structural and biochemical studies of mammalian membrane proteins remain hampered by inefficient production of pure protein. We explored codon optimization based on highly expressed Pichia pastoris genes to enhance co-translational folding and production of P-glycoprotein (Pgp), an ATP-dependent drug efflux pump involved in multidrug resistance of cancers. Methodology/Principal Findings Codon-optimized “Opti-Pgp” and wild-type Pgp, identical in primary protein sequence, were rigorously analyzed for differences in function or solution structure. Yeast expression levels and yield of purified protein from P. pastoris (∼130 mg per kg cells) were about three-fold higher for Opti-Pgp than for wild-type protein. Opti-Pgp conveyed full in vivo drug resistance against multiple anticancer and fungicidal drugs. ATP hydrolysis by purified Opti-Pgp was strongly stimulated ∼15-fold by verapamil and inhibited by cyclosporine A with binding constants of 4.2±2.2 µM and 1.1±0.26 µM, indistinguishable from wild-type Pgp. Maximum turnover number was 2.1±0.28 µmol/min/mg and was enhanced by 1.2-fold over wild-type Pgp, likely due to higher purity of Opti-Pgp preparations. Analysis of purified wild-type and Opti-Pgp by CD, DSC and limited proteolysis suggested similar secondary and ternary structure. Addition of lipid increased the thermal stability from Tm ∼40°C to 49°C, and the total unfolding enthalpy. The increase in folded state may account for the increase in drug-stimulated ATPase activity seen in presence of lipids. Conclusion The significantly higher yields of protein in the native folded state, higher purity and improved function establish the value of our gene optimization approach, and provide a basis to improve production of other membrane proteins. PMID:21826197

  8. Sublethal doses of neonicotinoid imidacloprid can interact with honey bee chemosensory protein 1 (CSP1) and inhibit its function.

    PubMed

    Li, Hongliang; Tan, Jing; Song, Xinmi; Wu, Fan; Tang, Mingzhu; Hua, Qiyun; Zheng, Huoqing; Hu, Fuliang

    2017-04-29

    As a frequently used neonicotinoid insecticide, imidacloprid can impair the chemoreceptive behavior of honey bees even at sublethal doses, while the physiochemical mechanism has not been further revealed. Here, multiple fluorescence spectra, thermodynamic method, and molecular docking were used to study the interaction and the functional inhibition of imidacloprid to the recombinant CSP1 protein in Asian honey bee, Apis cerana. The results showed that the fluorescence intensity (λem = 332 nm) of CSP1 could be significantly quenched by imidacloprid in a dynamic mode. During the quenching process, ΔH > 0, ΔS > 0, indicating that the acting forces of imidacloprid with CSP1 are mainly hydrophobic interactions. Synchronous fluorescence showed that the fluorescence of CSP1 was mainly derived from tryptophan, and the hydrophobicity of tryptophan decreased with the increase of imidacloprid concentration. Molecular docking predicted the optimal pose and the amino acid composition of the binding process. Circular dichroism (CD) spectra showed that imidacloprid reduced the α-helix of CSP1 and caused the extension of the CSP1 peptide chain. In addition, the binding of CSP1 to floral scent β-ionone was inhibited by nearly 50% of the apparent association constant (KA) in the presence of 0.28-2.53 ng/bee of imidacloprid, and the inhibition rate of nearly 95% at 3.75 ng/bee of imidacloprid at sublethal dose level. This study initially revealed the molecular physiochemical mechanism that sublethal doses of neonicotinoid still interact and inhibit the physiological function of the honey bees' chemoreceptive system.

  9. Optimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway

    PubMed Central

    Fernando, Ruani N.; Cotter, Laurent; Perrin-Tricaud, Claire; Berthelot, Jade; Bartolami, Sylvain; Pereira, Jorge A.; Gonzalez, Sergio; Suter, Ueli; Tricaud, Nicolas

    2016-01-01

    Fast nerve conduction relies on successive myelin segments that electrically isolate axons. Segment geometry—diameter and length—is critical for the optimization of nerve conduction and the molecular mechanisms allowing this optimized geometry are partially known. We show here that peripheral myelin elongation is dynamically regulated by stimulation of YAP (Yes-associated protein) transcription cofactor activity during axonal elongation and limited by inhibition of YAP activity via the Hippo pathway. YAP promotes myelin and non-myelin genes transcription while the polarity protein Crb3, localized at the tips of the myelin sheath, activates the Hippo pathway to temper YAP activity, therefore allowing for optimal myelin growth. Dystrophic Dy2j/2j mice mimicking human peripheral neuropathy with reduced internodal lengths have decreased nuclear YAP which, when corrected, leads to longer internodes. These data show a novel mechanism controlling myelin growth and nerve conduction, and provide a molecular ground for disease with short myelin segments. PMID:27435623

  10. Inhibition of viscous fluid fingering: A variational scheme for optimal flow rates

    NASA Astrophysics Data System (ADS)

    Miranda, Jose; Dias, Eduardo; Alvarez-Lacalle, Enrique; Carvalho, Marcio

    2012-11-01

    Conventional viscous fingering flow in radial Hele-Shaw cells employs a constant injection rate, resulting in the emergence of branched interfacial shapes. The search for mechanisms to prevent the development of these bifurcated morphologies is relevant to a number of areas in science and technology. A challenging problem is how best to choose the pumping rate in order to restrain growth of interfacial amplitudes. We use an analytical variational scheme to look for the precise functional form of such an optimal flow rate. We find it increases linearly with time in a specific manner so that interface disturbances are minimized. Experiments and nonlinear numerical simulations support the effectiveness of this particularly simple, but not at all obvious, pattern controlling process. J.A.M., E.O.D. and M.S.C. thank CNPq/Brazil for financial support. E.A.L. acknowledges support from Secretaria de Estado de IDI Spain under project FIS2011-28820-C02-01.

  11. The Structure of Executive Functions in Children: A Closer Examination of Inhibition, Shifting, and Updating

    ERIC Educational Resources Information Center

    van der Ven, Sanne H. G.; Kroesbergen, Evelyn H.; Boom, Jan; Leseman, Paul P. M.

    2013-01-01

    An increasing number of studies has investigated the latent factor structure of executive functions. Some studies found a three-factor structure of inhibition, shifting, and updating, but others could not replicate this finding. We assumed that the task choices and scoring methods might be responsible for these contradictory findings. Therefore,…

  12. Inhibition of phenotypic and functional maturation of dendritic cells by manassantin a.

    PubMed

    Kim, Jee Youn; Kang, Jong Soon; Kim, Hwan Mook; Kim, Young Kook; Lee, Hong Kyung; Song, Sukgil; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae

    2009-04-01

    Manassantin A (MSA) inhibits nitric oxide production by macrophages through the inhibition of NF-kappaB activation, but the effect of MSA on dendritic cells has not been elucidated yet. Here we investigated the inhibitory effects of MSA on immune functions of dendritic cells (DCs). MSA inhibited lipopolysaccharide (LPS)-induced phenotypic maturation of DCs, which was proved by the decreased expression of CD40, CD80, CD86, MHC-I, and MHC-II. MSA also inhibited functional maturation of DCs, that is, decreased the gene expression of IL-12, IL-1beta, TNF-alpha, and IFN-alpha/beta; enhanced antigen capture capacity of DCs; and impaired induction of allogenic T cell activation. As a mechanism of action, MSA inhibited LPS-induced activation of NF-kappaB, ERK, p38, and JNK, which played pivotal roles in toll-like receptor 4-mediated DC maturation. Collectively, these results suggested that MSA might be used for the treatment of DC-related immune diseases.

  13. Tribbles 3 Inhibits Brown Adipocyte Differentiation and Function by Suppressing Insulin Signaling

    PubMed Central

    Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L.; Piroli, Gerardo G.; Frizzell, Norma; Tseng, Yu-Hua; Goodyear, Laurie J.; Koh, Ho-Jin

    2016-01-01

    Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. PMID:26801556

  14. TLR4 plays a crucial role in MSC-induced inhibition of NK cell function

    SciTech Connect

    Lu, Ying; Liu, Jin; Liu, Yang; Qin, Yaru; Luo, Qun; Wang, Quanli; Duan, Haifeng

    2015-08-21

    Mesenchymal stem cells (MSC) are a kind of stromal cell within the tumor microenvironment. In our research, MSC derived from acute myeloid leukemia patients' bone marrow (AML-MSC) and lung cancer tissues (LC-MSC) as well as normal bone marrow-derived MSC (BM-MSC) cultured in conditioned medium of HeLa cells were found to have higher expressions of Toll-like receptor (TLR4) mRNA compared with BM-MSC. The sorted TLR4-positive MSC (TLR4+ MSC) differed in cytokine (interleukin-6, interleukin-8, and monocyte chemoattractant protein-1) secretion from those of unsorted MSC. MSC was reported to inhibit natural killer (NK) cell proliferation and function. In this research, we confirmed that TLR4+ MSC aggravate this suppression. Furthermore, when TLR4 in the sorted cells were stimulated by LPS or following blocked by antibody, the suppression on NK cell proliferation and cytotoxicity were more intensive or recovered respectively. Compared to unsorted MSC, NKG2D receptor expression on NK cells were also inhibited by TLR4+ MSC. These findings suggest that activation of TLR4 pathway is important for TLR4+ MSC and MSC to obstruct anti-tumor immunity by inhibiting NK cell function, which may provide a potential stroma-targeted tumor therapy. - Highlights: • TLR4+ MSC inhibit NK cell proliferation in vivo and in vitro. • TLR4+ MSC inhibit NKG2D expression on NK cells and NK cell cytotoxicity. • The distinguished cytokine expression of TLR4+ MSC may contribute to the inhibition on NK cell function.

  15. Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

    PubMed Central

    So, Lomon; Yea, Sung Su; Oak, Jean S.; Lu, Mengrou; Manmadhan, Arun; Ke, Qiao Han; Janes, Matthew R.; Kessler, Linda V.; Kucharski, Jeff M.; Li, Lian-Sheng; Martin, Michael B.; Ren, Pingda; Jessen, Katti A.; Liu, Yi; Rommel, Christian; Fruman, David A.

    2013-01-01

    Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110α in lymphocyte responses in vitro and in vivo. p110α inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110δ inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110α inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110δ inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110α inhibition partially diminishes AKT activation, selective p110α inhibitors are likely to be less immunosuppressive in vivo compared with p110δ or pan-class I inhibitors. PMID:23275335

  16. Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function.

    PubMed

    So, Lomon; Yea, Sung Su; Oak, Jean S; Lu, Mengrou; Manmadhan, Arun; Ke, Qiao Han; Janes, Matthew R; Kessler, Linda V; Kucharski, Jeff M; Li, Lian-Sheng; Martin, Michael B; Ren, Pingda; Jessen, Katti A; Liu, Yi; Rommel, Christian; Fruman, David A

    2013-02-22

    Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110α in lymphocyte responses in vitro and in vivo. p110α inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110δ inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110α inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110δ inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110α inhibition partially diminishes AKT activation, selective p110α inhibitors are likely to be less immunosuppressive in vivo compared with p110δ or pan-class I inhibitors.

  17. Solving Nonlinear Optimization Problems of Real Functions in Complex Variables by Complex-Valued Iterative Methods.

    PubMed

    Zhang, Songchuan; Xia, Youshen

    2016-12-28

    Much research has been devoted to complex-variable optimization problems due to their engineering applications. However, the complex-valued optimization method for solving complex-variable optimization problems is still an active research area. This paper proposes two efficient complex-valued optimization methods for solving constrained nonlinear optimization problems of real functions in complex variables, respectively. One solves the complex-valued nonlinear programming problem with linear equality constraints. Another solves the complex-valued nonlinear programming problem with both linear equality constraints and an ℓ₁-norm constraint. Theoretically, we prove the global convergence of the proposed two complex-valued optimization algorithms under mild conditions. The proposed two algorithms can solve the complex-valued optimization problem completely in the complex domain and significantly extend existing complex-valued optimization algorithms. Numerical results further show that the proposed two algorithms have a faster speed than several conventional real-valued optimization algorithms.

  18. Inhibition of Personally-Relevant Angry Faces Moderates the Effect of Empathy on Interpersonal Functioning

    PubMed Central

    Iacono, Vanessa; Ellenbogen, Mark A.; Wilson, Alexa L.; Desormeau, Philip; Nijjar, Rami

    2015-01-01

    While empathy is typically assumed to promote effective social interactions, it can sometimes be detrimental when it is unrestrained and overgeneralized. The present study explored whether cognitive inhibition would moderate the effect of empathy on social functioning. Eighty healthy young adults underwent two assessments six months apart. Participants’ ability to suppress interference from distracting emotional stimuli was assessed using a Negative Affective Priming Task that included both generic and personally-relevant (i.e., participants’ intimate partners) facial expressions of emotion. The UCLA Life Stress Interview and Empathy Quotient were administered to measure interpersonal functioning and empathy respectively. Multilevel modeling demonstrated that higher empathy was associated with worse concurrent interpersonal outcomes for individuals who showed weak inhibition of the personally-relevant depictions of anger. The effect of empathy on social functioning might be dependent on individuals’ ability to suppress interference from meaningful emotional distractors in their environment. PMID:25695426

  19. Prepulse Inhibition of the Acoustic Startle Reflex in High Functioning Autism

    PubMed Central

    Gruendler, Theo O. J.; Vogeley, Kai; Klosterkötter, Joachim; Kuhn, Jens

    2014-01-01

    Background High functioning autism is an autism spectrum disorder that is characterized by deficits in social interaction and communication as well as repetitive and restrictive behavior while intelligence and general cognitive functioning are preserved. According to the weak central coherence account, individuals with autism tend to process information detail-focused at the expense of global form. This processing bias might be reflected by deficits in sensorimotor gating, a mechanism that prevents overstimulation during the transformation of sensory input into motor action. Prepulse inhibition is an operational measure of sensorimotor gating, which indicates an extensive attenuation of the startle reflex that occurs when a startling pulse is preceded by a weaker stimulus, the prepulse. Methods In the present study, prepulse inhibition of acoustic startle was compared between 17 adults with high functioning autism and 17 sex-, age-, and intelligence-matched controls by means of electromyography. Results Results indicate that participants with high functioning autism exhibited significantly higher startle amplitudes than the control group. However, groups did not differ with regard to PPI or habituation of startle. Discussion These findings challenge the results of two previous studies that reported prepulse inhibition deficits in high-functioning autism and suggest that sensorimotor gating is only impaired in certain subgroups with autism spectrum disorder. PMID:24643088

  20. Research of trajectory optimization on feeding manipulator based on internal penalty function

    NASA Astrophysics Data System (ADS)

    Wei, Chunli

    2016-10-01

    This paper has discussed the problems of trajectory optimization of feeding manipulator based on penalty function. Has selected the types of feeding robot, which work on NC machining center of the flexible workshop, and created the mathematical model with penalty function, for the purpose not only to optimize its walking path to reduce the production cost, but also improve its safety and efficiency of production. It has been verified by theoretical analysis and practice, the path optimization method is feasible.

  1. Swarm algorithms with chaotic jumps for optimization of multimodal functions

    NASA Astrophysics Data System (ADS)

    Krohling, Renato A.; Mendel, Eduardo; Campos, Mauro

    2011-11-01

    In this article, the use of some well-known versions of particle swarm optimization (PSO) namely the canonical PSO, the bare bones PSO (BBPSO) and the fully informed particle swarm (FIPS) is investigated on multimodal optimization problems. A hybrid approach which consists of swarm algorithms combined with a jump strategy in order to escape from local optima is developed and tested. The jump strategy is based on the chaotic logistic map. The hybrid algorithm was tested for all three versions of PSO and simulation results show that the addition of the jump strategy improves the performance of swarm algorithms for most of the investigated optimization problems. Comparison with the off-the-shelf PSO with local topology (l best model) has also been performed and indicates the superior performance of the standard PSO with chaotic jump over the standard both using local topology (l best model).

  2. Culture Conditions for Production of Biomass, Adenosine, and Cordycepin from Cordyceps sinensis CS1197: Optimization by Desirability Function Method

    PubMed Central

    Ghatnur, Shashidhar M.; Parvatam, Giridhar; Balaraman, Manohar

    2015-01-01

    Background: Cordyceps sinensis (CS) is a traditional Chinese medicine contains potent active metabolites such as nucleosides and polysaccharides. The submerged cultivation technique is studied for the large scale production of CS for biomass and metabolites production. Objective: To optimize culture conditions for large-scale production of CS1197 biomass and metabolites production. Materials and Methods: The CS1197 strain of CS was isolated from dead larvae of natural CS and the authenticity was assured by the presence of two major markers adenosine and cordycepin by high performance liquid chromatography and mass spectrometry. A three-level Box-Behnken design was employed to optimize process parameters culturing temperature, pH, and inoculum volume for the biomass yield, adenosine and cordycepin. The experimental results were regressed to a second-order polynomial equation by a multiple regression analysis for the prediction of biomass yield, adenosine and cordycepin production. Multiple responses were optimized based on desirability function method. Results: The desirability function suggested the process conditions temperature 28°C, pH 7 and inoculum volume 10% for optimal production of nutraceuticals in the biomass. The water extracts from dried CS1197 mycelia showed good inhibition for 2 diphenyl-1-picrylhydrazyl and 2,2-azinobis-(3-ethyl-benzo-thiazoline-6-sulfonic acid-free radicals. Conclusion: The result suggests that response surface methodology-desirability function coupled approach can successfully optimize the culture conditions for CS1197. SUMMARY Authentication of CS1197 strain by the presence of adenosine and cordycepin and culturing period was determined to be for 14 daysContent of nucleosides in natural CS was found higher than in cultured CS1197 myceliumBox-Behnken design to optimize critical cultural conditions: temperature, pH and inoculum volumeWater extract showed better antioxidant activity proving credible source of natural antioxidants

  3. Alpha-1 antitrypsin inhibits RANKL-induced osteoclast formation and functions.

    PubMed

    Akbar, Mohammad Ahsanul; Nardo, David; Chen, Mong-Jen; Elshikha, Ahmed S; Ahamed, Rubina; Elsayed, Eslam M; Bigot, Claire; Holliday, Lexie Shannon; Song, Sihong

    2017-03-21

    Osteoporosis is a global public health problem affecting more than 200 million people worldwide. We previously showed that treatment with alpha-1 antitrypsin (AAT), a multifunctional protein with anti-inflammatory properties, mitigated bone loss in an ovariectomized mouse model. However, the underlying mechanisms of the protective effect of AAT on bone tissue are largely unknown. In this study, we investigated the effect of AAT on osteoclast formation and function in vitro. Our results showed that AAT dose-dependently inhibited the formation of RANKL (receptor activator of nuclear factor κB ligand) induced osteoclasts derived from mouse bone marrow macrophages/monocyte (BMM) lineage cells and the murine macrophage cell line, RAW 264.7 cells. In order to elucidate the possible mechanisms underlying this inhibition, we tested the effect of AAT on the gene expression of cell surface molecules, transcription factors, and cytokines associated with osteoclast formation. We showed that AAT inhibited M-CSF (macrophage colony-stimulating factor) induced cell surface RANK expression in osteoclast precursor cells. In addition, AAT inhibited RANKL-induced TNF-α production, cell surface CD9 expression, and dendritic cell-specific transmembrane protein (DC-STAMP) gene expression. Importantly, AAT treatment significantly inhibited osteoclast-associated mineral resorption. Together, these results uncovered new mechanisms for the protective effects of AAT and strongly support the notion that AAT has therapeutic potential for the treatment of osteoporosis.

  4. Optimizing Cross-Sectional Prediction of Social Functioning in Youth Referred for Neuropsychological Testing

    PubMed Central

    Lerner, Matthew D.; Potthoff, Lauren M.; Hunter, Scott J.

    2015-01-01

    The current study aimed to establish a fine-grained, efficient characterization of the concurrent neuropsychological contributions to social functioning in neuropsychologically-referred youth. A secondary aim was to demonstrate a useful statistic approach for such investigations (Partial Least Squares Regression; PLSR), which is underutilized in this field. Forty-five participants (70 – 164 months; Mage = 110.89; 34 male) were recruited from a large neuropsychological assessment clinic. Participants completed subtests from the NEPSY-II focusing on neuropsychological constructs that have been linked to social functioning (affect decoding, social memory, motor skills, visuomotor skills, response inhibition, attention and set-shifting, and verbal comprehension). Mothers completed the BASC-2, from which Atypicality and Social Skills scales were analyzed. PLSR revealed that difficulty with social memory, sensorimotor integration, and the ability to attend to and accurately discriminate auditory stimuli combine to best predict atypical or “odd” behavior. In terms of social skills, two factors emerged. The first factor indicated that, counterintuitively, greater emotional perception, visuospatial perception, ability to attend to and accurately discriminate auditory stimuli, and understand instructions was related to poorer social skills. The second factor indicated that a pattern of better facial memory, and sensorimotor ability (execution & integration) characterized a distinct profile of greater social ability. PLSR results were compared to traditional OLS and Backwards Stepwise regression approaches to demonstrate utility. Results also suggested that these findings were consistent across age, gender, and diagnostic group, indicating common neuropsychological substrates of social functioning in this sample of referred youth. Overall, this study provides the first characterization of optimized combinations of neuropsychological variables in predicting social

  5. Chitooligosaccharide Inhibits Scar Formation and Enhances Functional Recovery in a Mouse Model of Sciatic Nerve Injury.

    PubMed

    Hou, Hongping; Zhang, Lihai; Ye, Zuguang; Li, Jianrong; Lian, Zijian; Chen, Chao; He, Rong; Peng, Bo; Xu, Qihua; Zhang, Guangping; Gan, Wenbiao; Tang, Peifu

    2016-05-01

    Chitooligosaccharide (COS) has been shown to induce fibroblast apoptosis, indicating that it could be used as a material to inhibit scar formation. In the present study, we used a mouse model of sciatic nerve injury (SNI) to determine the role of COS in scar inhibition and functional recovery. The animals were divided into three groups: SNI, SNI + vehicle, and SNI + COS group. We performed a series of functional and histological examinations at ctrl, 0 min, 14 days, and 42 days, including behavioral recovery, percentage of regenerating axons, degree of scar formation, vascular changes, type I and type III collagen ratio, and percentage of demyelinated axons. The SNI + COS group exhibited better recovery of sensory and motor function and less scar formation. Two-photon microscopy showed that the percentage of regenerating axons was highest in the SNI + COS group at 14 and 42 days. Our results suggested that COS can inhibit scar formation and enhance functional recovery by inducing fibroblast death, altering the proportion of different vascular diameters, changing the ratio of type I/type III collagen, and reducing the percentage of demyelinated axons. COS might be a useful drug in the treatment of SNI to reduce scar formation, but additional research is required to clarify the relevant molecular pathways.

  6. Pseudomonas aeruginosa protease IV degrades surfactant proteins and inhibits surfactant host defense and biophysical functions.

    PubMed

    Malloy, Jaret L; Veldhuizen, Ruud A W; Thibodeaux, Brett A; O'Callaghan, Richard J; Wright, Jo Rae

    2005-02-01

    Pulmonary surfactant has two distinct functions within the lung: reduction of surface tension at the air-liquid interface and participation in innate host defense. Both functions are dependent on surfactant-associated proteins. Pseudomonas aeruginosa is primarily responsible for respiratory dysfunction and death in cystic fibrosis patients and is also a leading pathogen in nosocomial pneumonia. P. aeruginosa secretes a number of proteases that contribute to its virulence. We hypothesized that P. aeruginosa protease IV degrades surfactant proteins and results in a reduction in pulmonary surfactant host defense and biophysical functions. Protease IV was isolated from cultured supernatant of P. aeruginosa by gel chromatography. Incubation of cell-free bronchoalveolar lavage fluid with protease IV resulted in degradation of surfactant proteins (SP)-A, -D, and -B. SPs were degraded in a time- and dose-dependent fashion by protease IV, and degradation was inhibited by the trypsin-like serine protease inhibitor Nalpha-p-tosyl-L-lysine-chloromethyl ketone (TLCK). Degradation by protease IV inhibited SP-A- and SP-D-mediated bacterial aggregation and uptake by macrophages. Surfactant treated with protease IV was unable to reduce surface tension as effectively as untreated surfactant, and this effect was inhibited by TLCK. We speculate that protease IV may be an important contributing factor to the development and propagation of acute lung injury associated with P. aeruginosa via loss of surfactant function within the lung.

  7. Design optimization of a radial functionally graded dental implant.

    PubMed

    Ichim, Paul I; Hu, Xiaozhi; Bazen, Jennifer J; Yi, Wei

    2016-01-01

    In this work, we use FEA to test the hypothesis that a low-modulus coating of a cylindrical zirconia dental implant would reduce the stresses in the peri-implant bone and we use design optimization and the rule of mixture to estimate the elastic modulus and the porosity of the coating that provides optimal stress shielding. We show that a low-modulus coating of a dental implant significantly reduces the maximum stresses in the peri-implant bone without affecting the average stresses thus creating a potentially favorable biomechanical environment. Our results suggest that a resilient coating is capable of reducing the maximum compressive and tensile stresses in the peri-implant bone by up to 50% and the average stresses in the peri-implant bone by up to 15%. We further show that a transitional gradient between the high-modulus core and the low-modulus coating is not necessary and for a considered zirconia/HA composite the optimal thickness of the coating is 100 µ with its optimal elastic at the lowest value considered of 45 GPa.

  8. Family Functioning and Maladaptive Schemas: The Moderating Effects of Optimism

    ERIC Educational Resources Information Center

    Buri, John R.; Gunty, Amy L.

    2008-01-01

    Authoritarian parenting is often shown to be associated with negative outcomes for children, including the development of maladaptive schemas. However, this is not the case for all children who experience Authoritarian parenting. Optimism is examined as a moderator in the relationship between Authoritarian parenting and maladaptive schemas that…

  9. Functional lateralization of temporoparietal junction - imitation inhibition, visual perspective-taking and theory of mind.

    PubMed

    Santiesteban, Idalmis; Banissy, Michael J; Catmur, Caroline; Bird, Geoffrey

    2015-10-01

    Although neuroimaging studies have consistently identified the temporoparietal junction (TPJ) as a key brain region involved in social cognition, the literature is far from consistent with respect to lateralization of function. For example, during theory-of-mind tasks bilateral TPJ activation is found in some studies but only right hemisphere activation in others. Visual perspective-taking and imitation inhibition, which have been argued to recruit the same socio-cognitive processes as theory of mind, are associated with unilateral activation of either left TPJ (perspective taking) or right TPJ (imitation inhibition). The present study investigated the functional lateralization of TPJ involvement in the above three socio-cognitive abilities using transcranial direct current stimulation. Three groups of healthy adults received anodal stimulation over right TPJ, left TPJ or the occipital cortex prior to performing three tasks (imitation inhibition, visual perspective-taking and theory of mind). In contrast to the extant neuroimaging literature, our results suggest bilateral TPJ involvement in imitation inhibition and visual perspective-taking, while no effect of anodal stimulation was observed on theory of mind. The discrepancy between these findings and those obtained using neuroimaging highlight the efficacy of neurostimulation as a complementary methodological tool in cognitive neuroscience.

  10. Tussilagone inhibits dendritic cell functions via induction of heme oxygenase-1.

    PubMed

    Park, Yunsoo; Ryu, Hwa Sun; Lee, Hong Kyung; Kim, Ji Sung; Yun, Jieun; Kang, Jong Soon; Hwang, Bang Yeon; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae

    2014-10-01

    Sesquiterpenoid tussilagone (TUS) has a variety of pharmacological activities, such as anti-oxidant, anti-cancer, and anti-inflammatory activities. In this study, we investigated the effects of TUS on dendritic cell (DC) functions and the underlying mechanisms. TUS inhibited lipopolysaccharide (LPS)-induced activation of DCs, as shown by decrease in surface molecule expression, cytokine production, cell migration, and allo-T cell activation. In addition, TUS inhibited LPS-induced activation of NF-κB, MAPKs, and IRF-3 signalings in DCs, although it did not directly affect kinase activities of IRAK1/4, TAK1, and IKK, which suggests that TUS might indirectly inhibit TLR signaling in DCs. As a critical mechanism, we showed that TUS activated heme oxygenase-1 (HO-1), which degrades heme to immunosuppressive products, such as carbon monoxide and bilirubin. HO-1 inhibitor reversed the inhibitory activity of TUS in DCs. In conclusion, this study suggests that TUS inhibits DC function through the induction of HO-1.

  11. Coumestan inhibits radical-induced oxidation of DNA: is hydroxyl a necessary functional group?

    PubMed

    Xi, Gao-Lei; Liu, Zai-Qun

    2014-06-18

    Coumestan is a natural tetracycle with a C═C bond shared by a coumarin moiety and a benzofuran moiety. In addition to the function of the hydroxyl group on the antioxidant activity of coumestan, it is worth exploring the influence of the oxygen-abundant scaffold on the antioxidant activity as well. In this work, seven coumestans containing electron-withdrawing and electron-donating groups were synthesized to evaluate the abilities to trap 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(•+)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively, and to inhibit the oxidations of DNA mediated by (•)OH, Cu(2+)/glutathione (GSH), and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), respectively. It was found that all of the coumestans used herein can quench the aforementioned radicals and can inhibit (•)OH-, Cu(2+)/GSH-, and AAPH-induced oxidations of DNA. In particular, substituent-free coumestan exhibits higher ability to quench DPPH and to inhibit AAPH-induced oxidation of DNA than Trolox. In addition, nonsubstituted coumestan shows a similar ability to inhibit (•)OH- and Cu(2+)/GSH-induced oxidations of DNA relative to that of Trolox. The antioxidant effectiveness of the coumestan can be attributed to the lactone in the coumarin moiety and, therefore, a hydroxyl group may not be a necessary functional group for coumestan to be an antioxidant.

  12. The fungicide Pristine® inhibits mitochondrial function in vitro but not flight metabolic rates in honey bees

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Honey bees and other pollinators are exposed to fungicides that act by inhibiting mitochondrial function. Here we test whether a common fungicide (Pristine®) inhibits the function of mitochondria of honeybees, and whether consumption of ecologically-realistic concentrations can cause negative eff...

  13. The Role of Inhibition in Age-related Off-Topic Verbosity: Not Access but Deletion and Restraint Functions

    PubMed Central

    Yin, Shufei; Peng, Huamao

    2016-01-01

    The speech of older adults is commonly described as verbose and off-topic, which is thought to influence their social communication. This study investigated the role of inhibition in age-related off-topic verbosity (OTV). Inhibition consists of three functions: access, deletion, and restraint. The access function is responsible for preventing irrelevant information from accessing the attention center (pre-mechanism of inhibition); The deletion function is responsible for deleting previously relevant but currently irrelevant information from working memory, and the restraint function is responsible for restraining strong but inappropriate responses (post-mechanisms of inhibition). A referential communication task was used to determine whether OTV was influenced by the pre-mechanism of inhibition. A self-involved event interview task was used to investigate the effect of the post-mechanisms of inhibition on OTV. Results showed that the OTV of the elderly participants was associated with an age-related decline in the post-mechanisms of inhibition, while the OTV exhibited by young adults was most likely due to deficits in the pre-mechanism function of inhibition. This research contributed to fill gaps in the existing knowledge about the potential relationship between specific functions of inhibition and age-related OTV. PMID:27199793

  14. miR-454 functions as an oncogene by inhibiting CHD5 in hepatocellular carcinoma

    PubMed Central

    Sun, Lei; Yao, Hong; Lu, Baoling; Zhu, Liying

    2015-01-01

    Previous studies showed that miR-454 acted as an oncogene or tumor suppressor in cancer. However, its function in HCC remains unknown. In this study, we found that miR-454 expression was upregulated in HCC cell lines and tissues. Knockdown of miR-454 inhibited HCC cell proliferation and invasion and epithelial mesenchymal transition (EMT), whereas overexpression of miR-454 promoted HCC cell proliferation and invasion and EMT. Furthermore, we identified the CHD5 as a direct target of miR-454. CHD5 was downregulated in HCC tissues and cell lines and the expression level of CHD5 was inversely correlated with the expression of miR-454 in HCC tissues. In addition, knockdown of miR-454 inhibited the growth of HepG2-engrafted tumors in vivo. Taken together, these results indicated that miR-454 functioned as an oncogene in HCC. PMID:26287602

  15. Clarifying the factors that undermine behavioral inhibition system functioning in psychopathy.

    PubMed

    Baskin-Sommers, Arielle R; Wallace, John F; MacCoon, Donal G; Curtin, John J; Newman, Joseph P

    2010-10-01

    Psychopathic individuals are generally unresponsive to motivational and emotional cues that facilitate behavioral regulation. A putative mechanism for this deficiency is Gray’s (1981) behavioral inhibition system (BIS). To evaluate the association between psychopathy and BIS functioning, we administered a laboratory-based assessment of BIS functioning to a group of psychopathic offenders assessed with the Psychopathy Checklist–Revised (PCL–R; Hare, 2003). In addition, we tested the hypothesis that the effects of working memory load on BIS functioning would interact differentially with the PCL–R factors. Replicating previous results, psychopathic offenders were less sensitive to BIS-related cues than controls. As predicted, working memory load interacted with Factor 2 (antisocial/impulsive), with higher scores predicting weaker BIS functioning under high-load though not low-load conditions. Results suggest new insights concerning the relationship among working memory, reward sensitivity, and BIS functioning in psychopathy.

  16. A novel dRYBP-SCF complex functions to inhibit apoptosis in Drosophila.

    PubMed

    Fereres, Sol; Simón, Rocío; Busturia, Ana

    2013-12-01

    A balanced response to intrinsic and extrinsic apoptotic signals is crucial to support homeostatic development and animal survival. Regulation of activation and inhibition of apoptotic pathways involves diverse mechanisms including protein ubiquitylation to control expression levels of apoptotic factors. Here we report that drosophila Ring and YY1 Binding Protein (dRYBP) protein interacts both genetically and biochemically with the E3 ubiquitin ligase SKPA, dCULLIN, F-box (SCF) complex to synergistically inhibit apoptosis in Drosophila. Further, we show that the loss of skpA function activates the intrinsic pathway of apoptosis and down-regulates the levels of expression of the anti-apoptotic DIAP1 protein. Accordingly, the apoptosis induced by inactivation of skpA and dRYBP is rescued by loss of function of the pro-apoptotic gene reaper and overexpression of DIAP1. Of interest, we also find that high levels of SKPA protein rescue the wing phenotype induced by overexpression of Reaper protein. Finally, we demonstrate that overexpression of SKPA inhibits both developmental and radiation-induced apoptosis. We propose that the function of the dRYBP-SCF complex in the inhibition of apoptosis might possibly be to control the levels of the pro-apoptotic and anti-apoptotic proteins most likely by promoting their ubiquitylation and consequently, proteasomal degradation. Given the evolutionary conservation of the dRYBP and the SCF proteins, our results suggest that their mammalian homologs may function in balancing cell survival versus cell death during normal and pathological development.

  17. Optimal Experiment Design for Thermal Characterization of Functionally Graded Materials

    NASA Technical Reports Server (NTRS)

    Cole, Kevin D.

    2003-01-01

    The purpose of the project was to investigate methods to accurately verify that designed , materials meet thermal specifications. The project involved heat transfer calculations and optimization studies, and no laboratory experiments were performed. One part of the research involved study of materials in which conduction heat transfer predominates. Results include techniques to choose among several experimental designs, and protocols for determining the optimum experimental conditions for determination of thermal properties. Metal foam materials were also studied in which both conduction and radiation heat transfer are present. Results of this work include procedures to optimize the design of experiments to accurately measure both conductive and radiative thermal properties. Detailed results in the form of three journal papers have been appended to this report.

  18. Optimism and Cardiovascular Function in Children with Congenital Heart Disease

    DTIC Science & Technology

    2010-02-17

    optimism and reduced occurrence of nonfatal MI [present risk], angina pectoris (relative risk 0.45, 95% confidence interval = 0.29 - 0.68), and...individuals, including post surgical sternal wound infection, angina , MI, referal for angioplasty, and necessity for repeat bypass surgery (N=247, b=-.09...Demographic Factors (age, gender) Risk Factors (hypertension, IDDM, PVD) Cardiac Disease Severity (ejection fraction, angina , dyspenea

  19. Chylomicron components mediate intestinal lipid-induced inhibition of gastric motor function.

    PubMed

    Glatzle, Jörg; Kalogeris, Theodore J; Zittel, Tilman T; Guerrini, Stephania; Tso, Patrick; Raybould, Helen E

    2002-01-01

    Lipid, particularly long-chain triglyceride, initiates feedback regulation of gastrointestinal function. To determine whether the site of action of lipid is pre- or postabsorptive, we investigated the ability of mesenteric lipid-fed lymph to inhibit gastric motor function. Lymph was collected from awake lymph-fistula rats during intestinal infusion with either a glucose-saline maintenance solution or lipid. Intra-arterial injection of lymph collected during intestinal lipid infusion significantly inhibited gastric motility in anesthetized recipient rats compared with injection of equivalent amounts of triglyceride or lymph collected during intestinal infusion of maintenance solution. Lymph collected from rats during lipid infusion with Pluronic L-81 [an inhibitor of chylomicron formation and apolipoprotein (apo) A-IV secretion] compared with lymph injection from donor animals treated with Pluronic L-63 (a noninhibitory control for Pluronic L-81) was significantly less potent. Injection of purified recombinant apo A-IV significantly inhibited gastric motility. Products of lipid digestion and absorption, other than fatty acids or triglyceride, released by the intestine during lipid digestion likely serve as signals to initiate intestinal feedback regulation of gastrointestinal function. Most likely, apo A-IV is one of the signals involved.

  20. Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection

    PubMed Central

    Santiago, César; Mudgal, Gaurav; Reguera, Juan; Recacha, Rosario; Albrecht, Sébastien; Enjuanes, Luis; Casasnovas, José M.

    2017-01-01

    Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides and regulates numerous cell functions. APN participates in tumor cell expansion and motility, and is a target for cancer therapies. Small drugs that bind to the APN active site inhibit catalysis and suppress tumor growth. APN is also a major cell entry receptor for coronavirus, which binds to a region distant from the active site. Three crystal structures that we determined of human and pig APN ectodomains defined the dynamic conformation of the protein. These structures offered snapshots of closed, intermediate and open APN, which represent distinct functional states. Coronavirus envelope proteins specifically recognized the open APN form, prevented ectodomain progression to the closed form and substrate hydrolysis. In addition, drugs that bind the active site inhibited both coronavirus binding to cell surface APN and infection; the drugs probably hindered APN transition to the virus-specific open form. We conclude that allosteric inhibition of APN functions occurs by ligand suppression of ectodomain motions necessary for catalysis and virus cell entry, as validated by locking APN with disulfides. Blocking APN dynamics can thus be a valuable approach to development of drugs that target this ectoenzyme. PMID:28393915

  1. APP modulates KCC2 expression and function in hippocampal GABAergic inhibition.

    PubMed

    Chen, Ming; Wang, Jinzhao; Jiang, Jinxiang; Zheng, Xingzhi; Justice, Nicholas J; Wang, Kun; Ran, Xiangqian; Li, Yi; Huo, Qingwei; Zhang, Jiajia; Li, Hongmei; Lu, Nannan; Wang, Ying; Zheng, Hui; Long, Cheng; Yang, Li

    2017-01-05

    Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in App knock-out (App(-/-)) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K(+)-Cl(-) cotransporter that is essential for Cl(-) homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App(-/-) mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus.

  2. Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection.

    PubMed

    Santiago, César; Mudgal, Gaurav; Reguera, Juan; Recacha, Rosario; Albrecht, Sébastien; Enjuanes, Luis; Casasnovas, José M

    2017-04-10

    Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides and regulates numerous cell functions. APN participates in tumor cell expansion and motility, and is a target for cancer therapies. Small drugs that bind to the APN active site inhibit catalysis and suppress tumor growth. APN is also a major cell entry receptor for coronavirus, which binds to a region distant from the active site. Three crystal structures that we determined of human and pig APN ectodomains defined the dynamic conformation of the protein. These structures offered snapshots of closed, intermediate and open APN, which represent distinct functional states. Coronavirus envelope proteins specifically recognized the open APN form, prevented ectodomain progression to the closed form and substrate hydrolysis. In addition, drugs that bind the active site inhibited both coronavirus binding to cell surface APN and infection; the drugs probably hindered APN transition to the virus-specific open form. We conclude that allosteric inhibition of APN functions occurs by ligand suppression of ectodomain motions necessary for catalysis and virus cell entry, as validated by locking APN with disulfides. Blocking APN dynamics can thus be a valuable approach to development of drugs that target this ectoenzyme.

  3. APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

    PubMed Central

    Chen, Ming; Wang, Jinzhao; Jiang, Jinxiang; Zheng, Xingzhi; Justice, Nicholas J; Wang, Kun; Ran, Xiangqian; Li, Yi; Huo, Qingwei; Zhang, Jiajia; Li, Hongmei; Lu, Nannan; Wang, Ying; Zheng, Hui; Long, Cheng; Yang, Li

    2017-01-01

    Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in App knock-out (App-/-) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K+-Cl- cotransporter that is essential for Cl- homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App-/- mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus. DOI: http://dx.doi.org/10.7554/eLife.20142.001 PMID:28054918

  4. An indirect method for numerical optimization using the Kreisselmeir-Steinhauser function

    NASA Technical Reports Server (NTRS)

    Wrenn, Gregory A.

    1989-01-01

    A technique is described for converting a constrained optimization problem into an unconstrained problem. The technique transforms one of more objective functions into reduced objective functions, which are analogous to goal constraints used in the goal programming method. These reduced objective functions are appended to the set of constraints and an envelope of the entire function set is computed using the Kreisselmeir-Steinhauser function. This envelope function is then searched for an unconstrained minimum. The technique may be categorized as a SUMT algorithm. Advantages of this approach are the use of unconstrained optimization methods to find a constrained minimum without the draw down factor typical of penalty function methods, and that the technique may be started from the feasible or infeasible design space. In multiobjective applications, the approach has the advantage of locating a compromise minimum design without the need to optimize for each individual objective function separately.

  5. Pareto-Optimality, Efficiency Analysis and Empirical Production Functions.

    DTIC Science & Technology

    1983-05-01

    General, 120, 3, 253-281 (1957). 15. Fenchel , W., Convex Sets , Cones and Functions , Princeton University Press, Princeton, N.J. (1953). 16. Fbrsund, F...concave, piecewise linear function on DE" Proof: A necessary and sufficient condition for fr(x) to be concave is that its hypograph is a convex set (cf...34 production function . The work of R. Shephard [18], [19] under severe restrictions on the mathematical structure of production possibility sets and cost

  6. A general optimization method applied to a vdW-DF functional for water

    NASA Astrophysics Data System (ADS)

    Fritz, Michelle; Soler, Jose M.; Fernandez-Serra, Marivi

    In particularly delicate systems, like liquid water, ab initio exchange and correlation functionals are simply not accurate enough for many practical applications. In these cases, fitting the functional to reference data is a sensible alternative to empirical interatomic potentials. However, a global optimization requires functional forms that depend on many parameters and the usual trial and error strategy becomes cumbersome and suboptimal. We have developed a general and powerful optimization scheme called data projection onto parameter space (DPPS) and applied it to the optimization of a van der Waals density functional (vdW-DF) for water. In an arbitrarily large parameter space, DPPS solves for vector of unknown parameters for a given set of known data, and poorly sampled subspaces are determined by the physically-motivated functional shape of ab initio functionals using Bayes' theory. We present a new GGA exchange functional that has been optimized with the DPPS method for 1-body, 2-body, and 3-body energies of water systems and results from testing the performance of the optimized functional when applied to the calculation of ice cohesion energies and ab initio liquid water simulations. We found that our optimized functional improves the description of both liquid water and ice when compared to other versions of GGA exchange.

  7. An optimized B lymphocyte stimulator (BLyS) antagonist peptide inhibits the interaction of BLyS with BCMA.

    PubMed

    Tian, Yu; Zhu, Yan-Feng; Wu, Zhen; Feng, Jian-Nan; Li, Yan; Shen, Bei-Fen; Sun, Jian

    2013-04-01

    B lymphocyte stimulator (BLyS) antagonists are new therapeutic reagents for treating the autoimmune diseases. Peptibodies can inhibit the bioactivity of BLyS, the same as other BLyS antagonists: decoyed BLyS receptors and anti-BLyS antibodies. In this study, a new optimized BLyS antagonist peptide was designed according to our previous work by the computer-aided homology modeling. Competitive ELISA showed that the peptide at 100 μg/ml could inhibit 54 % of the BCMA-Fc binding to BLyS. To maintain its stability and spatial conformation, the peptide was fused to human IgG1 Fc to form a peptide-Fc fusion protein-a novel peptibody by gene engineering. ELISA indicated that the peptibody could bind with BLyS in dosage-dependent manner as BCMA-Fc did. This study highlights the possibility of designing and optimizing BLyS antagonist peptides with high biopotency by the computer-aided design. Thus, these peptides could neutralize BLyS activity and be potential antagonists to treat autoimmune diseases related with BLyS overexpression.

  8. Functional and Structural Optimality in Plant Growth: A Crop Modelling Case Study

    NASA Astrophysics Data System (ADS)

    Caldararu, S.; Purves, D. W.; Smith, M. J.

    2014-12-01

    Simple mechanistic models of vegetation processes are essential both to our understanding of plant behaviour and to our ability to predict future changes in vegetation. One concept that can take us closer to such models is that of plant optimality, the hypothesis that plants aim to achieve an optimal state. Conceptually, plant optimality can be either structural or functional optimality. A structural constraint would mean that plants aim to achieve a certain structural characteristic such as an allometric relationship or nutrient content that allows optimal function. A functional condition refers to plants achieving optimal functionality, in most cases by maximising carbon gain. Functional optimality conditions are applied on shorter time scales and lead to higher plasticity, making plants more adaptable to changes in their environment. In contrast, structural constraints are optimal given the specific environmental conditions that plants are adapted to and offer less flexibility. We exemplify these concepts using a simple model of crop growth. The model represents annual cycles of growth from sowing date to harvest, including both vegetative and reproductive growth and phenology. Structural constraints to growth are represented as an optimal C:N ratio in all plant organs, which drives allocation throughout the vegetative growing stage. Reproductive phenology - i.e. the onset of flowering and grain filling - is determined by a functional optimality condition in the form of maximising final seed mass, so that vegetative growth stops when the plant reaches maximum nitrogen or carbon uptake. We investigate the plants' response to variations in environmental conditions within these two optimality constraints and show that final yield is most affected by changes during vegetative growth which affect the structural constraint.

  9. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.

    PubMed

    Telliez, Jean-Baptiste; Dowty, Martin E; Wang, Lu; Jussif, Jason; Lin, Tsung; Li, Li; Moy, Erick; Balbo, Paul; Li, Wei; Zhao, Yajuan; Crouse, Kimberly; Dickinson, Caitlyn; Symanowicz, Peter; Hegen, Martin; Banker, Mary Ellen; Vincent, Fabien; Unwalla, Ray; Liang, Sidney; Gilbert, Adam M; Brown, Matthew F; Hayward, Matthew; Montgomery, Justin; Yang, Xin; Bauman, Jonathan; Trujillo, John I; Casimiro-Garcia, Agustin; Vajdos, Felix F; Leung, Louis; Geoghegan, Kieran F; Quazi, Amira; Xuan, Dejun; Jones, Lyn; Hett, Erik; Wright, Katherine; Clark, James D; Thorarensen, Atli

    2016-12-16

    PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1β production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.

  10. Structural insights into functional amyloid inhibition in Gram −ve bacteria

    PubMed Central

    Hawthorne, William; Rouse, Sarah; Sewell, Lee; Matthews, Stephen J.

    2016-01-01

    Amyloids are proteinaceous aggregates known for their role in debilitating degenerative diseases involving protein dysfunction. Many forms of functional amyloid are also produced in nature and often these systems require careful control of their assembly to avoid the potentially toxic effects. The best-characterised functional amyloid system is the bacterial curli system. Three natural inhibitors of bacterial curli amyloid have been identified and recently characterised structurally. Here, we compare common structural features of CsgC, CsgE and CsgH and discuss the potential implications for general inhibition of amyloid. PMID:27913673

  11. An Improved Ensemble of Random Vector Functional Link Networks Based on Particle Swarm Optimization with Double Optimization Strategy.

    PubMed

    Ling, Qing-Hua; Song, Yu-Qing; Han, Fei; Yang, Dan; Huang, De-Shuang

    2016-01-01

    For ensemble learning, how to select and combine the candidate classifiers are two key issues which influence the performance of the ensemble system dramatically. Random vector functional link networks (RVFL) without direct input-to-output links is one of suitable base-classifiers for ensemble systems because of its fast learning speed, simple structure and good generalization performance. In this paper, to obtain a more compact ensemble system with improved convergence performance, an improved ensemble of RVFL based on attractive and repulsive particle swarm optimization (ARPSO) with double optimization strategy is proposed. In the proposed method, ARPSO is applied to select and combine the candidate RVFL. As for using ARPSO to select the optimal base RVFL, ARPSO considers both the convergence accuracy on the validation data and the diversity of the candidate ensemble system to build the RVFL ensembles. In the process of combining RVFL, the ensemble weights corresponding to the base RVFL are initialized by the minimum norm least-square method and then further optimized by ARPSO. Finally, a few redundant RVFL is pruned, and thus the more compact ensemble of RVFL is obtained. Moreover, in this paper, theoretical analysis and justification on how to prune the base classifiers on classification problem is presented, and a simple and practically feasible strategy for pruning redundant base classifiers on both classification and regression problems is proposed. Since the double optimization is performed on the basis of the single optimization, the ensemble of RVFL built by the proposed method outperforms that built by some single optimization methods. Experiment results on function approximation and classification problems verify that the proposed method could improve its convergence accuracy as well as reduce the complexity of the ensemble system.

  12. An Improved Ensemble of Random Vector Functional Link Networks Based on Particle Swarm Optimization with Double Optimization Strategy

    PubMed Central

    Ling, Qing-Hua; Song, Yu-Qing; Han, Fei; Yang, Dan; Huang, De-Shuang

    2016-01-01

    For ensemble learning, how to select and combine the candidate classifiers are two key issues which influence the performance of the ensemble system dramatically. Random vector functional link networks (RVFL) without direct input-to-output links is one of suitable base-classifiers for ensemble systems because of its fast learning speed, simple structure and good generalization performance. In this paper, to obtain a more compact ensemble system with improved convergence performance, an improved ensemble of RVFL based on attractive and repulsive particle swarm optimization (ARPSO) with double optimization strategy is proposed. In the proposed method, ARPSO is applied to select and combine the candidate RVFL. As for using ARPSO to select the optimal base RVFL, ARPSO considers both the convergence accuracy on the validation data and the diversity of the candidate ensemble system to build the RVFL ensembles. In the process of combining RVFL, the ensemble weights corresponding to the base RVFL are initialized by the minimum norm least-square method and then further optimized by ARPSO. Finally, a few redundant RVFL is pruned, and thus the more compact ensemble of RVFL is obtained. Moreover, in this paper, theoretical analysis and justification on how to prune the base classifiers on classification problem is presented, and a simple and practically feasible strategy for pruning redundant base classifiers on both classification and regression problems is proposed. Since the double optimization is performed on the basis of the single optimization, the ensemble of RVFL built by the proposed method outperforms that built by some single optimization methods. Experiment results on function approximation and classification problems verify that the proposed method could improve its convergence accuracy as well as reduce the complexity of the ensemble system. PMID:27835638

  13. OPTIMIZING POTENTIAL GREEN REPLACEMENT CHEMICALS – BALANCING FUNCTION AND RISK

    EPA Science Inventory

    An important focus of green chemistry is the design of new chemicals that are inherently less toxic than the ones they might replace, but still retain required functional properties. A variety of methods exist to measure or model both functional and toxicity surrogates that could...

  14. A simple reliability-based topology optimization approach for continuum structures using a topology description function

    NASA Astrophysics Data System (ADS)

    Liu, Jie; Wen, Guilin; Zhi Zuo, Hao; Qing, Qixiang

    2016-07-01

    The structural configuration obtained by deterministic topology optimization may represent a low reliability level and lead to a high failure rate. Therefore, it is necessary to take reliability into account for topology optimization. By integrating reliability analysis into topology optimization problems, a simple reliability-based topology optimization (RBTO) methodology for continuum structures is investigated in this article. The two-layer nesting involved in RBTO, which is time consuming, is decoupled by the use of a particular optimization procedure. A topology description function approach (TOTDF) and a first order reliability method are employed for topology optimization and reliability calculation, respectively. The problem of the non-smoothness inherent in TOTDF is dealt with using two different smoothed Heaviside functions and the corresponding topologies are compared. Numerical examples demonstrate the validity and efficiency of the proposed improved method. In-depth discussions are also presented on the influence of different structural reliability indices on the final layout.

  15. Akt Deficiency Attenuates Muscle Size and Function but Not the Response to ActRIIB Inhibition

    PubMed Central

    Goncalves, Marcus D.; Pistilli, Emidio E.; Balduzzi, Anthony; Birnbaum, Morris J.; Lachey, Jennifer; Khurana, Tejvir S.; Ahima, Rexford S.

    2010-01-01

    Background Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment. Methodology and Principal Findings We analyzed body composition and muscle parameters in wild-type C57BL/6J and Akt1 and Akt2 knockout mice, and compared the responses to blockade of ActRIIB signaling via ActRIIB-mFc treatment. Mice lacking Akt1 or Akt2 had reduced muscle mass, grip strength and contractile force. However, deficiency of Akt1 or Akt2 did not prevent the ability of ActRIIB-mFc treatment to induce muscle hypertrophy, or increase grip strength and contractile force. Akt1 and Akt2 deficient mice responded similarly as wild type mice to ActRIIB-mFc treatment by increasing fiber size. Conclusions and Significance Akt1 and Akt2 are important for the regulation of skeletal muscle mass and function. However, these Akt isoforms are not essential for the ability of ActRIIB inhibition to regulate muscle size, fiber type, strength or contractile force. PMID:20856813

  16. Density Functional Theory and Electrochemical Studies: Structure-Efficiency Relationship on Corrosion Inhibition.

    PubMed

    Camacho-Mendoza, Rosa L; Gutiérrez-Moreno, Evelin; Guzmán-Percástegui, Edmundo; Aquino-Torres, Eliazar; Cruz-Borbolla, Julián; Rodríguez-Ávila, José A; Alvarado-Rodríguez, José G; Olvera-Neria, Oscar; Thangarasu, Pandiyan; Medina-Franco, José L

    2015-11-23

    The relationship between structure and corrosion inhibition of a series of 30 imidazol, benzimidazol, and pyridine derivatives has been established through the investigation of quantum descriptors calculated with PBE/6-311++G**. A quantitative structure-property relationship model was obtained by examination of these descriptors using a genetic functional approximation method based on a multiple linear regression analysis. Our results indicate that the efficiency of corrosion inhibitors is strongly associated with aromaticity, electron donor ability, and molecular volume descriptors. In order to calibrate and validate the proposed model, we performed electrochemical impedance spectroscopy (EIS) studies on imidazole, 2-methylimidazole, benzimidazole, 2-chloromethylbenzimidazole, pyridine, and 2-aminopyridine compounds. The experimental values for efficiency of corrosion inhibition are in good agreement with the estimated values obtained by our model, thus confirming that our approach represents a promising and suitable tool to predict the inhibition of corrosion attributes of nitrogen containing heterocyclic compounds. The adsorption behavior of imidazole or benzimidazole heterocyclic molecules on the Fe(110) surface was also studied to elucidate the inhibition mechanism; the aromaticity played an important role in the adsorbate-surface complex.

  17. Optimizing the patient transport function at Mayo Clinic.

    PubMed

    Kuchera, Dustin; Rohleder, Thomas R

    2011-01-01

    In this article, we report on the implementation of a computerized scheduling tool to optimize staffing for patient transport at the Mayo Clinic. The tool was developed and implemented in Microsoft Excel and Visual Basic for Applications and includes an easy-to-use interface. The tool allows transport management to consider the trade-offs between patient waiting time and staffing levels. While improved staffing efficiency was a desire of the project, it was important that patient service quality was also maintained. The results show that staffing could be reduced while maintaining historical patient service levels.

  18. Configuring artificial neural networks to implement function optimization

    NASA Astrophysics Data System (ADS)

    Sundaram, Ramakrishnan

    2002-04-01

    Threshold binary networks of the discrete Hopfield-type lead to the efficient retrieval of the regularized least-squares (LS) solution in certain inverse problem formulations. Partitions of these networks are identified based on forms of representation of the data. The objective criterion is optimized using sequential and parallel updates on these partitions. The algorithms consist of minimizing a suboptimal objective criterion in the currently active partition. Once the local minima is attained, an inactive partition is chosen to continue the minimization. This strategy is especially effective when substantial data must be processed by resources which are constrained either in space or available bandwidth.

  19. An efficient cuckoo search algorithm for numerical function optimization

    NASA Astrophysics Data System (ADS)

    Ong, Pauline; Zainuddin, Zarita

    2013-04-01

    Cuckoo search algorithm which reproduces the breeding strategy of the best known brood parasitic bird, the cuckoos has demonstrated its superiority in obtaining the global solution for numerical optimization problems. However, the involvement of fixed step approach in its exploration and exploitation behavior might slow down the search process considerably. In this regards, an improved cuckoo search algorithm with adaptive step size adjustment is introduced and its feasibility on a variety of benchmarks is validated. The obtained results show that the proposed scheme outperforms the standard cuckoo search algorithm in terms of convergence characteristic while preserving the fascinating features of the original method.

  20. Optimization of functionalization conditions for protein analysis by AFM

    NASA Astrophysics Data System (ADS)

    Arroyo-Hernández, María; Daza, Rafael; Pérez-Rigueiro, Jose; Elices, Manuel; Nieto-Márquez, Jorge; Guinea, Gustavo V.

    2014-10-01

    Activated vapor silanization (AVS) is used to functionalize silicon surfaces through deposition of amine-containing thin films. AVS combines vapor silanization and chemical vapor deposition techniques and allows the properties of the functionalized layers (thickness, amine concentration and topography) to be controlled by tuning the deposition conditions. An accurate characterization is performed to correlate the deposition conditions and functional-film properties. In particular, it is shown that smooth surfaces with a sufficient surface density of amine groups may be obtained with this technique. These surfaces are suitable for the study of proteins with atomic force microscopy.

  1. Common and unique neural networks for proactive and reactive response inhibition revealed by independent component analysis of functional MRI data.

    PubMed

    van Belle, Janna; Vink, Matthijs; Durston, Sarah; Zandbelt, Bram B

    2014-12-01

    Response inhibition involves proactive and reactive modes. Proactive inhibition is goal-directed, triggered by warning cues, and serves to restrain actions. Reactive inhibition is stimulus-driven, triggered by salient stop-signals, and used to stop actions completely. Functional MRI studies have identified brain regions that activate during proactive and reactive inhibition. It remains unclear how these brain regions operate in functional networks, and whether proactive and reactive inhibition depend on common networks, unique networks, or a combination. To address this we analyzed a large fMRI dataset (N=65) of a stop-signal task designed to measure proactive and reactive inhibition, using independent component analysis (ICA). We found 1) three frontal networks that were associated with both proactive and reactive inhibition, 2) one network in the superior parietal lobe, which also included dorsal premotor cortex and left putamen, that was specifically associated with proactive inhibition, and 3) two right-lateralized frontal and fronto-parietal networks, including the right inferior frontal gyrus and temporoparietal junction as well as a bilateral fronto-temporal network that were uniquely associated with reactive inhibition. Overlap between networks was observed in dorsolateral prefrontal and parietal cortices. Taken together, we offer a new perspective on the neural underpinnings of inhibitory control, by showing that proactive inhibition and reactive inhibition are supported by a group of common and unique networks that appear to integrate and interact in frontoparietal areas.

  2. Molecular cloning and functional analysis of three genes encoding polygalacturonase-inhibiting proteins from Capsicum annuum, and their relation to increased resistance to two fungal pathogens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polygalacturonase-inhibiting proteins (PGIPs) are plant cell wall glycoproteins that can inhibit fungal endopolygalacturonases (PGs). Inhibiting by PGIPs directly reduces potential PG activity in specific plant pathogenic fungi, reducing their aggressiveness. Here, we isolated and functionally chara...

  3. Metabolic and functional consequences of inhibiting adenosine deaminase during renal ischemia in rats.

    PubMed Central

    Stromski, M E; van Waarde, A; Avison, M J; Thulin, G; Gaudio, K M; Kashgarian, M; Shulman, R G; Siegel, N J

    1988-01-01

    The concentrations of renal ATP have been measured by 31P-nuclear magnetic resonance (NMR) before, during, and after bilateral renal artery occlusion. Using in vivo NMR, the initial postischemic recovery of ATP increased with the magnitude of the residual nucleotide pool at the end of ischemia. ATP levels after 120 min of reflow correlated with functional recovery at 24 h. In the present study the effect of blocking the degradation of ATP during ischemia upon the postischemic restoration of ATP was investigated. Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool. This increased the ATP initial recovery after 45 min of ischemia from 52% (in controls) to 62% (in the treated animals), as compared to the basal levels. The inhibition also caused an accelerated postischemic restoration of cellular ATP so that at 120 min it was 83% in treated rats vs. 63% in untreated animals. There was a corresponding improvement in the functional recovery from the insult (increase of 33% in inulin clearance 24 h after the injury). Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult. PMID:3263396

  4. R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram.

    PubMed

    Sánchez, Connie; Kreilgaard, Mads

    2004-02-01

    Escitalopram mediates the serotonin re-uptake inhibitory and antidepressant effect of citalopram racemate. However, recent studies have shown that R-citalopram inhibits the escitalopram-induced increase of extracellular 5-HT levels in the frontal cortex of rats. Here, we investigated the inhibitory effect of R-citalopram on the escitalopram-induced increase of 5-HT neurotransmission at the behavioural [potentiation of 5-hydroxytryptophan (5-HTP)-induced behavioural changes in mice and rats] and functional (increase in serum corticosterone in rats) levels. The effect of escitalopram was inhibited by R-citalopram in all three models, and R-citalopram, given alone, was inactive. The effects were more pronounced using an escitalopram to R-citalopram ratio of 1:4 than ratios of 1:2 and 1:1, suggesting a dose-dependent effect. The ED(50)-value of escitalopram in mouse 5-HTP potentiation studies corresponded to a serum concentration of approximately 50 ng/ml, which can be considered to be in the range of clinically relevant serum concentrations. In conclusion, R-citalopram inhibited the escitalopram-induced increase of 5-HT activity in functional, as well as behavioural, animal models. The mechanism involved in this interaction is currently unknown, but may be related to an improved clinical effect seen with escitalopram in comparison with citalopram.

  5. Prolactin inhibits a major tumor-suppressive function of wild type BRCA1.

    PubMed

    Chen, Kuan-Hui Ethan; Walker, Ameae M

    2016-06-01

    Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21.

  6. TLR4 plays a crucial role in MSC-induced inhibition of NK cell function.

    PubMed

    Lu, Ying; Liu, Jin; Liu, Yang; Qin, Yaru; Luo, Qun; Wang, Quanli; Duan, Haifeng

    2015-08-21

    Mesenchymal stem cells (MSC) are a kind of stromal cell within the tumor microenvironment. In our research, MSC derived from acute myeloid leukemia patients' bone marrow (AML-MSC) and lung cancer tissues (LC-MSC) as well as normal bone marrow-derived MSC (BM-MSC) cultured in conditioned medium of HeLa cells were found to have higher expressions of Toll-like receptor (TLR4) mRNA compared with BM-MSC. The sorted TLR4-positive MSC (TLR4+ MSC) differed in cytokine (interleukin-6, interleukin-8, and monocyte chemoattractant protein-1) secretion from those of unsorted MSC. MSC was reported to inhibit natural killer (NK) cell proliferation and function. In this research, we confirmed that TLR4+ MSC aggravate this suppression. Furthermore, when TLR4 in the sorted cells were stimulated by LPS or following blocked by antibody, the suppression on NK cell proliferation and cytotoxicity were more intensive or recovered respectively. Compared to unsorted MSC, NKG2D receptor expression on NK cells were also inhibited by TLR4+ MSC. These findings suggest that activation of TLR4 pathway is important for TLR4+ MSC and MSC to obstruct anti-tumor immunity by inhibiting NK cell function, which may provide a potential stroma-targeted tumor therapy.

  7. Antipsychotic clozapine inhibits the function of alpha7-nicotinic acetylcholine receptors.

    PubMed

    Singhal, Sachin K; Zhang, Li; Morales, Marisela; Oz, Murat

    2007-02-01

    The effects of the antipsychotic clozapine on the function of the cloned alpha(7) subunit of the nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Clozapine reversibly inhibited nicotine (10 microM)-induced currents in a concentration-dependent manner (300 nM to 90 microM), with an IC(50) value of 3.2+/-0.4 microM. The effect of clozapine was not dependent on the membrane potential. Clozapine did not affect the activity of endogenous Ca(2+)-dependent Cl(-) channels since the inhibition by clozapine was unaltered by the intracellularly injected Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free bathing solution containing 2mM Ba(2+). Clozapine decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on alpha(7)-nACh receptors. In hippocampal slices, the whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the GABA-mediated spontaneous inhibitory postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for alpha(7)-nACh receptors, were abolished after 10 min application of 5 microM clozapine. In conclusion, these results demonstrate that clozapine inhibits the function of alpha(7)-nACh receptors expressed in Xenopus oocytes and in hippocampal neurons.

  8. Cyanide levels found in infected cystic fibrosis sputum inhibit airway ciliary function.

    PubMed

    Nair, Chandrika; Shoemark, Amelia; Chan, Mario; Ollosson, Sarah; Dixon, Mellissa; Hogg, Claire; Alton, Eric W F W; Davies, Jane C; Williams, Huw D

    2014-11-01

    We have previously reported cyanide at concentrations of up to 150 μM in the sputum of cystic fibrosis patients infected with Pseudomonas aeruginosa and a negative correlation with lung function. Our aim was to investigate possible mechanisms for this association, focusing on the effect of pathophysiologically relevant cyanide levels on human respiratory cell function. Ciliary beat frequency measurements were performed on nasal brushings and nasal air-liquid interface (ALI) cultures obtained from healthy volunteers and cystic fibrosis patients. Potassium cyanide decreased ciliary beat frequency in healthy nasal brushings (n = 6) after 60 min (150 μM: 47% fall, p<0.0012; 75 μM: 32% fall, p<0.0001). Samples from cystic fibrosis patients (n = 3) showed similar results (150 μM: 55% fall, p = 0.001). Ciliary beat frequency inhibition was not due to loss of cell viability and was reversible. The inhibitory mechanism was independent of ATP levels. KCN also significantly inhibited ciliary beat frequency in ALI cultures, albeit to a lesser extent. Ciliary beat frequency measurements on ALI cultures treated with culture supernatants from P. aeruginosa mutants defective in virulence factor production implicated cyanide as a key component inhibiting the ciliary beat frequency. If cyanide production similarly impairs mucocilliary clearance in vivo, it could explain the link with increased disease severity observed in cystic fibrosis patients with detectable cyanide in their airway.

  9. Functional dissection of the human Bc12 protein: sequence requirements for inhibition of apoptosis.

    PubMed Central

    Hunter, J J; Bond, B L; Parslow, T G

    1996-01-01

    Overexpression of the cytoplasmic oncoprotein Bc12 blocks programmed cell death (apoptosis) in many cellular systems. To map the sequences in Bc12 that are necessary for its activity, we created a library of deletion-scanning mutants of this 239-amino-acid protein and tested their abilities to block staurosporine-induced fibroblast apoptosis, using a novel transient-transfection assay. Phenotypes of informative mutants were then confirmed by assaying for inhibition of steroid-induced apoptosis in stably transfected T-lymphoid cells. In accordance with earlier results, we found that Bc12 activity was only partially reduced after deletion of the hydrophobic tail that normally anchors it in cytoplasmic membranes. Essential sequences were found in the remainder of the protein and appeared to be organized in at least two discrete functional domains. The larger, more C-terminal region (within residues 90 to 203) encompassed, but extended beyond, two oligopeptide motifs called BH1 and BH2, which are known to mediate dimerization of Bc12 and related proteins. The second, more N-terminal regions (within residues 6 to 31) was not required for protein dimerization in vivo, but its deletion imparted a dominant negative phenotype, yielding mutants that promoted rather than inhibited apoptotic death. Residues 30 to 91 were not absolutely required for function; by deleting most of this region along with the hydrophobic tail, we derived a 155-residue mini-Bc12 that retains significant ability to inhibit apoptosis. PMID:8622689

  10. Functionalization of Titanium Alloy Surface by Graphene Nanoplatelets and Metal Oxides: Corrosion Inhibition.

    PubMed

    Mondal, Jayanta; Aarik, Lauri; Kozlova, Jekaterina; Niilisk, Ahti; Mändar, Hugo; Mäeorg, Uno; Simões, Alda; Sammelselg, Väino

    2015-09-01

    Corrosion inhibition of metallic substrates is an important and crucial step for great economical as well as environmental savings. In this paper, we introduce an extra thin effective corrosion inhibitive material having layered structure designed for protection and functionalization of Ti Grade 5 alloy substrates. The coating consists of a first layer made of thin graphene nanoplatelets, on top of which a multilayer Al2O3 and TiO2 films is applied by low-temperature atomic layer deposition. The amorphous structure of the metal oxide films was confirmed by micro-Raman and X-ray diffraction analysis. Corrosion inhibition ability of the prepared coatings was analyzed by open circuit potential, potentiodynamic plot and by voltammetric analysis, in aqueous potassium bromide solution. The open circuit potential of the graphene-metal oxide coated substrate showed much passive nature than bare substrate or graphene coated or only metal oxide coated substrates. The localized corrosion potential of the graphene-metal oxide coated, only metal oxide coated, and bare substrates were found 5.5, 3.0, and 1.1 V, respectively. In addition, corrosion current density values of the graphene-metal oxide and only metal oxide coated substrates showed much more passive nature than the bare and graphene coated substrates. Long immersion test in the salt solution further clarified the effective corrosion inhibition of the graphene-metal oxide coated substrate. The analyzed results reflect that the graphene-metal oxide films can be used to prepare better and effective corrosion inhibition coatings for the Ti Grade 5 alloy to increase their lifetime.

  11. Inhibition of bacterial adhesion and biofilm formation by dual functional textured and nitric oxide releasing surfaces.

    PubMed

    Xu, Li-Chong; Wo, Yaqi; Meyerhoff, Mark E; Siedlecki, Christopher A

    2017-03-15

    In separate prior studies, physical topographic surface modification or nitric oxide (NO) release has been demonstrated to each be an effective approach to inhibit and control bacterial adhesion and biofilm formation on polymeric surfaces. Such approaches can prevent biomaterial-associated infection without causing the antibiotic resistance of the strain. In this work, both techniques were successfully integrated and applied to a polyurethane (PU) biomaterial surface that bears ordered pillar topographies (400/400nm and 500/500nm patterns) at the top surface and a S-nitroso-N-acetylpenicillamine (SNAP, NO donor) doped sub-layer in the middle, via a soft lithography two-stage replication process. Upon placing the SNAP textured PU films into PBS at 37°C, the decomposition of SNAP within polymer film initiates NO release with a lifetime of up to 10days at flux levels >0.5×10(-10)molmin(-1)cm(-2) for a textured polyurethane layer containing 15wt% SNAP. The textured surface reduces the accessible surface area and the opportunity of bacteria-surface interaction, while the NO release from the same surface further inhibits bacterial growth and biofilm formation. Such dual functionality surfaces are shown to provide a synergistic effect on inhibition of Staphylococcus epidermidis bacterial adhesion that is significantly greater than the inhibition of bacterial adhesion achieved by either single treatment approach alone. Longer term experiments to observe biofilm formation demonstrate that the SNAP doped-textured PU surface can inhibit the biofilm formation for >28d and provide a practical approach to improve the biocompatibility of current biomimetic biomaterials and thereby reduce the risk of pathogenic infection.

  12. Cost benefit theory and optimal design of gene regulation functions

    NASA Astrophysics Data System (ADS)

    Kalisky, Tomer; Dekel, Erez; Alon, Uri

    2007-12-01

    Cells respond to the environment by regulating the expression of genes according to environmental signals. The relation between the input signal level and the expression of the gene is called the gene regulation function. It is of interest to understand the shape of a gene regulation function in terms of the environment in which it has evolved and the basic constraints of biological systems. Here we address this by presenting a cost-benefit theory for gene regulation functions that takes into account temporally varying inputs in the environment and stochastic noise in the biological components. We apply this theory to the well-studied lac operon of E. coli. The present theory explains the shape of this regulation function in terms of temporal variation of the input signals, and of minimizing the deleterious effect of cell-cell variability in regulatory protein levels. We also apply the theory to understand the evolutionary tradeoffs in setting the number of regulatory proteins and for selection of feed-forward loops in genetic circuits. The present cost-benefit theory can be used to understand the shape of other gene regulatory functions in terms of environment and noise constraints.

  13. Tailored SWCNT functionalization optimized for compatibility with epoxy matrices

    NASA Astrophysics Data System (ADS)

    Martinez-Rubi, Y.; Gonzalez-Dominguez, J. M.; Ansón-Casaos, A.; Kingston, C. T.; Daroszewska, M.; Barnes, M.; Hubert, P.; Cattin, C.; Martinez, M. T.; Simard, B.

    2012-07-01

    We have modified single walled carbon nanotubes (SWCNTs) with well defined matrix-based architectures to improve interface interaction in SWCNT/epoxy composites. The hardener and two pre-synthesized oligomers containing epoxy and hardener moieties were covalently attached to the SWCNT walls by in situ diazonium or carboxylic coupling reactions. In this way, SWCNTs bearing amine or epoxide-terminated fragments of different molecular weights, which resemble the chemical structure of the cured resin, were synthesized. A combination of characterization techniques such as Raman and infrared absorption (FTIR) spectroscopy, elemental analysis and coupled thermogravimetry-FTIR spectroscopy were used to identify both the functional groups and degree of functionalization of SWCNTs synthesized by the laser ablation and arc-discharge methods. Depending on the type of reaction employed for the chemical functionalization and the molecular weight of the attached fragment, it was possible to control the degree of functionalization and the electronic properties of the functionalized SWCNTs. Improved dispersion of SWCNTs in the epoxy matrix was achieved by direct integration without using solvents, as observed from optical microscopy and rheology measurements of the SWCNT/epoxy mixtures. Composite materials using these fillers are expected to exhibit improved properties while preserving the thermosetting architecture.

  14. Functional mutations in mouse norepinephrine transporter reduce sensitivity to cocaine inhibition

    PubMed Central

    Wei, Hua; Hill, Erik R; Gu, Howard H.

    2009-01-01

    Summary The transporters of dopamine, norepinephrine and serotonin are molecular targets of cocaine, amphetamine, and therapeutic antidepressants. The residues involved in binding these drugs are unknown. We have performed several rounds of random and site-directed mutagenesis in the mouse norepinephrine transporter and screened for mutants with altered sensitivity to cocaine inhibition of substrate uptake. We have identified a triple mutation that retains close to wild-type transport function but displays a 37-fold decrease in cocaine sensitivity and 24-fold decrease in desipramine sensitivity. In contrast, the mutant’s sensitivities to amphetamine, methamphetamine, and methylphenidate are only slightly changed. Our data reveal critical residues contributing to the potent uptake inhibitions by these important drugs. Furthermore, this drug-resistant triple mutant can be used to generate a unique knock-in mouse line to study the role of norepinephrine transporter in the addictive effects of cocaine and the therapeutic effects of desipramine. PMID:18824182

  15. Tsukushi functions as an organizer inducer by inhibition of BMP activity in cooperation with chordin.

    PubMed

    Ohta, Kunimasa; Lupo, Giuseppe; Kuriyama, Sei; Keynes, Roger; Holt, Christine E; Harris, William A; Tanaka, Hideaki; Ohnuma, Shin-ichi

    2004-09-01

    During chick gastrulation, inhibition of BMP signaling is required for primitive streak formation and induction of Hensen's node. We have identified a unique secreted protein, Tsukushi (TSK), which belongs to the Small Leucine-Rich Proteoglycan (SLRP) family and is expressed in the primitive streak and Hensen's node. Grafts of cells expressing TSK in combination with the middle primitive streak induce an ectopic Hensen's node, while electroporation of TSK siRNA inhibits induction of the node. In Xenopus embryos, TSK can block BMP function and induce a secondary dorsal axis, while it can dorsalize ventral mesoderm and induce neural tissue in embryonic explants. Biochemical analysis shows that TSK binds directly to both BMP and chordin and forms a ternary complex with them. These observations indicate that TSK is an essential dorsalizing factor involved in the induction of Hensen's node.

  16. c-Cbl Inhibition Improves Cardiac function and Survival in Response to Myocardial Ischemia

    PubMed Central

    Rafiq, Khadija; Kolpakov, Mikhail A; Seqqat, Rachid; Guo, Jianfen; Guo, Xinji; Qi, Zhao; Yu, Daohai; Mohapatra, Bhopal; Zutshi, Neha; An, Wei; Band, Hamid; Sanjay, Archana; Houser, Steven R; Sabri, Abdelkarim

    2014-01-01

    Background The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and non-receptor tyrosine kinases, resulting in their ubiquitination and down-regulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia. Methods and Results We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl deficient mice demonstrated a more robust functional recovery after myocardial ischemia reperfusion injury, as well as significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor (VEGF)-a and VEGF receptor type 2 in the infarcted region. Conclusions c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia. PMID:24583314

  17. [Inhibition of Staphylococcus epidermidis adhesion on titanium surface with bioactive water-soluble copolymers bearing sulfonate, phosphate or carboxylate functions].

    PubMed

    Poussard, L; Ouédraogo, C P; Pavon-Djavid, G; Migonney, V

    2012-04-01

    Implanted prostheses are sometimes subject to bacterial infections, which can threat their benefit rule on a long-term basis. Various methods are studied to fight against these infections. Among them, the grafting of bioactive polymers onto the prosthesis surface shows up as a promising way to the problem of infections. This work presents the influence of various water-soluble bioactive polymers on the inhibition of the Staphylococcus epidermidis adhesion on the titanium samples surfaces initially preadsorbed with various proteins. Whatever the studied protein is, it is shown that the bioactive polymer containing sulfonate functions generates an inhibition of the adhesion of Staphylococcus epidermidis. For a plasma preadsorption, the inhibition rate rises up to 68% when the concentration of sulfonate function is 2.5μmol/L. Titanium surfaces grafted with the bioactive polymer were also tested. We find an inhibitive activity of the adhesion close to that of the previous case. These preliminary results can point up a clinical interest in the fight against the medical devices infection, because they highlight a clear local effect of S. epidermidis adhesion inhibition. Copolymers containing other functional groups (phosphate or carboxylate) were dissolved in a bacterial suspension to monitor the influence of the composition on the adhesion inhibition. Their inhibition rates are not significantly lower than those of pNaSS homopolymers, as much as the sulfonate function proportion remains higher than 50%. Thus, the sulfonate function is the main responsible for the inhibition of the S. epidermidis adhesion.

  18. A new optimal sliding mode controller design using scalar sign function.

    PubMed

    Singla, Mithun; Shieh, Leang-San; Song, Gangbing; Xie, Linbo; Zhang, Yongpeng

    2014-03-01

    This paper presents a new optimal sliding mode controller using the scalar sign function method. A smooth, continuous-time scalar sign function is used to replace the discontinuous switching function in the design of a sliding mode controller. The proposed sliding mode controller is designed using an optimal Linear Quadratic Regulator (LQR) approach. The sliding surface of the system is designed using stable eigenvectors and the scalar sign function. Controller simulations are compared with another existing optimal sliding mode controller. To test the effectiveness of the proposed controller, the controller is implemented on an aluminum beam with piezoceramic sensor and actuator for vibration control. This paper includes the control design and stability analysis of the new optimal sliding mode controller, followed by simulation and experimental results. The simulation and experimental results show that the proposed approach is very effective.

  19. Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo

    PubMed Central

    Chen, Qiumei; Sievers, Richard E.; Varga, Monika; Kharait, Sourabh; Haddad, Daniel J.; Patton, Aaron K.; Delany, Christopher S.; Mutka, Sarah C.; Blonder, Joan P.; Dubé, Gregory P.; Rosenthal, Gary J.

    2013-01-01

    Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 ± 5.4 vs. 14.2 ± 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 ± 2.9 vs. 7.6 ± 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 ± 5.3/122.7 ± 6.4 vs. 203.8 ± 1.9/143.7 ± 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 ± 0.4 vs. 3.2 ± 1.0 mmHg·min·l−1 for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 ± 1.7%, day 0) to a level (13.0 ± 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension. PMID:23349456

  20. Inhibition of differentiation and function of osteoclasts by dimethyl sulfoxide (DMSO).

    PubMed

    Yang, Chunxi; Madhu, Vedavathi; Thomas, Candace; Yang, Xinlin; Du, Xeujun; Dighe, Abhijit S; Cui, Quanjun

    2015-12-01

    Dimethyl sulfoxide (DMSO) is an FDA-approved organosulfur solvent that is reported to have therapeutic value in osteoarthritis and osteopenia. DMSO is used as a cryoprotectant for the cryopreservation of bone grafts and mesenchymal stem cells which are later used for bone repair. It is also used as a solvent in the preparation of various scaffolds used for bone tissue engineering purposes. DMSO has been reported to inhibit osteoclast formation in vitro but the mechanism involved has remained elusive. We investigated the effect of DMSO on osteoclast differentiation and function using a conventional model system of RAW 264.7 cells. The differentiation of RAW 264.7 cells was induced by adding 50 ng/ml RANKL and the effect of DMSO (0.01 and 1% v/v) on RANKL-induced osteoclastogenesis was investigated. Addition of 1% DMSO significantly inhibited RANKL-induced formation of TRAP+, multinucleated, mature osteoclasts and osteoclast late-stage precursors (c-Kit(-) c-Fms(+) Mac-1(+) RANK(+)). While DMSO did not inhibit proliferation per se, it did inhibit the effect of RANKL on proliferation of RAW 264.7 cells. Key genes related to osteoclast function (TRAP, Integrin αVβ3, Cathepsin K and MMP9) were significantly down-regulated by DMSO. RANKL-induced expression of RANK gene was significantly reduced in the presence of DMSO. Our data, and reports from other investigators, that DMSO enhances osteoblastic differentiation of mesenchymal stem cells and also prevents bone loss in ovarietcomized rats, suggest that DMSO has tremendous potential in the treatment of osteoporosis and bone diseases arising from uncontrolled activities of the osteoclasts.

  1. [Optimization of cardiovascular function by peptide bio-regulators].

    PubMed

    Cherkashin, V A; Semin, G F; Veretenko, A A

    2002-01-01

    Effects of peptide bioregulators (thymaline, epithalamine, cortexine) on systemic hemodynamics in cardiovascular and cerebrovascular affections were studied. Assessment of functional stability and quality of cardiovascular system regulation was made according to methodological principles of automatic regulation theory. Peptide bioregulators showed high effectiveness in the above patients who markedly improved their hemodynamic parameters.

  2. Plant organelle proteomics: collaborating for optimal cell function.

    PubMed

    Agrawal, Ganesh Kumar; Bourguignon, Jacques; Rolland, Norbert; Ephritikhine, Geneviève; Ferro, Myriam; Jaquinod, Michel; Alexiou, Konstantinos G; Chardot, Thierry; Chakraborty, Niranjan; Jolivet, Pascale; Doonan, John H; Rakwal, Randeep

    2011-01-01

    Organelle proteomics describes the study of proteins present in organelle at a particular instance during the whole period of their life cycle in a cell. Organelles are specialized membrane bound structures within a cell that function by interacting with cytosolic and luminal soluble proteins making the protein composition of each organelle dynamic. Depending on organism, the total number of organelles within a cell varies, indicating their evolution with respect to protein number and function. For example, one of the striking differences between plant and animal cells is the plastids in plants. Organelles have their own proteins, and few organelles like mitochondria and chloroplast have their own genome to synthesize proteins for specific function and also require nuclear-encoded proteins. Enormous work has been performed on animal organelle proteomics. However, plant organelle proteomics has seen limited work mainly due to: (i) inter-plant and inter-tissue complexity, (ii) difficulties in isolation of subcellular compartments, and (iii) their enrichment and purity. Despite these concerns, the field of organelle proteomics is growing in plants, such as Arabidopsis, rice and maize. The available data are beginning to help better understand organelles and their distinct and/or overlapping functions in different plant tissues, organs or cell types, and more importantly, how protein components of organelles behave during development and with surrounding environments. Studies on organelles have provided a few good reviews, but none of them are comprehensive. Here, we present a comprehensive review on plant organelle proteomics starting from the significance of organelle in cells, to organelle isolation, to protein identification and to biology and beyond. To put together such a systematic, in-depth review and to translate acquired knowledge in a proper and adequate form, we join minds to provide discussion and viewpoints on the collaborative nature of organelles in

  3. Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

    PubMed Central

    Bhatt, Aaditya; Gurukumar, K. R.; Basu, Amartya; Patel, Maulik R.; Kaushik-Basu, Neerja; Talele, Tanaji T.

    2011-01-01

    Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of α,γ-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 μM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 μM] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 μM] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 μM] and 24a [IC50 = 2.4 μM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. PMID:21893371

  4. Optimal behavior by rats in a choice task is associated to a persistent conditioned inhibition effect.

    PubMed

    Trujano, R Emmanuel; López, Paulina; Rojas-Leguizamón, Maryed; Orduña, Vladimir

    2016-09-01

    When given a choice between an alternative with a low probability of reinforcement and discriminative stimuli, and another with a higher probability of reinforcement and non-discriminative stimuli, pigeons show a clear preference for the former but rats clearly prefer the later. It has been reported that pigeon's suboptimal choice is associated to a diminishing effect of the stimulus correlated with non-reinforcement. In the present paper, we explored the possibility that rats' optimal choice is more strongly influenced than pigeons' by the stimulus associated to non-reinforcement and that the effects of it do not dissipate during training. We trained rats to choose between an alternative with 0.50 probability of reinforcement and discriminative stimuli, and an alternative with 0.75 probability of reinforcement and non-discriminative stimuli. We replicated the strong preference for the optimal alternative. Then, after several sessions of training, we presented summation trials in which both the stimulus associated to reinforcement and the stimulus associated to non-reinforcement were simultaneously presented. The results showed that the stimulus associated to non-reinforcement exerted a strong effect on choice, and, more importantly, that it did not seem to dissipate across training. These results suggest that the strong difference found between pigeons and rats in the suboptimal choice procedure is potentially related to differences in the impact of conditioned inhibitors.

  5. Numerical experience with a class of algorithms for nonlinear optimization using inexact function and gradient information

    NASA Technical Reports Server (NTRS)

    Carter, Richard G.

    1989-01-01

    For optimization problems associated with engineering design, parameter estimation, image reconstruction, and other optimization/simulation applications, low accuracy function and gradient values are frequently much less expensive to obtain than high accuracy values. Here, researchers investigate the computational performance of trust region methods for nonlinear optimization when high accuracy evaluations are unavailable or prohibitively expensive, and confirm earlier theoretical predictions when the algorithm is convergent even with relative gradient errors of 0.5 or more. The proper choice of the amount of accuracy to use in function and gradient evaluations can result in orders-of-magnitude savings in computational cost.

  6. Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice

    PubMed Central

    Alia, Claudia; Spalletti, Cristina; Lai, Stefano; Panarese, Alessandro; Micera, Silvestro; Caleo, Matteo

    2016-01-01

    A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. The GABAergic system is one of the key modulators of neuronal plasticity, and plays an important role in the control of “critical periods” during brain development. Here, we report a key role for GABAergic inhibition in functional restoration following ischemia in the adult mouse forelimb motor cortex. After stroke, the majority of cortical sites in peri-infarct areas evoked simultaneous movements of forelimb, hindlimb and tail, consistent with a loss of inhibitory signalling. Accordingly, we found a delayed decrease in several GABAergic markers that accompanied cortical reorganization. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAA receptor function. We found that hampering GABAA signalling led to significant restoration of function in general motor tests (i.e., gridwalk and pellet reaching tasks), with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. These data demonstrate a key role for GABAergic inhibition in limiting motor improvements after cortical stroke. PMID:27897203

  7. An Empirical Comparison of Seven Iterative and Evolutionary Function Optimization Heuristics

    NASA Technical Reports Server (NTRS)

    Baluja, Shumeet

    1995-01-01

    This report is a repository of the results obtained from a large scale empirical comparison of seven iterative and evolution-based optimization heuristics. Twenty-seven static optimization problems, spanning six sets of problem classes which are commonly explored in genetic algorithm literature, are examined. The problem sets include job-shop scheduling, traveling salesman, knapsack, binpacking, neural network weight optimization, and standard numerical optimization. The search spaces in these problems range from 2368 to 22040. The results indicate that using genetic algorithms for the optimization of static functions does not yield a benefit, in terms of the final answer obtained, over simpler optimization heuristics. Descriptions of the algorithms tested and the encodings of the problems are described in detail for reproducibility.

  8. [Erythropoiesis and functional characteristics in bone marrow erythroblastic islets during stimulated adn inhibited erythropoiesis].

    PubMed

    Rassokhin, A G; Kruglov, D G; Zakharov, Iu M

    2000-01-01

    When erythropiesis is stimulated (acute blood loss) or inhibited (posttransfusion polycythemia), there are early changes in the cytochemical values of erythroblastic islets (EI): in the levels of acid and neutral glucoconjugates and in the activity of nonspecific esterase. A close correlation has been found between the erythropoiesis in EI and its functional characteristics. It is concluded that central macrophages play the key role in the modulation of EI erythropoiesis. It is suggested that EI macrophages are involved in the provision of bioenergetic and reparative processes in EI.

  9. Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate.

    PubMed Central

    Schmidt, A; Rutledge, S J; Endo, N; Opas, E E; Tanaka, H; Wesolowski, G; Leu, C T; Huang, Z; Ramachandaran, C; Rodan, S B; Rodan, G A

    1996-01-01

    Alendronate (ALN), an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its molecular target is still unknown. This study examines the effects of ALN on the activity of osteoclast protein-tyrosine phosphatase (PTP; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48), called PTPepsilon. Using osteoclast-like cells generated by coculturing mouse bone marrow cells with mouse calvaria osteoblasts, we found by molecular cloning and RNA blot hybridization that PTPepsilon is highly expressed in osteoclastic cells. A purified fusion protein of PTPepsilon expressed in bacteria was inhibited by ALN with an IC50 of 2 microM. Other PTP inhibitors--orthovanadate and phenylarsine oxide (PAO)-inhibited PTPepsilon with IC50 values of 0.3 microM and 18 microM, respectively. ALN and another bisphosphonate, etidronate, also inhibited the activities of other bacterially expressed PTPs such as PTPsigma and CD45 (also called leukocyte common antigen). The PTP inhibitors ALN, orthovanadate, and PAO suppressed in vitro formation of multinucleated osteoclasts from osteoclast precursors and in vitro bone resorption by isolated rat osteoclasts (pit formation) with estimated IC50 values of 10 microM, 3 microM, and 0.05 microM, respectively. These findings suggest that tyrosine phosphatase activity plays an important role in osteoclast formation and function and is a putative molecular target of bisphosphonate action. Images Fig. 2 Fig. 3 PMID:8610169

  10. Piperine, a Pungent Alkaloid from Black Pepper, Inhibits B Lymphocyte Activation and Effector Functions.

    PubMed

    Soutar, David A; Doucette, Carolyn D; Liwski, Robert S; Hoskin, David W

    2017-03-01

    Piperine has several well-documented anti-inflammatory properties; however, little is known regarding its effect on humoral immunity. In this study, we describe the immunosuppressive effect of piperine on B lymphocytes, which are integral to the humoral immune response. Mouse B cells were cultured in the absence or presence of non-cytotoxic concentrations (25, 50, and 100 μM) of piperine during T-dependent or T-independent stimulation. Piperine inhibited B cell proliferation by causing G0/G1 phase cell cycle arrest in association with reduced expression of cyclin D2 and D3. The inhibitory effect of piperine was not mediated through transient receptor potential vanilloid-1 ion channel (TRPV1) because piperine also inhibited the proliferation of B cells from TRPV1-deficient mice. Expression of class II major histocompatibility complex molecules and costimulatory CD40 and CD86 on B lymphocytes was reduced in the presence of piperine, as was B cell-mediated antigen presentation to syngeneic T cells. In addition, piperine inhibited B cell synthesis of interleukin (IL)-6 and IL-10 cytokines, as well as IgM, IgG2b, and IgG3 immunoglobulins. The inhibitory effect of piperine on B lymphocyte activation and effector function warrants further investigation for possible application in the treatment of pathologies related to inappropriate humoral immune responses. Copyright © 2017 John Wiley & Sons, Ltd.

  11. The bacterial effector Cif interferes with SCF ubiquitin ligase function by inhibiting deneddylation of Cullin1.

    PubMed

    Morikawa, Hanako; Kim, Minsoo; Mimuro, Hitomi; Punginelli, Claire; Koyama, Tomohiro; Nagai, Shinya; Miyawaki, Atsushi; Iwai, Kazuhiro; Sasakawa, Chihiro

    2010-10-15

    Cycle inhibiting factor (Cif) is one of the effectors delivered into epithelial cells by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC) via the type III secretion system (TTSS). Cif family proteins, which inhibit host cell-cycle progression via mechanisms not yet precisely understood, are highly conserved among EPEC, EHEC, Yersinia pseudotuberculosis, Photorhabdus luminescens and Burkholderia pseudomallei. Levels of several proteins relevant to cell-cycle progression are modulated by Cullin-RING ligases (CRLs), which in turn are activated by conjugation and deconjugation of NEDD8 to Cullins. Here we show that Cif interacts with NEDD8 and interferes with SCF (Skp1-Cullin1-F-box protein) complex ubiquitin ligase function. We found that neddylated Cullin family proteins accumulated and ubiquitination of p27 decreased in cells infected with EPEC. Consequently, Cif stabilized SCF substrates such as CyclinD1, Cdt1, and p27, and caused G1 cell-cycle arrest. Using time-lapse-imaging of fluorescent ubiquitination-based cell-cycle indicator (Fucci)-expressing cells, we were able to monitor cell-cycle progression during EPEC infection and confirmed the arrest of infected cells at G1. Our in vitro and in vivo data show that Cif-NEDD8 interaction inhibits deneddylation of Cullins, suppresses CRL activity and induces G1 arrest. We thus conclude that the bacterial effector Cif interferes with neddylation-mediated cell-cycle control.

  12. Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies.

    PubMed

    Calpe, Silvia; Wagner, Koen; El Khattabi, Mohamed; Rutten, Lucy; Zimberlin, Cheryl; Dolk, Edward; Verrips, C Theo; Medema, Jan Paul; Spits, Hergen; Krishnadath, Kausilia K

    2015-11-01

    Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4(+) malignancies.

  13. Reconstruction of the unknown optimization cost functions from experimental recordings during static multi-finger prehension.

    PubMed

    Niu, Xun; Terekhov, Alexander V; Latash, Mark L; Zatsiorsky, Vladimir M

    2012-04-01

    The goal of the research is to reconstruct the unknown cost (objective) function(s) presumably used by the neural controller for sharing the total force among individual fingers in multifinger prehension. The cost function was determined from experimental data by applying the recently developed Analytical Inverse Optimization (ANIO) method (Terekhov et al. 2010). The core of the ANIO method is the Theorem of Uniqueness that specifies conditions for unique (with some restrictions) estimation of the objective functions. In the experiment, subjects (n = 8) grasped an instrumented handle and maintained it at rest in the air with various external torques, loads, and target grasping forces applied to the object. The experimental data recorded from 80 trials showed a tendency to lie on a 2-dimensional hyperplane in the 4-dimensional finger-force space. Because the constraints in each trial were different, such a propensity is a manifestation of a neural mechanism (not the task mechanics). In agreement with the Lagrange principle for the inverse optimization, the plane of experimental observations was close to the plane resulting from the direct optimization. The latter plane was determined using the ANIO method. The unknown cost function was reconstructed successfully for each performer, as well as for the group data. The cost functions were found to be quadratic with nonzero linear terms. The cost functions obtained with the ANIO method yielded more accurate results than other optimization methods. The ANIO method has an evident potential for addressing the problem of optimization in motor control.

  14. Optimization of the acoustic absorption coefficients of certain functional absorbents

    NASA Technical Reports Server (NTRS)

    Pocsa, V.; Biborosch, L.; Veres, A.; Halpert, E.; Lorian, R.; Botos, T.

    1974-01-01

    The sound absorption coefficients of some functional absorbents (mineral wool plates) are determined by the reverberation chamber method. The influence of the angle of inclination of the sound absorbing material with respect to the surface to be treated is analyzed as well as the influence of the covering index, defined as the ratio of the designed area of a plate and the area of the treated surface belonging to another plate. As compared with the conventional method of applying sound-absorbing plates, the analyzed structures have a higher technological and economical efficiency. The optimum structure corresponds to an angle of inclination of 15 deg and a covering index of 0.8.

  15. The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions*

    PubMed Central

    Dyer, Douglas P.; Salanga, Catherina L.; Johns, Scott C.; Valdambrini, Elena; Fuster, Mark M.; Milner, Caroline M.; Day, Anthony J.; Handel, Tracy M.

    2016-01-01

    TNF-stimulated gene-6 (TSG-6) is a multifunctional protein secreted in response to pro-inflammatory stimuli by a wide range of cells, including neutrophils, monocytes, and endothelial cells. It has been shown to mediate anti-inflammatory and protective effects when administered in disease models, in part, by reducing neutrophil infiltration. Human TSG-6 inhibits neutrophil migration by binding CXCL8 through its Link module (Link_TSG6) and interfering with the presentation of CXCL8 on cell-surface glycosaminoglycans (GAGs), an interaction that is vital for the function of many chemokines. TSG-6 was also found to interact with chemokines CXCL11 and CCL5, suggesting the possibility that it may function as a broad specificity chemokine-binding protein, functionally similar to those encoded by viruses. This study was therefore undertaken to explore the ability of TSG-6 to regulate the function of other chemokines. Herein, we demonstrate that Link_TSG6 binds chemokines from both the CXC and CC families, including CXCL4, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21, and CCL27. We also show that the Link_TSG6-binding sites on chemokines overlap with chemokine GAG-binding sites, and that the affinities of Link_TSG6 for these chemokines (KD values 1–85 nm) broadly correlate with chemokine-GAG affinities. Link_TSG6 also inhibits chemokine presentation on endothelial cells not only through a direct interaction with chemokines but also by binding and therefore masking the availability of GAGs. Along with previous work, these findings suggest that TSG-6 functions as a pluripotent regulator of chemokines by modulating chemokine/GAG interactions, which may be a major mechanism by which TSG-6 produces its anti-inflammatory effects in vivo. PMID:27044744

  16. Computer modelling of antifolate inhibition of folate metabolism using hybrid functional petri nets.

    PubMed

    Assaraf, Yehuda G; Ifergan, Ilan; Kadry, Wisam N; Pinter, Ron Y

    2006-06-21

    Antifolates are used in the treatment of various human malignancies and exert their cytotoxic activity by inhibiting folate-dependent enzymes resulting in disruption of DNA synthesis and cell death. Here we devised a computerized hybrid functional petri nets (HFPN) modelling of folate metabolism under physiological and antifolate inhibitory conditions. This HFPN modelling proved valid as a good agreement was found between the simulated steady-state concentrations of various reduced folates and those published for cell extracts; consistently, the simulation derived total folate pool size (11.3 microM) was identical to that published for cell extracts. In silico experiments were conducted to characterize the inhibitory profile of four distinct antifolates including methotrexate (MTX), tomudex, and LY309887, which inhibit dihydrofolate reductase (DHFR), thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTFase), respectively, as well as pemetrexed which has the capacity to inhibit all three enzymes. In order to assess the inhibitory activity of antifolates on purines and pyrimidines, the biosynthesis rates of IMP (20.53 microM/min) and dTMP (23.8 microM/min) were first simulated. Whereas the biochemical inhibitory profile of MTX was characterized by increased dihydrofolate and decreased tetrahydrofolate (THF) concentrations, the remaining antifolates did not decrease THF levels. Furthermore, MTX was 766- and 10-fold more potent in decreasing the production rates of IMP and dTMP, respectively, than pemetrexed. LY309887 indirectly decreased the rate of dTMP production by reducing the levels of 5-CH2-THF, a folate cofactor for TS. Surprisingly, pemetrexed failed to inhibit DHFR even at high concentrations. This HFPN-based simulation offers an inexpensive, user-friendly, rapid and reliable means of pre-clinical evaluation of the inhibitory profiles of antifolates.

  17. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.

    PubMed

    Báez-Santos, Yahira M; St John, Sarah E; Mesecar, Andrew D

    2015-03-01

    Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of

  18. Hyperthermia inhibits platelet haemostatic functions and selectively regulates the release of alpha-granule proteins

    PubMed Central

    Etulain, J; Lapponi, MJ; Patrucchi, SJ; Romaniuk, MA; Benzadón, R; Klement, GL; Negrotto, S; Schattner, M

    2011-01-01

    Summary Background Hyperthermia is one of the main disturbances of homeostasis occurring during sepsis or hypermetabolic states such as cancer. Platelets are important mediators of the inflammation that accompany these processes, but very little is known about the changes in platelet function that occur at different temperatures. Objectives To explore the effect of higher temperatures on platelet physiology. Methods Platelet responses including adhesion, spreading (fluorescence microscopy), αIIbbeta;3 activation (flow cytometry), aggregation (turbidimetry), ATP release (luminescence), thromboxane A2 generation, alpha-granule protein secretion (ELISA), and protein phosphorylation from different signaling pathways (immunoblotting) were studied. Results Preincubation of platelets at temperatures higher than 37°C (38.5°–42°C) inhibited thrombin-induced haemostasis including platelet adhesion, aggregation, ATP release, and thromboxane A2 generation. The expression of P-selectin and CD63, as well as vascular endothelial growth factor (VEGF) release were completely inhibited by hyperthermia, whereas von Willebrand factor (vWF) and endostatin levels remained substantially increased at high temperatures. This suggested that release of proteins from platelet granules is modulated not only by classical platelet agonists but also by microenvironmental factors. The observed gradation of response involved not only antiangiogenesis regulators, but also other cargo proteins. Some signaling pathways were more stable than others. While ERK1/2 and AKT phosphorylation were resistant to changes in temperature, Src, Syk, p38 phosphorylation as well as IkappaB degradation were decreased in a temperature-dependent fashion. Conclusions Higher temperatures, such as those observed with fever or tissue invasion, inhibit the haemostatic functions of platelets and selectively regulate the release of alpha-granule proteins. PMID:21649851

  19. Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme.

    PubMed

    Matteucci, E; Giampietro, O

    2009-01-01

    Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions are largely unknown. Protein dimerisation should be required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturation-differentiation is well-established. Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offers a new potential therapeutic approach for type 2 diabetes mellitus, as monotherapy and adjunct therapy to other oral agents. The clinical use of presently available orally active inhibitors of DPP4, however, has been associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Indeed, it is noteworthy that CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder. All-cause infections were increased after sitagliptin treatment. It is noteworthy that the effects of DPP4 inhibition on the immune system have not been extensively investigated. So far, only routine laboratory safety variables have been measured in published randomised controlled trials. The review summarises present knowledge in the field and suggests some potential directions of future research.

  20. Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function.

    PubMed

    Del Mare, Sara; Aqeilan, Rami I

    2015-08-10

    Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases' seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

  1. Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

    PubMed Central

    Del Mare, Sara; Aqeilan, Rami I.

    2015-01-01

    Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases’ seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease. PMID:26256646

  2. Endothelial-specific inhibition of NF-κB enhances functional haematopoiesis

    PubMed Central

    Poulos, Michael G.; Ramalingam, Pradeep; Gutkin, Michael C.; Kleppe, Maria; Ginsberg, Michael; Crowley, Michael J. P.; Elemento, Olivier; Levine, Ross L.; Rafii, Shahin; Kitajewski, Jan; Greenblatt, Matthew B.; Shim, Jae-Hyuck; Butler, Jason M.

    2016-01-01

    Haematopoietic stem cells (HSCs) reside in distinct niches within the bone marrow (BM) microenvironment, comprised of endothelial cells (ECs) and tightly associated perivascular constituents that regulate haematopoiesis through the expression of paracrine factors. Here we report that the canonical NF-κB pathway in the BM vascular niche is a critical signalling axis that regulates HSC function at steady state and following myelosuppressive insult, in which inhibition of EC NF-κB promotes improved HSC function and pan-haematopoietic recovery. Mice expressing an endothelial-specific dominant negative IκBα cassette under the Tie2 promoter display a marked increase in HSC activity and self-renewal, while promoting the accelerated recovery of haematopoiesis following myelosuppression, in part through protection of the BM microenvironment following radiation and chemotherapeutic-induced insult. Moreover, transplantation of NF-κB-inhibited BM ECs enhanced haematopoietic recovery and protected mice from pancytopenia-induced death. These findings pave the way for development of niche-specific cellular approaches for the treatment of haematological disorders requiring myelosuppressive regimens. PMID:28000664

  3. Electrochemical evidence of self-substrate inhibition as functions regulation for cellobiose dehydrogenase from Phanerochaete chrysosporium.

    PubMed

    Stoica, Leonard; Ruzgas, Tautgirdas; Gorton, Lo

    2009-09-01

    The reaction mechanism of cellobiose dehydrogenase (CDH) from Phanerochaete chrysosporium, adsorbed on graphite electrodes, was investigated by following its catalytic reaction with cellobiose registered in both direct and mediated electron transfer modes between the enzyme and the electrode. A wall-jet flow through amperometric cell housing the CDH-modified graphite electrode was connected to a single line flow injection system. In the present study, it is proven that cellobiose, at concentrations higher than 200 microM, competes for the reduced state of the FAD cofactor and it slows down the transfer of electrons to any 2e(-)/H(+) acceptors or further to the heme cofactor, via the internal electron transfer pathway. Based on and proven by electrochemical results, a kinetic model of substrate inhibition is proposed and supported by the agreement between simulation of plots and experimental data. The implications of this kinetic model, called pseudo-ping-pong mechanism, on the possible functions CDH are also discussed. The enzyme exhibits catalytic activity also for lactose, but in contrast to cellobiose, this sugar does not inhibit the enzyme. This suggests that even if some other substrates are coincidentally oxidized by CDH, however, they do not trigger all the possible natural functions of the enzyme. In this respect, cellobiose is regarded as the natural substrate of CDH.

  4. Pathogenic Acinetobacter Species have a Functional Type I Secretion System and Contact-Dependent Inhibition Systems.

    PubMed

    Harding, Christian M; Pulido, Marina R; Di Venanzio, Gisela; Kinsella, Rachel L; Webb, Andrew I; Scott, Nichollas E; Pachón, Jerónimo; Feldman, Mario F

    2017-04-03

    Pathogenic Acinetobacter species, including A. baumannii and A. nosocomialis, are opportunistic human pathogens of increasing relevance worldwide. Although their mechanisms of drug resistance are well studied, the virulence factors that govern Acinetobacter pathogenesis are incompletely characterized. Here we define the complete secretome of A. nosocomialis strain M2 in minimal media and demonstrate that pathogenic Acinetobacter species produce both a functional type I secretion system (T1SS) and a contact dependent inhibition (CDI) system. Using bioinformatics, quantitative proteomics, and mutational analyses we show that Acinetobacter uses its T1SS for exporting two putative T1SS effectors, an RTX-Serralysin-like toxin and the biofilm associated protein (Bap). Moreover, we found that mutation of any component of the T1SS system abrogated type VI secretion activity under nutrient-limited conditions, indicating a previously unrecognized crosstalk between these two systems. We also demonstrate that the Acinetobacter T1SS is required for biofilm formation. Lastly, we show that both A. nosocomialis and A. baumannii produce functioning CDI systems that mediate growth inhibition of sister cells lacking the cognate immunity protein. The Acinetobacter CDI systems are widely distributed across pathogenic Acinetobacter species, with many A. baumannii isolates harboring two distinct CDI systems. Collectively, these data demonstrate the power of differential, quantitative proteomics approaches to study secreted proteins, define the role of previously uncharacterized protein export systems, and observe crosstalk between secretion systems in the pathobiology of medically relevant Acinetobacter The data are available via ProteomeXchange with identifier PXD005881.

  5. Inhibition of IRF8 Negatively Regulates Macrophage Function and Impairs Cutaneous Wound Healing.

    PubMed

    Guo, Yuanyuan; Yang, Zhiyin; Wu, Shan; Xu, Peng; Peng, Yinbo; Yao, Min

    2017-02-01

    The inflammatory response is essential for normal cutaneous wound healing. Macrophages, as critical inflammatory cells, coordinate inflammation and angiogenesis phases during wound healing. It has been reported that the transcription factor interferon regulatory factor 8 (IRF8), a member of the IRF family, plays a critical role in the development and function of macrophages and is associated with inflammation. However, the role of IRF8 in cutaneous wound healing and its underlying mechanism remain elusive. Through immunohistochemical (IHC) staining, we showed that IRF8 is involved in the wound repair process in mice and patients. Furthermore, we ascertain that the repression of IRF8 by small interfering RNA (siRNA) leads to delayed wound healing. To explore the mechanism by which IRF8 impacts wound healing, we observed its effect on macrophage-related mediators by IHC or real-time PCR. The results demonstrated that the inhibition of IRF8 decreases the mRNA expression of inflammatory mediators associated with M1 macrophage (il-1b, il-6, inos, and tnf-a) but no impact on M2 macrophage-related mediators (arg-1, mrc-1, and il-10) and the number of macrophages in the wounds. Furthermore, the inhibition of IRF8 induced apoptosis in the wounds. In summary, this study demonstrates that the down-regulation of IRF8 in the wound leads to impaired wound healing possibly through the regulation of macrophage function and apoptosis in skin wound.

  6. A Functional Gradient in the Rodent Prefrontal Cortex Supports Behavioral Inhibition.

    PubMed

    Hardung, Stefanie; Epple, Robert; Jäckel, Zoe; Eriksson, David; Uran, Cem; Senn, Verena; Gibor, Lihi; Yizhar, Ofer; Diester, Ilka

    2017-02-20

    The ability to plan and execute appropriately timed responses to external stimuli is based on a well-orchestrated balance between movement initiation and inhibition. In impulse control disorders involving the prefrontal cortex (PFC) [1], this balance is disturbed, emphasizing the critical role that PFC plays in appropriately timing actions [2-4]. Here, we employed optogenetic and electrophysiological techniques to systematically analyze the functional role of five key subareas of the rat medial PFC (mPFC) and orbitofrontal cortex (OFC) in action control [5-9]. Inactivation of mPFC subareas induced drastic changes in performance, namely an increase (prelimbic cortex, PL) or decrease (infralimbic cortex, IL) of premature responses. Additionally, electrophysiology revealed a significant decrease in neuronal activity of a PL subpopulation prior to premature responses. In contrast, inhibition of OFC subareas (mainly the ventral OFC, i.e., VO) significantly impaired the ability to respond rapidly after external cues. Consistent with these findings, mPFC activity during response preparation predicted trial outcomes and reaction times significantly better than OFC activity. These data support the concept of opposing roles of IL and PL in directing proactive behavior and argue for an involvement of OFC in predominantly reactive movement control. By attributing defined roles to rodent PFC sections, this study contributes to a deeper understanding of the functional heterogeneity of this brain area and thus may guide medically relevant studies of PFC-associated impulse control disorders in this animal model for neural disorders [10-12].

  7. Tetrahydrolipstatin Inhibition, Functional Analyses, and Three-dimensional Structure of a Lipase Essential for Mycobacterial Viability

    SciTech Connect

    Crellin, Paul K.; Vivian, Julian P.; Scoble, Judith; Chow, Frances M.; West, Nicholas P.; Brammananth, Rajini; Proellocks, Nicholas I.; Shahine, Adam; Le Nours, Jerome; Wilce, Matthew C.J.; Britton, Warwick J.; Coppel, Ross L.; Rossjohn, Jamie; Beddoe, Travis

    2010-09-17

    The highly complex and unique mycobacterial cell wall is critical to the survival of Mycobacteria in host cells. However, the biosynthetic pathways responsible for its synthesis are, in general, incompletely characterized. Rv3802c from Mycobacterium tuberculosis is a partially characterized phospholipase/thioesterase encoded within a genetic cluster dedicated to the synthesis of core structures of the mycobacterial cell wall, including mycolic acids and arabinogalactan. Enzymatic assays performed with purified recombinant proteins Rv3802c and its close homologs from Mycobacterium smegmatis (MSMEG{_}6394) and Corynebacterium glutamicum (NCgl2775) show that they all have significant lipase activities that are inhibited by tetrahydrolipstatin, an anti-obesity drug that coincidently inhibits mycobacterial cell wall biosynthesis. The crystal structure of MSMEG{_}6394, solved to 2.9 {angstrom} resolution, revealed an {alpha}/{beta} hydrolase fold and a catalytic triad typically present in esterases and lipases. Furthermore, we demonstrate direct evidence of gene essentiality in M. smegmatis and show the structural consequences of loss of MSMEG{_}6394 function on the cellular integrity of the organism. These findings, combined with the predicted essentiality of Rv3802c in M. tuberculosis, indicate that the Rv3802c family performs a fundamental and indispensable lipase-associated function in mycobacteria.

  8. Housefly larvae hydrolysate: orthogonal optimization of hydrolysis, antioxidant activity, amino acid composition and functional properties

    PubMed Central

    2013-01-01

    Background Antioxidant, one of the most important food additives, is widely used in food industry. At present, antioxidant is mostly produced by chemical synthesis, which would accumulate to be pathogenic. Therefore, a great interest has been developed to identify and use natural antioxidants. It was showed that there are a lot of antioxidative peptides in protein hydrolysates, possessing strong capacity of inhibiting peroxidation of macro-biomolecular and scavenging free redicals in vivo. Enzymatic hydrolysis used for preparation of antioxidative peptides is a new hot-spot in the field of natural antioxidants. It reacts under mild conditions, with accurate site-specific degradation, good repeatability and few damages to biological activity of protein. Substrates for enzymatic hydrolysis are usually plants and aqua-animals. Insects are also gaining attention because of their rich protein and resource. Antioxidative peptides are potential to be exploited as new natural antioxidant and functional food. There is a huge potential market in medical and cosmetic field as well. Result Protein hydrolysate with antioxidant activity was prepared from housefly larvae, by a two-step hydrolysis. Through orthogonal optimization of the hydrolysis conditions, the degree of hydrolysis was determined to be approximately 60%. Fractionated hydrolysate at 25 mg/mL, 2.5 mg/mL and 1 mg/mL exhibited approximately 50%, 60% and 50% of scavenging capacity on superoxide radicals, 1, 1-Diphenyl-2-picrylhydrazyl radicals and hydroxyl radicals, respectively. Hydrolysate did not exhibit substantial ion chelation. Using a linoneic peroxidation system, the inhibition activity of hydrolysate at 20 mg/mL was close to that of 20 μg/mL tertiary butylhydroquinone, suggesting a potential application of hydrolysate in the oil industry as an efficient antioxidant. The lyophilized hydrolysate presented almost 100% solubility at pH 3-pH 9, and maintained nearly 100% activity at pH 5-pH 8 at 0

  9. A technique for locating function roots and for satisfying equality constraints in optimization

    NASA Technical Reports Server (NTRS)

    Sobieszczanski-Sobieski, Jaroslaw

    1991-01-01

    A new technique for locating simultaneous roots of a set of functions is described. The technique is based on the property of the Kreisselmeier-Steinhauser function which descends to a minimum at each root location. It is shown that the ensuing algorithm may be merged into any nonlinear programming method for solving optimization problems with equality constraints.

  10. A technique for locating function roots and for satisfying equality constraints in optimization

    NASA Technical Reports Server (NTRS)

    Sobieszczanski-Sobieski, J.

    1992-01-01

    A new technique for locating simultaneous roots of a set of functions is described. The technique is based on the property of the Kreisselmeier-Steinhauser function which descends to a minimum at each root location. It is shown that the ensuing algorithm may be merged into any nonlinear programming method for solving optimization problems with equality constraints.

  11. Perceptually optimized gain function for cochlear implant signal-to-noise ratio based noise reduction.

    PubMed

    Mauger, Stefan J; Dawson, Pam W; Hersbach, Adam A

    2012-01-01

    Noise reduction in cochlear implants has achieved significant speech perception improvements through spectral subtraction and signal-to-noise ratio based noise reduction techniques. Current methods use gain functions derived through mathematical optimization or motivated by normal listening psychoacoustic experiments. Although these gain functions have been able to improve speech perception, recent studies have indicated that they are not optimal for cochlear implant noise reduction. This study systematically investigates cochlear implant recipients' speech perception and listening preference of noise reduction with a range of gain functions. Results suggest an advantageous gain function and show that gain functions currently used for noise reduction are not optimal for cochlear implant recipients. Using the cochlear implant optimised gain function, a 27% improvement over the current advanced combination encoder (ACE) stimulation strategy in speech weighted noise and a 7% improvement over current noise reduction strategies were observed in babble noise conditions. The optimized gain function was also most preferred by cochlear implant recipients. The CI specific gain function derived from this study can be easily incorporated into existing noise reduction strategies, to further improve listening performance for CI recipients in challenging environments.

  12. Admitting the Inadmissible: Adjoint Formulation for Incomplete Cost Functionals in Aerodynamic Optimization

    NASA Technical Reports Server (NTRS)

    Arian, Eyal; Salas, Manuel D.

    1997-01-01

    We derive the adjoint equations for problems in aerodynamic optimization which are improperly considered as "inadmissible." For example, a cost functional which depends on the density, rather than on the pressure, is considered "inadmissible" for an optimization problem governed by the Euler equations. We show that for such problems additional terms should be included in the Lagrangian functional when deriving the adjoint equations. These terms are obtained from the restriction of the interior PDE to the control surface. Demonstrations of the explicit derivation of the adjoint equations for "inadmissible" cost functionals are given for the potential, Euler, and Navier-Stokes equations.

  13. Optimizing high performance computing workflow for protein functional annotation.

    PubMed

    Stanberry, Larissa; Rekepalli, Bhanu; Liu, Yuan; Giblock, Paul; Higdon, Roger; Montague, Elizabeth; Broomall, William; Kolker, Natali; Kolker, Eugene

    2014-09-10

    Functional annotation of newly sequenced genomes is one of the major challenges in modern biology. With modern sequencing technologies, the protein sequence universe is rapidly expanding. Newly sequenced bacterial genomes alone contain over 7.5 million proteins. The rate of data generation has far surpassed that of protein annotation. The volume of protein data makes manual curation infeasible, whereas a high compute cost limits the utility of existing automated approaches. In this work, we present an improved and optmized automated workflow to enable large-scale protein annotation. The workflow uses high performance computing architectures and a low complexity classification algorithm to assign proteins into existing clusters of orthologous groups of proteins. On the basis of the Position-Specific Iterative Basic Local Alignment Search Tool the algorithm ensures at least 80% specificity and sensitivity of the resulting classifications. The workflow utilizes highly scalable parallel applications for classification and sequence alignment. Using Extreme Science and Engineering Discovery Environment supercomputers, the workflow processed 1,200,000 newly sequenced bacterial proteins. With the rapid expansion of the protein sequence universe, the proposed workflow will enable scientists to annotate big genome data.

  14. Optimization of the functional domain of flat plate collectors

    NASA Astrophysics Data System (ADS)

    Ritoux, G.; Irigaray, J.-L.

    1981-12-01

    The variations of the extracted heat flux as function of the temperature of the heat transfer fluid in black and selective surface solar collectors are examined. The heat flux is calculated based on the difference of the initial to the stage of thermal equilibrium of the fluid. A nonlinear system of equations is developed and solved by a fast, iterative method to obtain the equilibrium temperatures. It is found that more flux can be extracted from the solar heat by a collector with only one glass cover than with more than one cover. The captured flux is proportional to the coefficient of transmission of the glass coverings, to the coefficient of absorption of the collector, and to the incident flux. Black painted surfaces were more absorbent than selective surfaces, and highest collection efficiencies were displayed by low temperature collectors. Charts of effective uses of the respective types of collectors for heating swimming pools, hot water, home heat, and for refrigeration and air-conditioning are provided.

  15. Solvability of some partial functional integrodifferential equations with finite delay and optimal controls in Banach spaces.

    PubMed

    Ezzinbi, Khalil; Ndambomve, Patrice

    2016-01-01

    In this work, we consider the control system governed by some partial functional integrodifferential equations with finite delay in Banach spaces. We assume that the undelayed part admits a resolvent operator in the sense of Grimmer. Firstly, some suitable conditions are established to guarantee the existence and uniqueness of mild solutions for a broad class of partial functional integrodifferential infinite dimensional control systems. Secondly, it is proved that, under generally mild conditions of cost functional, the associated Lagrange problem has an optimal solution, and that for each optimal solution there is a minimizing sequence of the problem that converges to the optimal solution with respect to the trajectory, the control, and the functional in appropriate topologies. Our results extend and complement many other important results in the literature. Finally, a concrete example of application is given to illustrate the effectiveness of our main results.

  16. Processing and optimization of functional ceramic coatings and inorganic nanomaterials

    NASA Astrophysics Data System (ADS)

    Nyutu, Edward Kennedy G.

    Processing of functional inorganic materials including zero (0-D) dimensional (e.g. nanoparticles), 1-D (nanorods, nanofibers), and 2-D (films/coating) structures is of fundamental and technological interest. This research will have two major sections. The first part of section one focuses on the deposition of silicon dioxide onto a pre-deposited molybdenum disilicide coating on molybdenum substrates for both high (>1000 °C) and moderate (500-600 °C) temperature oxidation protection. Chemical vapor deposition (CVD/MOCVD) techniques will be utilized to deposit the metal suicide and oxide coatings. The focus of this study will be to establish optimum deposition conditions and evaluate the metal oxide coating as oxidation - thermal barriers for Mo substrates under both isothermal (static) and cyclic oxidation conditions. The second part of this section will involve a systematic evaluation of a boron nitride (BN) interface coating prepared by chemical vapor deposition. Ceramic matrix composites (CMCs) are prospective candidates for high (>1000 °C) temperature applications and fiber- matrix interfaces are the dominant design parameters in ceramic matrix composites (CMCs). An important goal of the study is to determine a set of process parameters, which would define a boron nitride (BN) interface coating by a chemical vapor deposition (CVD) process with respect to coating. In the first part of the second section, we will investigate a new approach to synthesize ultrafine metal oxides that combines microwave heating and an in-situ ultrasonic mixing of two or more liquid precursors with a tubular flow reactor. Different metal oxides such as nickel ferrite and zinc aluminate spinels will be studied. The synthesis of metal oxides were investigated in order to study the effects of the nozzle and microwave (INM process) on the purity, composition, and particle size of the resulting powders. The second part of this research section involves a study of microwave frequency

  17. Non-linear global optimization via parameterization and inverse function approximation: an artificial neural networks approach.

    PubMed

    Mayorga, René V; Arriaga, Mariano

    2007-10-01

    In this article, a novel technique for non-linear global optimization is presented. The main goal is to find the optimal global solution of non-linear problems avoiding sub-optimal local solutions or inflection points. The proposed technique is based on a two steps concept: properly keep decreasing the value of the objective function, and calculating the corresponding independent variables by approximating its inverse function. The decreasing process can continue even after reaching local minima and, in general, the algorithm stops when converging to solutions near the global minimum. The implementation of the proposed technique by conventional numerical methods may require a considerable computational effort on the approximation of the inverse function. Thus, here a novel Artificial Neural Network (ANN) approach is implemented to reduce the computational requirements of the proposed optimization technique. This approach is successfully tested on some highly non-linear functions possessing several local minima. The results obtained demonstrate that the proposed approach compares favorably over some current conventional numerical (Matlab functions) methods, and other non-conventional (Evolutionary Algorithms, Simulated Annealing) optimization methods.

  18. Extracellular citrullination inhibits the function of matrix associated TGF-β.

    PubMed

    Sipilä, Kalle H; Ranga, Vipin; Rappu, Pekka; Torittu, Annamari; Pirilä, Laura; Käpylä, Jarmo; Johnson, Mark S; Larjava, Hannu; Heino, Jyrki

    2016-09-01

    In inflammatory arthritis peptidyl arginine deiminase (PAD) enzymes can citrullinate arginine residues in extracellular matrix (ECM) proteins, such as collagens and fibronectin. This may lead to the generation of anti-citrullinated protein antibodies, important diagnostic markers in rheumatoid arthritis. In addition, the citrullination may directly affect protein function. Based on structural analysis, we found that most ECM-associated growth factors (GFs) have arginine residues in their receptor recognition sites. Thus, they are potential functional targets of extracellular citrullination. To examine this further, we focused on the citrullination of transforming growth factor-βs (TGF-β), well-known ECM-associated GFs. PAD-treatment of CHO-LTBP1 cell derived matrix, rich with TGF-β, decreased the level of TGF-β activity as detected by HaCaT and MLEC-PAI-1/Lu reporter cells. Additional experiments indicated that PAD-treatment inhibits the integrin-mediated TGF-β activation since PAD-treatment decreased the binding of integrin αVβ6 ectodomain as well as integrin-mediated spreading of MG-63 and HaCaT cells to β1-latency associated peptide (TGF-β1 LAP). The citrullination of the RGD site, an important integrin recognition motif, was confirmed by mass spectrometry. Furthermore, the citrullination of active TGF-β1 inhibited its binding to recombinant TGF-β receptor II, and prevented its ability to activate TGF-β signaling. Thus, extracellular PAD activity can affect the function of ECM-associated growth factors by different mechanisms. Importantly, the citrullination of both latent and active TGF-β has the potency to regulate the inflammatory process.

  19. Inhibition of electron transport chain assembly and function promotes photodynamic killing of Candida

    PubMed Central

    Chabrier-Roselló, Yeissa; Giesselman, Benjamin R.; De Jesús-Andino, Francisco J.; Foster, Thomas H.; Mitra, Soumya; Haidaris, Constantine G.

    2010-01-01

    Respiratory deficiency increases the sensitivity of the pathogenic fungi Candida albicans and C. glabrata to oxidative stress induced by photodynamic therapy (PDT) sensitized by the cationic porphyrin meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP-1363). Since disruption of electron transport chain (ETC) function increases intracellular levels of reactive oxygen species in yeast, we determined whether interference with ETC assembly or function increased sensitivity to TMP-1363-PDT in C. albicans, C. glabrata and the non-pathogenic yeast Saccharomyces cerevisiae. Metabolic inhibitor antimycin A and defined genetic mutants were used to identify ETC components that contribute to the sensitivity to PDT. Inhibition of cytochrome bc1 (Complex III) with antimycin A increases mitochondrial levels of reactive oxygen species. PDT performed following pretreatment with antimycin A reduced colony forming units (CFU) of C. albicans and C. glabrata by approximately two orders of magnitude relative to PDT alone. A S. cerevisiae mitochondrial glutaredoxin grx5 mutant, defective in assembly of Fe-S clusters critical for Complex III function, displayed increased sensitivity to PDT. Furthermore, C. glabrata and S. cerevisiae mutants in cytochrome c oxidase (Complex IV) synthesis and assembly were also significantly more sensitive to PDT. These included suv3, encoding an ATP-dependent RNA helicase critical for maturation of cytochrome c oxidase subunit transcripts, and pet117, encoding an essential cytochrome c oxidase assembly factor. Following PDT, the reduction in CFU of these mutants was one to two orders of magnitude greater than in their respective parental strains. The data demonstrate that selective inhibition of ETC Complexes III and IV significantly increases the sensitivity of C. albicans, C. glabrata and S. cerevisiae to PDT sensitized with TMP-1363. PMID:20381373

  20. Single residue deletions along the length of the influenza HA fusion peptide lead to inhibition of membrane fusion function

    SciTech Connect

    Langley, William A.; Thoennes, Sudha; Bradley, Konrad C.; Galloway, Summer E.; Talekar, Ganesh R.; Cummings, Sandra F.; Vareckova, Eva; Russell, Rupert J.; Steinhauer, David A.

    2009-11-25

    A panel of eight single amino acid deletion mutants was generated within the first 24 residues of the fusion peptide domain of the of the hemagglutinin (HA) of A/Aichi/2/68 influenza A virus (H3N2 subtype). The mutant HAs were analyzed for folding, cell surface transport, cleavage activation, capacity to undergo acid-induced conformational changes, and membrane fusion activity. We found that the mutant DELTAF24, at the C-terminal end of the fusion peptide, was expressed in a non-native conformation, whereas all other deletion mutants were transported to the cell surface and could be cleaved into HA1 and HA2 to activate membrane fusion potential. Furthermore, upon acidification these cleaved HAs were able to undergo the characteristic structural rearrangements that are required for fusion. Despite this, all mutants were inhibited for fusion activity based on two separate assays. The results indicate that the mutant fusion peptide domains associate with target membranes in a non-functional fashion, and suggest that structural features along the length of the fusion peptide are likely to be relevant for optimal membrane fusion activity.

  1. fMRI of Cocaine Self-Administration in Macaques Reveals Functional Inhibition of Basal Ganglia

    PubMed Central

    Mandeville, Joseph B; Choi, Ji-Kyung; Jarraya, Bechir; Rosen, Bruce R; Jenkins, Bruce G; Vanduffel, Wim

    2011-01-01

    Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion. PMID:21307843

  2. Mechanistic Insight into the Host Transcription Inhibition Function of Rift Valley Fever Virus NSs and Its Importance in Virulence.

    PubMed

    Terasaki, Kaori; Ramirez, Sydney I; Makino, Shinji

    2016-10-01

    Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear. To examine this, we generated two RVFV MP-12 strain-derived mutant viruses. Each carried mutations in NSs that specifically targeted its general transcription inhibition function without affecting its ability to degrade PKR and inhibit IFN-β promoter induction, through its interaction with Sin3-associated protein 30, a part of the repressor complex at the IFN-β promoter. Using these mutant viruses, we have dissected the transcription inhibition function of NSs and examined its importance in RVFV virulence. Both NSs mutant viruses exhibited a differentially impaired ability to inhibit host transcription when compared with MP-12. It has been reported that NSs suppresses general transcription by interfering with the formation of the transcription factor IIH complex, through the degradation of the p62 subunit and sequestration of the p44 subunit. Our study results lead us to suggest that the ability of NSs to induce p62 degradation is the major contributor to its general transcription inhibition property, whereas its interaction with p44 may not play a significant role in this function. Importantly, RVFV MP-12-NSs mutant viruses with an impaired general transcription inhibition function showed a reduced cytotoxicity in cell culture and attenuated virulence in young mice

  3. Mechanistic Insight into the Host Transcription Inhibition Function of Rift Valley Fever Virus NSs and Its Importance in Virulence

    PubMed Central

    Terasaki, Kaori; Ramirez, Sydney I.; Makino, Shinji

    2016-01-01

    Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear. To examine this, we generated two RVFV MP-12 strain-derived mutant viruses. Each carried mutations in NSs that specifically targeted its general transcription inhibition function without affecting its ability to degrade PKR and inhibit IFN-β promoter induction, through its interaction with Sin3-associated protein 30, a part of the repressor complex at the IFN-β promoter. Using these mutant viruses, we have dissected the transcription inhibition function of NSs and examined its importance in RVFV virulence. Both NSs mutant viruses exhibited a differentially impaired ability to inhibit host transcription when compared with MP-12. It has been reported that NSs suppresses general transcription by interfering with the formation of the transcription factor IIH complex, through the degradation of the p62 subunit and sequestration of the p44 subunit. Our study results lead us to suggest that the ability of NSs to induce p62 degradation is the major contributor to its general transcription inhibition property, whereas its interaction with p44 may not play a significant role in this function. Importantly, RVFV MP-12-NSs mutant viruses with an impaired general transcription inhibition function showed a reduced cytotoxicity in cell culture and attenuated virulence in young mice

  4. A Complex-Valued Projection Neural Network for Constrained Optimization of Real Functions in Complex Variables.

    PubMed

    Zhang, Songchuan; Xia, Youshen; Wang, Jun

    2015-12-01

    In this paper, we present a complex-valued projection neural network for solving constrained convex optimization problems of real functions with complex variables, as an extension of real-valued projection neural networks. Theoretically, by developing results on complex-valued optimization techniques, we prove that the complex-valued projection neural network is globally stable and convergent to the optimal solution. Obtained results are completely established in the complex domain and thus significantly generalize existing results of the real-valued projection neural networks. Numerical simulations are presented to confirm the obtained results and effectiveness of the proposed complex-valued projection neural network.

  5. Glycoxidized HDL, HDL enriched with oxidized phospholipids and HDL from diabetic patients inhibit platelet function

    PubMed Central

    Lê, Quang Huy; El Alaoui, Meddy; Véricel, Evelyne; Ségrestin, Bérénice; Soulère, Laurent; Guichardant, Michel; Lagarde, Michel; Moulin, Philippe; Calzada, Catherine

    2015-01-01

    Context High-density lipoproteins (HDL) possess atheroprotective properties including anti-thrombotic and antioxidant effects. Very few studies relate to the functional effects of oxidized HDL on platelets in type 2 diabetes (T2D). Objective The objective of our study was to investigate the effects of in vitro glycoxidized HDL, and HDL from T2D patients on platelet aggregation and arachidonic acid signaling cascade. At the same time, the contents of hydroxylated fatty acids were assessed in HDL. Results Compared to control HDL, in vitro glycoxidized HDL had decreased proportions of linoleic (LA) and arachidonic (AA) acids in phospholipids and cholesteryl esters, and increased concentrations of hydroxy-octadecadienoic acids (9-HODE and 13-HODE) and 15-hydroxy-eicosatetraenoic acid (15-HETE), derived from LA and AA respectively, especially hydroxy derivatives esterified in phospholipids. Glycoxidized HDL dose-dependently decreased collagen-induced platelet aggregation by binding to SR-BI. Glycoxidized HDL prevented collagen-induced increased phosphorylation of platelet p38 MAPK and cytosolic phospholipase A2, as well as intracellular calcium mobilization. HDL enriched with oxidized phospholipids, namely PC(16:0/13-HODE) dose-dependently inhibited platelet aggregation. Increased concentrations of 9-HODE, 13-HODE and 15-HETE in phospholipids (2.1, 2.1 and 2.4-fold increase respectively) were found in HDL from patients with T2D, and these HDL also inhibited platelet aggregation via SR-BI. Conclusions Altogether, our results indicate that in vitro glycoxidized HDL as well as HDL from T2D patients inhibit platelet aggregation, and suggest that oxidized LA-containing phospholipids may contribute to the anti-aggregatory effects of glycoxidized HDL and HDL from T2D patients. PMID:25794249

  6. Pycnogenol Ameliorates Asthmatic Airway Inflammation and Inhibits the Function of Goblet Cells.

    PubMed

    Liu, Zhaoe; Han, Bo; Chen, Xing; Wu, Qiaoling; Wang, Lijun; Li, Gang

    2016-11-01

    Pycnogenol(®) (PYC) is utilized in the treatment of various diseases ranging from chronic inflammation to circulatory diseases, but its efficacy and functional mechanism in pediatric asthma continue to remain obscure. Therefore, the purpose of this study was to investigate the effectiveness and molecular mechanism of PYC on regulation of asthmatic airway inflammation. We found that PYC with tail intravenous injection of 50 mg/kg or intragastric administration of 100 mg/kg all reduced ovalbumin (OVA)-induced airway injury. Pharmacokinetics of PYC was evaluated by high-performance liquid chromatography assay, indicating that PYC was quickly absorbed into the blood after intragastric administration, and PYC metabolism was later improved gradually with increase of time after PYC administration. PYC has a higher bioavailability of 71.96%, and it was more easily absorbed by the body. PYC inhibited the number of total inflammatory cells and levels of interleukin (IL)-4, IL-5, IL-9, and IL-13 in bronchoalveolar lavage fluid of OVA-induced mice. PYC inhibited IL-13 secretion from the Th2 cells, thereby causing a reduction in expression of the signaling molecules in JAK/STAT6 pathway in airway epithelial cells. STAT6 silence suppressed IL-13-increased acetylcholine level. STAT6 overexpression promoted expression of goblet cell metaplasia-associated molecules (FOXA3, SPDEF, and Muc5ac). PYC suppressed OVA-induced expression of FOXA3, SPDEF, and Muc5ac in lung. Our findings indicate that PYC has a higher bioavailability and it prevents emergence of OVA-induced airway injury and airway inflammation in mice by inhibiting IL-13/JAK/STAT6 pathway and blocking release of acetylcholine to reduce goblet cell metaplasia.

  7. Environmental contaminants perturb fragile protein assemblies and inhibit normal protein function.

    PubMed

    Lawrence, Sarah H; Selwood, Trevor; Jaffe, Eileen K

    2013-01-01

    The molecular mechanisms whereby small molecules that contaminate our environment cause physiological effects are largely unknown, in terms of both targets and mechanisms. The essential human enzyme porphobilinogen synthase (HsPBGS, a.k.a. 5-aminolevulinate dehydratase, ALAD) functions in heme biosynthesis. HsPBGS catalytic activity is regulated allosterically via an equilibrium of inactive hexamers and active octamers, and we have shown that certain drugs and drug-like small molecules can inhibit HsPBGS in vitro by stabilizing the hexamer. Here we address whether components of the National Toxicology Program library of environmental contaminants can stabilize the HsPBGS hexamer and inhibit activity in vitro. Native polyacrylamide gel electrophoresis was used to screen the library (1,408 compounds) for components that alter the oligomeric distribution of HsPBGS. Freshly purchased samples of 37 preliminary hits were used to confirm the electrophoretic results and to determine the dose-dependence of the perturbation of oligomeric distribution. Seventeen compounds were identified which alter the oligomeric distribution toward the hexamer and also inhibit HsPBGS catalytic activity, including the most potent HsPBGS inhibitor yet characterized (Mutagen X, IC50 = 1.4 μM). PBGS dysfunction is associated with the inborn error of metabolism know as ALAD porphyria and with lead poisoning. The identified hexamer-stabilizing inhibitors could potentiate these diseases. Allosteric regulation of activity via an equilibrium of alternate oligomers has been proposed for many proteins. Based on the precedent set herein, perturbation of these oligomeric equilibria by small molecules (such as environmental contaminants) can be considered as a mechanism of toxicity.

  8. Functional networks of motor inhibition in conversion disorder patients and feigning subjects.

    PubMed

    Hassa, Thomas; de Jel, Esther; Tuescher, Oliver; Schmidt, Roger; Schoenfeld, Mircea Ariel

    2016-01-01

    The neural correlates of motor inhibition leading to paresis in conversion disorder are not well known. The key question is whether they are different of those of normal subjects feigning the symptoms. Thirteen conversion disorder patients with hemiparesis and twelve healthy controls were investigated using functional magnetic resonance tomography under conditions of passive motor stimulation of the paretic/feigned paretic and the non-paretic hand. Healthy controls were also investigated in a non-feigning condition. During passive movement of the affected right hand conversion disorder patients exhibited activations in the bilateral triangular part of the inferior frontal gyri (IFG), with a left side dominance compared to controls in non-feigning condition. Feigning controls revealed for the same condition a weak unilateral activation in the right triangular part of IFG and an activity decrease in frontal midline areas, which couldn't be observed in patients. The results suggest that motor inhibition in conversion disorder patients is mediated by the IFG that was also involved in inhibition processes in normal subjects. The activity pattern in feigning controls resembled that of conversion disorder patients but with a clear difference in the medial prefrontal cortex. Healthy controls showed decreased activity in this region during feigning compared to non-feigning conditions suggesting a reduced sense of self-agency during feigning. Remarkably, no activity differences could be observed in medial prefrontal cortex for patients vs healthy controls in feigning or non-feigning conditions suggesting self-agency related activity in patients to be in between those of non-feigning and feigning healthy subjects.

  9. Evidence for Composite Cost Functions in Arm Movement Planning: An Inverse Optimal Control Approach

    PubMed Central

    Berret, Bastien; Chiovetto, Enrico; Nori, Francesco; Pozzo, Thierry

    2011-01-01

    An important issue in motor control is understanding the basic principles underlying the accomplishment of natural movements. According to optimal control theory, the problem can be stated in these terms: what cost function do we optimize to coordinate the many more degrees of freedom than necessary to fulfill a specific motor goal? This question has not received a final answer yet, since what is optimized partly depends on the requirements of the task. Many cost functions were proposed in the past, and most of them were found to be in agreement with experimental data. Therefore, the actual principles on which the brain relies to achieve a certain motor behavior are still unclear. Existing results might suggest that movements are not the results of the minimization of single but rather of composite cost functions. In order to better clarify this last point, we consider an innovative experimental paradigm characterized by arm reaching with target redundancy. Within this framework, we make use of an inverse optimal control technique to automatically infer the (combination of) optimality criteria that best fit the experimental data. Results show that the subjects exhibited a consistent behavior during each experimental condition, even though the target point was not prescribed in advance. Inverse and direct optimal control together reveal that the average arm trajectories were best replicated when optimizing the combination of two cost functions, nominally a mix between the absolute work of torques and the integrated squared joint acceleration. Our results thus support the cost combination hypothesis and demonstrate that the recorded movements were closely linked to the combination of two complementary functions related to mechanical energy expenditure and joint-level smoothness. PMID:22022242

  10. Comparison of penalty functions on a penalty approach to mixed-integer optimization

    NASA Astrophysics Data System (ADS)

    Francisco, Rogério B.; Costa, M. Fernanda P.; Rocha, Ana Maria A. C.; Fernandes, Edite M. G. P.

    2016-06-01

    In this paper, we present a comparative study involving several penalty functions that can be used in a penalty approach for globally solving bound mixed-integer nonlinear programming (bMIMLP) problems. The penalty approach relies on a continuous reformulation of the bMINLP problem by adding a particular penalty term to the objective function. A penalty function based on the `erf' function is proposed. The continuous nonlinear optimization problems are sequentially solved by the population-based firefly algorithm. Preliminary numerical experiments are carried out in order to analyze the quality of the produced solutions, when compared with other penalty functions available in the literature.

  11. Overexpression of Arabidopsis phytochrome B inhibits phytochrome A function in the presence of sucrose.

    PubMed

    Short, T W

    1999-04-01

    Overexpression of phytochrome B (phyB) in Arabidopsis has previously been demonstrated to result in dominant negative interference of phytochrome A (phyA)-mediated hypocotyl growth inhibition in far-red (FR) light. This phenomenon has been examined further in this study and has been found to be dependent on the FR fluence rate and on the availability of metabolizable sugars in the growth medium. Poorly metabolized sugars capable of activating the putative hexokinase sensory function were not effective in eliciting the phytochrome interference response. Overexpressed phyB lacking the chromophore-binding site was also effective at inhibiting the phyA response, especially at higher fluence rates of FR. Overexpressed phyB produces the dominant negative phenotype without any apparent effect on phyA abundance or degradation. It is possible that phyA and phyB interact with a common reaction partner but that either the energy state of the cell or a separate sugar-signaling mechanism modulates the phytochrome-signaling interactions.

  12. Identification of small molecules that inhibit the histone chaperone Asf1 and its chromatin function

    PubMed Central

    Seol, Ja-Hwan; Song, Tae-Yang; Oh, Se Eun; Jo, Chanhee; Choi, Ahreum; Kim, Byungho; Park, Jinyoung; Hong, Suji; Song, Ilrang; Jung, Kwan Young; Yang, Jae-Hyun; Park, Hwangseo; Ahn, Jin-Hyun; Han, Jeung-Whan; Cho, Eun-Jung

    2015-01-01

    The eukaryotic genome is packed into chromatin, which is important for the genomic integrity and gene regulation. Chromatin structures are maintained through assembly and disassembly of nucleosomes catalyzed by histone chaperones. Asf1 (anti-silencing function 1) is a highly conserved histone chaperone that mediates histone transfer on/off DNA and promotes histone H3 lysine 56 acetylation at globular core domain of histone H3. To elucidate the role of Asf1 in the modulation of chromatin structure, we screened and identified small molecules that inhibit Asf1 and H3K56 acetylation without affecting other histone modifications. These pyrimidine-2,4,6-trione derivative molecules inhibited the nucleosome assembly mediated by Asf1 in vitro, and reduced the H3K56 acetylation in HeLa cells. Furthermore, production of HSV viral particles was reduced by these compounds. As Asf1 is implicated in genome integrity, cell proliferation, and cancer, current Asf1 inhibitor molecules may offer an opportunity for the therapeutic development for treatment of diseases. [BMB Reports 2015; 48(12): 685-690] PMID:26058396

  13. Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor

    PubMed Central

    Kugel, Curtis H.; Hartsough, Edward J.; Davies, Michael A.; Setiady, Yulius Y.; Aplin, Andrew E.

    2014-01-01

    ERBB3/HER3 expression and signaling is upregulated in mutant BRAF melanoma as an adaptive, pro-survival response to FDA-approved RAF inhibitors. Since compensatory ERBB3 signaling counteracts the effects of RAF inhibitors, co-targeting ERBB3 may increase the efficacy of RAF inhibitors in mutant BRAF models of melanoma. Here we corroborate this concept by showing that the ERBB3 function-blocking monoclonal antibody huHER3-8 can inhibit neuregulin-1 (NRG1) activation of ERBB3 and downstream signaling in RAF-inhibited melanoma cells. Targeting mutant BRAF in combination with huHER3-8 decreased cell proliferation and increased cell death in vitro, and decreased tumor burden in vivo, compared to targeting either mutant BRAF or ERBB3 alone. Further, the likelihood of a durable tumor response in vivo was increased when huHER3-8 was combined with RAF inhibitor PLX4720. Together, these results offer a preclinical proof of concept for the application of ERBB3 neutralizing antibodies to enhance the efficacy of RAF inhibitors in melanoma to delay or prevent tumor re-growth. Insofar as ERBB3 is often upregulated in response to other kinase-targeted therapeutics, findings may have implications for other cancers as well. PMID:25035390

  14. Connexin43 with a cytoplasmic loop deletion inhibits the function of several connexins

    PubMed Central

    Wang, Min; Martínez, Agustín D.; Berthoud, Viviana M.; Seul, Kyung H.; Gemel, Joanna; Valiunas, Virginijus; Kumari, Sindhu; Brink, Peter R.; Beyer, Eric C.

    2009-01-01

    Connexins (Cx) form gap junction channels mediating direct intercellular communication. To study the role of amino acids within the cytoplasmic loop, we produced a recombinant adenovirus containing Cx43 with a deletion of amino acids 130–136 (Cx43del130–136). Cx43del130–136 expressed alone in HeLa cells localized within the cytoplasm and did not allow transfer of ions, neurobiotin or Lucifer yellow. When co-expressed with wild type Cx43, Cx43del130–136 blocked electrical coupling and transfer of neurobiotin or Lucifer yellow. Cx43del130–136 and Cx43 co-localized by immunofluorescence and were co-purified from Triton X-100-solubilized cell extracts. Intercellular transfer mediated by Cx37 and Cx45 (but not Cx26 or Cx40) was inhibited when co-expressed with Cx43del130–136. Cx43del130–136 co-localized with Cx37, Cx40, or Cx45, but not Cx26. These data suggest that Cx43del130–136 produces connexin-specific inhibition of intercellular communication through formation of heteromeric connexons that are non-functional and/or retained in the cytoplasm. PMID:15979566

  15. Functional brain networks underlying latent inhibition of conditioned disgust in rats.

    PubMed

    Gasalla, Patricia; Begega, Azucena; Soto, Alberto; Dwyer, Dominic Michael; López, Matías

    2016-12-15

    The present experiment examined the neuronal networks involved in the latent inhibition of conditioned disgust by measuring brain oxidative metabolism. Rats were given nonreinforced intraoral (IO) exposure to saccharin (exposed groups) or water (non-exposed groups) followed by a conditioning trial in which the animals received an infusion of saccharin paired (or unpaired) with LiCl. On testing, taste reactivity responses displayed by the rats during the infusion of the saccharin were examined. Behavioral data showed that preexposure to saccharin attenuated the development of LiCl-induced conditioned disgust reactions, indicating that the effects of taste aversion on hedonic taste reactivity had been reduced. With respect to cumulative oxidative metabolic activity across the whole study period, the parabrachial nucleus was the only single region examined which showed differential activity between groups which received saccharin-LiCl pairings with and without prior non-reinforced saccharin exposure, suggesting a key role in the effects of latent inhibition of taste aversion learning. In addition, many functional connections between brain regions were revealed through correlational analysis of metabolic activity, in particular an accumbens-amygdala interaction that may be involved in both positive and negative hedonic responses.

  16. HEMA inhibits interfacial nano-layering of the functional monomer MDP.

    PubMed

    Yoshida, Y; Yoshihara, K; Hayakawa, S; Nagaoka, N; Okihara, T; Matsumoto, T; Minagi, S; Osaka, A; Van Landuyt, K; Van Meerbeek, B

    2012-11-01

    Previous research showed that the functional monomer 10-methacryloxydecyl dihydrogen phosphate (MDP) ionically bonds to hydroxyapatite (HAp) and forms a nano-layered structure at the interface with HAp-based substrates. Such hydrophobic nano-layering is considered to contribute to the long-term durability of the bond to tooth tissue. However, dental adhesives are complex mixtures usually containing different monomers. This study investigated the effect of the monomer 2-hydroxyethylmethacrylate (HEMA) on the chemical interaction of MDP with HAp by x-ray diffraction (XRD), nuclear magnetic resonance (NMR), and quartz crystal microbalance (QCM). We examined the chemical interaction of 5 experimental MDP solutions with increasing concentrations of HEMA. XRD revealed that addition of HEMA inhibits nano-layering at the interface, while NMR confirmed that MDP remained adsorbed onto the HAp surface. QCM confirmed this adsorption of MDP to HAp, as well as revealed that the demineralization rate of HAp by MDP was reduced by HEMA. It was concluded that even though the adsorption of MDP to HAp was not hindered, addition of HEMA inhibited interfacial nano-layering. Potential consequences with regard to bond durability necessitate further research.

  17. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

    PubMed Central

    Sabha, Nesrin; Volpatti, Jonathan R.; Gonorazky, Hernan; Davidson, Ann E.; Li, Xingli; Eltayeb, Nadine M.; Dall’Armi, Claudia; Di Paolo, Gilbert; Brooks, Susan V.; Buj-Bello, Ana; Feldman, Eva L.; Dowling, James J.

    2016-01-01

    Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets. PMID:27548528

  18. Acupuncture-mediated inhibition of inflammation facilitates significant functional recovery after spinal cord injury.

    PubMed

    Choi, Doo C; Lee, Jee Y; Moon, Youn J; Kim, Shin W; Oh, Tae H; Yune, Tae Y

    2010-09-01

    Here, we first demonstrated the neuroprotective effect of acupuncture after SCI. Acupuncture applied at two specific acupoints, Shuigou (GV26) and Yanglingquan (GB34) significantly alleviated apoptotic cell death of neurons and oligodendrocytes, thereby leading to improved functional recovery after SCI. Acupuncture also inhibited caspase-3 activation and reduced the size of lesion cavity and extent of loss of axons. We also found that the activation of both p38 mitogen-activated protein kinase and resident microglia after injury are significantly attenuated by acupuncture. In addition, acupuncture significantly reduced the expression or activation of pro-nerve growth factor, proinflammatory factors such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, nitric oxide synthase, cycloxygenase-2, and matrix metalloprotease-9 after SCI. Thus, our results suggest that the neuroprotection by acupuncture may be partly mediated via inhibition of inflammation and microglial activation after SCI and acupuncture can be used as a potential therapeutic tool for treating acute spinal injury in human.

  19. Characterizing the low strain complex modulus of asphalt concrete specimens through optimization of frequency response functions.

    PubMed

    Gudmarsson, Anders; Ryden, Nils; Birgisson, Björn

    2012-10-01

    Measured and finite element simulated frequency response functions are used to characterize the low strain (~10(-7)) complex moduli of an asphalt concrete specimen. The frequency response functions of the specimen are measured at different temperatures by using an instrumented hammer to apply a load and an accelerometer to measure the dynamic response. Theoretical frequency response functions are determined by modeling the specimen as a three-dimensional (3D) linear isotropic viscoelastic material in a finite element program. The complex moduli are characterized by optimizing the theoretical frequency response functions against the measured ones. The method is shown to provide a good fit between the frequency response functions, giving an estimation of the complex modulus between minimum 500 Hz and maximum 18|000 Hz depending on the temperature. Furthermore, the optimization method is shown to give a good estimation of the complex modulus master curve.

  20. Plate/shell topological optimization subjected to linear buckling constraints by adopting composite exponential filtering function

    NASA Astrophysics Data System (ADS)

    Ye, Hong-Ling; Wang, Wei-Wei; Chen, Ning; Sui, Yun-Kang

    2016-08-01

    In this paper, a model of topology optimization with linear buckling constraints is established based on an independent and continuous mapping method to minimize the plate/shell structure weight. A composite exponential function (CEF) is selected as filtering functions for element weight, the element stiffness matrix and the element geometric stiffness matrix, which recognize the design variables, and to implement the changing process of design variables from "discrete" to "continuous" and back to "discrete". The buckling constraints are approximated as explicit formulations based on the Taylor expansion and the filtering function. The optimization model is transformed to dual programming and solved by the dual sequence quadratic programming algorithm. Finally, three numerical examples with power function and CEF as filter function are analyzed and discussed to demonstrate the feasibility and efficiency of the proposed method.

  1. Biological weighting function for the inhibition of phytoplankton photosynthesis by ultraviolet radiation

    NASA Technical Reports Server (NTRS)

    Cullen, John J.; Neale, Patrick J.; Lesser, Michael P.

    1992-01-01

    Severe reduction of stratospheric ozone over Antarctica has focused increasing concern on the biological effects of ultraviolet-B (UVB) radiation (280 to 320 nanometers). Measurements of photosynthesis from an experimental system, in which phytoplankton are exposed to a broad range of irradiance treatments, are fit to an analytical model to provide the spectral biological weighting function that can be used to predict the short-term effects of ozone depletion on aquatic photosynthesis. Results show that UVA (320 to 400 nanometers) significantly inhibits the photosynthesis of a marine diatom and a dinoflagellate, and that the effects of UVB are even more severe. Application of the model suggests that the Antarctic ozone hole might reduce near-surface photosynthesis by 12 to 15 percent, but less so at depth. The experimental system makes possible routine estimation of spectral weightings for natural phytoplankton.

  2. An Optimized Lock Solution Containing Micafungin, Ethanol and Doxycycline Inhibits Candida albicans and Mixed C. albicans – Staphyloccoccus aureus Biofilms

    PubMed Central

    Lown, Livia; Peters, Brian M.; Walraven, Carla J.; Noverr, Mairi C.; Lee, Samuel A.

    2016-01-01

    Candida albicans is a major cause of catheter-related bloodstream infections and is associated with high morbidity and mortality. Due to the propensity of C. albicans to form drug-resistant biofilms, the current standard of care includes catheter removal; however, reinsertion may be technically challenging or risky. Prolonged exposure of an antifungal lock solution within the catheter in conjunction with systemic therapy has been experimentally attempted for catheter salvage. Previously, we demonstrated excellent in vitro activity of micafungin, ethanol, and high-dose doxycycline as single agents for prevention and treatment of C. albicans biofilms. Thus, we sought to investigate optimal combinations of micafungin, ethanol, and/or doxycycline as a lock solution. We performed two- and three-drug checkerboard assays to determine the in vitro activity of pairwise or three agents in combination for prevention or treatment of C. albicans biofilms. Optimal lock solutions were tested for activity against C. albicans clinical isolates, reference strains and polymicrobial C. albicans-S. aureus biofilms. A solution containing 20% (v/v) ethanol, 0.01565 μg/mL micafungin, and 800 μg/mL doxycycline demonstrated a reduction of 98% metabolic activity and no fungal regrowth when used to prevent fungal biofilm formation; however there was no advantage over 20% ethanol alone. This solution was also successful in inhibiting the regrowth of C. albicans from mature polymicrobial biofilms, although it was not fully bactericidal. Solutions containing 5% ethanol with low concentrations of micafungin and doxycycline demonstrated synergistic activity when used to prevent monomicrobial C. albicans biofilm formation. A combined solution of micafungin, ethanol and doxycycline is highly effective for the prevention of C. albicans biofilm formation but did not demonstrate an advantage over 20% ethanol alone in these studies. PMID:27428310

  3. The importance of functional form in optimal control solutions of problems in population dynamics

    USGS Publications Warehouse

    Runge, M.C.; Johnson, F.A.

    2002-01-01

    Optimal control theory is finding increased application in both theoretical and applied ecology, and it is a central element of adaptive resource management. One of the steps in an adaptive management process is to develop alternative models of system dynamics, models that are all reasonable in light of available data, but that differ substantially in their implications for optimal control of the resource. We explored how the form of the recruitment and survival functions in a general population model for ducks affected the patterns in the optimal harvest strategy, using a combination of analytical, numerical, and simulation techniques. We compared three relationships between recruitment and population density (linear, exponential, and hyperbolic) and three relationships between survival during the nonharvest season and population density (constant, logistic, and one related to the compensatory harvest mortality hypothesis). We found that the form of the component functions had a dramatic influence on the optimal harvest strategy and the ultimate equilibrium state of the system. For instance, while it is commonly assumed that a compensatory hypothesis leads to higher optimal harvest rates than an additive hypothesis, we found this to depend on the form of the recruitment function, in part because of differences in the optimal steady-state population density. This work has strong direct consequences for those developing alternative models to describe harvested systems, but it is relevant to a larger class of problems applying optimal control at the population level. Often, different functional forms will not be statistically distinguishable in the range of the data. Nevertheless, differences between the functions outside the range of the data can have an important impact on the optimal harvest strategy. Thus, development of alternative models by identifying a single functional form, then choosing different parameter combinations from extremes on the likelihood

  4. Glycerol Monolaurate (GML) inhibits human T cell signaling and function by disrupting lipid dynamics

    PubMed Central

    Zhang, Michael S.; Sandouk, Aline; Houtman, Jon C. D.

    2016-01-01

    Glycerol Monolaurate (GML) is a naturally occurring fatty acid widely utilized in food, cosmetics, and homeopathic supplements. GML is a potent antimicrobial agent that targets a range of bacteria, fungi, and enveloped viruses but select findings suggest that GML also has immunomodulatory functions. In this study, we have mechanistically examined if GML affects the signaling and functional output of human primary T cells. We found that GML potently altered order and disorder dynamics in the plasma membrane that resulted in reduced formation of LAT, PLC-γ, and AKT microclusters. Altered membrane events induced selective inhibition of TCR-induced phosphorylation of regulatory P85 subunit of PI3K and AKT as well as abrogated calcium influx. Ultimately, GML treatment potently reduced TCR-induced production of IL-2, IFN-γ, TNF-α, and IL-10. Our data reveal that the widely used anti-microbial agent GML also alters the lipid dynamics of human T cells, leading to their defective signaling and function. PMID:27456316

  5. Electroacupuncture improves cardiac function and remodeling by inhibition of sympathoexcitation in chronic heart failure rats.

    PubMed

    Ma, Luyao; Cui, Baiping; Shao, Yongfeng; Ni, Buqing; Zhang, Weiran; Luo, Yonggang; Zhang, Shijiang

    2014-05-15

    Chronic heart failure (CHF) is responsible for significant morbidity and mortality worldwide, mainly as a result of neurohumoral activation. Acupuncture has been used to treat a wide range of diseases and conditions. In this study, we investigated the effects of electroacupuncture (EA) on the sympathetic nerve activity, heart function, and remodeling in CHF rats after ligation of the left anterior descending coronary artery. CHF rats were randomly selected to EA and control groups for acute and chronic experiments. In the acute experiment, both the renal sympathetic nerve activity and cardiac sympathetic afferent reflex elicited by epicardial application of capsaicin were recorded. In the chronic experiment, we performed EA for 30 min once a day for 1 wk to test the long-term EA effects on heart function, remodeling, as well as infarct size in CHF rats. The results show EA significantly decreased the renal sympathetic nerve activity effectively, inhibited cardiac sympathetic afferent reflex, and lowered the blood pressure of CHF rats. Treating CHF rats with EA for 1 wk dramatically increased left ventricular ejection fraction and left ventricular fraction shortening, reversed the enlargement of left ventricular end-systolic dimension and left ventricular end-diastolic dimension, and shrunk the infarct size. In this experiment, we demonstrated EA attenuates sympathetic overactivity. Additionally, long-term EA improves cardiac function and remodeling and reduces infarct size in CHF rats. EA is a novel and potentially useful therapy for treating CHF.

  6. Inhibition of NF-kappaB with Dehydroxymethylepoxyquinomicin modifies the function of human peritoneal mesothelial cells

    PubMed Central

    Sosińska, Patrycja; Baum, Ewa; Maćkowiak, Beata; Staniszewski, Ryszard; Jasinski, Tomasz; Umezawa, Kazuo; Bręborowicz, Andrzej

    2016-01-01

    Peritoneal mesothelial cells exposed to bioincompatible dialysis fluids contribute to damage of the peritoneum during chronic dialysis. Inflammatory response triggered in the mesothelium leading to neovascularization and fibrosis plays an important role in that process. We studied the effects of Dehydroxymethyepoxyquinmicin (DHMEQ)-an NF-κB inhibitor on function of human peritoneal mesothelial cells (HPMC) in in vitro culture. DHMEQ studied in concentrations of 1-10 µg/ml was not toxic to HPMC. Synthesis of IL-6, MCP-1 and hyaluronan in unstimulated and stimulated with interleukin-1 (100 pg/ml) HPMC was inhibited in the presence of DHMEQ and the effect was proportional to the dose of the drug. DHMEQ (10 µg/ml) reduced in unstimulated HPMC synthesis of IL-6 (-55%), MCP-1 (-58%) and hyaluronan (-41%). Respective values for stimulated HMPC were: -63% for IL-6, -57% for MCP-1 and -67% for hyaluronan. The observed effects were due to the suppression of the expression of genes responsible for the synthesis of these molecules. DHMEQ modified the effects of the effluent dialysates from CAPD patients on the function of HMPC. Dialysate induced accelerated growth of these cells, and synthesis of collagen was inhibited in the presence of DHMEQ 10 µg/ml, by 69% and 40%, respectively. The results of our study show that DHMEQ effectively reduces inflammatory response in HMPC and prevents excessive dialysate induced proliferation and collagen synthesis in these cells. All of these effects may be beneficial during chronic peritoneal dialysis and prevents progressive dialysis-induced damage to the peritoneum. PMID:28078047

  7. Three-input majority function as the unique optimal function for the bias amplification using nonlocal boxes

    NASA Astrophysics Data System (ADS)

    Mori, Ryuhei

    2016-11-01

    Brassard et al. [Phys. Rev. Lett. 96, 250401 (2006), 10.1103/PhysRevLett.96.250401] showed that shared nonlocal boxes with a CHSH (Clauser, Horne, Shimony, and Holt) probability greater than 3/+√{6 } 6 yield trivial communication complexity. There still exists a gap with the maximum CHSH probability 2/+√{2 } 4 achievable by quantum mechanics. It is an interesting open question to determine the exact threshold for the trivial communication complexity. Brassard et al.'s idea is based on recursive bias amplification by the three-input majority function. It was not obvious if another choice of function exhibits stronger bias amplification. We show that the three-input majority function is the unique optimal function, so that one cannot improve the threshold 3/+√{6 } 6 by Brassard et al.'s bias amplification. In this work, protocols for computing the function used for the bias amplification are restricted to be nonadaptive protocols or a particular adaptive protocol inspired by Pawłowski et al.'s protocol for information causality [Nature (London) 461, 1101 (2009), 10.1038/nature08400]. We first show an adaptive protocol inspired by Pawłowski et al.'s protocol, and then show that the adaptive protocol improves upon nonadaptive protocols. Finally, we show that the three-input majority function is the unique optimal function for the bias amplification if we apply the adaptive protocol to each step of the bias amplification.

  8. Inhibition of matrix metalloproteinase-2 improves endothelial function and prevents hypertension in insulin-resistant rats

    PubMed Central

    Nagareddy, PR; Rajput, PS; Vasudevan, H; McClure, B; Kumar, U; MacLeod, KM; McNeill, JH

    2012-01-01

    BACKGROUND AND PURPOSE Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90). EXPERIMENTAL APPROACH We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance. KEY RESULTS Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity. CONCLUSIONS AND IMPLICATIONS Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension. PMID:21740410

  9. Reconstruction of the unknown optimization cost functions from experimental recordings during static multi-finger prehension

    PubMed Central

    Niu, Xun; Terekhov, Alexander V.; Latash, Mark L.; Zatsiorsky, Vladimir M.

    2013-01-01

    The goal of the research is to reconstruct the unknown cost (objective) function(s) presumably used by the neural controller for sharing the total force among individual fingers in multi-finger prehension. The cost function was determined from experimental data by applying the recently developed Analytical Inverse Optimization (ANIO) method (Terekhov et al 2010). The core of the ANIO method is the Theorem of Uniqueness that specifies conditions for unique (with some restrictions) estimation of the objective functions. In the experiment, subjects (n=8) grasped an instrumented handle and maintained it at rest in the air with various external torques, loads, and target grasping forces applied to the object. The experimental data recorded from 80 trials showed a tendency to lie on a 2-dimensional hyperplane in the 4-dimensional finger-force space. Because the constraints in each trial were different, such a propensity is a manifestation of a neural mechanism (not the task mechanics). In agreement with the Lagrange principle for the inverse optimization, the plane of experimental observations was close to the plane resulting from the direct optimization. The latter plane was determined using the ANIO method. The unknown cost function was reconstructed successfully for each performer, as well as for the group data. The cost functions were found to be quadratic with non-zero linear terms. The cost functions obtained with the ANIO method yielded more accurate results than other optimization methods. The ANIO method has an evident potential for addressing the problem of optimization in motor control. PMID:22104742

  10. Optimism

    PubMed Central

    Carver, Charles S.; Scheier, Michael F.; Segerstrom, Suzanne C.

    2010-01-01

    Optimism is an individual difference variable that reflects the extent to which people hold generalized favorable expectancies for their future. Higher levels of optimism have been related prospectively to better subjective well-being in times of adversity or difficulty (i.e., controlling for previous well-being). Consistent with such findings, optimism has been linked to higher levels of engagement coping and lower levels of avoidance, or disengagement, coping. There is evidence that optimism is associated with taking proactive steps to protect one's health, whereas pessimism is associated with health-damaging behaviors. Consistent with such findings, optimism is also related to indicators of better physical health. The energetic, task-focused approach that optimists take to goals also relates to benefits in the socioeconomic world. Some evidence suggests that optimism relates to more persistence in educational efforts and to higher later income. Optimists also appear to fare better than pessimists in relationships. Although there are instances in which optimism fails to convey an advantage, and instances in which it may convey a disadvantage, those instances are relatively rare. In sum, the behavioral patterns of optimists appear to provide models of living for others to learn from. PMID:20170998

  11. Sexual Function and the Use of Medical Devices or Drugs to Optimize Potency After Prostate Brachytherapy

    SciTech Connect

    Whaley, J. Taylor; Levy, Lawrence B.; Swanson, David A.; Pugh, Thomas J.; Kudchadker, Rajat J.; Bruno, Teresa L.; Frank, Steven J.

    2012-04-01

    Purpose: Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Methods and Materials: Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated. Results: At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Conclusions: Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry.

  12. Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry

    NASA Technical Reports Server (NTRS)

    McElmurray, J. H. 3rd; Mukherjee, R.; New, R. B.; Sampson, A. C.; King, M. K.; Hendrick, J. W.; Goldberg, A.; Peterson, T. J.; Hallak, H.; Zile, M. R.; Spinale, F. G.

    1999-01-01

    The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.

  13. Maximum power, ecological function and efficiency of an irreversible Carnot cycle: a cost and effectiveness optimization

    NASA Astrophysics Data System (ADS)

    Aragón-González, G.; Canales-Palma, A.; León-Galicia, A.; Morales-Gómez, J. R.

    2008-12-01

    In this work we include, for the Carnot cycle, irreversibilities of linear finite rate of heat transferences between the heat engine and its reservoirs, heat leak between the reservoirs and internal dissipations of the working fluid. A first optimization of the power output, the efficiency and ecological function of an irreversible Carnot cycle, with respect to: internal temperature ratio, time ratio for the heat exchange and the allocation ratio of the heat exchangers; is performed. For the second and third optimizations, the optimum values for the time ratio and internal temperature ratio are substituted into the equation of power and, then, the optimizations with respect to the cost and effectiveness ratio of the heat exchangers are performed. Finally, a criterion of partial optimization for the class of irreversible Carnot engines is herein presented.

  14. Using symmetry-adapted optimized sum-of-products basis functions to calculate vibrational spectra

    NASA Astrophysics Data System (ADS)

    Leclerc, Arnaud; Carrington, Tucker

    2016-01-01

    Vibrational spectra can be computed without storing full-dimensional vectors by using low-rank sum-of-products (SOP) basis functions. We introduce symmetry constraints in the SOP basis functions to make it possible to separately calculate states in different symmetry subgroups. This is done using a power method to compute eigenvalues and an alternating least squares method to optimize basis functions. Owing to the fact that the power method favours the convergence of the lowest states, one must be careful not to exclude basis functions of some symmetries. Exploiting symmetry facilitates making assignments and improves the accuracy. The method is applied to the acetonitrile molecule.

  15. Shuttle ascent trajectory optimization with function space quasi-Newton techniques

    NASA Technical Reports Server (NTRS)

    Edge, E. R.; Powers, W. F.

    1974-01-01

    A Space Shuttle ascent trajectory optimization problem from lift-off to orbital insertion is solved with a function space version of a quasi-Newton parameter optimization method developed by Broyden. The problem includes five parameter and one bounded-function controls, two state-variable constraints, and four terminal conditions. The bounded controls are treated directly, while the remaining constraints are adjoined to the performance index (maximum payload) with penalty functions. The problem is formulated as a four-phase variational problem (liftoff, pitch-over, gravity-turn, linear tangent steering), and the appropriate gradients are developed by first variation theory. A projection operator is introduced to aid in the interpretation of the algorithm with mixed parameter and function controls.

  16. Optimizing fMRI Preprocessing Pipelines for Block-Design Tasks as a Function of Age.

    PubMed

    Churchill, Nathan W; Raamana, Pradeep; Spring, Robyn; Strother, Stephen C

    2017-02-12

    Functional Magnetic Resonance Imaging (fMRI) is a powerful neuroimaging tool, which is often hampered by significant noise confounds. There is evidence that our ability to detect activations in task fMRI is highly dependent on the preprocessing steps used to control noise and artifact. However, the vast majority of studies examining preprocessing pipelines in fMRI have focused on young adults. Given the widespread use of fMRI for characterizing the neurobiology of aging, it is critical to examine how the impact of preprocessing choices varies as a function of age. In this study, we employ the NPAIRS cross-validation framework, which optimizes pipelines based on metrics of prediction accuracy (P) and spatial reproducibility (R), to compare the effects of pipeline optimization between young (21-33 years) and older (61-82 years) cohorts, for three different block-design contrasts. Motion is shown to be a greater issue in the older cohort, and we introduce new statistical approaches to control for potential biases due to head motion during pipeline optimization. In comparison, data-driven methods of physiological noise correction show comparable benefits for both young and old cohorts. Using our optimization framework, we demonstrate that the optimal pipelines tend to be highly similar across age cohorts. In addition, there is a comparable, significant benefit of pipeline optimization across age cohorts, for (P, R) metrics and independent validation measures of activation overlap (both between-subject, within-session and within-subject, between-session). The choice of task contrast consistently shows a greater impact than the age cohort, for (P, R) metrics and activation overlap. Finally, adaptive pipeline optimization per task run shows improved sensitivity to age-related changes in brain activity, particularly for weaker, more complex cognitive contrasts. The current study provides the first detailed examination of preprocessing pipelines across age cohorts

  17. Optimization of head movement recognition using Augmented Radial Basis Function Neural Network.

    PubMed

    Yuwono, Mitchell; Handojoseno, A M Ardi; Nguyen, H T

    2011-01-01

    For people with severe spine injury, head movement recognition control has been proven to be one of the most convenient and intuitive ways to control a power wheelchair. While substantial research has been done in this area, the challenge to improve system reliability and accuracy remains due to the diversity in movement tendencies and the presence of movement artifacts. We propose a Neural-Network Configuration which we call Augmented Radial Basis Function Neural-Network (ARBF-NN). This network is constructed as a Radial Basis Function Neural-Network (RBF-NN) with a Multilayer Perceptron (MLP) augmentation layer to negate optimization limitation posed by linear classifiers in conventional RBF-NN. The RBF centroid is optimized through Regrouping Particle Swarm Optimization (RegPSO) seeded with K-Means. The trial results of ARBF-NN on Head-movement show a significant improvement on recognition accuracy up to 98.1% in sensitivity.

  18. Optimal tradeoff circular harmonic function correlation filter methods providing controlled in-plane rotation response.

    PubMed

    Vijaya Kumar, B K; Mahalanobis, A; Takessian, A

    2000-01-01

    Correlation methods are becoming increasingly attractive tools for image recognition and location. This renewed interest in correlation methods is spurred by the availability of high-speed image processors and the emergence of correlation filter designs that can optimize relevant figures of merit. In this paper, a new correlation filter design method is presented that allows one to optimally tradeoff among potentially conflicting correlation output performance criteria while achieving desired correlation peak value behavior in response to in-plane rotation of input images. Such controlled in-plane rotation response is useful in image analysis and pattern recognition applications where the sensor follows a pre-arranged trajectory while imaging an object. Since this new correlation filter design is based on circular harmonic function (CHF) theory, we refer to the resulting filters as optimal tradeoff circular harmonic function (OTCHF) filters. Underlying theory, OTCHF filter design method, and illustrative numerical results are presented.

  19. Materials design by evolutionary optimization of functional groups in metal-organic frameworks

    PubMed Central

    Collins, Sean P.; Daff, Thomas D.; Piotrkowski, Sarah S.; Woo, Tom K.

    2016-01-01

    A genetic algorithm that efficiently optimizes a desired physical or functional property in metal-organic frameworks (MOFs) by evolving the functional groups within the pores has been developed. The approach has been used to optimize the CO2 uptake capacity of 141 experimentally characterized MOFs under conditions relevant for postcombustion CO2 capture. A total search space of 1.65 trillion structures was screened, and 1035 derivatives of 23 different parent MOFs were identified as having exceptional CO2 uptakes of >3.0 mmol/g (at 0.15 atm and 298 K). Many well-known MOF platforms were optimized, with some, such as MIL-47, having their CO2 adsorption increase by more than 400%. The structures of the high-performing MOFs are provided as potential targets for synthesis. PMID:28138523

  20. Towards an Optimal Gradient-dependent Energy Functional of the PZ-SIC Form

    DOE PAGES

    Jónsson, Elvar Örn; Lehtola, Susi; Jónsson, Hannes

    2015-06-01

    Results of Perdew–Zunger self-interaction corrected (PZ-SIC) density functional theory calculations of the atomization energy of 35 molecules are compared to those of high-level quantum chemistry calculations. While the PBE functional, which is commonly used in calculations of condensed matter, is known to predict on average too high atomization energy (overbinding of the molecules), the application of PZ-SIC gives a large overcorrection and leads to significant underestimation of the atomization energy. The exchange enhancement factor that is optimal for the generalized gradient approximation within the Kohn-Sham (KS) approach may not be optimal for the self-interaction corrected functional. The PBEsol functional, wheremore » the exchange enhancement factor was optimized for solids, gives poor results for molecules in KS but turns out to work better than PBE in PZ-SIC calculations. The exchange enhancement is weaker in PBEsol and the functional is closer to the local density approximation. Furthermore, the drop in the exchange enhancement factor for increasing reduced gradient in the PW91 functional gives more accurate results than the plateaued enhancement in the PBE functional. A step towards an optimal exchange enhancement factor for a gradient dependent functional of the PZ-SIC form is taken by constructing an exchange enhancement factor that mimics PBEsol for small values of the reduced gradient, and PW91 for large values. The average atomization energy is then in closer agreement with the high-level quantum chemistry calculations, but the variance is still large, the F2 molecule being a notable outlier.« less

  1. Towards an Optimal Gradient-dependent Energy Functional of the PZ-SIC Form

    SciTech Connect

    Jónsson, Elvar Örn; Lehtola, Susi; Jónsson, Hannes

    2015-06-01

    Results of Perdew–Zunger self-interaction corrected (PZ-SIC) density functional theory calculations of the atomization energy of 35 molecules are compared to those of high-level quantum chemistry calculations. While the PBE functional, which is commonly used in calculations of condensed matter, is known to predict on average too high atomization energy (overbinding of the molecules), the application of PZ-SIC gives a large overcorrection and leads to significant underestimation of the atomization energy. The exchange enhancement factor that is optimal for the generalized gradient approximation within the Kohn-Sham (KS) approach may not be optimal for the self-interaction corrected functional. The PBEsol functional, where the exchange enhancement factor was optimized for solids, gives poor results for molecules in KS but turns out to work better than PBE in PZ-SIC calculations. The exchange enhancement is weaker in PBEsol and the functional is closer to the local density approximation. Furthermore, the drop in the exchange enhancement factor for increasing reduced gradient in the PW91 functional gives more accurate results than the plateaued enhancement in the PBE functional. A step towards an optimal exchange enhancement factor for a gradient dependent functional of the PZ-SIC form is taken by constructing an exchange enhancement factor that mimics PBEsol for small values of the reduced gradient, and PW91 for large values. The average atomization energy is then in closer agreement with the high-level quantum chemistry calculations, but the variance is still large, the F2 molecule being a notable outlier.

  2. Coniferyl Aldehyde Attenuates Radiation Enteropathy by Inhibiting Cell Death and Promoting Endothelial Cell Function

    PubMed Central

    Son, Yeonghoon; Jang, Jun-Ho; Lee, Yoon-Jin; Kim, Sung-Ho; Ko, Young-Gyo; Lee, Yun-Sil; Lee, Hae-June

    2015-01-01

    Radiation enteropathy is a common complication in cancer patients. The aim of this study was to investigate whether radiation-induced intestinal injury could be alleviated by coniferyl aldehyde (CA), an HSF1-inducing agent that increases cellular HSP70 expression. We systemically administered CA to mice with radiation enteropathy following abdominal irradiation (IR) to demonstrate the protective effects of CA against radiation-induced gastrointestinal injury. CA clearly alleviated acute radiation-induced intestinal damage, as reflected by the histopathological data and it also attenuated sub-acute enteritis. CA prevented intestinal crypt cell death and protected the microvasculature in the lamina propria during the acute and sub-acute phases of damage. CA induced HSF1 and HSP70 expression in both intestinal epithelial cells and endothelial cells in vitro. Additionally, CA protected against not only the apoptotic cell death of both endothelial and epithelial cells but also the loss of endothelial cell function following IR, indicating that CA has beneficial effects on the intestine. Our results provide novel insight into the effects of CA and suggest its role as a therapeutic candidate for radiation-induced enteropathy due to its ability to promote rapid re-proliferation of the intestinal epithelium by the synergic effects of the inhibition of cell death and the promotion of endothelial cell function. PMID:26029925

  3. Deep brain stimulation mechanisms: beyond the concept of local functional inhibition.

    PubMed

    Deniau, Jean-Michel; Degos, Bertrand; Bosch, Clémentine; Maurice, Nicolas

    2010-10-01

    Deep brain electrical stimulation has become a recognized therapy in the treatment of a variety of motor disorders and has potentially promising applications in a wide range of neurological diseases including neuropsychiatry. Behavioural observation that electrical high-frequency stimulation of a given brain area induces an effect similar to a lesion suggested a mechanism of functional inhibition. In vitro and in vivo experiments as well as per operative recordings in patients have revealed a variety of effects involving local changes of neuronal excitability as well as widespread effects throughout the connected network resulting from activation of axons, including antidromic activation. Here we review current data regarding the local and network activity changes induced by high-frequency stimulation of the subthalamic nucleus and discuss this in the context of motor restoration in Parkinson's disease. Stressing the important functional consequences of axonal activation in deep brain stimulation mechanisms, we highlight the importance of developing anatomical knowledge concerning the fibre connections of the putative therapeutic targets.

  4. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models

    PubMed Central

    Kagoya, Yuki; Nakatsugawa, Munehide; Yamashita, Yuki; Ochi, Toshiki; Guo, Tingxi; Anczurowski, Mark; Saso, Kayoko; Butler, Marcus O.; Arrowsmith, Cheryl H.

    2016-01-01

    Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8+ T cells with functional properties of stem cell–like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in CD8+ T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1-treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy. PMID:27548527

  5. Coniferyl aldehyde attenuates radiation enteropathy by inhibiting cell death and promoting endothelial cell function.

    PubMed

    Jeong, Ye-Ji; Jung, Myung Gu; Son, Yeonghoon; Jang, Jun-Ho; Lee, Yoon-Jin; Kim, Sung-Ho; Ko, Young-Gyo; Lee, Yun-Sil; Lee, Hae-June

    2015-01-01

    Radiation enteropathy is a common complication in cancer patients. The aim of this study was to investigate whether radiation-induced intestinal injury could be alleviated by coniferyl aldehyde (CA), an HSF1-inducing agent that increases cellular HSP70 expression. We systemically administered CA to mice with radiation enteropathy following abdominal irradiation (IR) to demonstrate the protective effects of CA against radiation-induced gastrointestinal injury. CA clearly alleviated acute radiation-induced intestinal damage, as reflected by the histopathological data and it also attenuated sub-acute enteritis. CA prevented intestinal crypt cell death and protected the microvasculature in the lamina propria during the acute and sub-acute phases of damage. CA induced HSF1 and HSP70 expression in both intestinal epithelial cells and endothelial cells in vitro. Additionally, CA protected against not only the apoptotic cell death of both endothelial and epithelial cells but also the loss of endothelial cell function following IR, indicating that CA has beneficial effects on the intestine. Our results provide novel insight into the effects of CA and suggest its role as a therapeutic candidate for radiation-induced enteropathy due to its ability to promote rapid re-proliferation of the intestinal epithelium by the synergic effects of the inhibition of cell death and the promotion of endothelial cell function.

  6. Inhibition of water activated by far infrared functional ceramics on proliferation of hepatoma cells.

    PubMed

    Zhang, Dongmei; Liang, Jinsheng; Ding, Yan; Meng, Junping; Zhang, Guangchuan

    2014-05-01

    Rare earth (RE)/tourmaline composite materials prepared by the precipitation method are added to the ceramic raw materials at a certain percentage and sintered into RE functional ceramics with high far infrared emission features. Then the far infrared functional ceramics are used to interact with water. The influence of the ceramics on the physical parameters of water is investigated, and the effect of the activated water on the growth of Bel-7402 hepatoma cells cultured in vitro is further studied. The results indicate that, compared with the raw water, the water activated by the ceramics can inhibit the proliferation of hepatoma cells, with statistical probability P < 0.01, which means that the effect is significant. It can be explained that the water activated by the ceramics has a higher concentration of H+, which decreases the potential difference across the cell membrane to release the apoptosis inducing factor (AIF). After entering the cells, the activated water stimulates the mitochondria to produce immune substances that lead tumor cells to apoptosis.

  7. Differences in latent inhibition as a function of the autogenous-reactive OCD subtype.

    PubMed

    Lee, Han-Joo; Telch, Michael J

    2010-07-01

    We examined differences in a visual search-based latent inhibition (LI) task in 48 non-treatment seeking individuals diagnosed with obsessive-compulsive disorder (OCD) and 26 non-OCD controls, using a visual search-based LI task as a function of participants' primary obsessional presentation based on the autogenous-reactive subtype model of obsessions (Lee & Kwon, 2003; Lee & Telch, 2007). We hypothesized that LI would be significantly attenuated among OCD participants whose primary obsessions were characterized by aversive impulses, images, or thoughts with sexual, aggressive, blasphemous, and repulsive themes (autogenous obsessions) due to their weakened attentional inhibitory mechanisms and elevated schizotypal personality features, as compared with those whose primary obsessions were characterized by somewhat realistic aversive mental intrusions about contamination, mistakes, accidents, or disarray (reactive obsession) and non-OCD controls. Results showed that those primarily displaying autogenous obsessions failed to display LI, whereas those primarily displaying reactive obsessions and non-OCD controls displayed significant LI effects. Our data suggest that the magnitude of LI varies as a function of primary obsessional presentations among individuals with OCD.

  8. Reduced dopamine function within the medial shell of the nucleus accumbens enhances latent inhibition.

    PubMed

    Nelson, A J D; Thur, K E; Horsley, R R; Spicer, C; Marsden, C A; Cassaday, H J

    2011-03-01

    Latent inhibition (LI) manifests as poorer conditioning to a CS that has previously been presented without consequence. There is some evidence that LI can be potentiated by reduced mesoaccumbal dopamine (DA) function but the locus within the nucleus accumbens of this effect is as yet not firmly established. Experiment 1 tested whether 6-hydroxydopamine (6-OHDA)-induced lesions of DA terminals within the core and medial shell subregions of the nucleus accumbens (NAc) would enhance LI under conditions that normally disrupt LI in controls (weak pre-exposure). LI was measured in a thirst motivated conditioned emotional response procedure with 10 pre-exposures (to a noise CS) and 2 conditioning trials. The vehicle-injected and core-lesioned animals did not show LI and conditioned to the pre-exposed CS at comparable levels to the non-pre-exposed controls. 6-OHDA lesions to the medial shell, however, produced potentiation of LI, demonstrated across two extinction tests. In a subsequent experiment, haloperidol microinjected into the medial shell prior to conditioning similarly enhanced LI. These results underscore the dissociable roles of core and shell subregions of the NAc in mediating the expression of LI and indicate that reduced DA function within the medial shell leads to enhanced LI.

  9. The optimization of single mode basis functions for polyatomic vibrational problems with application to the water molecule

    NASA Technical Reports Server (NTRS)

    Schwenke, David W.

    1992-01-01

    The optimization of the wave functions is considered for coupled vibrations represented by linear combinations of products of functions depending only on a single vibrational coordinate. The functions themselves are optimized as well as configuration list. For the H2O molecule highly accurate results are obtained for the lowest 15 levels using significantly shorter expansions than would otherwise be possible.

  10. Nonlinear stability in reaction-diffusion systems via optimal Lyapunov functions

    NASA Astrophysics Data System (ADS)

    Lombardo, S.; Mulone, G.; Trovato, M.

    2008-06-01

    We define optimal Lyapunov functions to study nonlinear stability of constant solutions to reaction-diffusion systems. A computable and finite radius of attraction for the initial data is obtained. Applications are given to the well-known Brusselator model and a three-species model for the spatial spread of rabies among foxes.

  11. A Linear Programming Model to Optimize Various Objective Functions of a Foundation Type State Support Program.

    ERIC Educational Resources Information Center

    Matzke, Orville R.

    The purpose of this study was to formulate a linear programming model to simulate a foundation type support program and to apply this model to a state support program for the public elementary and secondary school districts in the State of Iowa. The model was successful in producing optimal solutions to five objective functions proposed for…

  12. Balancing Multicultural Competence with Social Justice: Feminist Beliefs and Optimal Psychological Functioning

    ERIC Educational Resources Information Center

    Yoder, Janice D.; Snell, Andrea F.; Tobias, Ann

    2012-01-01

    To identify a multivariate configuration of feminist beliefs best associated with optimal psychological functioning, 215 mostly White college women completed an online survey measuring their feminist beliefs (Feminist Perspectives Scale, Attitudes toward Feminism and the Women's Movement, sense of common fate, and Feminist Identity Composite) and…

  13. Feedback Functions, Optimization, and the Relation of Response Rate to Reinforcer Rate

    ERIC Educational Resources Information Center

    Soto, Paul L.; McDowell, Jack J.; Dallery, Jesse

    2006-01-01

    The present experiment arranged a series of inverted U-shaped feedback functions relating reinforcer rate to response rate to test whether responding was consistent with an optimization account or with a one-to-one relation of response rate to reinforcer rate such as linear system theory's rate equation or Herrnstein's hyperbola. Reinforcer rate…

  14. Application of Sigmoidal Transformation Functions in Optimization of Micellar Liquid Chromatographic Separation of Six Quinolone Antibiotics.

    PubMed

    Hadjmohammadi, Mohammadreza; Salary, Mina

    2016-03-01

    A chemometrics approach has been used to optimize the separation of six quinolone compounds by micellar liquid chromatography (MLC). A Derringer's desirability function, a multicriteria decision-making (MCDM) method, was tested for evaluation of two different measures of chromatographic performance (resolution and analysis time). The effect of three experimental parameters on a chromatographic response function (CRF) expressed as a product of two sigmoidal desirability functions was investigated. The sigmoidal functions were used to transform the optimization criteria, resolution and analysis time into the desirability values. The factors studied were the concentration of sodium dodecyl sulfate, butanol content and pH of the mobile phase. The experiments were done according to the face-centered cube central composite design, and the calculated CRF values were fitted to a polynomial model to correlate the CRF values with the variables and their interactions. The developed regression model showed good descriptive and predictive ability (R(2) = 0.815, F = 6.919, SE = 0.038, [Formula: see text]) and used, by a grid search algorithm, to optimize the chromatographic conditions for the separation of the mixture. The efficiency of prediction of polynomial model was confirmed by performing the experiment under the optimal conditions.

  15. Optimization of the coherence function estimation for multi-core central processing unit

    NASA Astrophysics Data System (ADS)

    Cheremnov, A. G.; Faerman, V. A.; Avramchuk, V. S.

    2017-02-01

    The paper considers use of parallel processing on multi-core central processing unit for optimization of the coherence function evaluation arising in digital signal processing. Coherence function along with other methods of spectral analysis is commonly used for vibration diagnosis of rotating machinery and its particular nodes. An algorithm is given for the function evaluation for signals represented with digital samples. The algorithm is analyzed for its software implementation and computational problems. Optimization measures are described, including algorithmic, architecture and compiler optimization, their results are assessed for multi-core processors from different manufacturers. Thus, speeding-up of the parallel execution with respect to sequential execution was studied and results are presented for Intel Core i7-4720HQ и AMD FX-9590 processors. The results show comparatively high efficiency of the optimization measures taken. In particular, acceleration indicators and average CPU utilization have been significantly improved, showing high degree of parallelism of the constructed calculating functions. The developed software underwent state registration and will be used as a part of a software and hardware solution for rotating machinery fault diagnosis and pipeline leak location with acoustic correlation method.

  16. Mechanisms of Neuroblastoma Cell Growth Inhibition by CARP-1 Functional Mimetics

    PubMed Central

    Muthu, Magesh; Cheriyan, Vino T.; Munie, Sara; Levi, Edi; Frank, John; Ashour, Abdelkader E.; Singh, Mandip; Rishi, Arun K.

    2014-01-01

    Neuroblastomas (NBs) are a clinically heterogeneous group of extra cranial pediatric tumors. Patients with high-risk, metastatic NBs have a long-term survival rate of below 40%, and are often resistant to current therapeutic modalities. Due to toxic side effects associated with radiation and chemotherapies, development of new agents is warranted to overcome resistance and effectively treat this disease in clinic. CARP-1 functional mimetics (CFMs) are an emerging class of small molecule compounds that inhibit growth of diverse cancer cell types. Here we investigated NB inhibitory potential of CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited NB cell growth, in vitro, independent of their p53 and MYCN status. CFM-4 and -5 induced apoptosis in NB cells in part by activating pro-apoptotic stress-activated kinases (SAPKs) p38 and JNK, stimulating CARP-1 expression and cleavage of PARP1, while promoting loss of the oncogenes C and N-myc as well as mitotic cyclin B1. Treatments of NB cells with CFM-4 or -5 also resulted in loss of Inhibitory κB (IκB) α and β proteins. Micro-RNA profiling revealed upregulation of XIAP-targeting miR513a-3p in CFM-4-treated NB, mesothelioma, and breast cancer cells. Moreover, exposure of NB and breast cancer cells to CFM-4 or -5 resulted in diminished expression of anti-apoptotic XIAP1, cIAP1, and Survivin proteins. Expression of anti-miR513a-5p or miR513a-5p mimic, however, interfered with or enhanced, respectively, the breast cancer cell growth inhibition by CFM-4. CFMs also impacted biological properties of the NB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Our studies indicate anti-NB properties of CFM-4 and 5, and suggest that these CFMs and/or their future analogs have potential as anti-NB agents. PMID:25033461

  17. Hepatocyte insulin receptor is a calmodulin binding protein and is functionally inhibited by calmidazolium

    SciTech Connect

    Arnold, T.P.; Pollet, R.J.

    1986-05-01

    Insulin-induced autophosphorylation of the insulin receptor and changes in intracellular Ca/sup + +/ have been proposed as possible mediators of insulin action in target tissues. The authors have investigated the association of the 17kD calcium binding protein calmodulin with the insulin receptor solubilized from rat liver plasma membranes. Insulin receptors solubilized in 0.1% Triton X-100 exhibited strong binding to calmodulin-agarose affinity columns in the presence of 100..mu..M calcium and could be eluded with 100..mu..M ethelene glycol-bis (amino ethel ether) Tetra Acetic Acid (EGTA) with an 80% yield in insulin binding activity. In addition, /sup 125/I-Calmodulin was shown to bind to wheat germ agglutinin purified solubilized receptors, was specifically inhibited by EGTA (100 ..mu..M) and/or calmidazolium (10 ..mu..M) and was found to be insulin-dependent (max 10/sup -10/ M insulin). SDS-polyacrylamide gel electrophoresis data suggests that /sup 125/I-calmodulin may be associated with the 92 kD beta-subunit of the insulin receptor, consistent with the cytoplasmic domain of this subunit. While they have confirmed previous reports that the addition of calcium and calmodulin to solubilized insulin receptors preparations produces no demonstrable change in receptor phosphorylation, the addition of the calmodulin inhibitor calmidazolium did show more than 50% inhibition of insulin stimulated receptor phosphorylation, suggesting that a domain of the calmodulin molecule may be very tightly associated with the insulin receptor. These results indicate that calmodulin binds tightly and specifically to the insulin receptor of the hepatocyte and is insulin dependent. The findings also suggest that this interaction may be functionally significant in mediating insulin-induced receptor phosphorylation as well as other insulin actions. Thus, calmodulin may play a major role as an intracellular contributor to insulin action.

  18. Functional inhibition of aquaporin-3 with a gold-based compound induces blockage of cell proliferation.

    PubMed

    Serna, Ana; Galán-Cobo, Ana; Rodrigues, Claudia; Sánchez-Gomar, Ismael; Toledo-Aral, Juan José; Moura, Teresa F; Casini, Angela; Soveral, Graça; Echevarría, Miriam

    2014-11-01

    AQP3 has been correlated with higher transport of glycerol, increment of ATP content, and larger proliferation capacity. Recently, we described the gold(III) complex Auphen as a very selective and potent inhibitor of AQP3's glycerol permeability (Pgly ). Here we evaluated Auphen effect on the proliferation of various mammalian cell lines differing in AQP3 expression level: no expression (PC12), moderate (NIH/3T3) or high (A431) endogenous expression, cells stably expressing AQP3 (PC12-AQP3), and human HEK293T cells transiently transfected (HEK-AQP3) for AQP3 expression. Proliferation was evaluated in the absence or presence of Auphen (5 μM) by counting number of viable cells and analyzing 5-bromo-2'-deoxyuridine (BrdU) incorporation. Auphen reduced ≈50% the proliferation in A431 and PC12-AQP3, ≈15% in HEK-AQP3 and had no effect in PC12-wt and NIH/3T3. Strong arrest in the S-G2/M phases of the cell cycle, supported by analysis of cyclins (A, B1, D1, E) levels, was observed in AQP3-expressing cells treated with Auphen. Flow-cytometry of propidium iodide incorporation and measurements of mitochondrial dehydrogenases activity confirmed absence of cytotoxic effect of the drug. Functional studies evidenced ≈50% inhibition of A431 Pgly by Auphen, showing that the compound's antiproliferative effect correlates with its ability to inhibit AQP3 Pgly . Role of Cys-40 on AQP3 permeability blockage by Auphen was confirmed by analyzing the mutated protein (AQP3-Ser-40). Accordingly, cells transfected with mutated AQP3 gained resistance to the antiproliferative effect of Auphen. These results highlight an Auphen inhibitory effect on proliferation of cells expressing AQP3 and suggest a targeted therapeutic effect on carcinomas with large AQP3 expression.

  19. AMDE-1 Is a Dual Function Chemical for Autophagy Activation and Inhibition

    PubMed Central

    Li, Min; Yang, Zuolong; Vollmer, Laura L.; Gao, Ying; Fu, Yuanyuan; Liu, Cui; Chen, Xiaoyun; Liu, Peiqing; Vogt, Andreas; Yin, Xiao-Ming

    2015-01-01

    Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy. PMID:25894744

  20. A second-order unconstrained optimization method for canonical-ensemble density-functional methods.

    PubMed

    Nygaard, Cecilie R; Olsen, Jeppe

    2013-03-07

    A second order converging method of ensemble optimization (SOEO) in the framework of Kohn-Sham Density-Functional Theory is presented, where the energy is minimized with respect to an ensemble density matrix. It is general in the sense that the number of fractionally occupied orbitals is not predefined, but rather it is optimized by the algorithm. SOEO is a second order Newton-Raphson method of optimization, where both the form of the orbitals and the occupation numbers are optimized simultaneously. To keep the occupation numbers between zero and two, a set of occupation angles is defined, from which the occupation numbers are expressed as trigonometric functions. The total number of electrons is controlled by a built-in second order restriction of the Newton-Raphson equations, which can be deactivated in the case of a grand-canonical ensemble (where the total number of electrons is allowed to change). To test the optimization method, dissociation curves for diatomic carbon are produced using different functionals for the exchange-correlation energy. These curves show that SOEO favors symmetry broken pure-state solutions when using functionals with exact exchange such as Hartree-Fock and Becke three-parameter Lee-Yang-Parr. This is explained by an unphysical contribution to the exact exchange energy from interactions between fractional occupations. For functionals without exact exchange, such as local density approximation or Becke Lee-Yang-Parr, ensemble solutions are favored at interatomic distances larger than the equilibrium distance. Calculations on the chromium dimer are also discussed. They show that SOEO is able to converge to ensemble solutions for systems that are more complicated than diatomic carbon.

  1. Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition

    PubMed Central

    Oosterhoff, Dinja; Lougheed, Sinéad; van de Ven, Rieneke; Lindenberg, Jelle; van Cruijsen, Hester; Hiddingh, Lotte; Kroon, Jan; van den Eertwegh, Alfons J.M.; Hangalapura, Basav; Scheper, Rik J.; de Gruijl, Tanja D.

    2012-01-01

    Targeting dendritic cells (DC) through the release of suppressive factors is an effective means for tumors to escape immune control. We assessed the involvement of downstream signaling through the JAK2/STAT3 and p38 MAPK pathways in tumor-induced suppression of human DC development. Whereas the JAK2/STAT3 pathway has been pinpointed in mouse studies as a key regulator of myeloid suppression, in human DC this is less well established. We studied the effects of STAT3 inhibition on the suppression of monocyte-derived DC differentiation mediated by a short-list of four predominant suppressive factors and found that pharmacological STAT3 inhibition could only counteract the effects of IL-6. Accordingly, in testing a panel of supernatants derived from 11 cell lines representing various types of solid tumors, STAT3 inhibition only modestly affected the suppressive effects of a minority of supernatants. Importantly, combined interference in the STAT3 and p38 pathways completely prevented inhibition of DC differentiation by all tested supernatants and effected superior DC function, evidenced by increased allogeneic T cell reactivity with elevated IL-12p70/IL-10 ratios and Th1 skewing. Combined STAT3 and p38 inhibition also afforded superior protection against the suppressive effects of primary glioma and melanoma supernatants and induced a shift from CD14+ cells to CD1a+ cells in metastatic melanoma single-cell suspensions, indicating a potential for improved DC differentiation in the tumor microenvironment. We conclude that combined interference in the STAT3 and p38 MAPK signaling pathways is a promising approach to overcome tumor-induced inhibitory signaling in DC precursors and will likely support clinical immunotherapeutic strategies. PMID:22934257

  2. miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice

    PubMed Central

    Hu, Cheng-Hu; Sui, Bing-Dong; Du, Fang-Ying; Shuai, Yi; Zheng, Chen-Xi; Zhao, Pan; Yu, Xiao-Rui; Jin, Yan

    2017-01-01

    MicroRNAs emerge as critical post-transcriptional regulators in bone metabolism. We have previously reported in vitro that miR-21 promotes osteogenesis, while studies have also revealed miR-21 as a regulator of osteoclastogenesis and a promoter of osteoclast differentiation in vitro. However, in vivo data are still lacking in identifying skeletal function of miR-21, particularly its effects on osteoporosis. Here, using miR-21 knockout (miR-21−/−) mice, we investigated effects of miR-21 on bone development, bone remodeling and bone loss. Unexpectedly, miR-21−/− mice demonstrated normal skeletal phenotype in development and maintained osteoblastogenesis in vivo. Besides, miR-21−/− mice showed increased receptor activator of nuclear factor κB ligand (RANKL) and decreased osteoprotegerin (OPG) through miR-21 targeting Sprouty 1 (Spry1). Nevertheless, interestingly, miR-21 deficiency promoted trabecular bone mass accrual physiologically. Furthermore, in pathological states, the protection of bone mass was prominent in miR-21−/− mice. These skeletal effects were attributed to inhibition of bone resorption and osteoclast function by miR-21 deficiency through miR-21 targeting programmed cell death 4 (PDCD4), despite the existence of RANKL. As far as we know, this is the first in vivo evidence of a pro-osteoclastic microRNA. Together, these findings clarified function of miR-21 in bone metabolism, particularly uncovering osteo-protective potential of miR-21 inactivation in osteoporosis. PMID:28240263

  3. Mesenchymal stem cells attenuated PLGA-induced inflammatory responses by inhibiting host DC maturation and function.

    PubMed

    Zhu, Heng; Yang, Fei; Tang, Bo; Li, Xi-Mei; Chu, Ya-Nan; Liu, Yuan-Lin; Wang, Shen-Guo; Wu, De-Cheng; Zhang, Yi

    2015-01-01

    The poly lactic-co-glycolic acid (PLGA) bio-scaffold is a biodegradable scaffold commonly used for tissue repair. However, implanted PLGA scaffolds usually cause serious inflammatory responses around grafts. To improve PLGA scaffold-based tissue repair, it is important to control the PLGA-mediated inflammatory responses. Recent evidence indicated that PLGA induce dendritic cell (DC) maturation in vitro, which may initiate host immune responses. In the present study, we explored the modulatory effects of mesenchymal stem cells (MSC) on PLGA-induced DCs (PLGA-DC). We found that mouse MSCs inhibited PLGA-DC dendrite formation, as well as co-stimulatory molecule and pro-inflammatory factor expression. Functionally, MSC-educated PLGA-DCs promoted Th2 and regulatory T cell differentiation but suppressed Th1 and Th17 cell differentiation. Mechanistically, we determined that PLGA elicited DC maturation via inducing phosphorylation of p38/MAPK and ERK/MAPK pathway proteins in DCs. Moreover, MSCs suppressed PLGA-DCs by partially inactivating those pathways. Most importantly, we found that the MSCs were capable of suppressing DC maturation and immune function in vivo. Also, the proportion of mature DCs in the mice that received MSC-PLGA constructs greatly decreased compared with that of their PLGA-film implantation counterparts. Additionally, MSCs co-delivery increased regulatory T and Th2 cells but decreased the Th1 and Th17 cell numbers in the host spleens. Histological analysis showed that MSCs alleviated the inflammatory responses around the grafted PLGA scaffolds. In summary, our findings reveal a novel function for MSCs in suppressing PLGA-induced host inflammatory response and suggest that DCs are a new cellular target in improving PLGA scaffold-based tissue repair.

  4. A Hybrid PSO-BFGS Strategy for Global Optimization of Multimodal Functions.

    PubMed

    Shutao Li; Mingkui Tan; Tsang, I W; Kwok, James Tin-Yau

    2011-08-01

    Particle swarm optimizer (PSO) is a powerful optimization algorithm that has been applied to a variety of problems. It can, however, suffer from premature convergence and slow convergence rate. Motivated by these two problems, a hybrid global optimization strategy combining PSOs with a modified Broyden-Fletcher-Goldfarb-Shanno (BFGS) method is presented in this paper. The modified BFGS method is integrated into the context of the PSOs to improve the particles' local search ability. In addition, in conjunction with the territory technique, a reposition technique to maintain the diversity of particles is proposed to improve the global search ability of PSOs. One advantage of the hybrid strategy is that it can effectively find multiple local solutions or global solutions to the multimodal functions in a box-constrained space. Based on these local solutions, a reconstruction technique can be adopted to further estimate better solutions. The proposed method is compared with several recently developed optimization algorithms on a set of 20 standard benchmark problems. Experimental results demonstrate that the proposed approach can obtain high-quality solutions on multimodal function optimization problems.

  5. Automated ARGET ATRP Accelerates Catalyst Optimization for the Synthesis of Thiol-Functionalized Polymers.

    PubMed

    Siegwart, Daniel J; Leiendecker, Matthias; Langer, Robert; Anderson, Daniel G

    2012-02-14

    Conventional synthesis of polymers by ATRP is relatively low throughput, involving iterative optimization of conditions in an inert atmosphere. Automated, high-throughput controlled radical polymerization was developed to accelerate catalyst optimization and production of disulfide-functionalized polymers without the need of an inert gas. Using ARGET ATRP, polymerization conditions were rapidly identified for eight different monomers, including the first ARGET ATRP of 2-(diethylamino)ethyl methacrylate and di(ethylene glycol) methyl ether methacrylate. In addition, butyl acrylate, oligo(ethylene glycol) methacrylate 300 and 475, 2-(dimethylamino)ethyl methacrylate, styrene, and methyl methacrylate were polymerized using bis(2-hydroxyethyl) disulfide bis(2-bromo-2-methylpropionate) as the initiator, tris(2-pyridylmethyl)amine as the ligand, and tin(II) 2-ethylhexanoate as the reducing agent. The catalyst and reducing agent concentration was optimized specifically for each monomer, and then a library of polymers was synthesized systematically using the optimized conditions. The disulfide-functionalized chains could be cleaved to two thiol-terminated chains upon exposure to dithiothreitol, which may have utility for the synthesis of polymer bioconjugates. Finally, we demonstrated that these new conditions translated perfectly to conventional batch polymerization. We believe the methods developed here may prove generally useful to accelerate the systematic optimization of a variety of chemical reactions and polymerizations.

  6. Expanded explorations into the optimization of an energy function for protein design.

    PubMed

    Huang, Yao-Ming; Bystroff, Christopher

    2013-01-01

    Nature possesses a secret formula for the energy as a function of the structure of a protein. In protein design, approximations are made to both the structural representation of the molecule and to the form of the energy equation, such that the existence of a general energy function for proteins is by no means guaranteed. Here, we present new insights toward the application of machine learning to the problem of finding a general energy function for protein design. Machine learning requires the definition of an objective function, which carries with it the implied definition of success in protein design. We explored four functions, consisting of two functional forms, each with two criteria for success. Optimization was carried out by a Monte Carlo search through the space of all variable parameters. Cross-validation of the optimized energy function against a test set gave significantly different results depending on the choice of objective function, pointing to relative correctness of the built-in assumptions. Novel energy cross terms correct for the observed nonadditivity of energy terms and an imbalance in the distribution of predicted amino acids. This paper expands on the work presented at the 2012 ACM-BCB.

  7. Antisense oligodeoxynucleotide inhibition as a potent diagnostic tool for gene function in plant biology

    SciTech Connect

    Jansson, Christer; Sun, Chuanxin; Ghebramedhin, Haile; Hoglund, Anna-Stina; Jansson, Christer

    2008-01-15

    Antisense oligodeoxynucleotide (ODN) inhibition emerges as an effective means for probing gene function in plant cells. Employing this method we have established the importance of the SUSIBA2 transcription factor for regulation of starch synthesis in barley endosperm, and arrived at a model for the role of the SUSIBAs in sugar signaling and source-sink commutation during cereal endosperm development. In this addendum we provide additional data demonstrating the suitability of the antisense ODN technology in studies on starch branching enzyme activities in barley leaves. We also comment on the mechanism for ODN uptake in plant cells. Antisense ODNs are short (12-25 nt-long) stretches of single-stranded ODNs that hybridize to the cognate mRNA in a sequence-specific manner, thereby inhibiting gene expression. They are naturally occurring in both prokaryotes and eukaryotes where they partake in gene regulation and defense against viral infection. The mechanisms for antisense ODN inhibition are not fully understood but it is generally considered that the ODN either sterically interferes with translation or promotes transcript degradation by RNase H activation. The earliest indication of the usefulness of antisense ODN technology for the purposes of molecular biology and medical therapy was the demonstration in 1978 that synthetic ODNs complementary to Raos sarcoma virus could inhibit virus replication in tissue cultures of chick embryo fibroblasts. Since then the antisense ODN technology has been widely used in animal sciences and as an important emerging therapeutic approach in clinical medicine. However, antisense ODN inhibition has been an under-exploited strategy for plant tissues, although the prospects for plant cells in suspension cultures to take up single-stranded ODNs was reported over a decade ago. In 2001, two reports from Malho and coworker demonstrated the use of cationic-complexed antisense ODNs to suppress expression of genes encoding pollen

  8. Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis.

    PubMed

    Wang, Chun-Juan; Qu, Chuan-Qiang; Zhang, Jie; Fu, Pei-Cai; Guo, Shou-Gang; Tang, Rong-Hua

    2014-12-01

    Lingo-1 is a negative regulator of myelination. Repairment of demyelinating diseases, such as multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), requires activation of the myelination program. In this study, we observed the effect of RNA interference on Lingo-1 expression, and the impact of Lingo-1 suppression on functional recovery and myelination/remyelination in EAE mice. Lentiviral vectors encoding Lingo-1 short hairpin RNA (LV/Lingo-1-shRNA) were constructed to inhibit Lingo-1 expression. LV/Lingo-1-shRNA of different titers were transferred into myelin oligodendrocyte glycoprotein-induced EAE mice by intracerebroventricular (ICV) injection. Meanwhile, lentiviral vectors carrying nonsense gene sequence (LVCON053) were used as negative control. The Lingo-1 expression was detected and locomotor function was evaluated at different time points (on days 1,3,7,14,21, and 30 after ICV injection). Myelination was investigated by luxol fast blue (LFB) staining.LV/Lingo-1-shRNA administration via ICV injection could efficiently down-regulate the Lingo-1 mRNA and protein expression in EAE mice on days 7,14,21, and 30 (P < 0.01), especially in the 5 × 10(8) TU/mL and 5 × 10(9) TU/mL LV/Lingo-1-shRNA groups. The locomotor function score in the LV/Lingo-1-shRNA treated groups were significantly lower than the untreated or LVCON053 group from day 7 on. The 5 × 10(8) TU/mL LV/Lingo-1-shRNA group achieved the best functional improvement (0.87 ± 0.11 vs. 3.05 ± 0.13, P < 0.001). Enhanced myelination/remyelination was observed in the 5 × 10(7) , 5 × 10(8) , 5 × 10(9) TU/mL LV/Lingo-1-shRNA groups by LFB staining (P < 0.05, P < 0.01, and P < 0.05).The data showed that administering LV/Lingo-1-shRNA by ICV injection could efficiently knockdown Lingo-1 expression in vivo, improve functional recovery and enhance myelination/remyelination. Antagonism of Lingo-1 by RNA interference is, therefore, a promising approach for the

  9. Optimally Functionalized Adhesion for Contact Transfer Printing of Plasmonic Nanostructures on Flexible Substrate.

    PubMed

    Lee, Jihye; Lee, Jun-Young; Yeo, Jong-Souk

    2017-02-01

    This paper demonstrates a facile method to achieve high yield and uniform fabrication for the transfer printing of nanoplasmonic structures on a flexible substrate by providing novel understanding on adhesion layers. The mercapto alkyl carboxylic acids and the alkyl dithiols are used as functionalized adhesion layers and further optimized by controlling the terminal group as well as the length and composition of the functionalization on flat and nanostructured gold surfaces. Our approach of optimized adhesion has been successfully implemented to the transfer printing of functionalized gold nanostructure arrays, thus producing much higher yield of 97.6% and uniform fabrication of nanostructures on a flexible substrate and enabling applications such as flexible nanoplasmonic devices and biosensing platforms.

  10. Optimizing rTMS treatment of a balance disorder with EEG neural synchrony and functional connectivity.

    PubMed

    Guofa Shou; Han Yuan; Urbano, Diamond; Yoon-Hee Cha; Lei Ding

    2016-08-01

    Repetitive transcranial magnetic stimulation (rTMS) has been increasingly used for its potential treatment effects across diverse mental disorders. However, the treatment effect is elusive and the rate of positive responders is not high, which make it in great demand of optimizing rTMS protocols to improve the treatment effects and the rate. In this regard, neural activity guided optimization has indicated great potential in several neuroimaging studies. In this paper, we present our ongoing work on optimizing rTMS treatment of a balance disorder, i.e., Mal de Debarquement syndrome (MdDS), by investigating treatment-related EEG neural synchrony and functional connectivity changes. Motivated by our previous pilot study of rTMS on MdDS, we firstly applied a bilateral dorsolateral prefrontal cortex (DLPFC) rTMS protocol to evaluate its efficacy and the treatment-related neural responses via an independent component analysis (ICA)-based framework. Thereafter, guided by identified EEG neural synchrony and functional connectivity patterns, we proposed three potential stimulation targets covering posterior nodes of the default mode network (DMN), and implemented a new rTMS protocol by stimulating the target with the great symptoms relief. The preliminary clinical response data has indicated that the new rTMS protocol significantly increase the rate of positive responders and the degrees of the improvement. The present study demonstrates that it is promising to integrate EEG neural synchrony and functional connectivity into the optimization of rTMS protocols for different mental disorders.

  11. Optimal contrast function in the unbalanced fiber optic Michelson interferometer for dislocation sensor

    NASA Astrophysics Data System (ADS)

    Szustakowski, Mieczyslaw; Palka, Norbert; Ciurapinski, Wieslaw M.

    2004-09-01

    Theoretical description of a contrast in an unbalanced fiber optic Michelson's interferometer with a multimode laser was shown. Periodic contrast oscillations, which depend on a laser spectrum, occur if a measuring arm of the interferometer is elongated. Required characteristic features of the contrast for an elongation sensor were determined. Influences of laser spectrum parameters (wavelength, halfwidth and mode spacing) as well as laser mode amplitudes on the contrast were simulated. Optimal spectrum for the dislocation sensor was determined theoretically. A laser which parameters fulfilled the requirements was found and its spectrum was measured. The measured contrast function was very similar to the optimal theoretical plot what proves correctness of the calculations.

  12. Optimization of global model composed of radial basis functions using the term-ranking approach

    SciTech Connect

    Cai, Peng; Tao, Chao Liu, Xiao-Jun

    2014-03-15

    A term-ranking method is put forward to optimize the global model composed of radial basis functions to improve the predictability of the model. The effectiveness of the proposed method is examined by numerical simulation and experimental data. Numerical simulations indicate that this method can significantly lengthen the prediction time and decrease the Bayesian information criterion of the model. The application to real voice signal shows that the optimized global model can capture more predictable component in chaos-like voice data and simultaneously reduce the predictable component (periodic pitch) in the residual signal.

  13. A Sequential Optimization Sampling Method for Metamodels with Radial Basis Functions

    PubMed Central

    Pan, Guang; Ye, Pengcheng; Yang, Zhidong

    2014-01-01

    Metamodels have been widely used in engineering design to facilitate analysis and optimization of complex systems that involve computationally expensive simulation programs. The accuracy of metamodels is strongly affected by the sampling methods. In this paper, a new sequential optimization sampling method is proposed. Based on the new sampling method, metamodels can be constructed repeatedly through the addition of sampling points, namely, extrema points of metamodels and minimum points of density function. Afterwards, the more accurate metamodels would be constructed by the procedure above. The validity and effectiveness of proposed sampling method are examined by studying typical numerical examples. PMID:25133206

  14. Estimating Contrast Transfer Function and Associated Parameters by Constrained Nonlinear Optimization

    SciTech Connect

    Yang, Chao; Jiang, Wen; Chen, Dong-Hua; Adiga, Umesh; Ng, Esmond G.; Chiu, Wah

    2008-07-28

    The three-dimensional reconstruction of macromolecules from two-dimensional single-particle electron images requires determination and correction of the contrast transfer function (CTF) and envelope function. A computational algorithm based on constrained non-linear optimization is developed to estimate the essential parameters in the CTF and envelope function model simultaneously and automatically. The application of this estimation method is demonstrated with focal series images of amorphous carbon film as well as images of ice-embedded icosahedral virus particles suspended across holes.

  15. Inhibition of vascular endothelial growth factor by small interfering RNA upregulates differentiation, maturation and function of dendritic cells

    PubMed Central

    WANG, HAIYAN; ZHANG, LUPING; ZHANG, SHAOYAN; LI, YANNIAN

    2015-01-01

    This study aimed to investigate the effects of vascular endothelial growth factor (VEGF) secreted by MCF-7 breast cancer cells on the differentiation, maturation and function of dendritic cells (DCs). Small interfering RNAs (siRNAs) directed against the VEGF gene were designed and transfected into MCF-7 breast cancer cells at an optimal concentration (100 nmol/l) using cationic liposome transfection reagent, whereas the control group was transfected with only transfection reagent. Western blot analysis and ELISA were used to determine VEGF protein expression and VEGF concentration, respectively. Mononuclear cells were cultured with the culture supernatants from primary MCF-7 cells (control group) and siRNA-treated MCF-7 cells (siRNA group). The DC phenotypes, including CD1a, CD80, CD83, CD86 and HLA-DR, were evaluated by flow cytometry. The MTT assay was used to assess the cytotoxicity of DC-mediated tumor-specific cytotoxic T lymphocytes (CTLs) against MCF-7 cells in the two different culture supernatants. The VEGF-targeted constructed siRNA inhibited VEGF expression in MCF-7 cells. Cultivation with the culture supernatants from MCF-7 cells treated with siRNA affected DC morphology. DCs in the siRNA group exhibited a significantly higher expression of CD86, CD80, CD83 and HLA-DR compared to the cells in the control group, whereas the expression of CD1a in the siRNA group was significantly lower compared to that in the control group. The cytotoxic activity of CTLs mediated by DCs was significantly altered by siRNA transfection. These results indicated that VEGF may play a significant role in tumor development, progression and immunosuppression. PMID:25452786

  16. Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies.

    PubMed

    Hossain, Fokhrul; Al-Khami, Amir A; Wyczechowska, Dorota; Hernandez, Claudia; Zheng, Liqin; Reiss, Krzystoff; Valle, Luis Del; Trillo-Tinoco, Jimena; Maj, Tomasz; Zou, Weiping; Rodriguez, Paulo C; Ochoa, Augusto C

    2015-11-01

    Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies.

  17. Achyrocline satureioides (Lam.) D.C. Hydroalcoholic Extract Inhibits Neutrophil Functions Related to Innate Host Defense

    PubMed Central

    Barioni, Eric Diego; Machado, Isabel Daufenback; Rodrigues, Stephen Fernandes de Paula; Ferraz-de-Paula, Viviane; Wagner, Theodoro Marcel; Cogliati, Bruno; Corrêa dos Santos, Matheus; Machado, Marina da Silva; de Andrade, Sérgio Faloni; Niero, Rivaldo; Farsky, Sandra Helena Poliselli

    2013-01-01

    Achyrocline satureioides (Lam.) D.C. is a herb native to South America, and its inflorescences are popularly employed to treat inflammatory diseases. Here, the effects of the in vivo actions of the hydroalcoholic extract obtained from inflorescences of A. satureioides on neutrophil trafficking into inflamed tissue were investigated. Male Wistar rats were orally treated with A. satureioides extract, and inflammation was induced one hour later by lipopolysaccharide injection into the subcutaneous tissue. The number of leukocytes and the amount of chemotactic mediators were quantified in the inflammatory exudate, and adhesion molecule and toll-like receptor 4 (TLR-4) expressions and phorbol-myristate-acetate- (PMA-) stimulated oxidative burst were quantified in circulating neutrophils. Leukocyte-endothelial interactions were quantified in the mesentery tissue. Enzymes and tissue morphology of the liver and kidney were evaluated. Treatment with A. satureioides extract reduced neutrophil influx and secretion of leukotriene B4 and CINC-1 in the exudates, the number of rolling and adhered leukocytes in the mesentery postcapillary venules, neutrophil L-selectin, β2-integrin and TLR-4 expression, and oxidative burst, but did not cause an alteration in the morphology and activities of liver and kidney. Together, the data show that A. satureioides extract inhibits neutrophil functions related to the innate response and does not cause systemic toxicity. PMID:23476704

  18. Targeting Hsp90-Cdc37: a promising therapeutic strategy by inhibiting Hsp90 chaperone function.

    PubMed

    Wang, Lei; Li, Li; Gu, Kai; Xu, Xiao-Li; You, Qi-Dong; Sun, Hao-Peng

    2016-05-27

    The Hsp90 chaperone protein regulates the folding, maturation and stability of a wide variety of oncoproteins. In recent years, many Hsp90 inhibitors have entered into the clinical trials while all of them target ATPase showing similar binding capacity and kinds of side-effects so that none have reached to the market. During the regulation progress, numerous protein-protein interactions (PPI) such as Hsp90 and client proteins or cochaperones are involved. With the Hsp90-cochaperones PPI networks being more and more clear, many cancerous proteins have been reported to be tightly correlated to Hsp90-cochaperones PPI. Among them, Hsp90-Cdc37 PPI has been widely reported to associate with numerous protein kinases, making it a novel target for the treatment of cancers. In this paper, we briefly review the strategies and modulators targeting Hsp90-Cdc37 complex including direct and indirect regulation mechanism. Through these discussions we expect to present inspirations for new insights into an alternative way to inhibit Hsp90 chaperone function.

  19. Properdistatin inhibits angiogenesis and improves vascular function in human melanoma xenografts with low thrombospondin-1 expression

    PubMed Central

    Gaustad, Jon-Vidar; Simonsen, Trude G.; Andersen, Lise Mari K.; Rofstad, Einar K.

    2016-01-01

    In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function. PMID:27756886

  20. Low-power laser irradiation of blood inhibits platelet function: role of cyclic GMP

    NASA Astrophysics Data System (ADS)

    Brill, Alexander G.; Brill, Gregory E.; Shenkman, Boris; Tamarin, Ilya; Dardik, Rima; Varon, David; Savion, Naphtali

    1998-12-01

    The aim of the present work was to investigate effect of low power laser irradiation (LPLI) on platelet function in vitro. He-Ne laser (Optronix, USA; (lambda) - 632.8 nm, output power - 7 mW) was employed. Platelet adhesion and aggregation in whole blood (WB) under defined shear conditions were assayed by a Cone and Plate(let) Analyzer. Platelet activation was evaluated by flow cytometry. Level of platelet cGMP was estimated by immunoenzyme assay. Experiments performed showed that LPLI of WB resulted in decrease of platelet deposition on extracellular matrix at high shear rate (1300 s-1). Similar results were obtained using surfaces precoated with either collagen type I or von Willebrand factor. LPLI inhibited fibrinogen binding as well as P-selectin expression on the platelet membrane, induced by thrombin analogue. It was found out that primary acceptor of laser energy responsible for the effect on platelets was located in platelets themselves and not in blood plasma or in other blood cells. LPLI of gel- filtered platelets resulted in increase of intracellular level of cGMP both in the absence and in presence of izobutylmethylxantine (phosphodiesterase inhibitor) suggesting stimulation of synthesis rather than destruction of cGMP under the influence of LPLI. It is suggested that guanylate cyclase and/or NO-synthase might serve as primary acceptors of He-Ne laser light in platelets.

  1. Development of inhibition as a function of the presence of a supernatural agent.

    PubMed

    King, Ashley C

    2011-01-01

    In this study the author examined the developmental differences in inhibition and cognition of 4-8-year-old children as a function of the suggested presence of a supernatural agent. Previous evolutionarily-relevant research has suggested that humans are naturally primed to think in terms of supernatural agents and that, given the correct context, individuals readily accept novel supernatural entities and alter their behavior accordingly. All children in this study played 4 games designed to assess their present level of inhibitory and cognitive development. Children in the experimental condition were also introduced to an invisible Princess Alice and were told that she was watching during the games. Following these measures, all children engaged in a resistance-to-temptation task. Results revealed that cognitively advanced children were more likely to express belief in Princess Alice than were less cognitively advanced children. This research provides support that cognitive maturity, rather than immaturity, may be necessary for children to express belief in novel supernatural agents.

  2. Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2

    PubMed Central

    Jayathilaka, Nimanthi; Gaffney, Kevin J.; Dey, Raja; Jarusiewicz, Jamie A.; Noridomi, Kaori; Philips, Michael A.; Lei, Xiao; He, Ju; Ye, Jun; Gao, Tao; Petasis, Nicos A.; Chen, Lin

    2012-01-01

    Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and 19F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development. PMID:22396528

  3. Mean-variance portfolio optimization by using time series approaches based on logarithmic utility function

    NASA Astrophysics Data System (ADS)

    Soeryana, E.; Fadhlina, N.; Sukono; Rusyaman, E.; Supian, S.

    2017-01-01

    Investments in stocks investors are also faced with the issue of risk, due to daily price of stock also fluctuate. For minimize the level of risk, investors usually forming an investment portfolio. Establishment of a portfolio consisting of several stocks are intended to get the optimal composition of the investment portfolio. This paper discussed about optimizing investment portfolio of Mean-Variance to stocks by using mean and volatility is not constant based on logarithmic utility function. Non constant mean analysed using models Autoregressive Moving Average (ARMA), while non constant volatility models are analysed using the Generalized Autoregressive Conditional heteroscedastic (GARCH). Optimization process is performed by using the Lagrangian multiplier technique. As a numerical illustration, the method is used to analyse some Islamic stocks in Indonesia. The expected result is to get the proportion of investment in each Islamic stock analysed.

  4. Experimental design and multiple response optimization. Using the desirability function in analytical methods development.

    PubMed

    Candioti, Luciana Vera; De Zan, María M; Cámara, María S; Goicoechea, Héctor C

    2014-06-01

    A review about the application of response surface methodology (RSM) when several responses have to be simultaneously optimized in the field of analytical methods development is presented. Several critical issues like response transformation, multiple response optimization and modeling with least squares and artificial neural networks are discussed. Most recent analytical applications are presented in the context of analytLaboratorio de Control de Calidad de Medicamentos (LCCM), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, C.C. 242, S3000ZAA Santa Fe, ArgentinaLaboratorio de Control de Calidad de Medicamentos (LCCM), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, C.C. 242, S3000ZAA Santa Fe, Argentinaical methods development, especially in multiple response optimization procedures using the desirability function.

  5. Membrane Vesicles Released by Intestinal Epithelial Cells Infected with Rotavirus Inhibit T-Cell Function

    PubMed Central

    Barreto, Alfonso; Rodríguez, Luz-Stella; Rojas, Olga Lucía; Wolf, Marie; Greenberg, Harry B.; Franco, Manuel A.

    2010-01-01

    Abstract Rotavirus (RV) predominantly replicates in intestinal epithelial cells (IEC), and “danger signals” released by these cells may modulate viral immunity. We have recently shown that human model IEC (Caco-2 cells) infected with rhesus-RV release a non-inflammatory group of immunomodulators that includes heat shock proteins (HSPs) and TGF-β1. Here we show that both proteins are released in part in association with membrane vesicles (MV) obtained from filtrated Caco-2 supernatants concentrated by ultracentrifugation. These MV express markers of exosomes (CD63 and others), but not of the endoplasmic reticulum (ER) or nuclei. Larger quantities of proteins associated with MV were released by RV-infected cells than by non-infected cells. VP6 co-immunoprecipitated with CD63 present in these MV, and VP6 co-localized with CD63 in RV-infected cells, suggesting that this viral protein is associated with the MV, and that this association occurs intracellularly. CD63 present in MV preparations from stool samples from 36 children with gastroenteritis due or not due to RV were analyzed. VP6 co-immunoprecipitated with CD63 in 3/8 stool samples from RV-infected children, suggesting that these MV are released by RV-infected cells in vivo. Moreover, fractions that contained MV from RV-infected cells induced death and inhibited proliferation of CD4+ T cells to a greater extent than fractions from non-infected cells. These effects were in part due to TGF-β, because they were reversed by treatment of the T cells with the TGF-β-receptor inhibitor ALK5i. MV from RV-infected and non-infected cells were heterogeneous, with morphologies and typical flotation densities described for exosomes (between 1.10 and 1.18 g/mL), and denser vesicles (>1.24 g/mL). Both types of MV from RV-infected cells were more efficient at inhibiting T-cell function than were those from non-infected cells. We propose that RV infection of IEC releases MV that modulate viral immunity. PMID:21142445

  6. Optimization of in vitro inhibition of HT-29 colon cancer cell cultures by Solanum tuberosum L. extracts.

    PubMed

    Zuber, T; Holm, D; Byrne, P; Ducreux, L; Taylor, M; Kaiser, M; Stushnoff, C

    2015-01-01

    Secondary metabolites in potato have been reported to possess bioactive properties, including growth inhibition of cancer cells. Because potatoes are widely consumed globally, potential health benefits may have broad application. Thus we investigated growth inhibition of HT-29 colon cancer cell cultures by extracts from 13 diverse genetic breeding clones. Extracts from three pigmented selections (CO97226-2R/R, CO97216-1P/P, CO04058-3RW/RW) inhibited growth of in vitro HT-29 cell cultures more effectively than other clones tested. While inhibition was highest from pigmented selections and pigmented tuber tissue sectors, not all pigmented breeding lines tested had appreciable inhibitory properties. Thus, inhibition was not uniquely linked to pigmentation. Immature tubers had the highest inhibitory properties, and in most cases mature tubers retained very low inhibition properties. Flowers and skins inhibited strongly at lower extract concentrations. An extract consisting of 7.2 mg mL⁻¹ cell culture medium was the lowest effective concentration. While raw tuber extracts inhibited most effectively, a few clones at higher concentrations retained inhibition after cooking. Heated whole tubers retained higher inhibition than heated aqueous extracts. While all aqueous extracts from the two tuber selections (CO97216-1P/P and CO97226-2R/R) inhibited HT-29 cell cultures, inhibition was significantly enhanced in purple pigmented tubers of CO97216-1P/P prepared cryogenically as liquid nitrogen powders compared to extracts from freeze dried samples. Upregulation of caspase-3 protease activity, indicative of apoptosis, was highest among the most inhibitory clone samples. The unique sectorial red pigment expressing selection (CO04058-3RW/RW) provided a model system that isolated expression in pigmented sectors, and thus eliminated developmental, environmental and genetic confounding.

  7. Optimized goniometer for determination of the scattering phase function of suspended particles: simulations and measurements

    NASA Astrophysics Data System (ADS)

    Foschum, Florian; Kienle, Alwin

    2013-08-01

    We present simulations and measurements with an optimized goniometer for determination of the scattering phase function of suspended particles. We applied the Monte Carlo method, using a radially layered cylindrical geometry and mismatched boundary conditions, in order to investigate the influence of reflections caused by the interfaces of the glass cuvette and the scatterer concentration on the accurate determination of the scattering phase function. Based on these simulations we built an apparatus which allows direct measurement of the phase function from ϑ=7 deg to ϑ=172 deg without any need for correction algorithms. Goniometric measurements on polystyrene and SiO2 spheres proved this concept. Using the validated goniometer, we measured the phase function of yeast cells, demonstrating the improvement of the new system compared to standard goniometers. Furthermore, the scattering phase function of different fat emulsions, like Intralipid, was determined precisely.

  8. A Preliminary Transcranial Magnetic Stimulation Study of Cortical Inhibition and Excitability in High-Functioning Autism and Asperger Disorder

    ERIC Educational Resources Information Center

    Enticott, Peter G.; Rinehart, Nicole J.; Tonge, Bruce J.; Bradshaw, John L.; Fitzgerald, Paul B.

    2010-01-01

    Aim: Controversy surrounds the distinction between high-functioning autism (HFA) and Asperger disorder, but motor abnormalities are associated features of both conditions. This study examined motor cortical inhibition and excitability in HFA and Asperger disorder using transcranial magnetic stimulation (TMS). Method: Participants were diagnosed by…

  9. Optimization of the dressing parameters in cylindrical grinding based on a generalized utility function

    NASA Astrophysics Data System (ADS)

    Aleksandrova, Irina

    2016-01-01

    The existing studies, concerning the dressing process, focus on the major influence of the dressing conditions on the grinding response variables. However, the choice of the dressing conditions is often made, based on the experience of the qualified staff or using data from reference books. The optimal dressing parameters, which are only valid for the particular methods and dressing and grinding conditions, are also used. The paper presents a methodology for optimization of the dressing parameters in cylindrical grinding. The generalized utility function has been chosen as an optimization parameter. It is a complex indicator determining the economic, dynamic and manufacturing characteristics of the grinding process. The developed methodology is implemented for the dressing of aluminium oxide grinding wheels by using experimental diamond roller dressers with different grit sizes made of medium- and high-strength synthetic diamonds type ??32 and ??80. To solve the optimization problem, a model of the generalized utility function is created which reflects the complex impact of dressing parameters. The model is built based on the results from the conducted complex study and modeling of the grinding wheel lifetime, cutting ability, production rate and cutting forces during grinding. They are closely related to the dressing conditions (dressing speed ratio, radial in-feed of the diamond roller dresser and dress-out time), the diamond roller dresser grit size/grinding wheel grit size ratio, the type of synthetic diamonds and the direction of dressing. Some dressing parameters are determined for which the generalized utility function has a maximum and which guarantee an optimum combination of the following: the lifetime and cutting ability of the abrasive wheels, the tangential cutting force magnitude and the production rate of the grinding process. The results obtained prove the possibility of control and optimization of grinding by selecting particular dressing

  10. Geometry Design Optimization of Functionally Graded Scaffolds for Bone Tissue Engineering: A Mechanobiological Approach

    PubMed Central

    Boccaccio, Antonio; Uva, Antonio Emmanuele; Fiorentino, Michele; Mori, Giorgio; Monno, Giuseppe

    2016-01-01

    Functionally Graded Scaffolds (FGSs) are porous biomaterials where porosity changes in space with a specific gradient. In spite of their wide use in bone tissue engineering, possible models that relate the scaffold gradient to the mechanical and biological requirements for the regeneration of the bony tissue are currently missing. In this study we attempt to bridge the gap by developing a mechanobiology-based optimization algorithm aimed to determine the optimal graded porosity distribution in FGSs. The algorithm combines the parametric finite element model of a FGS, a computational mechano-regulation model and a numerical optimization routine. For assigned boundary and loading conditions, the algorithm builds iteratively different scaffold geometry configurations with different porosity distributions until the best microstructure geometry is reached, i.e. the geometry that allows the amount of bone formation to be maximized. We tested different porosity distribution laws, loading conditions and scaffold Young’s modulus values. For each combination of these variables, the explicit equation of the porosity distribution law–i.e the law that describes the pore dimensions in function of the spatial coordinates–was determined that allows the highest amounts of bone to be generated. The results show that the loading conditions affect significantly the optimal porosity distribution. For a pure compression loading, it was found that the pore dimensions are almost constant throughout the entire scaffold and using a FGS allows the formation of amounts of bone slightly larger than those obtainable with a homogeneous porosity scaffold. For a pure shear loading, instead, FGSs allow to significantly increase the bone formation compared to a homogeneous porosity scaffolds. Although experimental data is still necessary to properly relate the mechanical/biological environment to the scaffold microstructure, this model represents an important step towards optimizing geometry

  11. Functional inhibition of chemokine receptor CCR2 by dicer-substrate-siRNA prevents pain development

    PubMed Central

    Midavaine, Élora; Dansereau, Marc-André; Tétreault, Pascal; Longpré, Jean-Michel; Jacobi, Ashley M; Rose, Scott D; Behlke, Mark A; Beaudet, Nicolas; Sarret, Philippe

    2016-01-01

    Background Accumulating evidence suggests that the C-C chemokine ligand 2 (CCL2, or monocyte chemoattractant protein 1) acts as a neuromodulator in the central nervous system through its binding to the C-C chemokine receptor 2 (CCR2). Notably, it is well established that the CCL2/CCR2 axis plays a key role in neuron-glia communication as well as in spinal nociceptive transmission. Gene silencing through RNA interference has recently emerged as a promising avenue in research and drug development, including therapeutic management of chronic pain. In the present study, we used 27-mer Dicer-substrate small interfering RNA (DsiRNA) targeting CCR2 and assessed their ability to reverse the nociceptive behaviors induced by spinal CCL2 injection or following intraplantar injection of complete Freund’s adjuvant. Results To this end, we first developed high-potency DsiRNAs designed to target different sequences distributed across the rat CCR2 (rCCR2) messenger RNA. For optimization, methyl groups were added to the two most potent DsiRNA candidates (Evader and M7 2′-O-methyl modified duplexes) in order to improve in vivo duplex stability and to reduce potential immunostimulatory activity. Our results demonstrated that all modified candidates formulated with the cell-penetrating peptide reagent Transductin showed strong RNAi activity following intrathecal delivery, exhibiting >50% rCCR2 knockdown in lumbar dorsal root ganglia. Accordingly, we found that these DsiRNA duplexes were able to reduce spinal microglia activation and were effective at blocking CCL2-induced mechanical hypersensitivity. Along with similar reductions of rCCR2 messenger RNA, both sequences and methylation patterns were similarly effective in inhibiting the CCL2 nociceptive action for the whole seven days testing period, compared to mismatch DsiRNA. DsiRNAs against CCR2 also reversed the hypernociceptive responses observed in the complete Freund’s adjuvant-induced inflammatory chronic pain model

  12. Optimizing the general linear model for functional near-infrared spectroscopy: an adaptive hemodynamic response function approach

    PubMed Central

    Uga, Minako; Dan, Ippeita; Sano, Toshifumi; Dan, Haruka; Watanabe, Eiju

    2014-01-01

    Abstract. An increasing number of functional near-infrared spectroscopy (fNIRS) studies utilize a general linear model (GLM) approach, which serves as a standard statistical method for functional magnetic resonance imaging (fMRI) data analysis. While fMRI solely measures the blood oxygen level dependent (BOLD) signal, fNIRS measures the changes of oxy-hemoglobin (oxy-Hb) and deoxy-hemoglobin (deoxy-Hb) signals at a temporal resolution severalfold higher. This suggests the necessity of adjusting the temporal parameters of a GLM for fNIRS signals. Thus, we devised a GLM-based method utilizing an adaptive hemodynamic response function (HRF). We sought the optimum temporal parameters to best explain the observed time series data during verbal fluency and naming tasks. The peak delay of the HRF was systematically changed to achieve the best-fit model for the observed oxy- and deoxy-Hb time series data. The optimized peak delay showed different values for each Hb signal and task. When the optimized peak delays were adopted, the deoxy-Hb data yielded comparable activations with similar statistical power and spatial patterns to oxy-Hb data. The adaptive HRF method could suitably explain the behaviors of both Hb parameters during tasks with the different cognitive loads during a time course, and thus would serve as an objective method to fully utilize the temporal structures of all fNIRS data. PMID:26157973

  13. Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function.

    PubMed

    Varanasi, Siva Karthik; Reddy, Pradeep B J; Bhela, Siddheshvar; Jaggi, Ujjaldeep; Gimenez, Fernanda; Rouse, Barry T

    2017-04-01

    Ocular infection with herpes simplex virus 1 (HSV-1) sets off an inflammatory reaction in the cornea which leads to both virus clearance and chronic lesions that are orchestrated by CD4 T cells. Approaches that enhance the function of regulatory T cells (Treg) and dampen effector T cells can be effective to limit stromal keratitis (SK) lesion severity. In this report, we explore the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (Aza; a cytosine analog) to limit HSV-1-induced ocular lesions. We show that therapy begun after infection when virus was no longer actively replicating resulted in a pronounced reduction in lesion severity, with markedly diminished numbers of T cells and nonlymphoid inflammatory cells, along with reduced cytokine mediators. The remaining inflammatory reactions had a change in the ratio of CD4 Foxp3(+) Treg to effector Th1 CD4 T cells in ocular lesions and lymphoid tissues, with Treg becoming predominant over the effectors. In addition, compared to those from control mice, Treg from Aza-treated mice showed more suppressor activity in vitro and expressed higher levels of activation molecules. Additionally, cells induced in vitro in the presence of Aza showed epigenetic differences in the Treg-specific demethylated region (TSDR) of Foxp3 and were more stable when exposed to inflammatory cytokines. Our results show that therapy with Aza is an effective means of controlling a virus-induced inflammatory reaction and may act mainly by the effects on Treg.IMPORTANCE HSV-1 infection has been shown to initiate an inflammatory reaction in the cornea that leads to tissue damage and loss of vision. The inflammatory reaction is orchestrated by gamma interferon (IFN-γ)-secreting Th1 cells, and regulatory T cells play a protective role. Hence, novel therapeutics that can rebalance the ratio of regulatory T cells to effectors are a relevant issue. This study opens up a new avenue in treating HSV-induced SK lesions by

  14. Parametric Optimization of Some Critical Operating System Functions--An Alternative Approach to the Study of Operating Systems Design

    ERIC Educational Resources Information Center

    Sobh, Tarek M.; Tibrewal, Abhilasha

    2006-01-01

    Operating systems theory primarily concentrates on the optimal use of computing resources. This paper presents an alternative approach to teaching and studying operating systems design and concepts by way of parametrically optimizing critical operating system functions. Detailed examples of two critical operating systems functions using the…

  15. Hull-form optimization of a container ship based on bell-shaped modification function

    NASA Astrophysics Data System (ADS)

    Choi, Hee Jong

    2015-09-01

    In the present study, a hydrodynamic hull-form optimization algorithm for a container ship was presented in terms of the minimum wave-making resistance. Bell-shaped modification functions were developed to modify the original hull-form and a sequential quadratic programming algorithm was used as an optimizer. The wave-making resistance as an objective function was obtained by the Rankine source panel method in which non-linear free surface conditions and the trim and sinkage of the ship were fully taken into account. Numerical computation was performed to investigate the validity and effectiveness of the proposed hull-form modification algorithm for the container carrier. The computational results were validated by comparing them with the experimental data.

  16. Altered brain activation during response inhibition and error processing in subjects with Internet gaming disorder: a functional magnetic imaging study.

    PubMed

    Ko, Chih-Hung; Hsieh, Tsyh-Jyi; Chen, Chiao-Yun; Yen, Cheng-Fang; Chen, Cheng-Sheng; Yen, Ju-Yu; Wang, Peng-Wei; Liu, Gin-Chung

    2014-12-01

    The aim of the present study was to evaluate the impulsivity and brain correlates of response inhibition and error processing among subjects with Internet gaming disorder (IGD). We evaluated the response inhibition and error processing by functional magnetic resonance imaging (fMRI) in subjects with IGD and controls. Twenty-six men with IGD for at least 2 years and 23 controls with no history of IGD were recruited as the IGD and control groups, respectively. All subjects performed the event-related designed Go/No-go task under fMRI and completed questionnaires related to Internet addiction and impulsivity. The IGD group exhibited a higher score for impulsivity than the control group. The IGD group also exhibited higher brain activation when processing response inhibition over the left orbital frontal lobe and bilateral caudate nucleus than controls. Both the IGD and control groups exhibited activation of the insula and anterior cingulate cortex during error processing. The activation over the right insula was lower in the subjects with IGD than the control group. Our results support the fact that the fronto-striatal network involved in response inhibition, and the salience network, anchored by the anterior cingulate and insula, contributes to error processing. Further, adults with IGD have impaired insular function in error processing and greater activation of the fronto-striatal network in order to maintain their response inhibition performance.

  17. Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

    PubMed Central

    Peter, Stefanie; Bultinck, Jennyfer; Myant, Kevin; Jaenicke, Laura A; Walz, Susanne; Müller, Judith; Gmachl, Michael; Treu, Matthias; Boehmelt, Guido; Ade, Carsten P; Schmitz, Werner; Wiegering, Armin; Otto, Christoph; Popov, Nikita; Sansom, Owen; Kraut, Norbert; Eilers, Martin

    2014-01-01

    Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. See also: FX Schaub & JL Cleveland (December 2014) PMID:25253726

  18. Myofibroblast differentiation and its functional properties are inhibited by nicotine and e-cigarette via mitochondrial OXPHOS complex III

    PubMed Central

    Lei, Wei; Lerner, Chad; Sundar, Isaac K.; Rahman, Irfan

    2017-01-01

    Nicotine is the major stimulant in tobacco products including e-cigarettes. Fibroblast to myofibroblast differentiation is a key process during wound healing and is dysregulated in lung diseases. The role of nicotine and e-cigarette derived nicotine on cellular functions including profibrotic response and other functional aspects is not known. We hypothesized that nicotine and e-cigarettes affect myofibroblast differentiation, gel contraction, and wound healing via mitochondria stress through nicotinic receptor-dependent mechanisms. To test the hypothesis, we exposed human lung fibroblasts with various doses of nicotine and e-cigarette condensate and determined myofibroblast differentiation, mitochondrial oxidative phosphorylation (OXPHOS), wound healing, and gel contraction at different time points. We found that both nicotine and e-cigarette inhibit myofibroblast differentiation as shown by smooth muscle actin and collagen type I, alpha 1 abundance. Nicotine and e-cigarette inhibited OXPHOS complex III accompanied by increased MitoROS, and this effect was augmented by complex III inhibitor antimycin A. These mitochondrial associated effects by nicotine resulted in inhibition of myofibroblast differentiation. These effects were associated with inhibition of wound healing and gel contraction suggesting that nicotine is responsible for dysregulated repair during injurious responses. Thus, our data suggest that nicotine causes dysregulated repair by inhibition of myofibroblast differentiation via OXPHOS pathway. PMID:28256533

  19. Estimation of an Optimal Stimulus Amplitude for Using Vestibular Stochastic Stimulation to Improve Balance Function

    NASA Technical Reports Server (NTRS)

    Goel, R.; Kofman, I.; DeDios, Y. E.; Jeevarajan, J.; Stepanyan, V.; Nair, M.; Congdon, S.; Fregia, M.; Peters, B.; Cohen, H.; Wood, S.; Bloomberg, J. J.; Mulavara, A. P.

    2015-01-01

    Sensorimotor changes such as postural and gait instabilities can affect the functional performance of astronauts when they transition across different gravity environments. We are developing a method, based on stochastic resonance (SR), to enhance information transfer by applying non-zero levels of external noise on the vestibular system (vestibular stochastic resonance, VSR). The goal of this project was to determine optimal levels of stimulation for SR applications by using a defined vestibular threshold of motion detection.

  20. Role of functional imaging in treatment plan optimization of stereotactic body radiation therapy for liver cancer.

    PubMed

    De Bari, Berardino; Jumeau, Raphael; Deantonio, Letizia; Adib, Salim; Godin, Sarah; Zeverino, Michele; Moeckli, Raphael; Bourhis, Jean; Prior, John O; Ozsahin, Mahmut

    2016-10-13

    We report the first known instance of the clinical use of 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) for the optimization of radiotherapy treatment planning and for the follow-up of acute toxicity in a patient undergoing stereotactic body radiation therapy for hepatocellular carcinoma. In our experience, HBS allowed the identification and the sparing of more functioning liver areas, thus potentially reducing the risk of radiation-induced liver toxicity.

  1. The European flounder (Platichthys flesus) TP53 functions as a temperature-sensitive transcription factor which inhibits cell growth in yeast.

    PubMed

    Cachot, J; Flaman, J M; Frébourg, T; Leboulenger, F

    2004-01-07

    Numerous studies focus on biological roles of the TP53 tumor suppressor gene in mammals but little is known about the actual function of TP53 in lower vertebrates. In this study, we used an in vivo functional assay in yeast to address the transactivation capacity of the flounder TP53 protein. We showed that the flounder TP53 acts as a sequence-specific transcription factor which is able to transactivate various human promoters containing a p53-responsive element (RE). This transcriptional activity was completely abrogated in the Val147Glu TP53 mutant previously identified in two flounder hepatic hyperplasia. In addition, we showed that the wild-type (wt) flounder TP53 but not the Val147Glu mutant inhibits cell growth when expressed in yeast. We finally reported that transcription regulation and growth inhibition by the wild-type flounder TP53 is temperature-dependent. The flounder TP53 optimal temperature appeared lower than those reported for the Xenopus and human homologues.

  2. Optimization of current modulation function for proton spread-out Bragg peak fields

    SciTech Connect

    Lu, H.-M.; Kooy, Hanne

    2006-05-15

    Proton treatments with spread-out Bragg peak (SOBP) fields often use a rotating modulation wheel of varying thickness to modulate the pristine Bragg peak in depth and intensity. The technique of modulating also the beam current independently over the wheel rotation provides an additional control over the intensities of the pulled-back Bragg peaks. As a result, a single wheel can be used over a large range of energies and SOBP parameters and field-specific wheels are no longer necessary. An essential task in commissioning a particular treatment depth is the determination of this current modulation function. We have developed a method for the optimization of the current modulation function. The basic idea is to treat the entire beam nozzle, housing the various beam scattering and modulating components, as a whole and to characterize its effect as a transformation from a modulating beam current to a depth-dose distribution. While this transformation is difficult to calculate theoretically due to the complex scattering paths in the nozzle and the phantom, it can, however, be determined by time-resolved dose measurements. Using this transformation, we can calculate SOBP depth-dose distributions for any current modulation function and optimize it by a simple numerical optimization. We have applied the new method to a number of proton beams with satisfactory results.

  3. Modeling and multi-response optimization of pervaporation of organic aqueous solutions using desirability function approach.

    PubMed

    Cojocaru, C; Khayet, M; Zakrzewska-Trznadel, G; Jaworska, A

    2009-08-15

    The factorial design of experiments and desirability function approach has been applied for multi-response optimization in pervaporation separation process. Two organic aqueous solutions were considered as model mixtures, water/acetonitrile and water/ethanol mixtures. Two responses have been employed in multi-response optimization of pervaporation, total permeate flux and organic selectivity. The effects of three experimental factors (feed temperature, initial concentration of organic compound in feed solution, and downstream pressure) on the pervaporation responses have been investigated. The experiments were performed according to a 2(3) full factorial experimental design. The factorial models have been obtained from experimental design and validated statistically by analysis of variance (ANOVA). The spatial representations of the response functions were drawn together with the corresponding contour line plots. Factorial models have been used to develop the overall desirability function. In addition, the overlap contour plots were presented to identify the desirability zone and to determine the optimum point. The optimal operating conditions were found to be, in the case of water/acetonitrile mixture, a feed temperature of 55 degrees C, an initial concentration of 6.58% and a downstream pressure of 13.99 kPa, while for water/ethanol mixture a feed temperature of 55 degrees C, an initial concentration of 4.53% and a downstream pressure of 9.57 kPa. Under such optimum conditions it was observed experimentally an improvement of both the total permeate flux and selectivity.

  4. Implementation of transmission functions for an optimized three-terminal quantum dot heat engine

    NASA Astrophysics Data System (ADS)

    Schiegg, Christian H.; Dzierzawa, Michael; Eckern, Ulrich

    2017-03-01

    We consider two modifications of a recently proposed three-terminal quantum dot heat engine. First, we investigate the necessity of the thermalization assumption, namely that electrons are always thermalized by inelastic processes when traveling across the cavity where the heat is supplied. Second, we analyze various arrangements of tunneling-coupled quantum dots in order to implement a transmission function that is superior to the Lorentzian transmission function of a single quantum dot. We show that the maximum power of the heat engine can be improved by about a factor of two, even for a small number of dots, by choosing an optimal structure.

  5. Implementation of transmission functions for an optimized three-terminal quantum dot heat engine.

    PubMed

    Schiegg, Christian H; Dzierzawa, Michael; Eckern, Ulrich

    2017-03-01

    We consider two modifications of a recently proposed three-terminal quantum dot heat engine. First, we investigate the necessity of the thermalization assumption, namely that electrons are always thermalized by inelastic processes when traveling across the cavity where the heat is supplied. Second, we analyze various arrangements of tunneling-coupled quantum dots in order to implement a transmission function that is superior to the Lorentzian transmission function of a single quantum dot. We show that the maximum power of the heat engine can be improved by about a factor of two, even for a small number of dots, by choosing an optimal structure.

  6. Numerical Methods for a Kohn-Sham Density Functional Model Based on Optimal Transport.

    PubMed

    Chen, Huajie; Friesecke, Gero; Mendl, Christian B

    2014-10-14

    In this paper, we study numerical discretizations to solve density functional models in the "strictly correlated electrons" (SCE) framework. Unlike previous studies, our work is not restricted to radially symmetric densities. In the SCE framework, the exchange-correlation functional encodes the effects of the strong correlation regime by minimizing the pairwise Coulomb repulsion, resulting in an optimal transport problem. We give a mathematical derivation of the self-consistent Kohn-Sham-SCE equations, construct an efficient numerical discretization for this type of problem for N = 2 electrons, and apply it to the H2 molecule in its dissociating limit.

  7. Optimal approximation method to characterize the resource trade-off functions for media servers

    NASA Astrophysics Data System (ADS)

    Chang, Ray-I.

    1999-08-01

    We have proposed an algorithm to smooth the transmission of the pre-recorded VBR media stream. It takes O(n) time complexity, where n is large, this algorithm is not suitable for online resource management and admission control in media servers. To resolve this drawback, we have explored the optimal tradeoff among resources by an O(nlogn) algorithm. Based on the pre-computed resource tradeoff function, the resource management and admission control procedure is as simple as table hashing. However, this approach requires O(n) space to store and maintain the resource tradeoff function. In this paper, while giving some extra resources, a linear-time algorithm is proposed to approximate the resource tradeoff function by piecewise line segments. We can prove that the number of line segments in the obtained approximation function is minimized for the given extra resources. The proposed algorithm has been applied to approximate the bandwidth-buffer-tradeoff function of the real-world Star War movie. While an extra 0.1 Mbps bandwidth is given, the storage space required for the approximation function is over 2000 times smaller than that required for the original function. While an extra 10 KB buffer is given, the storage space for the approximation function is over 2200 over times smaller than that required for the original function. The proposed algorithm is really useful for resource management and admission control in real-world media servers.

  8. Evaluating dispersion forces for optimization of van der Waals complexes using a non-empirical functional

    NASA Astrophysics Data System (ADS)

    Arabi, Alya A.

    2016-11-01

    Modelling dispersion interactions with traditional density functional theory (DFT) is a challenge that has been extensively addressed in the past decade. The exchange-dipole moment (XDM), among others, is a non-empirical add-on dispersion correction model in DFT. The functional PW86+PBE+XDM for exchange, correlation and dispersion, respectively, compromises an accurate functional for thermochemistry and for van der Waals (vdW) complexes at equilibrium and non-equilibrium geometries. To use this functional in optimizing vdW complexes, rather than computing single point energies, it is necessary to evaluate accurate forces. The purpose of this paper is to validate that, along the potential energy surface, the distance at which the energy is minimum is commensurate with the distance at which the forces vanish to zero. This test was validated for 10 rare gas diatomic molecules using various integration grids and different convergence criteria. It was found that the use of either convergence criterion, 10-6 or 10-8, in Gaussian09, does not affect the accuracy of computed optimal distances and binding energies. An ultra-fine grid needs to be used when computing accurate energies using generalized gradient approximation functionals. This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'.

  9. Evaluating dispersion forces for optimization of van der Waals complexes using a non-empirical functional.

    PubMed

    Arabi, Alya A

    2016-11-13

    Modelling dispersion interactions with traditional density functional theory (DFT) is a challenge that has been extensively addressed in the past decade. The exchange-dipole moment (XDM), among others, is a non-empirical add-on dispersion correction model in DFT. The functional PW86+PBE+XDM for exchange, correlation and dispersion, respectively, compromises an accurate functional for thermochemistry and for van der Waals (vdW) complexes at equilibrium and non-equilibrium geometries. To use this functional in optimizing vdW complexes, rather than computing single point energies, it is necessary to evaluate accurate forces. The purpose of this paper is to validate that, along the potential energy surface, the distance at which the energy is minimum is commensurate with the distance at which the forces vanish to zero. This test was validated for 10 rare gas diatomic molecules using various integration grids and different convergence criteria. It was found that the use of either convergence criterion, 10(-6) or 10(-8), in Gaussian09, does not affect the accuracy of computed optimal distances and binding energies. An ultra-fine grid needs to be used when computing accurate energies using generalized gradient approximation functionals.This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'.

  10. Alternative derivation of an exchange-only density-functional optimized effective potential

    SciTech Connect

    Joubert, D. P.

    2007-10-15

    An alternative derivation of the exchange-only density-functional optimized effective potential equation is given. It is shown that the localized Hartree-Fock-common energy denominator Green's function approximation (LHF-CEDA) for the density-functional exchange potential proposed independently by Della Sala and Goerling [J. Chem. Phys. 115, 5718 (2001)] and Gritsenko and Baerends [Phys. Rev. A 64, 42506 (2001)] can be derived as an approximation to the OEP exchange potential in a similar way that the KLI approximation [Phys. Rev. A 45, 5453 (1992)] was derived. An exact expression for the correction term to the LHF-CEDA approximation can thus be found. The correction term can be expressed in terms of the first-order perturbation-theory many-electron wave function shift when the Kohn-Sham Hamiltonian is subjected to a perturbation equal to the difference between the density-functional exchange potential and the Hartree-Fock nonlocal potential, expressed in terms of the Kohn-Sham orbitals. An explicit calculation shows that the density weighted mean of the correction term is zero, confirming that the LHF-CEDA approximation can be interpreted as a mean-field approximation. The corrected LHF-CEDA equation and the optimized effective potential equation are shown to be identical, with information distributed differently between terms in the equations. For a finite system the correction term falls off at least as fast as 1/r{sup 4} for large r.

  11. Analysis and selection of optimal function implementations in massively parallel computer

    DOEpatents

    Archer, Charles Jens; Peters, Amanda; Ratterman, Joseph D.

    2011-05-31

    An apparatus, program product and method optimize the operation of a parallel computer system by, in part, collecting performance data for a set of implementations of a function capable of being executed on the parallel computer system based upon the execution of the set of implementations under varying input parameters in a plurality of input dimensions. The collected performance data may be used to generate selection program code that is configured to call selected implementations of the function in response to a call to the function under varying input parameters. The collected performance data may be used to perform more detailed analysis to ascertain the comparative performance of the set of implementations of the function under the varying input parameters.

  12. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity.

    PubMed

    Pietra, Gabriella; Manzini, Claudia; Rivara, Silvia; Vitale, Massimo; Cantoni, Claudia; Petretto, Andrea; Balsamo, Mirna; Conte, Romana; Benelli, Roberto; Minghelli, Simona; Solari, Nicola; Gualco, Marina; Queirolo, Paola; Moretta, Lorenzo; Mingari, Maria Cristina

    2012-03-15

    Natural killer (NK) cells play a key role in tumor immune surveillance. However, adoptive immunotherapy protocols using NK cells have shown limited clinical efficacy to date, possibly due to tumor escape mechanisms that inhibit NK cell function. In this study, we analyzed the effect of coculturing melanoma cells and NK cells on their phenotype and function. We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cell-mediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2). Together, our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression.

  13. Sequential RBF surrogate-based efficient optimization method for engineering design problems with expensive black-box functions

    NASA Astrophysics Data System (ADS)

    Peng, Lei; Liu, Li; Long, Teng; Guo, Xiaosong

    2014-11-01

    As a promising technique, surrogate-based design and optimization(SBDO) has been widely used in modern engineering design optimizations. Currently, static surrogate-based optimization methods have been successfully applied to expensive optimization problems. However, due to the low efficiency and poor flexibility, static surrogate-based optimization methods are difficult to efficiently solve practical engineering cases. At the aim of enhancing efficiency, a novel surrogate-based efficient optimization method is developed by using sequential radial basis function(SEO-SRBF). Moreover, augmented Lagrangian multiplier method is adopted to solve the problems involving expensive constraints. In order to study the performance of SEO-SRBF, several numerical benchmark functions and engineering problems are solved by SEO-SRBF and other well-known surrogate-based optimization methods including EGO, MPS, and IARSM. The optimal solutions, number of function evaluations, and algorithm execution time are recorded for comparison. The comparison results demonstrate that SEO-SRBF shows satisfactory performance in both optimization efficiency and global convergence capability. The CPU time required for running SEO-SRBF is dramatically less than that of other algorithms. In the torque arm optimization case using FEA simulation, SEO-SRBF further reduces 21% of the material volume compared with the solution from static-RBF subject to the stress constraint. This study provides the efficient strategy to solve expensive constrained optimization problems.

  14. DDT inhibits the functional activation of murine macrophages and decreases resistance to infection by Mycobacterium microti.

    PubMed

    Nuñez G, María Andrea; Estrada, Iris; Calderon-Aranda, Emma S

    2002-06-05

    DDT is still widely used in several parts of the world to control malaria, typhoid and dengue vectors, even though its use was banned in many countries based on toxicity data in wild life species. DDT has been shown to have immunotoxic effects in mice and to increase susceptibility to intracellular pathogens such as Mycobacterium leprae. However, little is known about the mechanisms underlying this effect. Activated macrophages play an important defensive role against intracellular pathogens, therefore our objective was to evaluate the effect of in vitro exposure to technical grade DDT (a mixture of three forms: 1,1,1-thricloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) (85%), o,p'-DDT (15%) and o,o'-DDT (trace amounts)), p,p'-DDT, 1,1-dicloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane on the functional activation of J774A.1 macrophages and their capability to limit growth of intracellular pathogens, using Mycobacterium microti as a model. We evaluated cytotoxicity and the effect on cell proliferation of 2.5, 5.0 and 10 microg/ml of DDT compounds. Functional macrophage activity (NO(*) and O(2)(-) production, and mRNA expression of TNF-alpha, IL-1beta and iNO synthase) and the ability of treated cells to limit infection by M. microti in IFN-gamma-activated macrophages were evaluated in cells exposed to 2.5 microg/ml of DDT compounds. Doses of 5 and 10 microg/ml induced direct cytotoxic effects precluding meaningful analysis of the above parameters, whereas 2.5 microg/ml of all DDT compounds inhibited macrophage activity and reduced their ability to limit the intracellular growth of M. microti without inducing cytotoxicity. Technical grade DDT and p,p'-DDE were the more potent compounds. Therefore, exposure to DDT compounds could represent an important risk for infection development by those intracellular pathogens against which NO(*) and/or O(2)(-) production represent the main immune protective mechanism.

  15. Economic design of bar X & S control charts based on Taguchi's loss function and its optimization

    NASA Astrophysics Data System (ADS)

    Guo, Yu; Yang, Wen'an; Liao, Wenhe; Gao, Shiwen

    2012-05-01

    Much research effort has been devoted to economic design of bar X & S control charts, however, there are some problems in usual methods. On the one hand, it is difficult to estimate the relationship between costs and other model parameters, so the economic design method is often not effective in producing charts that can quickly detect small shifts before substantial losses occur; on the other hand, in many cases, only one type of process shift or only one pair of process shifts are taken into consideration, which may not correctly reflect the actual process conditions. To improve the behavior of economic design of control chart, a cost & loss model with Taguchi's loss function for the economic design of bar X & S control charts is embellished, which is regarded as an optimization problem with multiple statistical constraints. The optimization design is also carried out based on a number of combinations of process shifts collected from the field operation of the conventional control charts, thus more hidden information about the shift combinations is mined and employed to the optimization design of control charts. At the same time, an improved particle swarm optimization (IPSO) is developed to solve such an optimization problem in design of bar X & S control charts, IPSO is first tested for several benchmark problems from the literature and evaluated with standard performance metrics. Experimental results show that the proposed algorithm has significant advantages on obtaining the optimal design parameters of the charts. The proposed method can substantially reduce the total cost (or loss) of the control charts, and it will be a promising tool for economic design of control charts.

  16. Binding of Hepatitis A Virus to its Cellular Receptor 1 Inhibits T-Regulatory Cell Functions in Humans

    PubMed Central

    Manangeeswaran, Mohanraj; Jacques, Jérôme; Tami, Cecilia; Konduru, Krishnamurthy; Amharref, Nadia; Perrella, Oreste; Casasnovas, Jose M.; Umetsu, Dale T.; DeKruyff, Rosemarie H.; Freeman, Gordon J.; Perrella, Alessandro; Kaplan, Gerardo G.

    2012-01-01

    Background & Aims CD4+ T regulatory (Treg) cells suppress immune responses and control self-tolerance and immunity to pathogens, cancer, and alloantigens. Most pathogens activate Treg cells to minimize immune-mediated tissue damage and prevent clearance, which promotes chronic infections. However, hepatitis A virus (HAV) temporarily inhibits Treg-cell functions. We investigated whether the interaction of HAV with its cellular receptor 1 (HAVCR1), a T-cell co-stimulatory molecule, inhibits the function of Treg cells to control HAV infection. Methods We studied the effects of HAV interaction with HAVCR1 on human T cells using binding, signal transduction, apoptosis, activation, suppression, cytokine production, and confocal microscopy analyses. Cytokines were analyzed in sera from 14 patients with HAV infection using bead arrays. Results Human Treg cells constitutively express HAVCR1. Binding of HAV to HAVCR1 blocked phosphorylation of Akt, prevented activation of the T-cell receptor, and inhibited function of Treg cells. At the peak viremia, patients with acute HAV infection had no Treg-cell suppression function, produced low levels of transforming growth factor-β (TGF–β), which limited leukocyte recruitment and survival, and high levels of interleukin-22, which prevented liver damage. Conclusions Interaction between HAV and its receptor HAVCR1 inhibits Treg cell function, resulting in an immune imbalance that allows viral expansion with limited hepatocellular damage during early stages of infection—a characteristic of HAV pathogenesis. The mechanism by which HAV is cleared in the absence of Treg-cell function could be used as a model to develop anti-cancer therapies, modulate autoimmune and allergic responses, and prevent transplant rejection. PMID:22430395

  17. Integrating the switching, inhibition, and updating model of executive function with the Cattell-Horn-Carroll model.

    PubMed

    Jewsbury, Paul A; Bowden, Stephen C; Strauss, Milton E

    2016-02-01

    Executive function is an important concept in neuropsychological and cognitive research, and is often viewed as central to effective clinical assessment of cognition. However, the construct validity of executive function tests is controversial. The switching, inhibition, and updating model is the most empirically supported and replicated factor model of executive function (Miyake et al., 2000). To evaluate the relation between executive function constructs and nonexplicitly executive cognitive constructs, we used confirmatory factor reanalysis guided by the comprehensive Cattell-Horn-Carroll (CHC) model of cognitive abilities. Data from 7 of the best studies supporting the executive function model were reanalyzed, contrasting executive function models and CHC models. Where possible, we examined the effect of specifying executive function factors in addition to the CHC factors. The results suggested that little evidence is available to support updating as a separate factor from general memory factors; that inhibition does not separate from general speed; and that switching is supported as a narrow factor under general speed, but with a more restricted definition than some clinicians and researchers have conceptualized. The replicated executive function factor structure was integrated with the larger body of research on individual difference in cognition, as represented by the CHC model.

  18. An optimized protocol for hip joint centre determination using the functional method.

    PubMed

    Camomilla, Valentina; Cereatti, Andrea; Vannozzi, Giuseppe; Cappozzo, Aurelio

    2006-01-01

    The functional method identifies the hip joint centre (HJC) as the centre of rotation of the femur relative to the pelvis during an ad hoc movement normally recorded using stereophotogrammetry. This method may be used for the direct determination of subject-specific HJC coordinates or for creating a database from which regression equations may be derived that allow for the prediction of those coordinates. In order to contribute to the optimization of the functional method, the effects of the following factors were investigated: the algorithm used to estimate the HJC coordinates from marker coordinates, the type and amplitude of the movement of the femur relative to the pelvis, marker cluster location and dimensions, and the number of data samples. This was done using a simulation approach which, in turn, was validated using experiments made on a physical analogue of the pelvis and femur system. The algorithms used in the present context were classified and, in some instances, modified in order to optimize both accuracy and computation time, and submitted to a comparative evaluation. The type of movement that allowed for the most accurate results consisted of several flexion-extension/abduction-adduction movements performed on vertical planes of different orientations, followed by a circumduction movement. The accuracy of the HJC estimate improved, with an increasing rate, as a function of the amplitude of these movements. A sharp improvement was found as the number of the photogrammetric data samples used to describe the movement increased up to 500. For optimal performance with the recommended algorithms, markers were best located as far as possible from each other and with their centroid as close as possible to the HJC. By optimizing the analytical and experimental protocol, HJC location error not caused by soft tissue artefacts may be reduced by a factor of ten with a maximal expected value for such error of approximately 1mm.

  19. Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity.

    PubMed

    Seals, Douglas R; Justice, Jamie N; LaRocca, Thomas J

    2016-04-15

    Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been 'compression of morbidity' and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, 'geroscience', is focused on healthspan extension. Superimposed on this background are new attitudes and demand for 'optimal longevity' - living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel 'nutraceutical' compounds, serving as potential

  20. Adolescent development of inhibition as a function of SES and gender: Converging evidence from behavior and fMRI.

    PubMed

    Spielberg, Jeffrey M; Galarce, Ezequiel M; Ladouceur, Cecile D; McMakin, Dana L; Olino, Thomas M; Forbes, Erika E; Silk, Jennifer S; Ryan, Neal D; Dahl, Ronald E

    2015-08-01

    The ability to adaptively inhibit responses to tempting/distracting stimuli in the pursuit of goals is an essential set of skills necessary for adult competence and wellbeing. These inhibitory capacities develop throughout childhood, with growing evidence of important maturational changes occurring in adolescence. There also has been intense interest in the role of social adversity on the development of executive function, including inhibitory control. We hypothesized that the onset of adolescence could be a time of particular opportunity/vulnerability in the development of inhibition due to the large degree of maturational changes in neural systems involved in regulatory control. We investigated this hypothesis in a longitudinal study of adolescents by examining the impact of socioeconomic status (SES) on the maturation of inhibition and concurrent brain function. Furthermore, we examined gender as a potential moderator of this relationship, given evidence of gender-specificity in the developmental pathways of inhibition as well as sex differences in adolescent development. Results reveal that lower SES is associated with worse behavioral inhibition over time and a concurrent increase in anterior cingulate (ACC) activation, but only in girls. We also found that lower SES girls exhibited decreased ACC ↔ dorsolateral prefrontal cortex (dlPFC) coupling over time. Our findings suggest that female adolescents with lower SES appear to develop less efficient inhibitory processing in dlPFC, requiring greater and relatively unsuccessful compensatory recruitment of ACC. In summary, the present study provides a novel window into the neural mechanisms by which the influence of SES on inhibition may be transmitted during adolescence.

  1. Structure–function relationships of inhibition of mosquito cytochrome P450 enzymes by flavonoids of Andrographis paniculata.

    PubMed

    Kotewong, Rattanawadee; Duangkaew, Panida; Srisook, Ekaruth; Sarapusit, Songklod; Rongnoparut, Pornpimol

    2014-09-01

    The cytochrome P450 monooxygenases are known to play a major role in pyrethroid resistance, by means of increased rate of insecticide detoxification as a result of their overexpression. Inhibition of detoxification enzymes may help disrupting insect detoxifying defense system. The Anopheles minimus CYP6AA3 and CYP6P7 have shown pyrethroid degradation activity and been implicated in pyrethroid resistance. In this study inhibition of the extracts and constituents of Andrographis paniculata Nees. leaves and roots was examined against benzyloxyresorufin O-debenzylation (BROD) of CYP6AA3 and CYP6P7. Four purified flavones (5,7,4′-trihydroxyflavone, 5-hydroxy-7,8-dimethoxyflavone, 5-hydroxy-7,8,2′,3′-tetramethoxyflavone, and 5,4′-dihydroxy-7,8,2′,3′-tetramethoxyflavone), one flavanone (5-hydroxy-7,8-dimethoxyflavanone) and a diterpenoid (14-deoxy-11,12-didehydroandrographolide) containing inhibitory effects toward both enzymes were isolated from A. paniculata. Structure–function relationships were observed for modes and kinetics of inhibition among flavones, while diterpenoid and flavanone were inferior to flavones. Docking of flavones onto enzyme homology models reinforced relationships on flavone structures and inhibition modes. Cell-based inhibition assays employing 3-(4,5-dimethylthiazol-2-y-l)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that these flavonoids efficiently increased susceptibility of CYP6AA3- and CYP6P7-expressing Spodoptera frugiperda (Sf9) cells to cypermethrin toxicity, due to inhibition effects on mosquito enzymes. Thus synergistic effects on cypermethrin toxicity of A. paniculata compounds as a result of enzyme inhibition could be useful for mosquito vector control and insecticide resistance management in the future.

  2. Evaluation of the selection methods used in the exIWO algorithm based on the optimization of multidimensional functions

    NASA Astrophysics Data System (ADS)

    Kostrzewa, Daniel; Josiński, Henryk

    2016-06-01

    The expanded Invasive Weed Optimization algorithm (exIWO) is an optimization metaheuristic modelled on the original IWO version inspired by dynamic growth of weeds colony. The authors of the present paper have modified the exIWO algorithm introducing a set of both deterministic and non-deterministic strategies of individuals' selection. The goal of the project was to evaluate the modified exIWO by testing its usefulness for multidimensional numerical functions optimization. The optimized functions: Griewank, Rastrigin, and Rosenbrock are frequently used as benchmarks because of their characteristics.

  3. Feedback Functions, Optimization, and the Relation of Response Rate to Reinforcer Rate

    PubMed Central

    Soto, Paul L; McDowell, Jack J; Dallery, Jesse

    2006-01-01

    The present experiment arranged a series of inverted U-shaped feedback functions relating reinforcer rate to response rate to test whether responding was consistent with an optimization account or with a one-to-one relation of response rate to reinforcer rate such as linear system theory's rate equation or Herrnstein's hyperbola. Reinforcer rate was arranged according to a quadratic equation with a maximum at a unique response rate. The experiment consisted of two phases, during which 6 Long Evans rats lever pressed for food. In the first phase of the experiment, the rats responded on six fixed-interval-plus-quadratic-feedback schedules, and in the second phase the rats responded on three variable-interval-plus-quadratic-feedback schedules. Responding in both phases was inconsistent with a one-to-one relation of response rate to reinforcer rate. Instead, different response rates were obtained at equivalent reinforcer rates. Responding did vary directly with the vertex of the feedback function in both phases, a finding consistent with optimization of reinforcer rate. The present results suggest that the feedback function relating reinforcer rate to response rate imposed by a reinforcement schedule can be an important determinant of behavior. Furthermore, the present experiment illustrates the benefit of arranging feedback functions to investigate assumptions about the variables that control schedule performance. PMID:16602376

  4. Optimization of the functional characteristics, pasting and rheological properties of pearl millet-based composite flour.

    PubMed

    Awolu, Olugbenga Olufemi

    2017-02-01

    Optimisation of composite flour comprising pearl millet, kidney beans and tigernut with xanthan gum was evaluated for rheological evaluations. The functional properties of the composite flour were optimized using optimal design of response surface methodology. The optimum blends, defined as blends with overall best functional characteristics were run 3 (75.956% pearl millet, 17.692% kidney beans, 6.352% tigernut flours), run 7 (85.000% pearl millet, 10.000% kidney beans, 5.000% tigernut flours) and run 13 (75.000% pearl millet, 20.000% kidney beans, 5.000% tigernut flours). The pasting characteristics and rheological evaluation of the optimized blends were further evaluated in rapid visco units (RVU). Run 7 had the overall best pasting characteristics; peak viscosity (462 RVU), trough (442 RVU), breakdown viscosity (20 RVU), final viscosity (975 RVU), setback (533 RVU), peak time (5.47 min) and pasting temperature (89.60 °C). These values were found to be better than several composite flours consisting mixture of wheat and non-wheat crops. In addition, the rheological characteristics (measured by Mixolab) showed that run 7 is the best in terms of dough stability, swelling, water absorption and shelf stability. Composite flour with 85% pearl millet flour in addition to kidney beans and tigernut flours could therefore serve as a viable alternative to 100% wheat flour in bread production.

  5. Optimization of flow-sensitive alternating inversion recovery (FAIR) for perfusion functional MRI of rodent brain.

    PubMed

    Nasrallah, Fatima A; Lee, Eugene L Q; Chuang, Kai-Hsiang

    2012-11-01

    Arterial spin labeling (ASL) MRI provides a noninvasive method to image perfusion, and has been applied to map neural activation in the brain. Although pulsed labeling methods have been widely used in humans, continuous ASL with a dedicated neck labeling coil is still the preferred method in rodent brain functional MRI (fMRI) to maximize the sensitivity and allow multislice acquisition. However, the additional hardware is not readily available and hence its application is limited. In this study, flow-sensitive alternating inversion recovery (FAIR) pulsed ASL was optimized for fMRI of rat brain. A practical challenge of FAIR is the suboptimal global inversion by the transmit coil of limited dimensions, which results in low effective labeling. By using a large volume transmit coil and proper positioning to optimize the body coverage, the perfusion signal was increased by 38.3% compared with positioning the brain at the isocenter. An additional 53.3% gain in signal was achieved using optimized repetition and inversion times compared with a long TR. Under electrical stimulation to the forepaws, a perfusion activation signal change of 63.7 ± 6.3% can be reliably detected in the primary somatosensory cortices using single slice or multislice echo planar imaging at 9.4 T. This demonstrates the potential of using pulsed ASL for multislice perfusion fMRI in functional and pharmacological applications in rat brain.

  6. Optimization of correlated multi-response quality engineering by the upside-down normal loss function

    NASA Astrophysics Data System (ADS)

    Zeybek, Melis; Köksoy, Onur

    2016-08-01

    Most of the published literature on robust design is basically concerned with a single response. However, the reality is that common industrial problems usually involve several quality characteristics, which are often correlated. Traditional approaches to multidimensional quality do not offer much information on how much better or worse a process is when finding optimal settings. Köksoy and Fan [Engineering Optimization 44 (8): 935-945] pointed out that the upside-down normal loss function provides a more reasonable risk assessment to the losses of being off-target in product engineering research. However, they only consider the single-response case. This article generalizes their idea to more than one response under possible correlations and co-movement effects of responses on the process loss. The response surface methodology has been adapted, estimating the expected multivariate upside-down normal loss function of a multidimensional system to find the optimal control factor settings of a given problem. The procedure and its merits are illustrated through an example.

  7. The fungicide Pristine® inhibits mitochondrial function in vitro but not flight metabolic rates in honey bees.

    PubMed

    Campbell, Jacob B; Nath, Rachna; Gadau, Juergen; Fox, Trevor; DeGrandi-Hoffman, Gloria; Harrison, Jon F

    2016-03-01

    Honey bees and other pollinators are exposed to fungicides that act by inhibiting fungal mitochondria. Here we test whether a common fungicide (Pristine®) inhibits the function of mitochondria of honeybees, and whether consumption of ecologically-realistic concentrations can cause negative effects on the mitochondria of flight muscles, or the capability for flight, as judged by CO2 emission rates and thorax temperatures during flight. Direct exposure of mitochondria to Pristine® levels above 5 ppm strongly inhibited mitochondrial oxidation rates in vitro. However, bees that consumed pollen containing Pristine® at ecologically-realistic concentrations (≈ 1 ppm) had normal flight CO2 emission rates and thorax temperatures. Mitochondria isolated from the flight muscles of the Pristine®-consuming bees had higher state 3 oxygen consumption rates than control bees, suggesting that possibly Pristine®-consumption caused compensatory changes in mitochondria. It is likely that the lack of a strong functional effect of Pristine®-consumption on flight performance and the in vitro function of flight muscle mitochondria results from maintenance of Pristine® levels in the flight muscles at much lower levels than occur in the food, probably due to metabolism and detoxification. As Pristine® has been shown to negatively affect feeding rates and protein digestion of honey bees, it is plausible that Pristine® consumption negatively affects gut wall function (where mitochondria may be exposed to higher concentrations of Pristine®).

  8. The roles of sensory function and cognitive load in age differences in inhibition: Evidence from the Stroop task.

    PubMed

    Peng, Huamao; Gao, Yue; Mao, Xiaofei

    2017-02-01

    To explore the roles of visual function and cognitive load in aging of inhibition, the present study adopted a 2 (visual perceptual stress: noise, nonnoise) × 2 (cognitive load: low, high) × 2 (age: young, old) mixed design. The Stroop task was adopted to measure inhibition. The task presentation was masked with Gaussian noise according to the visual function of each individual in order to match visual perceptual stress between age groups. The results indicated that age differences in the Stroop effect were influenced by visual function and cognitive load. When the cognitive load was low, older adults exhibited a larger Stroop effect than did younger adults in the nonnoise condition, and this age difference disappeared when the visual noise of the 2 age groups was matched. Conversely, in the high cognitive load condition, we observed significant age differences in the Stroop effect in both the nonnoise and noise conditions. The additional cognitive load made the age differences in the Stroop task reappear even when visual perceptual stress was equivalent. These results demonstrate that visual function plays an important role in the aging of inhibition and its role is moderated by cognitive load. (PsycINFO Database Record

  9. Targeted inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis and Preserves Heart Function in Adverse Cardiac Remodeling

    PubMed Central

    Zhang, Jie; Fan, Guangpu; Zhao, Hui; Wang, Zhiwei; Li, Fei; Zhang, Peide; Zhang, Jing; Wang, Xu; Wang, Wei

    2017-01-01

    Cardiac fibrosis in post-myocardial infarction (MI), seen in both infarcted and non-infarcted myocardium, is beneficial to the recovery of heart function. But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis. FAK has recently received attention as a potential mediator of fibrosis, our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models. However, the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated. In this study, we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts and ECM synthesis relevant to the development of adverse cardiac remolding in vivo and in vitro. Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner. Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation; our in vivo data demonstrated that a FAK inhibitor significantly decreases fibrotic score, and preserves partial left ventricular function. Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis; this process also involves lysyl oxidase (LOX). These findings suggest that pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis. PMID:28225063

  10. Modeling and optimization of microbial hyaluronic acid production by Streptococcus zooepidemicus using radial basis function neural network coupling quantum-behaved particle swarm optimization algorithm.

    PubMed

    Liu, Long; Sun, Jun; Xu, Wenbo; Du, Guocheng; Chen, Jian

    2009-01-01

    Hyaluronic acid (HA) is a natural biopolymer with unique physiochemical and biological properties and finds a wide range of applications in biomedical and cosmetic fields. It is important to increase HA production to meet the increasing HA market demand. This work is aimed to model and optimize the amino acids addition to enhance HA production of Streptococcus zooepidemicus with radial basis function (RBF) neural network coupling quantum-behaved particle swarm optimization (QPSO) algorithm. In the RBF-QPSO approach, RBF neural network is used as a bioprocess modeling tool and QPSO algorithm is applied to conduct the optimization with the established RBF neural network black model as the objective function. The predicted maximum HA yield was 6.92 g/L under the following conditions: arginine 0.062 g/L, cysteine 0.036 g/L, and lysine 0.043 g/L. The optimal amino acids addition allowed HA yield increased from 5.0 g/L of the control to 6.7 g/L in the validation experiments. Moreover, the modeling and optimization capacity of the RBF-QPSO approach was compared with that of response surface methodology (RSM). It was indicated that the RBF-QPSO approach gave a slightly better modeling and optimization result compared with RSM. The developed RBF-QPSO approach in this work may be helpful for the modeling and optimization of the other multivariable, nonlinear, time-variant bioprocesses.

  11. Comparison of Cytotoxicity and Inhibition of Membrane ABC Transporters Induced by MWCNTs with Different Length and Functional Groups.

    PubMed

    Yu, Jing; Liu, Su; Wu, Bing; Shen, Zhuoyan; Cherr, Gary N; Zhang, Xu-Xiang; Li, Mei

    2016-04-05

    Experimental studies indicate that multiwalled carbon nanotubes (MWCNTs) have the potential to induce cytotoxicity. However, the reports are often inconsistent and even contradictory. Additionally, adverse effects of MWCNTs at low concentration are not well understood. In this study, we systemically compared adverse effects of six MWCNTs including pristine MWCNTs, hydroxyl-MWCNTs and carboxyl-MWCNTs of two different lengths (0.5-2 μm and 10-30 μm) on human hepatoma cell line HepG2. Results showed that MWCNTs induced cytotoxicity by increasing reactive oxygen species (ROS) generation and damaging cell function. Pristine short MWCNTs induced higher cytotoxicity than pristine long MWCNTs. Functionalization increased cytotoxicity of long MWCNTs, but reduced cytotoxicity of short MWCNTs. Further, our results indicated that the six MWCNTs, at nontoxic concentration, might not be environmentally safe as they inhibited ABC transporters' efflux capabilities. This inhibition was observed even at very low concentrations, which were 40-1000 times lower than their effective concentrations on cytotoxicity. The inhibition of ABC transporters significantly increased cytotoxicity of arsenic, a known substrate of ABC transporters, indicating a chemosensitizing effect of MWCNTs. Plasma membrane damage was likely the mechanism by which the six MWCNTs inhibited ABC transporter activity. This study provides insight into risk assessments of low levels of MWCNTs in the environment.

  12. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

    PubMed Central

    Milella, Michele; Falcone, Italia; Conciatori, Fabiana; Matteoni, Silvia; Sacconi, Andrea; De Luca, Teresa; Bazzichetto, Chiara; Corbo, Vincenzo; Simbolo, Michele; Sperduti, Isabella; Benfante, Antonina; Del Curatolo, Anais; Cesta Incani, Ursula; Malusa, Federico; Eramo, Adriana; Sette, Giovanni; Scarpa, Aldo; Konopleva, Marina; Andreeff, Michael; McCubrey, James Andrew; Blandino, Giovanni; Todaro, Matilde; Stassi, Giorgio; De Maria, Ruggero; Cognetti, Francesco; Del Bufalo, Donatella; Ciuffreda, Ludovica

    2017-01-01

    Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies. PMID:28220839

  13. Inhibition of let-7 augments the recruitment of epicardial cells and improves cardiac function after myocardial infarction.

    PubMed

    Seeger, Timon; Xu, Quan-Fu; Muhly-Reinholz, Marion; Fischer, Ariane; Kremp, Eva-Maria; Zeiher, Andreas M; Dimmeler, Stefanie

    2016-05-01

    Heart failure due to myocardial infarction is a major cause of mortality. The microRNA (miR) family let-7 is expressed during embryonic development and is up-regulated in differentiated cells. The aim of this study was to study the role of let-7 after acute myocardial infarction (AMI). We designed an antimiR to inhibit the highest expressed members of the let-7 family, let-7 a, b and c. Administration at day 0 and day 2 after AMI resulted in sustained knockdown of let-7 after 28days. Let-7 inhibition prevented deterioration of cardiac functions compared to control treatment which was especially due to improvements in the infarcted, apical cardiac segments. We observed higher contents of fibrosis in the border zone as well as increased numbers of cells positive for TCF21, which is also expressed in epicardial cells. Markers were augmented after let-7 inhibition and let-7 blocked EMT in epicardial cells in vitro. Lineage tracing in TCF21(iCre/+):R26R(tdT) mice showed abundant tomato positive cells in the infarct and border zone. In conclusion, let-7 inhibition resulted in functional benefits due to an increase in recruitment of epicardial cells and EMT.

  14. Adapting to aging losses: do resources facilitate strategies of selection, compensation, and optimization in everyday functioning?

    PubMed

    Lang, Frieder R; Rieckmann, Nina; Baltes, Margret M

    2002-11-01

    Previous cross-sectional research has shown that older people who are rich in sensorimotor-cognitive and social-personality resources are better functioning in everyday life and exhibit fewer negative age differences than resource-poor adults. Longitudinal data from the Berlin Aging Study was used to examine these findings across a 4-year time interval and to compare cross-sectional indicators of adaptive everyday functioning among survivors and nonsurvivors. Apart from their higher survival rate, resource-rich older people (a) invest more social time with their family members, (b) reduce the diversity of activities within the most salient leisure domain, (c) sleep more often and longer during daytime, and (d) increase the variability of time investments across activities after 4 years. Overall, findings suggest a greater use of selection, compensation, and optimization strategies in everyday functioning among resource-rich older adults as compared with resource-poor older adults.

  15. Numerical optimization in Hilbert space using inexact function and gradient evaluations

    NASA Technical Reports Server (NTRS)

    Carter, Richard G.

    1989-01-01

    Trust region algorithms provide a robust iterative technique for solving non-convex unstrained optimization problems, but in many instances it is prohibitively expensive to compute high accuracy function and gradient values for the method. Of particular interest are inverse and parameter estimation problems, since function and gradient evaluations involve numerically solving large systems of differential equations. A global convergence theory is presented for trust region algorithms in which neither function nor gradient values are known exactly. The theory is formulated in a Hilbert space setting so that it can be applied to variational problems as well as the finite dimensional problems normally seen in trust region literature. The conditions concerning allowable error are remarkably relaxed: relative errors in the gradient error condition is automatically satisfied if the error is orthogonal to the gradient approximation. A technique for estimating gradient error and improving the approximation is also presented.

  16. Parameter estimation of copula functions using an optimization-based method

    NASA Astrophysics Data System (ADS)

    Abdi, Amin; Hassanzadeh, Yousef; Talatahari, Siamak; Fakheri-Fard, Ahmad; Mirabbasi, Rasoul

    2016-02-01

    Application of the copulas can be useful for the accurate multivariate frequency analysis of hydrological phenomena. There are many copula functions and some methods were proposed for estimating the copula parameters. Since the copula functions are mathematically complicated, estimating of the copula parameter is an effortful work. In the present study, an optimization-based method (OBM) is proposed to obtain the parameters of copulas. The usefulness of the proposed method is illustrated on drought events. For this purpose, three commonly used copulas of Archimedean family, namely, Clayton, Frank, and Gumbel copulas are used to construct the joint probability distribution of drought characteristics of 60 gauging sites located in East-Azarbaijan province, Iran. The performance of OBM was compared with two conventional methods, namely, method of moments and inference function for margins. The results illustrate the supremacy of the OBM to estimate the copula parameters compared to the other considered methods.

  17. Optimized Effective Potential for Quantum Electrodynamical Time-Dependent Density Functional Theory

    NASA Astrophysics Data System (ADS)

    Pellegrini, Camilla; Flick, Johannes; Tokatly, Ilya V.; Appel, Heiko; Rubio, Angel

    2015-08-01

    We propose an orbital exchange-correlation functional for applying time-dependent density functional theory to many-electron systems coupled to cavity photons. The time nonlocal equation for the electron-photon optimized effective potential (OEP) is derived. In the static limit our OEP energy functional reduces to the Lamb shift of the ground state energy. We test the new approximation in the Rabi model. It is shown that the OEP (i) reproduces quantitatively the exact ground-state energy from the weak to the deep strong coupling regime and (ii) accurately captures the dynamics entering the ultrastrong coupling regime. The present formalism opens the path to a first-principles description of correlated electron-photon systems, bridging the gap between electronic structure methods and quantum optics for real material applications.

  18. Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function

    PubMed Central

    Drannik, Anna; Martin, Joan; Peterson, Randy; Ma, Xiaoxing; Jiang, Fan; Turnbull, John

    2017-01-01

    Sonic hedgehog (Shh) is a morphogen essential to the developing nervous system that continues to play an important role in adult life by contributing to cell proliferation and differentiation, maintaining blood-brain barrier integrity, and being cytoprotective against oxidative and excitotoxic stress, all features of importance in amyotrophic lateral sclerosis (ALS). ALS is a fatal disease characterized by selective loss of motor neurons due to poorly understood mechanisms. Evidence indicates that Shh might play an important role in ALS, and that Shh signaling might be also adversely affected in ALS. Since little is known about the functional status of Shh pathway in patients with ALS, we therefore sought to determine whether Shh protein levels or biological activity in cerebrospinal fluid (CSF) was less in ALS patients than controls, and whether these measures could be correlated with ALS disease severity and disease progression, and with other CSF analytes of biological interest in ALS. Comparing Shh levels in the CSF of normal controls (n = 13), neurological controls (n = 12), and ALS patients (n = 9) measured by ELISA, we found that CSF Shh levels were not different between controls and ALS patients. However, when assessing Shh biological activity in CSF using in vitro cell-based assays, which measure Shh activity as inducible Gli-driven luminescence, we found that in the presence of exogenous recombinant Shh or the Shh agonist, purmorphamine, the inducible activity of CSF was significantly augmented in the control groups as expected, but not in the ALS group, suggesting the presence of an inhibitor of Shh signaling in ALS CSF samples. Since purmorphamine acts on Smoothened, downstream of Shh and its receptor Patched, the inhibitory action is downstream of Smoothened. Our results also demonstrated that while the inhibitory effect of ALS CSF on Shh signaling did not correlate significantly with ALS disease characteristics, the levels of IL-1β and TNF-α did. In

  19. Influenza C virus esterase: analysis of catalytic site, inhibition, and possible function

    SciTech Connect

    Vlasak, R.; Muster, T.; Lauro, A.M.; Powers, J.C.; Palese, P.

    1989-05-01

    The active site serine of the acetylesterase of influenza C virus was localized to amino acid 71 of the hemagglutinin-esterase protein by affinity labeling with /sup 3/H-labeled diisopropylfluorophosphate. This serine and the adjacent amino acids (Phe-Gly-Asp-Ser) are part of a consensus sequence motif found in serine hydrolases. Since comparative analysis failed to reveal esterase sequence similarities with other serine hydrolases, the authors suggest that this viral enzyme is a serine hydrolase constituting a new family of serine esterases. Furthermore, they found that the influenza C virus esterase was inhibited by isocoumarin derivatives, with 3,4-dichloroisocoumarin being the most potent inhibitor. Addition of this compound prevented elution of influenza C virus from erythrocytes and inhibited virus infectivity, possibly through inhibition of virus entry into cells.

  20. Polarized notum activation at wounds inhibits Wnt function to promote planarian head regeneration.

    PubMed

    Petersen, Christian P; Reddien, Peter W

    2011-05-13

    Regeneration requires initiation of programs tailored to the identity of missing parts. Head-versus-tail regeneration in planarians presents a paradigm for study of this phenomenon. After injury, Wnt signaling promotes tail regeneration. We report that wounding elicits expression of the Wnt inhibitor notum preferentially at anterior-facing wounds. This expression asymmetry occurs at essentially any wound, even if the anterior pole is intact. Inhibition of notum with RNA interference (RNAi) causes regeneration of an anterior-facing tail instead of a head, and double-RNAi experiments indicate that notum inhibits Wnt signaling to promote head regeneration. notum expression is itself controlled by Wnt signaling, suggesting that regulation of feedback inhibition controls the binary head-tail regeneration outcome. We conclude that local detection of wound orientation with respect to tissue axes results in distinct signaling environments that initiate appropriate regeneration responses.

  1. Inhibition of DAT function attenuates manganese accumulation in the globus pallidus.

    PubMed

    Anderson, Joel G; Cooney, Paula T; Erikson, Keith M

    2007-03-01

    Manganese (Mn) is an essential nutrient, though exposure to high concentrations may result in neurotoxicity characterized by alterations in dopamine neurobiology. To date, it remains elusive how and why Mn targets dopaminergic neurons although recently the role of the dopamine transporter has been suggested. Our primary goal of this study was to examine the potential roles of the monoamine transporters, dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET), in neuronal Mn transport. Using striatal synaptosomes, we found that only inhibition of DAT significantly decreased Mn accumulation. Furthermore, weanling rats chronically exposed to Mn, significantly accumulated Mn in several brain regions. However, rats receiving the specific DAT inhibitor GBR12909 (1 mg/kg bw, three times/week; four weeks) had significantly lower Mn levels only in the globus pallidus compared to saline-treated rats (p<0.05). Our data show that inhibition of DAT exclusively inhibits Mn accumulation in the globus pallidus during chronic exposure.

  2. Icecolors`93: Biological weighting function for the ultraviolet inhibition of carbon fixation in a natural antarctic phytoplankton community

    SciTech Connect

    Boucher, N.; Prezelin, B.B.; Evens, T.

    1994-12-31

    The goals of the Icecolors 1993 expedition were (1) to develop a space/time climatology of incident and penetrating spectral irradiance for the southern oceans, (2) to quantify the ultraviolet (UV) dependency of primary production for pelagic and substrate-associated antarctic phytoplankton communities, and (3) to determine the UV inhibition effects on key target sites. The study was conducted at Palmer Station, Antarctica, prior to the opening of the ozone `hole` and during the onset of depletion of ozone, the most severe ever recorded over the Antarctic Peninsula. This paper discusses results from an experiment designed to estimate a biological weight function for primary production inhibition in Antarctic phytoplankton under natural irradiance. The newly derived function is presented and it is shown that the sensitivity of in situ phytoplankton to ambient UV-B at the end of winter was greater than that measured under artificial light conditions for temperate marine phytoplankton and terrestrial plants. 18 refs., 3 figs.

  3. Design, characterization, and in vitro cellular inhibition and uptake of optimized genistein-loaded NLC for the prevention of posterior capsular opacification using response surface methodology.

    PubMed

    Zhang, Wenji; Li, Xuedong; Ye, Tiantian; Chen, Fen; Sun, Xiao; Kong, Jun; Yang, Xinggang; Pan, Weisan; Li, Sanming

    2013-09-15

    This study was to design an innovative nanostructured lipid carrier (NLC) for drug delivery of genistein applied after cataract surgery for the prevention of posterior capsular opacification. NLC loaded with genistein (GEN-NLC) was produced with Compritol 888 ATO, Gelucire 44/14 and Miglyol 812N, stabilized by Solutol(®) HS15 by melt emulsification method. A 2(4) central composite design of 4 independent variables was performed for optimization. Effects of drug concentration, Gelucire 44/14 concentration in total solid lipid, liquid lipid concentration, and surfactant concentration on the mean particle size, polydispersity index, zeta potential and encapsulation efficiency were investigated. Analysis of variance (ANOVA) statistical test was used to assess the optimization. The optimized GEN-NLC showed a homogeneous particle size of 90.16 nm (with PI=0.33) of negatively charged surface (-25.08 mv) and high encapsulation efficiency (91.14%). Particle morphology assessed by TEM revealed a spherical shape. DSC analyses confirmed that GEN was mostly entrapped in amorphous state. In vitro release experiments indicated a prolonged and controlled genistein release for 72 h. In vitro growth inhibition assay showed an effective growth inhibition of GEN-NLCs on human lens epithelial cells (HLECs). Preliminary cellular uptake test proved a enhanced penetration of genistein into HLECs when delivered in NLC.

  4. Modified Sigmoid Function Based Gray Scale Image Contrast Enhancement Using Particle Swarm Optimization

    NASA Astrophysics Data System (ADS)

    Verma, Harish Kumar; Pal, Sandeep

    2016-06-01

    The main objective of an image enhancement is to improve eminence by maximizing the information content in the test image. Conventional contrast enhancement techniques either often fails to produce reasonable results for a broad variety of low-contrast and high contrast images, or cannot be automatically applied to different images, because they are parameters dependent. Hence this paper introduces a novel hybrid image enhancement approach by taking both the local and global information of an image. In the present work, sigmoid function is being modified on the basis of contrast of the images. The gray image enhancement problem is treated as nonlinear optimization problem with several constraints and solved by particle swarm optimization. The entropy and edge information is included in the objective function as quality measure of an image. The effectiveness of modified sigmoid function based enhancement over conventional methods namely linear contrast stretching, histogram equalization, and adaptive histogram equalization are better revealed by the enhanced images and further validated by statistical analysis of these images.

  5. Executive functions in extremely low birth weight and late-preterm preschoolers: effects on working memory and response inhibition.

    PubMed

    Baron, Ida Sue; Kerns, Kimberly A; Müller, Ulrich; Ahronovich, Margot D; Litman, Fern R

    2012-01-01

    Executive function (EF) refers to fundamental capacities that underlie more complex cognition and have ecological relevance across the individual's lifespan. However, emerging executive functions have rarely been studied in young preterm children (age 3) whose critical final stages of fetal development are interrupted by their early birth. We administered four novel touch-screen computerized measures of working memory and inhibition to 369 participants born between 2004 and 2006 (52 Extremely Low Birth Weight [ELBW]; 196 late preterm; 121 term-born). ELBW performed worse than term-born on simple and complex working memory and inhibition tasks and had the highest percentage of incomplete performance on a continuous performance test. The latter finding indicates developmental immaturity and the ELBW group's most at-risk preterm status. Additionally, late-preterm participants performed worse compared with term-born on measures of complex working memory but did not differ from those term-born on response inhibition measures. These results are consistent with a recent literature that identifies often subtle but detectable neurocognitive deficits in late-preterm children. Our results support the development and standardization of computerized touch-screen measures to assess EF subcomponent abilities during the formative preschool period. Such measures may be useful to monitor the developmental trajectory of critical executive function abilities in preterm children, and their use is necessary for timely recognition of deficit and application of appropriate interventional strategies.

  6. Interaction of Finger Representations in the Cortex of Individuals with Autism: A Functional Window into Cortical Inhibition

    PubMed Central

    Coskun, Mehmet A.; Loveland, Katherine A.; Pearson, Deborah A.; Papanicolaou, Andrew C.; Sheth, Bhavin R.

    2013-01-01

    An established neural biomarker of autism spectrum disorder (ASD) has the potential to provide novel biological and pharmacological targets for treatment. Lower level of inhibition in brain circuits is a leading biomarker candidate. A physiological investigation of the functional levels of inhibition in the cortex of individuals with autism can provide a strong test of the hypothesis. The amplitude of cortical response to the stimulation of adjacent fingers is controlled by the level of cortical inhibition and provides just such a test. Using magnetoencephalography, we recorded the response of the somatosensory cortex to the passive tactile stimulation of the thumb (D1), and index finger (D2), and to the simultaneous stimulation of both fingers combined (D1, D2) of the dominant (right) hand of young subjects with and without autism. For each participant, we measured the response to the stimulation of both fingers combined (D1, D2) relative to the post hoc sum of the responses to the stimulation of each finger alone (D1+D2) in multiple different ways and linearly regressed the ASD and neurotypical (NT) groups’ responses. The resulting slopes were then compared: Smaller slope values imply attenuated response to paired finger stimulation, and enhanced levels of inhibition. The short-latency M40 and mid-latency M80 response slopes of the group with autism obtained in different ways were either significantly smaller, or statistically indistinguishable from NT. The result does not support reduced inhibition in the somatosensory cortex of individuals with autism, contrary to the seminal hypothesis of reduced inhibition. Implications are discussed including refinements of current theory. PMID:23983203

  7. Methanandamide allosterically inhibits in vivo the function of peripheral nicotinic acetylcholine receptors containing the alpha 7-subunit.

    PubMed

    Baranowska, Urszula; Göthert, Manfred; Rudz, Radoslaw; Malinowska, Barbara

    2008-09-01

    Methanandamide (MAEA), the stable analog of the endocannabinoid anandamide, has been proven in Xenopus oocytes to allosterically inhibit the function of the alpha7-nicotinic acetylcholine receptors (nAChRs) in a cannabinoid (CB) receptor-independent manner. The present study aimed at demonstrating that this mechanism can be activated in vivo. In anesthetized and vagotomized pithed rats treated with atropine, we determined the tachycardic response to electrical stimulation of preganglionic sympathetic nerves via the pithing rod or to i.v. nicotine (0.7 micromol/kg) activating nAChRs on the cardiac postganglionic sympathetic neurons. MAEA (3 and 10 micromol/kg) inhibited the electrically induced tachycardia (maximally by 15-20%; abolished by the CB(1) receptor antagonist AM 251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]; 3 micromol/kg) in pentobarbitone-anesthetized pithed rats, but not in urethane-anesthetized pithed rats, which, thus, are suitable to study the CB(1) receptor-independent inhibition of nicotine-evoked tachycardia. The subunit-nonselective nAChR antagonist hexamethonium (100 micromol/kg) and the selective alpha7-subunit antagonist methyllycaconitine (MLA; 3 and 10 micromol/kg) decreased the nicotine-induced tachycardia by 100 and 40%, respectively (maximal effects), suggesting that nAChRs containing the alpha7-subunit account for 40% of the nicotine-induced tachycardia. MAEA (3 micromol/kg) produced an AM 251-insensitive inhibition (maximum again by 40%) of the nicotine-induced tachycardia. Simultaneous or sequential coadministration of MLA and MAEA inhibited the nicotine-induced tachycardia to the same extent (maximally by 40%) as each of the drugs alone. In conclusion, according to nonadditivity of the effects, MAEA mediates in vivo inhibition by the same receptors as MLA, namely alpha7-subunit-containing nAChRs, although at an allosteric instead of the orthosteric site.

  8. Different Culture Metabolites of the Red Sea Fungus Fusarium equiseti Optimize the Inhibition of Hepatitis C Virus NS3/4A Protease (HCV PR)

    PubMed Central

    Hawas, Usama W.; Al-Farawati, Radwan; Abou El-Kassem, Lamia T.; Turki, Adnan J.

    2016-01-01

    The endophytic fungus Fusarium equiseti was isolated from the brown alga Padina pavonica, collected from the Red Sea. The fungus was identified by its morphology and 18S rDNA. Cultivation of this fungal strain in biomalt-peptone medium led to isolation of 12 known metabolites of diketopeprazines and anthraquinones. The organic extract and isolated compounds were screened for their inhibition of hepatitis C virus NS3/4A protease (HCV PR). As a result, the fungal metabolites showed inhibition of HCV protease (IC50 from 19 to 77 μM), and the fungus was subjected to culture on Czapek’s (Cz) media, with a yield of nine metabolites with potent HCV protease inhibition ranging from IC50 10 to 37 μM. The Cz culture extract exhibited high-level inhibition of HCV protease (IC50 27.6 μg/mL) compared to the biomalt culture extract (IC50 56 μg/mL), and the most potent HCV PR isolated compound (Griseoxanthone C, IC50 19.8 μM) from the bio-malt culture extract showed less of an inhibitory effect compared to isolated ω-hydroxyemodin (IC50 10.7 μM) from the optimized Cz culture extract. Both HCV PR active inhibitors ω-hydroxyemodin and griseoxanthone C were considered as the lowest selective safe constituents against Trypsin inhibitory effect with IC50 48.5 and 51.3 μM, respectively. PMID:27775589

  9. Advanced Targeting Cost Function Design for Evolutionary Optimization of Control of Logistic Equation

    NASA Astrophysics Data System (ADS)

    Senkerik, Roman; Zelinka, Ivan; Davendra, Donald; Oplatkova, Zuzana

    2010-06-01

    This research deals with the optimization of the control of chaos by means of evolutionary algorithms. This work is aimed on an explanation of how to use evolutionary algorithms (EAs) and how to properly define the advanced targeting cost function (CF) securing very fast and precise stabilization of desired state for any initial conditions. As a model of deterministic chaotic system, the one dimensional Logistic equation was used. The evolutionary algorithm Self-Organizing Migrating Algorithm (SOMA) was used in four versions. For each version, repeated simulations were conducted to outline the effectiveness and robustness of used method and targeting CF.

  10. An Optimal Density Functional Theory Method for GaN and ZnO

    SciTech Connect

    Yu, H.G.

    2011-08-25

    We report an optimal DFT method (bBLYP) for studying the GaN and ZnO systems. It is developed by modifying the exchange functional in the hybrid BLYP method in order to overcome the flaw of traditional DFT that often predict a rather small band gap for those semiconductors. Results show that the bBLYP method can describe not only correct band gaps of both GaN and ZnO wurtzite crystals, but also accurate properties of relevant small molecules. The application study of crystal-cut nanoparticles and nanowires reveals a new mechanism for band gap narrowing in GaN/ZnO.

  11. Atypical effect of dopamine in modulating the functional inhibition of NMDA receptors of cultured retina cells.

    PubMed

    Do Nascimento, J L; Kubrusly, R C; Reis, R A; De Mello, M C; De Mello, F G

    1998-02-05

    Cultured retina cells released accumulated [3H]GABA (gamma-aminobutyric acid) when stimulated by L-glutamate, N-methyl-D-aspartate (NMDA) and kainate. In the absence of Mg2+, dopamine at 200 microM (IC50 60 microM), inhibited in more than 50% the release of [3H]GABA induced by L-glutamate and NMDA, but not by kainate. This effect was not blocked by the D1-like dopamine receptor antagonist, R-(+)-7-chloro-8-hydroxy-3-methyl- -phenyl-2,3,4,5-tetrahydro- H-3-benzazepine hydrochloride (SCH 23390), neither by haloperidol nor spiroperidol (dopamine D2-like receptor antagonists). The dopamine D1-like receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,diol hydrochloride (SKF 38393) at 50 microM, but not its enantiomer, also inhibited the release of [3H]GABA induced by NMDA, but not by kainate; an effect that was not prevented by the antagonists mentioned above. (+/-)-6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin e hydrobromide (SKF 812497) had no effect. Neither 8BrcAMP (5 mM) nor forskolin (10 microM) inhibited the release of [3H]GABA. Our results suggest that dopamine and (+)-SKF 38393 inhibit the glutamate and NMDA-evoked [3H]GABA release through mechanisms that seem not to involve known dopaminergic receptor systems.

  12. Genetically controlled random search: a global optimization method for continuous multidimensional functions

    NASA Astrophysics Data System (ADS)

    Tsoulos, Ioannis G.; Lagaris, Isaac E.

    2006-01-01

    A new stochastic method for locating the global minimum of a multidimensional function inside a rectangular hyperbox is presented. A sampling technique is employed that makes use of the procedure known as grammatical evolution. The method can be considered as a "genetic" modification of the Controlled Random Search procedure due to Price. The user may code the objective function either in C++ or in Fortran 77. We offer a comparison of the new method with others of similar structure, by presenting results of computational experiments on a set of test functions. Program summaryTitle of program: GenPrice Catalogue identifier:ADWP Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADWP Program available from: CPC Program Library, Queen's University of Belfast, N. Ireland Computer for which the program is designed and others on which it has been tested: the tool is designed to be portable in all systems running the GNU C++ compiler Installation: University of Ioannina, Greece Programming language used: GNU-C++, GNU-C, GNU Fortran-77 Memory required to execute with typical data: 200 KB No. of bits in a word: 32 No. of processors used: 1 Has the code been vectorized or parallelized?: no No. of lines in distributed program, including test data, etc.:13 135 No. of bytes in distributed program, including test data, etc.: 78 512 Distribution format: tar. gz Nature of physical problem: A multitude of problems in science and engineering are often reduced to minimizing a function of many variables. There are instances that a local optimum does not correspond to the desired physical solution and hence the search for a better solution is required. Local optimization techniques are frequently trapped in local minima. Global optimization is hence the appropriate tool. For example, solving a nonlinear system of equations via optimization, employing a "least squares" type of objective, one may encounter many local minima that do not correspond to solutions, i.e. minima with values

  13. New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells.

    PubMed

    Abate, Getahun; Ruminiski, Peter G; Kumar, Malkeet; Singh, Kawaljit; Hamzabegovic, Fahreta; Hoft, Daniel F; Eickhoff, Christopher S; Selimovic, Asmir; Campbell, Mary; Chibale, Kelly

    2015-12-07

    There is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and gamma interferon (IFN-γ). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5(flox/flox) (control) and ATG5(flox/flox) Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis-specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis-specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structure-activity relationship studies aimed at identifying more effective analogs.

  14. New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

    PubMed Central

    Ruminiski, Peter G.; Kumar, Malkeet; Singh, Kawaljit; Hamzabegovic, Fahreta; Hoft, Daniel F.; Eickhoff, Christopher S.; Selimovic, Asmir; Campbell, Mary; Chibale, Kelly

    2015-01-01

    There is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and gamma interferon (IFN-γ). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5flox/flox (control) and ATG5flox/flox Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis-specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis-specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structure-activity relationship studies aimed at identifying more effective analogs. PMID:26643325

  15. A Synergy-Based Optimally Designed Sensing Glove for Functional Grasp Recognition

    PubMed Central

    Ciotti, Simone; Battaglia, Edoardo; Carbonaro, Nicola; Bicchi, Antonio; Tognetti, Alessandro; Bianchi, Matteo

    2016-01-01

    Achieving accurate and reliable kinematic hand pose reconstructions represents a challenging task. The main reason for this is the complexity of hand biomechanics, where several degrees of freedom are distributed along a continuous deformable structure. Wearable sensing can represent a viable solution to tackle this issue, since it enables a more natural kinematic monitoring. However, the intrinsic accuracy (as well as the number of sensing elements) of wearable hand pose reconstruction (HPR) systems can be severely limited by ergonomics and cost considerations. In this paper, we combined the theoretical foundations of the optimal design of HPR devices based on hand synergy information, i.e., the inter-joint covariation patterns, with textile goniometers based on knitted piezoresistive fabrics (KPF) technology, to develop, for the first time, an optimally-designed under-sensed glove for measuring hand kinematics. We used only five sensors optimally placed on the hand and completed hand pose reconstruction (described according to a kinematic model with 19 degrees of freedom) leveraging upon synergistic information. The reconstructions we obtained from five different subjects were used to implement an unsupervised method for the recognition of eight functional grasps, showing a high degree of accuracy and robustness. PMID:27271621

  16. A Synergy-Based Optimally Designed Sensing Glove for Functional Grasp Recognition.

    PubMed

    Ciotti, Simone; Battaglia, Edoardo; Carbonaro, Nicola; Bicchi, Antonio; Tognetti, Alessandro; Bianchi, Matteo

    2016-06-02

    Achieving accurate and reliable kinematic hand pose reconstructions represents a challenging task. The main reason for this is the complexity of hand biomechanics, where several degrees of freedom are distributed along a continuous deformable structure. Wearable sensing can represent a viable solution to tackle this issue, since it enables a more natural kinematic monitoring. However, the intrinsic accuracy (as well as the number of sensing elements) of wearable hand pose reconstruction (HPR) systems can be severely limited by ergonomics and cost considerations. In this paper, we combined the theoretical foundations of the optimal design of HPR devices based on hand synergy information, i.e., the inter-joint covariation patterns, with textile goniometers based on knitted piezoresistive fabrics (KPF) technology, to develop, for the first time, an optimally-designed under-sensed glove for measuring hand kinematics. We used only five sensors optimally placed on the hand and completed hand pose reconstruction (described according to a kinematic model with 19 degrees of freedom) leveraging upon synergistic information. The reconstructions we obtained from five different subjects were used to implement an unsupervised method for the recognition of eight functional grasps, showing a high degree of accuracy and robustness.

  17. Optimization of carboxymethyl chitosan synthesis using response surface methodology and desirability function.

    PubMed

    Bukzem, Andrea L; Signini, Roberta; Dos Santos, Danilo M; Lião, Luciano M; Ascheri, Diego Palmiro R

    2016-04-01

    In this paper, chitosan was reacted with monochloroacetic acid under alkaline conditions to prepare carboxymethyl chitosan. A 2(3) full-factorial central composite design was applied to evaluate the effect of molar ratio sodium hydroxide (NaOH)/Chitosan (Ch), time and molar ratio monochloroacetic acid (MCA)/Chitosan (Ch) on the reaction yield and on the characteristics of carboxymethyl chitosan such as average degree of substitution (DS¯) and solubility. An optimization strategy based on response surface methodology was used together with the desirability function approach to optimize this process. The occurrence of carboxymethylation was evidenced by FTIR and (1)H NMR spectroscopy. The optimum conditions for carboxymethylation process were found to be 12.4, 10.6h and 5 for molar ratio sodium hydroxide (NaOH)/Chitosan (Ch), time and molar ratio monochloroacetic acid (MCA)/Chitosan (Ch), respectively. Under these optimal conditions, it was possible to obtain carboxymethyl chitosan with DS¯ of 1.86 and solubility of 99.6%. X-ray diffraction and thermogravimetry analysis showed that crystallinity and thermal stability of derivatives was lower than chitosan and decreased with increase of DS¯.

  18. Evolutionary optimization of radial basis function classifiers for data mining applications.

    PubMed

    Buchtala, Oliver; Klimek, Manuel; Sick, Bernhard

    2005-10-01

    In many data mining applications that address classification problems, feature and model selection are considered as key tasks. That is, appropriate input features of the classifier must be selected from a given (and often large) set of possible features and structure parameters of the classifier must be adapted with respect to these features and a given data set. This paper describes an evolutionary algorithm (EA) that performs feature and model selection simultaneously for radial basis function (RBF) classifiers. In order to reduce the optimization effort, various techniques are integrated that accelerate and improve the EA significantly: hybrid training of RBF networks, lazy evaluation, consideration of soft constraints by means of penalty terms, and temperature-based adaptive control of the EA. The feasibility and the benefits of the approach are demonstrated by means of four data mining problems: intrusion detection in computer networks, biometric signature verification, customer acquisition with direct marketing methods, and optimization of chemical production processes. It is shown that, compared to earlier EA-based RBF optimization techniques, the runtime is reduced by up to 99% while error rates are lowered by up to 86%, depending on the application. The algorithm is independent of specific applications so that many ideas and solutions can be transferred to other classifier paradigms.

  19. Formulation for a practical implementation of electromagnetic induction coils optimized using stream functions

    NASA Astrophysics Data System (ADS)

    Reed, Mark A.; Scott, Waymond R.

    2016-05-01

    Continuous-wave (CW) electromagnetic induction (EMI) systems used for subsurface sensing typically employ separate transmit and receive coils placed in close proximity. The closeness of the coils is desirable for both packaging and object pinpointing; however, the coils must have as little mutual coupling as possible. Otherwise, the signal from the transmit coil will couple into the receive coil, making target detection difficult or impossible. Additionally, mineralized soil can be a significant problem when attempting to detect small amounts of metal because the soil effectively couples the transmit and receive coils. Optimization of wire coils to improve their performance is difficult but can be made possible through a stream-function representation and the use of partially convex forms. Examples of such methods have been presented previously, but these methods did not account for certain practical issues with coil implementation. In this paper, the power constraint introduced into the optimization routine is modified so that it does not penalize areas of high current. It does this by representing the coils as plates carrying surface currents and adjusting the sheet resistance to be inversely proportional to the current, which is a good approximation for a wire-wound coil. Example coils are then optimized for minimum mutual coupling, maximum sensitivity, and minimum soil response at a given height with both the earlier, constant sheet resistance and the new representation. The two sets of coils are compared both to each other and other common coil types to show the method's viability.

  20. The Recovery of Plastid Function Is Required for Optimal Response to Low Temperatures in Arabidopsis

    PubMed Central

    Kindgren, Peter; Dubreuil, Carole; Strand, Åsa

    2015-01-01

    Cold acclimation is an essential response in higher plants to survive freezing temperatures. Here, we report that two independent mutant alleles of the H-subunit of Mg-chelatase, CHLH, gun5-1 and cch in Arabidopsis are sensitive to low temperatures. Plants were grown in photoperiodic conditions and exposed to low temperatures for short- and long-term periods. Tetrapyrrole biosynthesis was initially significantly inhibited in response to low temperature but recovered in wild type (Col-0), although the tetrapyrrole levels were lower in cold compared to control conditions. The gun5-1 and cch alleles showed an inability to recover chlorophyll biosynthesis in addition to a significant decrease in freezing tolerance. We found that the impaired plastid function in the CHLH mutant plants resulted in compromised de novo protein synthesis at low temperatures. The expression of the transcription factors CBF1-3 was super-induced in gun5-1 and cch mutant alleles but expression levels of their target genes, COR15a, COR47 and COR78 were similar or even lower compared to Col-0. In addition, the protein levels of COR15a were lower in gun5-1 and cch and a general defect in protein synthesis could be seen in the gun5-1 mutant following a 35S labelling experiment performed at low temperature. Taken together, our results demonstrate the importance of a functional chloroplast for the cold acclimation process and further suggest that impaired plastid function could result in inhibition of protein synthesis at low temperature. PMID:26366569

  1. Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition.

    PubMed

    Cocaign, Angélique; Kubiak, Xavier; Xu, Ximing; Garnier, Guillaume; Li de la Sierra-Gallay, Inès; Chi-Bui, Linh; Dairou, Julien; Busi, Florent; Abuhammad, Areej; Haouz, Ahmed; Dupret, Jean Marie; Herrmann, Jean Louis; Rodrigues-Lima, Fernando

    2014-11-01

    Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

  2. Oseltamivir produces hypothermic and neuromuscular effects by inhibition of nicotinic acetylcholine receptor functions: comparison to procaine and bupropion.

    PubMed

    Fukushima, Akihiro; Chazono, Kaori; Hashimoto, Yuichi; Iwajima, Yui; Yamamoto, Shohei; Maeda, Yasuhiro; Ohsawa, Masahiro; Ono, Hideki

    2015-09-05

    Oseltamivir, an anti-influenza virus drug, induces marked hypothermia in normal mice. We have proposed that the hypothermic effect arises from inhibition of the nicotinic acetylcholine receptor function of sympathetic ganglion neurons which innervate the brown adipose tissue (a heat generator). It has been reported that local anesthetics inhibit nicotinic acetylcholine receptor function by acting on its ionic channels, and that bupropion, a nicotinic antagonist, induces hypothermia. In this study, we compared the effects of oseltamivir, procaine and bupropion on body temperature, cardiovascular function and neuromuscular transmission. Intraperitoneal administration of oseltamivir (100mg/kg), procaine (86.6mg/kg) and bupropion (86.7mg/kg) lowered the core body temperature of normal mice. At lower doses (10-30mg/kg oseltamivir, 8.7-26mg/kg procaine and bupropion), when administered subcutaneously, the three drugs antagonized the hypothermia induced by intraperitoneal injection of nicotine (1mg/kg). In anesthetized rats, intravenous oseltamivir (30-100mg/kg), procaine (10mg/kg) and bupropion (10mg/kg) induced hypotension and bradycardia. Oseltamivir alone (100mg/kg) did not inhibit neuromuscular twitch contraction of rats, but at 3-30mg/kg it augmented the muscle-relaxing effect of d-tubocurarine. Similar effects were observed when lower doses of procaine (10-30mg/kg) and bupropion (3-10mg/kg) were administered, suggesting that systemic administration of oseltamivir inhibits muscular nicotinic acetylcholine receptors. These results support the idea that the hypothermic effect of oseltamivir is due to its effects on sympathetic ganglia which innervate the brown adipose tissue, and suggest that oseltamivir may exert non-selective ion channel blocking effects like those of ester-type local anesthetics.

  3. Physalins B, F and G, seco-steroids purified from Physalis angulata L., inhibit lymphocyte function and allogeneic transplant rejection.

    PubMed

    Soares, M B P; Brustolim, D; Santos, L A; Bellintani, M C; Paiva, F P; Ribeiro, Y M; Tomassini, T C B; Ribeiro Dos Santos, R

    2006-03-01

    Physalis angulata is a solanaceae widely used in folk medicine in various tropical countries in the world. We have previously described that seco-steroids (physalins) purified from P. angulata are potent inhibitors of macrophage activation, blocking the production of pro-inflammatory cytokines and LPS-induced lethality. Herein we investigated the immunomodulatory activities of these substances in lymphocyte proliferation and cytokine production and in transplantation. The addition of physalins B, F or G to concanavalin A-activated splenocyte cultures induced a concentration-dependent inhibition of proliferation. Physalin B also inhibited IL-2 production by Con A-activated spleen cells. The addition of 2 mug/ml physalin B to mixed lymphocyte reaction (MLR) caused a 100% inhibition of proliferation. More importantly, treatment of mice with physalin B, F or G prevented the rejection of allogeneic heterotopic heart transplant. Our results demonstrate the suppressive activity of physalins B, F and G in lymphocyte function and indicate the potential use of physalins as immunosuppressive agents for treatments of pathologies in which inhibition of immune responses is desired.

  4. Pain-inducing imagery as a function of hypnotisability and of the activity of Gray's Behavioral Inhibition/Activation Systems.

    PubMed

    Santarcangelo, Enrica L; Varanini, Maurizio; Paoletti, Giulia; Castellani, Eleonora; Palombo, Carlo; Carli, Giancarlo

    2013-12-17

    The aim of the study was to test the efficacy of pain imagery as a function of hypnotisability and of the activity of Behavioral Inhibition/Activation Systems. Questionnaires of imagery abilities (Betts) for the visual, cutaneous and organic modalities, absorption in cognitive tasks (TAS), proneness to inhibit stressful/painful experience/seek out positive experiences (BIS BAS), trait anxiety (STAI-Y2) and psychological well-being (PWB) were administered to 21 subjects with high hypnotisability (highs) and 21 subjects with low hypnotisability (lows). Self-reports of pain intensity and of neutral tactile perception were collected during imagery of nociceptive (Pain) and neutral tactile stimulation (NT). ECG and skin conductance were recorded. Highs exhibited greater imagery abilities, absorption, Behavioral Inhibition System Activity and psychological well-being with respect to lows. They reported lower scores of pain intensity than of tactile perception, while in lows Pain and NT scores did not differ. However, controlling for BAS, but not for BIS, revealed differences in the efficacy of pain imagery between highs and lows. Heart rate decreased in both tasks and groups; heart rate variability and skin conductance did not change significantly during imageries. Our findings suggest that the Behavioral Inhibition/Activation Systems interact with imagery abilities reducing the efficacy of pain imagery and prompt investigation of possible similar interactions in the modulation of physically induced experimental pain and of chronic pain in the general population.

  5. Human Pegivirus (HPgV; formerly known as GBV-C) inhibits IL-12 dependent natural killer cell function.

    PubMed

    Chivero, Ernest T; Bhattarai, Nirjal; McLinden, James H; Xiang, Jinhua; Stapleton, Jack T

    2015-11-01

    Human Pegivirus (HPgV, formally GB virus C) infects lymphocytes and NK cells in vivo, and infection is associated with reduced T cell and NK cell activation in HIV-infected individuals. The mechanism by which HPgV inhibits NK cell activation has not been assessed. Following IL-12 stimulation, IFNγ expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects (p=0.02). In addition, HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited NK cell IL-12-mediated IFNγ release. E2 protein also inhibited Tyk2 activation following IL-12 stimulation. In contrast, cytolytic NK cell function was not altered by HPgV. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV persistence and reduced immune activation during HIV-coinfection. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases.

  6. Specifying Associations Between Conscientiousness and Executive Functioning: Mental Set Shifting, Not Prepotent Response Inhibition or Working Memory Updating.

    PubMed

    Fleming, Kimberly A; Heintzelman, Samantha J; Bartholow, Bruce D

    2016-06-01

    Conscientiousness is characterized by self-control, organization, and goal orientation and is positively related to a number of health and professional outcomes. Thus, it is commonly suggested that conscientiousness should be related to superior executive functioning (EF) abilities, especially prepotent response inhibition. However, little empirical support for this notion has emerged, perhaps due to oversimplified and underspecified modeling of EF. The current study sought to fill this gap by testing relations between conscientiousness and three facets of EF using a nested factors latent variable approach. Participants (N = 420; Mage  = 22.5; 50% male; 91% Caucasian) completed a measure of conscientiousness and nine EF tasks designed to tap three related yet distinguishable facets of EF: working memory updating, mental set shifting, and prepotent response inhibition. Structural equation models showed that conscientiousness is positively associated with the EF facet of mental set shifting but not response inhibition or working memory updating. Despite the common notion that conscientiousness is associated with cognitive abilities related to rigid control over impulses (i.e., inhibition), the current results suggest the cognitive ability most associated with conscientiousness is characterized by flexibility and the ability to adapt to changing environmental contingencies and task demands.

  7. NK026680 inhibits T-cell function in an IL-2-dependent manner and prolongs cardiac allograft survival in rats.

    PubMed

    Shibasaki, Susumu; Yamashita, Kenichiro; Goto, Ryoichi; Oura, Tetsu; Wakayama, Kenji; Hirokata, Gentaro; Shibata, Tomohiro; Igarashi, Rumi; Haga, Sanae; Ozaki, Michitaka; Todo, Satoru

    2012-01-01

    NK026680 is a triazolopyrimidine derivative that has been shown to inhibit dendritic cell maturation and activation. Here, we examined the immunosuppressive properties of NK026680 on T-cell function and assessed its immunosuppressive efficacy in an ACI (RT1(av1) haplotype) to Lewis (RT1(l)) rat heart transplantation model. The effects of NK026680 on T-cell proliferation, activation, and cytokine production were investigated in vitro. Heart transplant recipient rats were administered NK026680 daily for 14 days post-transplantation. In addition to graft survival time, alloimmune responses and graft histology at 4-10 days post-transplantation were assessed. NK026680 was found to inhibit proliferation, CD25 upregulation, IL-2 production, and cell cycle progression in αCD3/αCD28-stimulated murine T cells. These effects were likely due to suppression of the p38 mitogen-activated protein kinase pathway and the subsequent inhibition of p65, c-Fos, and to a lesser extent, c-Jun. Daily NK026680 treatment suppressed alloimmune responses, prevented cellular infiltration into allografts, and prolonged graft survival. The anti-rejection effects of NK026680 were enhanced by tacrolimus. In conclusion, NK026680 inhibits the activation of T cells and prolongs cardiac allograft survival in rats. These features make it a potential candidate immunosuppressant for the treatment of organ transplant patients in the future.

  8. Optimization of polysaccharides extraction from watermelon rinds: Structure, functional and biological activities.

    PubMed

    Romdhane, Molka Ben; Haddar, Anissa; Ghazala, Imen; Jeddou, Khawla Ben; Helbert, Claire Boisset; Ellouz-Chaabouni, Semia

    2017-02-01

    In the present work, optimization of hot water extraction, structural characteristics, functional properties, and biological activities of polysaccharides extracted from watermelon rinds (WMRP) were investigated. The physicochemical characteristics and the monosaccharide composition of these polysaccharides were then determined using chemical composition analysis, Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM) and gas chromatography-flame ionization detection (GC-FID). SEM images showed that extracted polysaccharides had a rough surface with many cavities. GC-FID results proved that galactose was the dominant sugar in the extracted polysaccharides, followed by arabinose, glucose, galacturonic acid, rhamnose, mannose, xylose and traces of glucuronic acid. The findings revealed that WMRP displayed excellent antihypertensive and antioxidant activities. Those polysaccharides had also a protection effect against hydroxyl radical-induced DNA damage. Functional properties of extracted polysaccharides were also evaluated. WMRP showed good interfacial dose-dependent proprieties. Overall, the results suggested that WMRP presents a promising natural source of antioxidants and antihypertensive agents.

  9. Particle swarm optimization-based radial basis function network for estimation of reference evapotranspiration

    NASA Astrophysics Data System (ADS)

    Petković, Dalibor; Gocic, Milan; Shamshirband, Shahaboddin; Qasem, Sultan Noman; Trajkovic, Slavisa

    2016-08-01

    Accurate estimation of the reference evapotranspiration (ET0) is important for the water resource planning and scheduling of irrigation systems. For this purpose, the radial basis function network with particle swarm optimization (RBFN-PSO) and radial basis function network with back propagation (RBFN-BP) were used in this investigation. The FAO-56 Penman-Monteith equation was used as reference equation to estimate ET0 for Serbia during the period of 1980-2010. The obtained simulation results confirmed the proposed models and were analyzed using the root mean-square error (RMSE), the mean absolute error (MAE), and the coefficient of determination ( R 2). The analysis showed that the RBFN-PSO had better statistical characteristics than RBFN-BP and can be helpful for the ET0 estimation.

  10. Chemical Synthesis, Versatile Structures and Functions of Tailorable Adjuvants for Optimizing Oral Vaccination.

    PubMed

    Zhang, Lei; Hu, Chaohua; Yang, Wendi; Liu, Xiaolin; Wu, Yunkun

    2016-12-28

    Oral vaccines have become a recent focus because of their potential significance in disease prevention and therapy. In the development of oral vaccine-based therapeutics, synthetic materials with tailorable structures and versatile functions can act as antigen conveyers with adjuvant effects, reduce the time cost for vaccine optimization, and provide high security and enhanced immunity. This review presents an overview of the current status of tailoring synthetic adjuvants for oral vaccination, modification strategies for producing effectors with specific structures and functions, enhancement of immune-associated efficiencies, including the barrier-crossing capability to protect antigens in the gastrointestinal tract, coordination of the antigens penetrating mucosa and cell barriers, targeting of concentrated antigens to immune-associated cells, and direct stimulation of immune cells. Finally, we focus on prospective synthetic adjuvants that facilitate the use of oral vaccines via two approaches, namely, in vivo antigen expression and cancer immunotherapy.

  11. Inhibition of NAMPT pathway by FK866 activates the function of p53 in HEK293T cells

    SciTech Connect

    Thakur, Basant Kumar; Dittrich, Tino; Chandra, Prakash; Becker, Annette; Lippka, Yannick; Selvakumar, Divakarvel; Klusmann, Jan-Henning; Reinhardt, Dirk; Welte, Karl

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer In 293T cells, p53 is considered to be inactive due to its interaction with the large T-antigen. Black-Right-Pointing-Pointer Acetylation of p53 at lysine 382 is important for its functional activation. Black-Right-Pointing-Pointer First evidence to document the presence of a functional p53 in 293T cells. Black-Right-Pointing-Pointer Inhibition of NAMPT/SIRT pathway by FK866 in 293T cells increases the functional activity of p53. Black-Right-Pointing-Pointer This activation of p53 involves reversible acetylation of p53 at lysine 382. -- Abstract: Inactivation of p53 protein by endogenous and exogenous carcinogens is involved in the pathogenesis of different human malignancies. In cancer associated with SV-40 DNA tumor virus, p53 is considered to be non-functional mainly due to its interaction with the large T-antigen. Using the 293T cell line (HEK293 cells transformed with large T antigen) as a model, we provide evidence that p53 is one of the critical downstream targets involved in FK866-mediated killing of 293T cells. A reduced rate of apoptosis and an increased number of cells in S-phase was accompanied after knockdown of p53 in these cells. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway. Additionally, knockdown of p53 attenuated the effect of FK866 on cell proliferation, apoptosis, and cell cycle arrest. The data presented here shed light on two important facts: (1) that p53 in 293T cells is active in the presence of FK866, an inhibitor of NAMPT pathway; (2) the apoptosis induced by FK866 in 293T cells is associated with increased acetylation of p53 at Lys382, which is required for the functional activity of p53.

  12. The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage

    SciTech Connect

    Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S; Kafka, Michael; Danilenko, Michael; Studzinski, George P

    2015-01-01

    Intracellular signaling pathways present targets for pharmacological agents with potential for treatment of neoplastic diseases, with some disease remissions already recorded. However, cellular compensatory mechanisms usually negate the initial success. For instance, attempts to interrupt aberrant signaling downstream of the frequently mutated ras by inhibiting ERK1/2 has shown only limited usefulness for cancer therapy. Here, we examined how ERK5, that overlaps the functions of ERK1/2 in cell proliferation and survival, functions in a manner distinct from ERK1/2 in human AML cells induced to differentiate by 1,25D-dihydroxyvitamin D{sub 3} (1,25D). Using inhibitors of ERK1/2 and of MEK5/ERK5 at concentrations specific for each kinase in HL60 and U937 cells, we observed that selective inhibition of the kinase activity of ERK5, but not of ERK1/2, in the presence of 1,25D resulted in macrophage-like cell morphology and enhancement of phagocytic activity. Importantly, this was associated with increased expression of the macrophage colony stimulating factor receptor (M-CSFR), but was not seen when M-CSFR expression was knocked down. Interestingly, inhibition of ERK1/2 led to activation of ERK5 in these cells. Our results support the hypothesis that ERK5 negatively regulates the expression of M-CSFR, and thus has a restraining function on macrophage differentiation. The addition of pharmacological inhibitors of ERK5 may influence trials of differentiation therapy of AML. - Highlights: • ERK5 has at least some functions in AML cells which are distinct from those of ERK1/2. • ERK5 activity negatively controls the expression of M-CSFR. • ERK5 retards the progression of differentiation from monocyte to functional macrophage.

  13. Design of the inverse function delayed neural network for solving combinatorial optimization problems.

    PubMed

    Hayakawa, Yoshihiro; Nakajima, Koji

    2010-02-01

    We have already proposed the inverse function delayed (ID) model as a novel neuron model. The ID model has a negative resistance similar to Bonhoeffer-van der Pol (BVP) model and the network has an energy function similar to Hopfield model. The neural network having an energy can converge on a solution of the combinatorial optimization problem and the computation is in parallel and hence fast. However, the existence of local minima is a serious problem. The negative resistance of the ID model can make the network state free from such local minima by selective destabilization. Hence, we expect that it has a potential to overcome the local minimum problems. In computer simulations, we have already shown that the ID network can be free from local minima and that it converges on the optimal solutions. However, the theoretical analysis has not been presented yet. In this paper, we redefine three types of constraints for the particular problems, then we analytically estimate the appropriate network parameters giving the global minimum states only. Moreover, we demonstrate the validity of estimated network parameters by computer simulations.

  14. Glue function of optimally and overdoped cuprates from inversion of the Raman spectra

    NASA Astrophysics Data System (ADS)

    Fanfarillo, L.; Mori, M.; Campetella, M.; Grilli, M.; Caprara, S.

    2016-02-01

    We address the issue of identifying the mediators of effective interactions in cuprates superconductors. Specifically, we use inversion theory to analyze Raman spectra of optimally and over-doped La2-x Sr x CuO4 samples. This allows us to extract the so-called glue function without making any a priori assumption based on any specific model. We use instead two different techniques, namely the singular value decomposition and a multi-rectangle decomposition. With both techniques we find consistent results showing that: (i) two distinct excitations are responsible for the glue function, which have completely different doping dependence. One excitation becomes weak above optimal doping, where on the contrary the other keeps (or even slightly increases) its strength; (ii) there is a marked temperature dependence on the weight and spectral distribution of these excitations, which therefore must have a somewhat critical character. It is quite natural to identify and characterize these two distinct excitations as damped antiferromagnetic spin waves and damped charge density waves, respectively. This sets the stage for a scenario in which superconductivity is concomitant and competing with a charge ordering instability.

  15. Glue function of optimally and overdoped cuprates from inversion of the Raman spectra.

    PubMed

    Fanfarillo, L; Mori, M; Campetella, M; Grilli, M; Caprara, S

    2016-02-17

    We address the issue of identifying the mediators of effective interactions in cuprates superconductors. Specifically, we use inversion theory to analyze Raman spectra of optimally and over-doped La2-x Sr x CuO4 samples. This allows us to extract the so-called glue function without making any a priori assumption based on any specific model. We use instead two different techniques, namely the singular value decomposition and a multi-rectangle decomposition. With both techniques we find consistent results showing that: (i) two distinct excitations are responsible for the glue function, which have completely different doping dependence. One excitation becomes weak above optimal doping, where on the contrary the other keeps (or even slightly increases) its strength; (ii) there is a marked temperature dependence on the weight and spectral distribution of these excitations, which therefore must have a somewhat critical character. It is quite natural to identify and characterize these two distinct excitations as damped antiferromagnetic spin waves and damped charge density waves, respectively. This sets the stage for a scenario in which superconductivity is concomitant and competing with a charge ordering instability.

  16. ZD7288 inhibits low-threshold Ca(2+) channel activity and regulates sperm function.

    PubMed

    Felix, Ricardo; Sandoval, Alejandro; Sánchez, Daniel; Gómora, Juan Carlos; De la Vega-Beltrán, José L; Treviño, Claudia L; Darszon, Alberto

    2003-11-07

    In this study, ZD7288, a blocker of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, has been found to inhibit the mouse sperm acrosome reaction (AR). HCN channels have not yet been either recorded or implicated in mouse sperm AR, but low-threshold (T-type) Ca(2+) channels have. Interestingly, ZD7288 blocked native T-type Ca(2+) currents in mouse spermatogenic cells with an IC(50) of about 100 microM. This blockade was more effective at voltages producing low levels of inactivation, suggesting a differential affinity of ZD7288 for different channel conformations. Furthermore, ZD7288 inhibited all cloned T-type but not high-threshold N-type channels heterologously expressed in HEK-293 cells. Our results further support the role of T-type Ca(2+) channels in the mouse sperm AR.

  17. Latent Inhibition as a Function of US Intensity in a Two-Stage CER Procedure

    ERIC Educational Resources Information Center

    Rodriguez, Gabriel; Alonso, Gumersinda

    2004-01-01

    An experiment is reported in which the effect of unconditioned stimulus (US) intensity on latent inhibition (LI) was examined, using a two-stage conditioned emotional response (CER) procedure in rats. A tone was used as the pre-exposed and conditioned stimulus (CS), and a foot-shock of either a low (0.3 mA) or high (0.7 mA) intensity was used as…

  18. meso-Transdiene analogs inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release.

    PubMed

    Horton, David B; Siripurapu, Kiran B; Norrholm, Seth D; Culver, John P; Hojahmat, Marhaba; Beckmann, Joshua S; Harrod, Steven B; Deaciuc, Agripina G; Bardo, Michael T; Crooks, Peter A; Dwoskin, Linda P

    2011-03-01

    Lobeline, a nicotinic receptor antagonist and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for methamphetamine abuse. meso-Transdiene (MTD), a lobeline analog, lacks nicotinic receptor affinity, retains affinity for vesicular monoamine transporter 2 (VMAT2), and, surprisingly, has enhanced affinity for dopamine (DA) and serotonin transporters [DA transporter (DAT) and serotonin transporter (SERT), respectively]. In the current study, MTD was evaluated for its ability to decrease methamphetamine self-administration in rats relative to food-maintained responding. MTD specifically decreased methamphetamine self-administration, extending our previous work. Classical structure-activity relationships revealed that more conformationally restricted MTD analogs enhanced VMAT2 selectivity and drug likeness, whereas affinity at the dihydrotetrabenazine binding and DA uptake sites on VMAT2 was not altered. Generally, MTD analogs exhibited 50- to 1000-fold lower affinity for DAT and were equipotent or had 10-fold higher affinity for SERT, compared with MTD. Representative analogs from the series potently and competitively inhibited [(3)H]DA uptake at VMAT2. (3Z,5Z)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-106), the 3Z,5Z-2,4-dichlorophenyl MTD analog, had improved selectivity for VMAT2 over DAT and importantly inhibited methamphetamine-evoked DA release from striatal slices. In contrast, (3Z,5E)-3,5-bis(2,4-dichlorobenzylidene)-1-methylpiperidine (UKMH-105), the 3Z,5E-geometrical isomer, inhibited DA uptake at VMAT2, but did not inhibit methamphetamine-evoked DA release. Taken together, these results suggest that these geometrical isomers interact at alternate sites on VMAT2, which are associated with distinct pharmacophores. Thus, structural modification of the MTD molecule resulted in analogs exhibiting improved drug likeness and improved selectivity for VMAT2, as well as the ability to decrease methamphetamine-evoked DA release

  19. Suppression of cognitive function in hyperthermia; From the viewpoint of executive and inhibitive cognitive processing

    NASA Astrophysics Data System (ADS)

    Shibasaki, Manabu; Namba, Mari; Oshiro, Misaki; Kakigi, Ryusuke; Nakata, Hiroki

    2017-03-01

    Climate change has had a widespread impact on humans and natural systems. Heat stroke is a life-threatening condition in severe environments. The execution or inhibition of decision making is critical for survival in a hot environment. We hypothesized that, even with mild heat stress, not only executive processing, but also inhibitory processing may be impaired, and investigated the effectiveness of body cooling approaches on these processes using the Go/No-go task with electroencephalographic event-related potentials. Passive heat stress increased esophageal temperature (Tes) by 1.30 ± 0.24 °C and decreased cerebral perfusion and thermal comfort. Mild heat stress reduced the amplitudes of the Go-P300 component (i.e. execution) and No-go-P300 component (i.e. inhibition). Cerebral perfusion and thermal comfort recovered following face/head cooling, however, the amplitudes of the Go-P300 and No-go-P300 components remained reduced. During whole-body cooling, the amplitude of the Go-P300 component returned to the pre-heat baseline, whereas that of the No-go-P300 component remained reduced. These results suggest that local cooling of the face and head does not restore impaired cognitive processing during mild heat stress, and response inhibition remains impaired despite the return to normothermia.

  20. Suppression of cognitive function in hyperthermia; From the viewpoint of executive and inhibitive cognitive processing

    PubMed Central

    Shibasaki, Manabu; Namba, Mari; Oshiro, Misaki; Kakigi, Ryusuke; Nakata, Hiroki

    2017-01-01

    Climate change has had a widespread impact on humans and natural systems. Heat stroke is a life-threatening condition in severe environments. The execution or inhibition of decision making is critical for survival in a hot environment. We hypothesized that, even with mild heat stress, not only executive processing, but also inhibitory processing may be impaired, and investigated the effectiveness of body cooling approaches on these processes using the Go/No-go task with electroencephalographic event-related potentials. Passive heat stress increased esophageal temperature (Tes) by 1.30 ± 0.24 °C and decreased cerebral perfusion and thermal comfort. Mild heat stress reduced the amplitudes of the Go-P300 component (i.e. execution) and No-go-P300 component (i.e. inhibition). Cerebral perfusion and thermal comfort recovered following face/head cooling, however, the amplitudes of the Go-P300 and No-go-P300 components remained reduced. During whole-body cooling, the amplitude of the Go-P300 component returned to the pre-heat baseline, whereas that of the No-go-P300 component remained reduced. These results suggest that local cooling of the face and head does not restore impaired cognitive processing during mild heat stress, and response inhibition remains impaired despite the return to normothermia.

  1. Association of COMT and SLC6A3 polymorphisms with impulsivity, response inhibition and brain function.

    PubMed

    Kasparbauer, Anna-Maria; Merten, Natascha; Aichert, Désirée S; Wöstmann, Nicola; Meindl, Thomas; Rujescu, Dan; Ettinger, Ulrich

    2015-10-01

    Evidence of the genetic correlates of inhibitory control is scant. Two previously studied dopamine-related polymorphisms, COMT rs4680 and the SLC6A3 3' UTR 40-base-pair VNTR (rs28363170), have been associated with response inhibition, however with inconsistent findings. Here, we investigated the influence of these two polymorphisms in a large healthy adult sample (N = 515) on a response inhibition battery including the antisaccade, stop-signal, go/no-go and Stroop tasks as well as a psychometric measure of impulsivity (Barratt Impulsiveness Scale) (Experiment 1). Additionally, a subsample (N = 144) was studied while performing the go/no-go, stop-signal and antisaccade tasks in 3T fMRI (Experiment 2). In Experiment 1, we did not find any significant associations of COMT or SLC6A3 with inhibitory performance or impulsivity. In Experiment 2, no association of COMT with BOLD was found. However, there were consistent main effects of SLC6A3 genotype in all inhibitory contrasts: Homozygosity of the 10R allele was associated with greater fronto-striatal BOLD response than genotypes with at least one 9R allele. These findings are consistent with meta-analyses showing that the 10R allele is associated with reduced striatal dopamine transporter expression, which in animal studies has been found to lead to increased extracellular dopamine levels. Our study thus supports the involvement of striatal dopamine in the neural mechanisms of cognitive control, in particular response inhibition.

  2. GP43 from Paracoccidioides brasiliensis inhibits macrophage functions. An evasion mechanism of the fungus.

    PubMed

    Flavia Popi, Ana Flavia; Lopes, José Daniel; Mariano, Mario

    2002-01-01

    Macrophages constitute one of the primary cellular mechanisms that impairs parasite invasion of host tissues. The phagocytic and microbicidal properties of these cells can be modulated by specific membrane receptors involved in cell-microorganism interactions. Gp43, the main antigen secreted by Paracoccidiodes brasiliensis (Pb), the causative agent of Paracoccidioidomycosis, is a high mannose glycoprotein. The role played by gp43 in the pathogenesis of the disease is not completely known. Here, we describe the influence of this molecule on the interaction between peritoneal murine macrophages and Pb. Phagocytosis of Pb, live or heat-killed, by adherent peritoneal cells from both, B10.A (susceptible) and A/Sn (resistant) mice, was evaluated. Addition of different concentrations of gp43 to the culture medium inhibited, in a dose-dependent pattern, phagocytosis of live or heat-killed Pb by peritoneal macrophages from both B10.A and A/Sn mice. Gp43 also inhibits phagocytosis of zymosan particles but did not interfere with the uptake of opsonized sheep red blood cells. It was also shown that both gp43 and heat-killed Pb have an inhibitory effect on the release of NO by zymosan stimulated macrophages. Finally, we demonstrated that gp43 inhibits the fungicidal ability of macrophages from both lineages. Based on these data, it is suggested that gp43 can be considered one of the evasion mechanisms for the installation of primary infection in susceptible hosts.

  3. Effects of Acute Nitric Oxide Synthase Inhibition on Lower Leg Vascular Function in Chronic Tetraplegia

    PubMed Central

    La Fountaine, Michael F; Radulovic, Miroslav; Cardozo, Christopher P; Spungen, Ann M; DeMeersman, Ronald E; Bauman, William A

    2009-01-01

    Background/Objective: To improve our understanding of the lower-leg vascular responses of nitric oxide synthase inhibition in persons with tetraplegia. Participants: Six people with chronic tetraplegia and 6 age-matched controls. Methods: Lower-leg relative vascular resistance and venous volume variation were obtained by venous occlusion plethysmography and blood pressure by auscultation at baseline. Postintravenous infusion of the nitric oxide synthase inhibitor NG-nitro-l-arginine-methyl-ester (1 mg·kg−1) or placebo on separate days. Results: At baseline in the group with tetraplegia compared with controls, mean arterial pressure and relative vascular resistance of the leg were significantly lower. After nitric oxide synthase inhibition, mean arterial pressure and lower leg vascular resistance were significantly elevated in both groups. There were no group or intervention differences in venous volume variation. Conclusion: These preliminary results suggest that nitric oxide synthase inhibition with 1 mg·kg−1 NG-nitro-l-arginine-methyl-ester normalizes seated blood pressure and lower leg vascular resistance to control group baseline levels. PMID:20025149

  4. Functional inhibition of intestinal and uterine muscles by non-permeant triphenylethylene derivatives.

    PubMed

    Marrero-Alonso, Jorge; García Marrero, Benito; Gómez, Tomás; Díaz, Mario

    2006-02-17

    We have previously shown that the triphenylethylene antiestrogen tamoxifen reversibly inhibited spontaneous contractile activity in isolated duodenal muscle. Now, we have synthesized different quaternary ammonium salts of tamoxifen by changing the substituents on the nitrogen of the alkylaminoethoxy side-chain, to obtain plasma membrane impermeable compounds. Synthesized molecules were N-desmethyl-tamoxifen-hydrochloride, ethylbromide-tamoxifen and butylbromide-tamoxifen, which differed in the size of their ionic side-chain. All compounds rapidly and reversibly inhibited spontaneous and CaCl(2)-induced contractions in mouse duodenum and uterus. Dose-response analyses revealed a structure-activity relationship where the larger the side-chain the higher the inhibitory potency. Fourier analyses on triphenylethylene-relaxed duodenal tissues showed that harmonic components of contractile activity were readily recovered upon exposure to the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K644). Likewise, BAY-K644 completely reversed triphenylethylene-induced effects on uterine tonic tension. Our experiments suggest that impermeant tamoxifen derivatives relax visceral smooth muscle through a membrane-mediated non-genomic mechanism that involves inhibition of L-type calcium channels.

  5. Impact of physical activity on executive functions in aging: a selective effect on inhibition among old adults.

    PubMed

    Boucard, Geoffroy K; Albinet, Cédric T; Bugaiska, Aurélia; Bouquet, Cédric A; Clarys, David; Audiffren, Michel

    2012-12-01

    The purposes of this study were to determine the impact of physical activity on three different executive functions (shifting, inhibition, and updating) and to examine whether cardiovascular fitness was a good mediator of the positive link(s) between these variables. Sixty-three young adults (18-28 years), 30 young-old adults (60-70 years) and 30 old adults (71-81 years) were divided into physically active and sedentary groups according to physical activity level (assessed from an accelerometer and the Historical Leisure Activity Questionnaire). Cardiovascular fitness was assessed by VO2max from the Rockport 1 mile. Each executive function was assessed through three different experimental tasks. ANCOVAs revealed that the effect of physical activity level was specific to the old adults and significant for inhibition, but not for updating and shifting. Mediation analysis showed that this positive effect in the old adults group was mediated by cardiovascular fitness level. The present findings highlight the positive linkages among physical activity, cardiovascular fitness, and inhibition in aging.

  6. Anticonvulsants Based on the α-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors.

    PubMed

    Krivoshein, Arcadius V

    2016-03-16

    Although the antiepileptic properties of α-substituted lactams, acetamides, and cyclic imides have been known for over 60 years, the mechanism by which they act remains unclear. I report here that these compounds bind to the nicotinic acetylcholine receptor (nAChR) and inhibit its function. Using transient kinetic measurements with functionally active, nondesensitized receptors, I have discovered that (i) α-substituted lactams and cyclic imides are noncompetitive inhibitors of heteromeric subtypes (such as α4β2 and α3β4) of neuronal nAChRs and (ii) the binding affinity of these compounds toward the nAChR correlates with their potency in preventing maximal electroshock (MES)-induced convulsions in mice. Based on the hypothesis that α-substituted amide group is the essential pharmacophore of these drugs, I found and tested a simple compound, 2-phenylbutyramide. This compound indeed inhibits nAChR and shows good anticonvulsant activity in mice. Molecular docking simulations suggest that α-substituted lactams, acetamides, and cyclic imides bind to the same sites on the extracellular domain of the receptor. These new findings indicate that inhibition of brain nAChRs may play an important role in the action of these antiepileptic drugs, a role that has not been previously recognized.

  7. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

    DOE PAGES

    Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; ...

    2015-03-12

    Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties ofmore » PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.« less

  8. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

    SciTech Connect

    Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; Choi, Jae-Yeon; Augagneur, Yoann; Voelker, Dennis R.; Nair, Satish; Mamoun, Choukri Ben

    2015-03-12

    Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.

  9. PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma

    PubMed Central

    Wang, Shaoqiang; Cheng, Yuanda; Zheng, Yingying; He, Zhiwei; Chen, Wei; Zhou, Wolong; Duan, Chaojun; Zhang, Chunfang

    2016-01-01

    Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target. PMID:27995993

  10. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

    PubMed Central

    Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; Choi, Jae-Yeon; Augagneur, Yoann; Voelker, Dennis R.; Nair, Satish; Mamoun, Choukri Ben

    2015-01-01

    Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs. PMID:25761669

  11. The Neural and Genetic Basis of Executive Function: Attention, Cognitive Flexibility, and Response Inhibition

    PubMed Central

    Logue, Sheree F; Gould, Thomas J

    2013-01-01

    Executive function is a collection of cognitive processes essential for higher order mental function. Processes involved in executive function include, but are not limited to, working memory, attention, cognitive flexibility, and impulse control. These complex behaviors are largely mediated by prefrontal cortical function but are modulated by dopaminergic, noradrenergic, serotonergic, and cholinergic input. The ability of these neurotransmitter systems to modulate executive function allows for adaption in cognitive behavior in response to changes in the environment. Because of the important role these neurotransmitter systems play in regulating executive function, changes in these systems can also have a grave impact on executive function. In addition, polymorphisms in genes associated with these neurotransmitters are associated with phenotypic differences in executive function. Understanding how these naturally occurring polymorphisms contribute to different executive function phenotypes will advance basic knowledge of cognition and potentially further understanding and treatment of mental illness that involve changes in executive function. In this review, we will examine the influence of dopamine, norepinephrine, serotonin, and acetylcholine on the following measures of executive function: attention, cognitive flexibility, and impulse control. We will also review the effects of polymorphisms in genes associated with these neurotransmitter systems on these measures of executive function. PMID:23978501

  12. The neural and genetic basis of executive function: attention, cognitive flexibility, and response inhibition.

    PubMed

    Logue, Sheree F; Gould, Thomas J

    2014-08-01

    Executive function is a collection of cognitive processes essential for higher order mental function. Processes involved in executive function include, but are not limited to, working memory, attention, cognitive flexibility, and impulse control. These complex behaviors are largely mediated by prefrontal cortical function but are modulated by dopaminergic, noradrenergic, serotonergic, and cholinergic input. The ability of these neurotransmitter systems to modulate executive function allows for adaptation in cognitive behavior in response to changes in the environment. Because of the important role these neurotransmitter systems play in regulating executive function, changes in these systems can also have a grave impact on executive function. In addition, polymorphisms in genes associated with these neurotransmitters are associated with phenotypic differences in executive function. Understanding how these naturally occurring polymorphisms contribute to different executive function phenotypes will advance basic knowledge of cognition and potentially further understanding and treatment of mental illness that involve changes in executive function. In this review, we will examine the influence of dopamine, norepinephrine, serotonin, and acetylcholine on the following measures of executive function: attention, cognitive flexibility, and impulse control. We will also review the effects of polymorphisms in genes associated with these neurotransmitter systems on these measures of executive function.

  13. Specific α- and β-Tubulin Isotypes Optimize the Functions of Sensory Cilia in Caenorhabditis elegans

    PubMed Central

    Hurd, Daryl D.; Miller, Renee M.; Núñez, Lizbeth; Portman, Douglas S.

    2010-01-01

    Primary cilia have essential roles in transducing signals in eukaryotes. At their core is the ciliary axoneme, a microtubule-based structure that defines cilium morphology and provides a substrate for intraflagellar transport. However, the extent to which axonemal microtubules are specialized for sensory cilium function is unknown. In the nematode Caenorhabditis elegans, primary cilia are present at the dendritic ends of most sensory neurons, where they provide a specialized environment for the transduction of particular stimuli. Here, we find that three tubulin isotypes—the α-tubulins TBA-6 and TBA-9 and the β-tubulin TBB-4—are specifically expressed in overlapping sets of C. elegans sensory neurons and localize to the sensory cilia of these cells. Although cilia still form in mutants lacking tba-6, tba-9, and tbb-4, ciliary function is often compromised: these mutants exhibit a variety of sensory deficits as well as the mislocalization of signaling components. In at least one case, that of the CEM cephalic sensory neurons, cilium architecture is disrupted in mutants lacking specific ciliary tubulins. While there is likely to be some functional redundancy among C. elegans tubulin genes, our results indicate that specific tubulins optimize the functional properties of C. elegans sensory cilia. PMID:20421600

  14. Effect of heparin and alendronate coating on titanium surfaces on inhibition of osteoclast and enhancement of osteoblast function

    SciTech Connect

    Moon, Ho-Jin; Yun, Young-Pil; Han, Choong-Wan; Kim, Min Sung; Kim, Sung Eun; Bae, Min Soo; Kim, Gyu-Tae; Choi, Yong-Suk; Hwang, Eui-Hwan; Lee, Joon Woo; Lee, Jin-Moo; Lee, Chang-Hoon; Kim, Duck-Su; Kwon, Il Keun

    2011-09-23

    Highlights: {yields} We examine bone metabolism of engineered alendronate attached to Ti surfaces. {yields} Alendronate-immobilized Ti enhances activation of osteoblast differentiation. {yields} Alendronate-immobilized Ti inhibits osteoclast differentiation. {yields} Alendronate-immobilized Ti may be a bioactive implant with dual functions. -- Abstract: The failure of orthopedic and dental implants has been attributed mainly to loosening of the implant from host bone, which may be due to weak bonding of the implant material to bone tissue. Titanium (Ti) is used in the field of orthopedic and dental implants because of its excellent biocompatibility and outstanding mechanical properties. Therefore, in the field of materials science and tissue engineering, there has been extensive research to immobilize bioactive molecules on the surface of implant materials in order to provide the implants with improved adhesion to the host bone tissue. In this study, chemically active functional groups were introduced on the surface of Ti by a grafting reaction with heparin and then the Ti was functionalized by immobilizing alendronate onto the heparin-grafted surface. In the MC3T3-E1 cell osteogenic differentiation study, the alendronate-immobilized Ti substrates significantly enhanced alkaline phosphatase activity (ALP) and calcium content. Additionally, nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation of RAW264.7 cells was inhibited with the alendronate-immobilized Ti as confirmed by TRAP analysis. Real time PCR analysis showed that mRNA expressions of osteocalcin and osteopontin, which are markers for osteogenesis, were upregulated in MC3T3-E1 cells cultured on alendronate-immobilized Ti. The mRNA expressions of TRAP and Cathepsin K, markers for osteoclastogenesis, in RAW264.7 cells cultured on alendronate-immobilized Ti were down-regulated. Our study suggests that alendronate-immobilized Ti may be a bioactive implant with dual functions to enhance

  15. Battle of the eternal rivals: restoring functional p53 and inhibiting Polo-like kinase 1 as cancer therapy.

    PubMed

    Louwen, Frank; Yuan, Juping

    2013-07-01

    Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.

  16. Determine Optimal Stimulus Amplitude for Using Vestibular Stochastic Stimulation to Improve Balance Function

    NASA Technical Reports Server (NTRS)

    Goel, R.; Kofman, I.; DeDios, Y. E.; Jeevarajan, J.; Stepanyan, V.; Nair, M.; Congdon, S.; Fregia, M.; Cohen, H.; Bloomberg, J.J.; Mulavara, A.P.

    2015-01-01

    Sensorimotor changes such as postural and gait instabilities can affect the functional performance of astronauts when they transition across different gravity environments. We are developing a method, based on stochastic resonance (SR), to enhance information transfer by applying non-zero levels of external noise on the vestibular system (vestibular stochastic resonance, VSR). Our previous work has shown the advantageous effects of VSR in a balance task of standing on an unstable surface [1]. This technique to improve detection of vestibular signals uses a stimulus delivery system that provides imperceptibly low levels of white noise-based binaural bipolar electrical stimulation of the vestibular system. The goal of this project is to determine optimal levels of stimulation for SR applications by using a defined vestibular threshold of motion detection. A series of experiments were carried out to determine a robust paradigm to identify a vestibular threshold that can then be used to recommend optimal stimulation levels for sensorimotor adaptability (SA) training applications customized to each crewmember. The amplitude of stimulation to be used in the VSR application has varied across studies in the literature such as 60% of nociceptive stimulus thresholds [2]. We compared subjects' perceptual threshold with that obtained from two measures of body sway. Each test session was 463s long and consisted of several 15s long sinusoidal stimuli, at different current amplitudes (0-2 mA), interspersed with 20-20.5s periods of no stimulation. Subjects sat on a chair with their eyes closed and had to report their perception of motion through a joystick. A force plate underneath the chair recorded medio-lateral shear forces and roll moments. Comparison of threshold of motion detection obtained from joystick data versus body sway suggests that perceptual thresholds were significantly lower. In the balance task, subjects stood on an unstable surface and had to maintain balance

  17. Glucose inhibition of epinephrine stimulation of hepatic gluconeogenesis by blockade of the alpha-receptor function.

    PubMed

    Kneer, N M; Bosch, A L; Clark, M G; Lardy, H A

    1974-11-01

    For isolated rat hepatocytes, glucagon, 3':5'-cyclic AMP, 3':5'-cyclic GMP, and epinephrine stimulate the rate of gluconeogenesis from substrates not involving pathways of mitochondrial metabolism. From estimation of the rates of glucose formation, fructose 6-phosphate phosphorylation, and lactate and pyruvate formation it is concluded that epinephrine and 3':5'-cyclic GMP stimulate gluconeogenesis from either galactose or fructose by influencing the rate of reactions involving fructose 6-phosphate in a manner similar to that already reported for glucagon and 3':5'-cyclic AMP. Each agent acts to inhibit flux through phosphofructokinase (EC 2.7.1.11) and enhance flux through fructose diphosphatase (EC 3.1.3.11), resulting in the re-direction of carbon from lactate and pyruvate formation to glucose synthesis. In addition to 3':5'-cyclic GMP, dibutyryl 3':5'-cyclic GMP, 8-bromo 3':5'-cyclic GMP, 8-benzyl-thio 3':5'-cyclic GMP and 8-(4-chlorophenyl)thio 3':5'-cyclic GMP stimulate glucose formation and inhibit lactate and pyruvate formation from galactose. Guanosine monophosphate and 2':3'-cyclic GMP are inactive. As the stimulatory effect of epinephrine is inhibited by phenoxybenzamine and not by propranolol, and is not simulated by isoproterenol, it is concluded that catecholamine activity is expressed through the alpha-receptor. Increased extracellular glucose concentration (>10 mM) decreases the stimulatory effect of epinephrine, 3':5'-cyclic GMP, and partially that of 3':5'-cyclic AMP but does not alter the efficacy of glucagon.

  18. Trace amines inhibit insect odorant receptor function through antagonism of the co-receptor subunit

    PubMed Central

    Chen, Sisi; Luetje, Charles W.

    2014-01-01

    Many insect behaviors are driven by olfaction, making insect olfactory receptors (ORs) appealing targets for insect control.  Insect ORs are odorant-gated ion channels, with each receptor thought to be composed of a representative from a large, variable family of odorant binding subunits and a highly conserved co-receptor subunit (Orco), assembled in an unknown stoichiometry.  Synthetic Orco directed agonists and antagonists have recently been identified.  Several Orco antagonists have been shown to act via an allosteric mechanism to inhibit OR activation by odorants.  The high degree of conservation of Orco across insect species results in Orco antagonists having broad activity at ORs from a variety of insect species and suggests that the binding site for Orco ligands may serve as a modulatory site for compounds endogenous to insects or may be a target of exogenous compounds, such as those produced by plants.  To test this idea, we screened a series of biogenic and trace amines, identifying several as Orco antagonists.  Of particular interest were tryptamine, a plant-produced amine, and tyramine, an amine endogenous to the insect nervous system.  Tryptamine was found to be a potent antagonist of Orco, able to block Orco activation by an Orco agonist and to allosterically inhibit activation of ORs by odorants.  Tyramine had effects similar to those of tryptamine, but was less potent.  Importantly, both tryptamine and tyramine displayed broad activity, inhibiting odorant activation of ORs of species from three different insect orders (Diptera, Lepidoptera and Coleoptera), as well as odorant activation of six diverse ORs from a single species (the human malaria vector mosquito, Anopheles gambiae).  Our results suggest that endogenous and exogenous natural compounds serve as Orco ligands modulating insect olfaction and that Orco can be an important target for the development of novel insect repellants. PMID:25075297

  19. PPARγ antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function

    PubMed Central

    Sato, Kazuya; Feng, Xingmin; Chen, Jichun; Li, Jungang; Muranski, Pawel; Desierto, Marie J.; Keyvanfar, Keyvan; Malide, Daniela; Kajigaya, Sachiko; Young, Neal S.

    2016-01-01

    Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically “fatless” mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation. PMID:26589913

  20. PPARγ antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function.

    PubMed

    Sato, Kazuya; Feng, Xingmin; Chen, Jichun; Li, Jungang; Muranski, Pawel; Desierto, Marie J; Keyvanfar, Keyvan; Malide, Daniela; Kajigaya, Sachiko; Young, Neal S

    2016-01-01

    Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically "fatless" mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation.

  1. Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

    PubMed

    Strick, Christine A; Li, Cheryl; Scott, Liam; Harvey, Brian; Hajós, Mihály; Steyn, Stefanus J; Piotrowski, Mary A; James, Larry C; Downs, James T; Rago, Brian; Becker, Stacey L; El-Kattan, Ayman; Xu, Youfen; Ganong, Alan H; Tingley, F David; Ramirez, Andres D; Seymour, Patricia A; Guanowsky, Victor; Majchrzak, Mark J; Fox, Carol B; Schmidt, Christopher J; Duplantier, Allen J

    2011-01-01

    Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.

  2. Preventive effect of rikkunshito on gastric motor function inhibited by L-dopa in rats.

    PubMed

    Wang, Lixin; Mogami, Sachiko; Karasawa, Hiroshi; Yamada, Chihiro; Yakabi, Seiichi; Yakabi, Koji; Hattori, Tomohisa; Taché, Yvette

    2014-05-01

    We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson's disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mgkg(-1)) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg(-1)) reduced the LD/CD (20/2 mg kg(-1)) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys(3)]-GHRP-6 (1 mg kg(-1)) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg(-1)) blocked LD/CD (20/2 mg kg(-1))-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson's disease rat model, rikkunshito (1.0 g kg(-1), og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms.

  3. Anti-inflammatory function of Nodosin via inhibition of IL-2.

    PubMed

    Li, Jiyu; Du, Junming; Sun, Lijuan; Liu, Jianwen; Quan, Zhiwei

    2010-01-01

    In order to explore the anti-inflammatory effects of Nodosin from Isodon serra, a traditional Chinese herb medicine, mouse T lymphocytes were incubated with Nodosin. In the current study, Nodosin suppressed the overproduction of the T lymphocytes; moreover, cell mitosis cycle was modulated by interfering with DNA replication in G1 stages via inhibition of IL-2 cytokine secretion at the mRNA level by Nodosin. Interestingly, Xylene-induced mouse tumescence model results suggested Nodosin depressed the murine ear-swelling extent and the level of IL-2 in the blood serum. Finally, Nodosin possessed significant anti-inflammatory effects and is a potential candidate for further clinical trial.

  4. Manganese inhibits NMDA receptor channel function: implications to psychiatric and cognitive effects.

    PubMed

    Guilarte, Tomás R; Chen, Ming-Kai

    2007-11-01

    Humans exposed to excess levels of manganese (Mn(2+)) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn(2+) produces such effects. We now report that Mn(2+) is a potent inhibitor of [(3)H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [(3)H]-MK-801 to the NMDA receptor channel by Mn(2+) was activity-dependent since Mn(2+) was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (K(i)=35.9+/-3.1 microM) than in their absence (K(i)=157.1+/-6.5 microM). We also show that Mn(2+) is a NMDA receptor channel blocker since its inhibition of [(3)H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn(2+) significantly increased the affinity constant (K(d)) with no significant effect on the maximal number of [(3)H]-MK-801 binding sites (B(max)). Under stimulating conditions, Mn(2+) was equipotent in inhibiting [(3)H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn(2+) was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn(2+) exposure in non-human primates increases Cu(2+), but not zinc or iron concentrations in the basal ganglia [Guilarte TR, Chen M-K, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 2006a;202:381-90]. Therefore, we also tested the inhibitory effects of Cu(2+) on [(3)H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu(2+) in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn(2

  5. Optimal Stimulus Amplitude for Vestibular Stochastic Stimulation to Improve Sensorimotor Function

    NASA Technical Reports Server (NTRS)

    Goel, R.; Kofman, I.; DeDios, Y. E.; Jeevarajan, J.; Stepanyan, V.; Nair, M.; Congdon, S.; Fregia, M.; Cohen, H.; Bloomberg, J. J.; Mulavara, A. P.

    2014-01-01

    Sensorimotor changes such as postural and gait instabilities can affect the functional performance of astronauts when they transition across different gravity environments. We are developing a method, based on stochastic resonance (SR), to enhance information transfer by applying non-zero levels of external noise on the vestibular system (vestibular stochastic resonance, VSR). Our previous work has shown the advantageous effects of VSR in a balance task of standing on an unstable surface. This technique to improve detection of vestibular signals uses a stimulus delivery system that is wearable or portable and provides imperceptibly low levels of white noise-based binaural bipolar electrical stimulation of the vestibular system. The goal of this project is to determine optimal levels of stimulation for SR applications by using a defined vestibular threshold of motion detection. A series of experiments were carried out to determine a robust paradigm to identify a vestibular threshold that can then be used to recommend optimal stimulation levels for SR training applications customized to each crewmember. Customizing stimulus intensity can maximize treatment effects. The amplitude of stimulation to be used in the VSR application has varied across studies in the literature such as 60% of nociceptive stimulus thresholds. We compared subjects' perceptual threshold with that obtained from two measures of body sway. Each test session was 463s long and consisted of several 15s sinusoidal stimuli, at different current amplitudes (0-2 mA), interspersed with 20-20.5s periods of no stimulation. Subjects sat on a chair with their eyes closed and had to report their perception of motion through a joystick. A force plate underneath the chair recorded medio-lateral shear forces and roll moments. First we determined the percent time during stimulation periods for which perception of motion (activity above a pre-defined threshold) was reported using the joystick, and body sway (two

  6. Inhibition of Porcine Pancreatic Amylase Activity by Sulfamethoxazole: Structural and Functional Aspect.

    PubMed

    Maity, Sujan; Mukherjee, Koel; Banerjee, Amrita; Mukherjee, Suman; Dasgupta, Dipak; Gupta, Suvroma

    2016-06-01

    Combating Type-2 diabetes mellitus is a pivotal challenge in front of the present world. Several lines of therapy are in practice for resisting this deadly disease which often culminates with cardiovascular complexities, neuropathy and retinopathy. Among various therapies, administration of alpha glucosidase inhibitors is common and widely practiced. Sulfonylurea category of anti diabetic drug often suffers from cross reactivity with sulfamethoxazole (SMX), a common drug in use to treat a handful of microbial infections. However the specific cellular target generating postprandial hypoglycemia on SMX administration is till date unraveled. The present work has been initiated to elucidate the effects of a group of sulfonamide drugs inclusive of SMX for their amylase inhibitory role. SMX inhibits porcine pancreatic amylase (PPA) in a noncompetitive mode with an average IC50 value 0.94 mM respectively. Interaction of SMX with PPA is manifested with gradual quenching of tryptophan fluorescence with concomitant shift in lambda max value (λmax). Binding is governed by entropy driven factor (24.8 cal mol(-1) K(-1)) with unfavorable contribution from enthalpy change. SMX interferes with the activity of acarbose in a synergistic mode to reduce the effective dose of acarbose as evident from the in vitro PPA inhibition study. In summary, loss of PPA activity in presence of SMX is indicative of structural changes of PPA which is further augmented in the presence of acarbose as explained in the schematic model and docking study.

  7. A novel regulatory mechanism of naringenin through inhibition of T lymphocyte function in contact hypersensitivity suppression

    SciTech Connect

    Fang, Feng; Tang, Yijun; Gao, Zhe; Xu, Qiang

    2010-06-25

    Naringenin, a flavonoid in grapefruits and citrus fruits, has been reported to exhibit anti-inflammatory and anti-oxidative activities. Contact hypersensitivity (CHS) is a T cell-mediated immune reaction, and the factors released from macrophages also contribute to this response. Previous studies showed that naringenin suppressed CHS by inhibiting activation and migration of macrophages. However, little is known about naringenin's effects on T lymphocytes. Our study indicated that naringenin potently suppressed picryl chloride (PCl)-induced contact hypersensitivity by inhibiting the proliferation and activation of T lymphocytes. In vitro, both of the activated hapten-specific T cells and the T cells stimulated with anti-CD3/anti-CD28 showed growth arrest after naringenin treatment. Furthermore, naringenin reduced CD69 (the protein level) and cytokines such as IL-2, TNF-{alpha}, and IFN-{gamma} (the mRNA level) expressions which highly expressed by activated T cells. Meanwhile, naringenin also induced T cell apoptosis by upregulation of Bax, Bad, PARP, cleaved-caspase 3 and downregulation of phosphorylated Akt, Bcl-2. These findings suggest that, besides its anti-inflammatory activities in macrophages, naringenin also showed inhibitory effects on the activation and proliferation of T cells to alleviate symptoms of contact hypersensitivity.

  8. Paeoniflorin Ameliorates Experimental Autoimmune Encephalomyelitis via Inhibition of Dendritic Cell Function and Th17 Cell Differentiation

    PubMed Central

    Zhang, Han; Qi, Yuanyuan; Yuan, Yuanyang; Cai, Li; Xu, Haiyan; Zhang, Lili; Su, Bing; Nie, Hong

    2017-01-01

    Paeoniflorin (PF) is a monoterpene glycoside and exhibits multiple effects, including anti-inflammation and immunoregulation. To date, the effect of PF on multiple sclerosis (MS) has not been investigated. In this study, we investigated the effect of PF in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. After administered with PF, the onset and clinical symptoms of EAE mice were significantly ameliorated, and the number of Th17 cells infiltrated in central nervous system (CNS) and spleen was also dramatically decreased. Instead of inhibiting the differentiation of Th17 cells directly, PF influenced Th17 cells via suppressing the expression of costimulatory molecules and the production of interlukin-6 (IL-6) of dendritic cells (DCs) in vivo and in vitro, which may be attributable to the inhibition of IKK/NF-κB and JNK signaling pathway. When naïve CD4+ T cells were co-cultured with PF-treated dendritic cells under Th17-polarizing condition, the percentage of Th17 cells and the phosphorylation of STAT3 were decreased, as well as the mRNA levels of IL-17, RORα, and RORγt. Our study provided insights into the role of PF as a unique therapeutic agent for the treatment of multiple sclerosis and illustrated the underlying mechanism of PF from a new perspective. PMID:28165507

  9. Growth inhibition of MCF-7 tumor cell line by phenylacetate linked to functionalized dextran.

    PubMed

    Frank, L; Avramoglou, T; Sainte-Catherine, O; Jozefonvicz, J; Kraemer, M

    2004-01-01

    We investigated the antiproliferative effect of phenylacetate covalently linked to dextran derivatives (DMCBPA conjugates) on human breast cancer MCF-7 cells. We show that free sodium phenylacetate (NaPA) inhibits the cell growth (IC50 = 14 mM), while an important inhibitory effect is observed for DMCBPA conjugates. The IC50 dose of these conjugates is as low as 1.0 mg/ml, corresponding to 1.3 mM of phenylacetate. The precursors, dextran substituted with methylcarboxylate and benzylamide groups, did not affect the growth of MCF-7 tumor cells. We have observed that MCF-7 cell growth inhibition depends on amount of phenylacetate linked to the conjugate. The data indicated that an optimum antiproliferative effect is more significant when the amount of phenylacetate groups present on the dextran backbone is high. Analysis of doubling time by growth kinetics study shows that conjugates have more time-sustained effect than free NaPA. It is noteworthy that the inhibitory effect is observed at non-toxic concentration. Theses conjugates could be considered as acceptable derivatives to prevent tumor progression.

  10. Inhibition of human natural killer cell functional activity by human aspartyl β-hydroxylase.

    PubMed

    Huyan, Ting; Li, Qi; Ye, Lin-Jie; Yang, Hui; Xue, Xiao-Ping; Zhang, Ming-Jie; Huang, Qing-Sheng; Yin, Da-Chuan; Shang, Peng

    2014-12-01

    Natural killer (NK) cells are a key component of the innate immune system and play pivotal roles as inflammatory regulators and in tumor surveillance. Human aspartyl β-hydroxylase (HAAH) is a plasma membrane and endoplasmic reticulum protein with hydroxylation activity, which is over-expressed in many malignant neoplasms and can be detected from the sera of tumor patients. HAAH is involved in regulating tumor cell infiltration and metastasis. Escaping from immune surveillance may help tumor cell infiltration and metastasis. However, the effects of HAAH on tumor immune surveillance have not yet been investigated carefully. The present study investigated the potential use of HAAH as an immune regulator of human NK cells. We assessed the effects of recombinant HAAH (r-HAAH) on primary human NK cell morphology, viability, cytotoxicity, apoptosis, receptors expression and cytokine/cytolytic proteins production. Our results demonstrated that r-HAAH negatively affects NK cell activity in a time and dose-dependent manner. It noticeably reduces the viability of the NK cells by increasing apoptosis and necrosis via caspase signaling pathways. Moreover, r-HAAH reduces the NK cell cytotoxicity by inhibiting surface expression of NKG2D, NKp44 and IFN-γ secretion. These findings suggest that one of the ways by which HAAH actively promotes tumor formation and proliferation is by inhibiting NK cell-surveillance activity.

  11. Mechanisms underlying the endogenous dopaminergic inhibition of spinal locomotor circuit function in Xenopus tadpoles

    PubMed Central

    Picton, Laurence D.; Sillar, Keith T.

    2016-01-01

    Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5–100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel. PMID:27760989

  12. PEDF improves cardiac function in rats with acute myocardial infarction via inhibiting vascular permeability and cardiomyocyte apoptosis.

    PubMed

    Zhang, Hao; Wang, Zheng; Feng, Shou-Jie; Xu, Lei; Shi, He-Xian; Chen, Li-Li; Yuan, Guang-Da; Yan, Wei; Zhuang, Wei; Zhang, Yi-Qian; Zhang, Zhong-Ming; Dong, Hong-Yan

    2015-03-11

    Pigment epithelium-derived factor (PEDF) is a pleiotropic gene with anti-inflammatory, antioxidant and anti-angiogenic properties. However, recent reports about the effects of PEDF on cardiomyocytes are controversial, and it is not known whether and how PEDF acts to inhibit hypoxic or ischemic endothelial injury in the heart. In the present study, adult Sprague-Dawley rat models of acute myocardial infarction (AMI) were surgically established. PEDF-small interfering RNA (siRNA)-lentivirus (PEDF-RNAi-LV) or PEDF-LV was delivered into the myocardium along the infarct border to knockdown or overexpress PEDF, respectively. Vascular permeability, cardiomyocyte apoptosis, myocardial infarct size and animal cardiac function were analyzed. We also evaluated PEDF's effect on the suppression of the endothelial permeability and cardiomyocyte apoptosis under hypoxia in vitro. The results indicated that PEDF significantly suppressed the vascular permeability and inhibited hypoxia-induced endothelial permeability through PPARγ-dependent tight junction (TJ) production. PEDF protected cardiomyocytes against ischemia or hypoxia-induced cell apoptosis both in vivo and in vitro via preventing the activation of caspase-3. We also found that PEDF significantly reduced myocardial infarct size and enhanced cardiac function in rats with AMI. These data suggest that PEDF could protect cardiac function from ischemic injury, at least by means of reducing vascular permeability, cardiomyocyte apoptosis and myocardial infarct size.

  13. In vivo analysis of Argos structure-function. Sequence requirements for inhibition of the Drosophila epidermal growth factor receptor.

    PubMed

    Howes, R; Wasserman, J D; Freeman, M

    1998-02-13

    The Drosophila Argos protein is the only known extracellular inhibitor of the epidermal growth factor receptor (EGFR). It is structurally related to the activating ligands, in that it is a secreted protein with a single epidermal growth factor (EGF) domain. To understand the mechanism of Argos inhibition, we have investigated which regions of the protein are essential. A series of deletions were made and tested in vivo; furthermore, by analyzing chimeric proteins between Argos and the activating ligand, Spitz (a transforming growth factor-alpha-like factor), we have examined what makes one inhibitory and the other activating. Our results reveal that Argos has structural requirements that differ from all known EGFR activating ligands; domains flanking the EGF domain are essential for its function. We have also defined the important regions of the atypical Argos EGF domain. The extended B-loop is necessary, whereas the C-loop can be replaced with the equivalent Spitz region without substantially affecting Argos function. Comparison of the argos genes from Drosophila melanogaster and the housefly, Musca domestica, supports our structure-function analysis. These studies are a prerequisite for understanding how Argos inhibits the Drosophila EGFR and provide a basis for designing mammalian EGFR inhibitors.

  14. Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

    PubMed Central

    Chokshi, Rikki H.; Larsen, Aaron T.; Bhayana, Brijesh

    2015-01-01

    Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2ʹ′-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore (K2P) potassium channel function and stimulate breathing. To better understand the molecular mechanism(s) of action of these drugs, we undertook studies to identify amino acid residues in the TASK-3 protein that mediate this inhibition. Guided by homology modeling and molecular docking, we hypothesized that PKTHPP and A1899 bind in the TASK-3 intracellular pore. To test our hypothesis, we mutated each residue in or near the predicted PKTHPP and A1899 binding site (residues 118–128 and 228–248), individually, to a negatively charged aspartate. We quantified each mutation's effect on TASK-3 potassium channel concentration response to PKTHPP. Studies were conducted on TASK-3 transiently expressed in Fischer rat thyroid epithelial monolayers; channel function was measured in an Ussing chamber. TASK-3 pore mutations at residues 122 (L122D, E, or K) and 236 (G236D) caused the IC50 of PKTHPP to increase more than 1000-fold. TASK-3 mutants L122D, G236D, L239D, and V242D were resistant to block by PKTHPP, A1899, and doxapram. Our data are consistent with a model in which breathing stimulant compounds PKTHPP, A1899, and doxapram inhibit TASK-3 function by binding at a common site within the channel intracellular pore region, although binding outside the channel pore cannot yet be excluded. PMID:26268529

  15. Tranilast inhibits the function of cancer-associated fibroblasts responsible for the induction of immune suppressor cell types.

    PubMed

    Ohshio, Y; Hanaoka, J; Kontani, K; Teramoto, K

    2014-12-01

    Cancer-associated fibroblasts (CAFs) are the dominant stromal component in the tumour microenvironment (TME), playing critical roles in generation of pro-tumourigenic TME; however, their contribution to suppression of antitumour immune responses has not been fully understood. To elucidate the interaction between CAFs and immune suppressor cells, we examined whether inhibition of CAFs function would impair the induction of immune suppressor cell types in vitro. In this study, we applied an anti-allergic and antifibrotic agent tranilast, which is used clinically, and evaluated a potential of tranilast to serve as a CAFs inhibitor. CAFs that had been isolated from E.G7 or LLC1 tumour-bearing mice were cultured in the presence of tranilast, and thereafter, CAFs functions on the secretion of some soluble factors as well as the induction of immune suppressor cells were evaluated. As a result, tranilast inhibited the proliferation of CAFs and reduced the levels of stromal cell-derived factor-1, prostaglandin E2 and transforming growth factor-β1 from CAFs in a dose-dependent manner. On the other hand, tranilast exerted no inhibitory effects on immune cells at doses under 100 μm. The induction of regulatory T cells and myeloid-derived suppressor cells from their progenitor cells was suppressed in the medium that CAFs had been cultured in the presence of tranilast; however, these findings were not observed when those progenitor cells were cultured in the medium containing tranilast alone. These data demonstrate that tranilast inhibits CAFs function, which is responsible for the induction of immune suppressor cells, and possesses a potential to serve as a specific CAFs inhibitor.

  16. THE MAPK ERK5, BUT NOT ERK1/2, INHIBITS THE PROGRESSION OF MONOCYTIC PHENOTYPE TO THE FUNCTIONING MACROPHAGE

    PubMed Central

    Wang, Xuening; Pesakhov, Stella; Harrison, Jonathan S; Kafka, Michael; Danilenko, Michael; Studzinski, George P

    2014-01-01

    Intracellular signaling pathways present targets for pharmacological agents with potential for treatment of neoplastic diseases, with some disease remissions already recorded. However, cellular compensatory mechanisms usually negate the initial success. For instance, attempts to interrupt aberrant signaling downstream of the frequently mutated ras by inhibiting ERK1/2 has shown only limited usefulness for cancer therapy. Here, we examined how ERK5, that overlaps the functions of ERK1/2 in cell proliferation and survival, functions in a manner distinct from ERK1/2 in human AML cells induced to differentiate by 1,25D-dihydroxyvitamin D3 (1,25D). Using inhibitors of ERK1/2 and of MEK5/ERK5 at concentrations specific for each kinase in HL60 and U937 cells, we observed that selective inhibition of the kinase activity of ERK5, but not of ERK1/2, in the presence of 1,25D resulted in macrophage-like cell morphology and enhancement of phagocytic activity. Importantly, this was associated with increased expression of the macrophage colony stimulating factor receptor (M-CSFR), but was not seen when M-CSFR expression was knocked down. Interestingly, inhibition of ERK1/2 led to activation of ERK5 in these cells. Our results support the hypothesis that ERK5 negatively regulates the expression of M-CSFR, and thus has a restraining function on macrophage differentiation. The addition of pharmacological inhibitors of ERK5 may influence trials of differentiation therapy of AML. PMID:25447310

  17. Streamlining the functioning of the FSO systems by choosing the optimal transmission/reception components

    NASA Astrophysics Data System (ADS)

    Manea, Viorel; Puşcoci, Sorin; Stoichescu, Dan Alexandru

    2016-12-01

    FSO systems are becoming more and more used taking under consideration the ease of installation and exploitation under the conditions of the supply of a major fraction of optical fiber bandwidth at reasonable cost. Choosing elements for manufacturing FSO transceivers must keep into account their destination. FSO transceivers can be made using LED or LASER devices at the transmission side, the reception side could be equipped with PIN or APD diodes. This paper makes an analysis of the behavior of semiconductor LASER and LED sources, as well as semiconductor devices PIN and APD for reception side, in various attenuation scenarios, with the aim of achieving an optimization of FSO transceiver, corresponding to different geographical areas, taking into account the specific area and attenuation induced by atmospheric factors, in order to obtain an optimal functioning/price ratio. In this paper it is calculated the bit error rate versus transmission distance for various combinations of sources/receivers, using the Matlab and Optiwave modeling environment, for point to point optical system communication.

  18. Optimization of the ITER electron cyclotron equatorial launcher for improved heating and current drive functional capabilities

    SciTech Connect

    Farina, D.; Figini, L.; Henderson, M.; Saibene, G.

    2014-06-15

    The design of the ITER Electron Cyclotron Heating and Current Drive (EC H and CD) system has evolved in the last years both in goals and functionalities by considering an expanded range of applications. A large effort has been devoted to a better integration of the equatorial and the upper launchers, both from the point of view of the performance and of the design impact on the engineering constraints. However, from the analysis of the ECCD performance in two references H-mode scenarios at burn (the inductive H-mode and the advanced non-inductive scenario), it was clear that the EC power deposition was not optimal for steady-state applications in the plasma region around mid radius. An optimization study of the equatorial launcher is presented here aiming at removing this limitation of the EC system capabilities. Changing the steering of the equatorial launcher from toroidal to poloidal ensures EC power deposition out to the normalized toroidal radius ρ ≈ 0.6, and nearly doubles the EC driven current around mid radius, without significant performance degradation in the core plasma region. In addition to the improved performance, the proposed design change is able to relax some engineering design constraints on both launchers.

  19. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance.

    PubMed

    Aston-Jones, Gary; Cohen, Jonathan D

    2005-01-01

    Historically, the locus coeruleus-norepinephrine (LC-NE) system has been implicated in arousal, but recent findings suggest that this system plays a more complex and specific role in the control of behavior than investigators previously thought. We review neurophysiological and modeling studies in monkey that support a new theory of LC-NE function. LC neurons exhibit two modes of activity, phasic and tonic. Phasic LC activation is driven by the outcome of task-related decision processes and is proposed to facilitate ensuing behaviors and to help optimize task performance (exploitation). When utility in the task wanes, LC neurons exhibit a tonic activity mode, associated with disengagement from the current task and a search for alternative behaviors (exploration). Monkey LC receives prominent, direct inputs from the anterior cingulate (ACC) and orbitofrontal cortices (OFC), both of which are thought to monitor task-related utility. We propose that these frontal areas produce the above patterns of LC activity to optimize utility on both short and long timescales.

  20. Synthesis and Optimization of Surface Functionalized Mesoporous Silica Nanoparticles for Bioconjugation Platforms

    NASA Astrophysics Data System (ADS)

    Gopalan, Anand Srinath

    A large amount of emphasis has been dedicated in recent years to introduce nanoparticles as a viable candidate for targeted therapies. In comparison to other candidates, mesoporous silica nanoparticles have the advantages of being biocompatible, easy to produce, and have the ability to prove to be a theranostic platform. To better study the specific targeting of diseased cells, adhesion studies of drug carrying bioconjugation constructs in fluid environments is required. The goal of this project was to develop a platform based on mesoporous silica nanoparticles that will be used for future multivalent adhesion studies. Specifically, mesoporous silica nanoparticles were synthesized with various sizes and aspect ratios, containing fluorescent dye to enable tracking studies, and with surface treatments that optimized stability and introduced primary-amine functional groups to facilitate attachment with targeted proteins and biomarkers. The effects of various parameters such as solvents, washing methods, secondary modifications and difference in concentrations of the starting materials for the synthesis mixture on the nanoparticles were studied in detail in this thesis. A portion of the study is also dedicated to optimizing a washing procedure to stabilize the particles in an aqueous medium in order to facilitate further modifications. The results of the work in this project can be utilized to provide a platform for further assays in flow chambers after bioconjugation with targeting proteins through orthogonal chemistries to study the adhesion properties in much greater detail.

  1. An Efficient Radial Basis Function Mesh Deformation Scheme within an Adjoint-Based Aerodynamic Optimization Framework

    NASA Astrophysics Data System (ADS)

    Poirier, Vincent

    Mesh deformation schemes play an important role in numerical aerodynamic optimization. As the aerodynamic shape changes, the computational mesh must adapt to conform to the deformed geometry. In this work, an extension to an existing fast and robust Radial Basis Function (RBF) mesh movement scheme is presented. Using a reduced set of surface points to define the mesh deformation increases the efficiency of the RBF method; however, at the cost of introducing errors into the parameterization by not recovering the exact displacement of all surface points. A secondary mesh movement is implemented, within an adjoint-based optimization framework, to eliminate these errors. The proposed scheme is tested within a 3D Euler flow by reducing the pressure drag while maintaining lift of a wing-body configured Boeing-747 and an Onera-M6 wing. As well, an inverse pressure design is executed on the Onera-M6 wing and an inverse span loading case is presented for a wing-body configured DLR-F6 aircraft.

  2. Optimizing parameters of a technical system using quality function deployment method

    NASA Astrophysics Data System (ADS)

    Baczkowicz, M.; Gwiazda, A.

    2015-11-01

    The article shows the practical use of Quality Function Deployment (QFD) on the example of a mechanized mining support. Firstly it gives a short description of this method and shows how the designing process, from the constructor point of view, looks like. The proposed method allows optimizing construction parameters and comparing them as well as adapting to customer requirements. QFD helps to determine the full set of crucial construction parameters and then their importance and difficulty of their execution. Secondly it shows chosen technical system and presents its construction with figures of the existing and future optimized model. The construction parameters were selected from the designer point of view. The method helps to specify a complete set of construction parameters, from the point of view, of the designed technical system and customer requirements. The QFD matrix can be adjusted depending on designing needs and not every part of it has to be considered. Designers can choose which parts are the most important. Due to this QFD can be a very flexible tool. The most important is to define relationships occurring between parameters and that part cannot be eliminated from the analysis.

  3. Interaction between Vestibular Compensation Mechanisms and Vestibular Rehabilitation Therapy: 10 Recommendations for Optimal Functional Recovery.

    PubMed

    Lacour, Michel; Bernard-Demanze, Laurence

    2014-01-01

    This review questions the relationships between the plastic events responsible for the recovery of vestibular function after a unilateral vestibular loss (vestibular compensation), which has been well described in animal models in the last decades, and the vestibular rehabilitation (VR) therapy elaborated on a more empirical basis for vestibular loss patients. The main objective is not to propose a catalog of results but to provide clinicians with an understandable view on when and how to perform VR therapy, and why VR may benefit from basic knowledge and may influence the recovery process. With this perspective, 10 major recommendations are proposed as ways to identify an optimal functional recovery. Among them are the crucial role of active and early VR therapy, coincidental with a post-lesion sensitive period for neuronal network remodeling, the instructive role that VR therapy may play in this functional reorganization, the need for progression in the VR therapy protocol, which is based mainly on adaptation processes, the necessity to take into account the sensorimotor, cognitive, and emotional profile of the patient to propose individual or "à la carte" VR therapies, and the importance of motivational and ecologic contexts. More than 10 general principles are very likely, but these principles seem crucial for the fast recovery of vestibular loss patients to ensure good quality of life.

  4. Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group.

    PubMed

    Deutz, Nicolaas E P; Bauer, Jürgen M; Barazzoni, Rocco; Biolo, Gianni; Boirie, Yves; Bosy-Westphal, Anja; Cederholm, Tommy; Cruz-Jentoft, Alfonso; Krznariç, Zeljko; Nair, K Sreekumaran; Singer, Pierre; Teta, Daniel; Tipton, Kevin; Calder, Philip C

    2014-12-01

    The aging process is associated with gradual and progressive loss of muscle mass along with lowered strength and physical endurance. This condition, sarcopenia, has been widely observed with aging in sedentary adults. Regular aerobic and resistance exercise programs have been shown to counteract most aspects of sarcopenia. In addition, good nutrition, especially adequate protein and energy intake, can help limit and treat age-related declines in muscle mass, strength, and functional abilities. Protein nutrition in combination with exercise is considered optimal for maintaining muscle function. With the goal of providing recommendations for health care professionals to help older adults sustain muscle strength and function into older age, the European Society for Clinical Nutrition and Metabolism (ESPEN) hosted a Workshop on Protein Requirements in the Elderly, held in Dubrovnik on November 24 and 25, 2013. Based on the evidence presented and discussed, the following recommendations are made (a) for healthy older people, the diet should provide at least 1.0-1.2 g protein/kg body weight/day, (b) for older people who are malnourished or at risk of malnutrition because they have acute or chronic illness, the diet should provide 1.2-1.5 g protein/kg body weight/day, with even higher intake for individuals with severe illness or injury, and (c) daily physical activity or exercise (resistance training, aerobic exercise) should be undertaken by all older people, for as long as possible.

  5. Interaction between Vestibular Compensation Mechanisms and Vestibular Rehabilitation Therapy: 10 Recommendations for Optimal Functional Recovery

    PubMed Central

    Lacour, Michel; Bernard-Demanze, Laurence

    2015-01-01

    This review questions the relationships between the plastic events responsible for the recovery of vestibular function after a unilateral vestibular loss (vestibular compensation), which has been well described in animal models in the last decades, and the vestibular rehabilitation (VR) therapy elaborated on a more empirical basis for vestibular loss patients. The main objective is not to propose a catalog of results but to provide clinicians with an understandable view on when and how to perform VR therapy, and why VR may benefit from basic knowledge and may influence the recovery process. With this perspective, 10 major recommendations are proposed as ways to identify an optimal functional recovery. Among them are the crucial role of active and early VR therapy, coincidental with a post-lesion sensitive period for neuronal network remodeling, the instructive role that VR therapy may play in this functional reorganization, the need for progression in the VR therapy protocol, which is based mainly on adaptation processes, the necessity to take into account the sensorimotor, cognitive, and emotional profile of the patient to propose individual or “à la carte” VR therapies, and the importance of motivational and ecologic contexts. More than 10 general principles are very likely, but these principles seem crucial for the fast recovery of vestibular loss patients to ensure good quality of life. PMID:25610424

  6. Protein intake and exercise for optimal muscle function with aging: Recommendations from the ESPEN Expert Group

    PubMed Central

    Deutz, Nicolaas E. P.; Bauer, Jurgen M.; Barazzoni, Rocco; Biolo, Gianni; Boirie, Yves; Bosy-Westphal, Anja; Cederholm, Tommy; Cruz-Jentoft, Alfonso; Krznaric, Zeljko; Nair, K. Sreekumaran; Singer, Pierre; Teta, Daniel; Tipton, Kevin; Calder, Philip C.

    2014-01-01

    The aging process is associated with gradual and progressive loss of muscle mass along with lowered strength and physical endurance. This condition, sarcopenia, has been widely observed with aging in sedentary adults. Regular aerobic and resistance exercise programs have been shown to counteract most aspects of sarcopenia. In addition, good nutrition, especially adequate protein and energy intake, can help limit and treat age-related declines in muscle mass, strength, and functional abilities. Protein nutrition in combination with exercise is considered optimal for maintaining muscle function. With the goal of providing recommendations for health care professionals to help older adults sustain muscle strength and function into older age, the European Society for Clinical Nutrition and Metabolism (ESPEN) hosted a Workshop on Protein Requirements in the Elderly, held in Dubrovnik on November 24 and 25, 2013. Based on the evidence presented and discussed, the following recommendations are made: (1) for healthy older people, the diet should provide at least 1.0 to 1.2 g protein/kg body weight/day (2) for older people who are malnourished or at risk of malnutrition because they have acute or chronic illness, the diet should provide 1.2 to 1.5 g protein/kg body weight/day, with even higher intake for individuals with severe illness or injury, and (3) daily physical activity or exercise (resistance training, aerobic exercise) should be undertaken by all older people, for as long as possible. PMID:24814383

  7. Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury

    PubMed Central

    Koehn, Liam M.; Noor, Natassya M.; Dong, Qing; Er, Sing-Yan; Rash, Lachlan D.; King, Glenn F.; Dziegielewska, Katarzyna M.; Saunders, Norman R.; Habgood, Mark D.

    2016-01-01

    Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a “ treatment window” through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies. PMID:28105306

  8. Calibrating floor field cellular automaton models for pedestrian dynamics by using likelihood function optimization

    NASA Astrophysics Data System (ADS)

    Lovreglio, Ruggiero; Ronchi, Enrico; Nilsson, Daniel

    2015-11-01

    The formulation of pedestrian floor field cellular automaton models is generally based on hypothetical assumptions to represent reality. This paper proposes a novel methodology to calibrate these models using experimental trajectories. The methodology is based on likelihood function optimization and allows verifying whether the parameters defining a model statistically affect pedestrian navigation. Moreover, it allows comparing different model specifications or the parameters of the same model estimated using different data collection techniques, e.g. virtual reality experiment, real data, etc. The methodology is here implemented using navigation data collected in a Virtual Reality tunnel evacuation experiment including 96 participants. A trajectory dataset in the proximity of an emergency exit is used to test and compare different metrics, i.e. Euclidean and modified Euclidean distance, for the static floor field. In the present case study, modified Euclidean metrics provide better fitting with the data. A new formulation using random parameters for pedestrian cellular automaton models is also defined and tested.

  9. LQG optimal compensator transfer function for the NASA LaRC CSI Evolutionary Model

    NASA Technical Reports Server (NTRS)

    Balakrishnan, A. V.

    1994-01-01

    Following the general form for LQG optimal compensators for flexible structures with collocated rate sensors we develop an explicit compensator transfer function for the NASA LaRC CSI Evolutionary model in the form: psi(i omega) = g i omega B(sub u)(sup *)(-M(sub b)omega(exp 2) + T(i omega) + i gamma omega B(sub u)Bu(sub u)(sup *))(exp -1)B(sub u) where T(i omega) is a 48 x 48 positive definite matrix whose derivation is the main result of this report. The undamped mode frequencies can be expressed in terms of T(i omega) as the zeros of Det (-omega(exp 2)M(sub b) + T(i omega)) while 'clamped-clamped' modes of the structure (with all nodes clamped) are the poles.

  10. Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing

    SciTech Connect

    Whitehead, Timothy A.; Chevalier, Aaron; Song, Yifan; Dreyfus, Cyrille; Fleishman, Sarel J.; De Mattos, Cecilia; Myers, Chris A.; Kamisetty, Hetunandan; Blair, Patrick; Wilson, Ian A.; Baker, David

    2012-06-19

    We show that comprehensive sequence-function maps obtained by deep sequencing can be used to reprogram interaction specificity and to leapfrog over bottlenecks in affinity maturation by combining many individually small contributions not detectable in conventional approaches. We use this approach to optimize two computationally designed inhibitors against H1N1 influenza hemagglutinin and, in both cases, obtain variants with subnanomolar binding affinity. The most potent of these, a 51-residue protein, is broadly cross-reactive against all influenza group 1 hemagglutinins, including human H2, and neutralizes H1N1 viruses with a potency that rivals that of several human monoclonal antibodies, demonstrating that computational design followed by comprehensive energy landscape mapping can generate proteins with potential therapeutic utility.

  11. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis.

    PubMed

    Yang, Tieshan; Yao, Qian; Cao, Fei; Liu, Qianqian; Liu, Binlei; Wang, Xiu-Hong

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs), which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF-1α protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis.

  12. Inhibition of leukotriene B4 receptor 1 attenuates lipopolysaccharide-induced cardiac dysfunction: role of AMPK-regulated mitochondrial function

    PubMed Central

    Sun, Meng; Wang, Rui; Han, Qinghua

    2017-01-01

    Leukotriene B4 (LTB4)-mediated leukocyte recruitment and inflammatory cytokine production make crucial contributions to chronic inflammation and sepsis; however, the role of LTB4 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains unclear. Therefore, the present study addressed this issue using an LTB4 receptor 1 (BLT1) inhibitor. Administration of LPS to mice resulted in decreased cardiovascular function. Inhibition of LTB4/BLT1 with the BLT1 inhibitor U75302 significantly improved survival and attenuated the LPS-induced acute cardiac dysfunction. During LPS challenge, the phosphorylated AMPK/ACC signaling pathway was slightly activated, and this effect was enhanced by U75302. Additionally, pNF-κB, Bax and cleaved caspase-3 were upregulated by LPS, and Bcl-2, IκB-α, mitochondrial complex I, complex II, and OPA1 were downregulated; however, these effects were reversed by U75302. The results indicated that the BLT1 antagonist suppressed cardiac apoptosis, inflammation, and mitochondrial impairment. Furthermore, the protection provided by the BLT1 inhibitor against LPS-induced cardiac dysfunction was significantly reversed by the AMPK inhibitor Compound C. In conclusion, inhibiting the LTB4/BLT1 signaling pathway via AMPK activation is a potential treatment strategy for septic cardiac dysfunction because it efficiently attenuates cardiac apoptosis, which may occur via the inhibition of inflammation and mitochondrial dysfunction. PMID:28290498

  13. Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Barton, Elisabeth R.; Sweeney, H. Lee

    2016-01-01

    Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA. PMID:27870893

  14. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis

    PubMed Central

    Yang, Tieshan; Yao, Qian; Cao, Fei; Liu, Qianqian; Liu, Binlei; Wang, Xiu-Hong

    2016-01-01

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs), which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF-1α protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis. PMID:27994464

  15. Social Function and Communication in Optimal Outcome Children and Adolescents with an Autism History on Structured Test Measures

    ERIC Educational Resources Information Center

    Orinstein, Alyssa J.; Suh, Joyce; Porter, Kaitlyn; De Yoe, Kaitlin A.; Tyson, Katherine E.; Troyb, Eva; Barton, Marianne L.; Eigsti, Inge-Marie; Stevens, Michael C.; Fein, Deborah A.

    2015-01-01

    Youth who lose their ASD diagnosis may have subtle social and communication difficulties. We examined social and communication functioning in 44 high-functioning autism (HFA), 34 optimal outcome (OO) and 34 typically developing (TD) youth. Results indicated that OO participants had no autism communication symptoms, no pragmatic language deficits,…

  16. Optimized multimodal functional magnetic resonance imaging/near-infrared spectroscopy probe for ultrahigh-resolution mapping

    PubMed Central

    Hocke, Lia Maria; Cayetano, Kenroy; Tong, Yunjie; Frederick, Blaise

    2015-01-01

    Abstract. Functional near-infrared spectroscopy (fNIRS) is an increasingly important noninvasive method in neuroscience due to its high temporal resolution and ability to independently measure oxy- and deoxy-hemoglobin. However, the relatively low spatial resolution of fNIRS makes it difficult to relate this signal to underlying anatomy. Simultaneous functional magnetic resonance imaging (fMRI) can complement fNIRS with superior spatial resolution and the ability to image the entire brain, providing additional information to improve fNIRS localization. However, current simultaneous fMRI/fNIRS acquisition methods are not optimal, due to the poor physical compatibility of existing MR coils and fNIRS optodes. Here, we present a technique to manufacture a true multimodal fMRI/fNIRS probe in which both modalities can be used with maximal sensitivity. To achieve this, we designed custom MR coils with integral fNIRS optodes using three-dimensional printing. This multimodal probe can be used to optimize spatial (1.2×1.2×1.8  mm) and temporal resolution (2.5 Hz) of fMRI, and it provides maximal MRI sensitivity, while allowing for high flexibility in the location and density of fNIRS optodes within the area of interest. Phantom and human data are shown to confirm the improvement in sensitivity in both modalities. This probe shows promise for addressing fundamental questions of the relation of fNIRS to physiology. PMID:26668816

  17. Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.

    PubMed

    Newcomb, Elizabeth W; Lukyanov, Yevgeniy; Schnee, Tona; Ali, M Aktar; Lan, Li; Zagzag, David

    2006-05-01

    Overexpression of hypoxia-inducible factor-1 (HIF-1) is a common feature in solid malignancies related to oxygen deficiency. Since increased HIF-1 expression correlates with advanced disease stage, increased angiogenesis and poor prognosis, HIF-1 and its signaling pathway have become targets for cancer chemotherapy. In this study, we identified noscapine to be a novel small molecule inhibitor of the HIF-1 pathway based on its structure-function relation-ships with HIF-1 pathway inhibitors belonging to the benzylisoquinoline class of plant metabolites and/or to microtubule binding agents. We demonstrate that noscapine treatment of human glioma U87MG and T98G cell lines exposed to the hypoxic mimetic agent, CoCl2, inhibits hypoxia-mediated HIF-1alpha expression and transcriptional activity as measured by decreased secretion of VEGF, a HIF-1 target gene. Inhibition of hypoxia-mediated HIF-1alpha expression was due, in part, to its ability to inhibit accumulation of HIF-1alpha in the nucleus and target it for degradation via the proteasome. One mechanism of action of microtubule binding agents is their antiangiogenic activity associated with disruption of endothelial tubule formation. We show that noscapine has similar properties in vitro. Thus, noscapine may possess novel antiangiogenic activity associated with two broad mechanisms of action: first, by decreasing HIF-1alpha expression in hypoxic tumor cells, upregulation of target genes, such as VEGF, would be decreased concomitant with its associated angiogenic activity; second, by inhibiting endothelial cells from forming blood vessels in response to VEGF stimulation, it may limit the process of neo-vascularization, correlating with antitumor activity in vivo. For more than 75 years, noscapine has traditionally been used as an oral cough suppressant with no known toxic side effects in man. Thus, the studies reported here have found a novel function for an old drug. Given its low toxicity profile, its demonstrated

  18. EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function.

    PubMed

    Phuchareon, Janyaporn; McCormick, Frank; Eisele, David W; Tetsu, Osamu

    2015-07-21

    Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.

  19. Aspartic acid functions as carbonyl trapper to inhibit the formation of advanced glycation end products by chemical chaperone activity.

    PubMed

    Prasanna, Govindarajan; Saraswathi, N T

    2016-05-01

    Advanced glycation end products (AGEs) were implicated in pathology of numerous diseases. In this study, we present the bioactivity of aspartic acid (Asp) to inhibit the AGEs. Hemoglobin and bovine serum albumin (BSA) were glycated with glucose, fructose, and ribose in the presence and absence of Asp (100-200 μM). HbA1c inhibition was investigated using human blood and characterized by micro-column ion exchange chromatography. The effect of methyl glyoxal (MG) on hemoglobin and BSA was evaluated by fluorescence spectroscopy and gel electrophoresis. The effect of MG on red blood cells morphology was characterized by scanning electron micrographs. Molecular docking was performed on BSA with Asp. Asp is capable of inhibiting the formation of fluorescent AGEs by reacting with the reducing sugars. The presence of Asp as supplement in whole blood reduced the HbA1c% from 8.8 to 6.1. The presence of MG showed an increase in fluorescence and the presence of Asp inhibited the glycation thereby the fluorescence was quenched. MG also affected the electrophoretic mobility of hemoglobin and BSA by forming high molecular weight aggregates. Normal RBCs showed typical biconcave shape. MG modified RBCs showed twisted and elongated shape whereas the presence of ASP tends to protect RBC from twisting. Asp interacted with arginine residues of bovine serum albumin particularly ARG 194, ARG 198, and