Robust TLR4-induced gene expression patterns are not an accurate indicator of human immunity

PubMed Central

2010-01-01

Background Activation of Toll-like receptors (TLRs) is widely accepted as an essential event for defence against infection. Many TLRs utilize a common signalling pathway that relies on activation of the kinase IRAK4 and the transcription factor NFκB for the rapid expression of immunity genes. Methods 21 K DNA microarray technology was used to evaluate LPS-induced (TLR4) gene responses in blood monocytes from a child with an IRAK4-deficiency. In vitro responsiveness to LPS was confirmed by real-time PCR and ELISA and compared to the clinical predisposition of the child and IRAK4-deficient mice to Gram negative infection. Results We demonstrated that the vast majority of LPS-responsive genes in IRAK4-deficient monocytes were greatly suppressed, an observation that is consistent with the described role for IRAK4 as an essential component of TLR4 signalling. The severely impaired response to LPS, however, is inconsistent with a remarkably low incidence of Gram negative infections observed in this child and other children with IRAK4-deficiency. This unpredicted clinical phenotype was validated by demonstrating that IRAK4-deficient mice had a similar resistance to infection with Gram negative S. typhimurium as wildtype mice. A number of immunity genes, such as chemokines, were expressed at normal levels in human IRAK4-deficient monocytes, indicating that particular IRAK4-independent elements within the repertoire of TLR4-induced responses are expressed. Conclusions Sufficient defence to Gram negative immunity does not require IRAK4 or a robust, 'classic' inflammatory and immune response. PMID:20105294

High-intensity high-volume swimming induces more robust signaling through PGC-1α and AMPK activation than sprint interval swimming in m. triceps brachii

PubMed Central

Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco J.; Aragón-Vela, Jerónimo; Robles-Sanchez, Cándido; Nordsborg, Nikolai B.; Hebberecht, Marina; Salmeron, Luis M.; Huertas, Jesus R.

2017-01-01

We aimed to test whether high-intensity high-volume training (HIHVT) swimming would induce more robust signaling than sprint interval training (SIT) swimming within the m. triceps brachii due to lower metabolic and oxidation. Nine well-trained swimmers performed the two training procedures on separate randomized days. Muscle biopsies from m. triceps brachii and blood samples were collected at three different time points: a) before the intervention (pre), b) immediately after the swimming procedures (post) and c) after 3 h of rest (3 h). Hydroperoxides, creatine kinase (CK), and lactate dehydrogenase (LDH) were quantified from blood samples, and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and the AMPKpTHR172/AMPK ratio were quantified by Western blot analysis. PGC-1α, sirtuin 3 (SIRT3), superoxide-dismutase 2 (SOD2), and vascular endothelial growth factor (VEGF) mRNA levels were also quantified. SIT induced a higher release of LDH (p < 0.01 at all time points) and CK (p < 0.01 at post) than HIHVT, but neither SIT nor HIHVT altered systemic hydroperoxides. Additionally, neither SIRT3 nor SOD2 mRNA levels increased, while PGC-1α transcription increased at 3 h after SIT (p < 0.01) and after HIHVT (p < 0.001). However, PGC-1α protein was higher after HIHVT than after SIT (p < 0.05). Moreover, the AMPKpTHR172/AMPK ratio increased at post after SIT (p < 0.05), whereas this effect was delayed after HIHVT as it increased after 3 h (p < 0.05). In addition, VEGF transcription was higher in response to HIHVT (p < 0.05). In conclusion, SIT induces higher muscular stress than HIHVT without increasing systemic oxidation. In addition, HIHVT may induce more robust oxidative adaptations through PGC-1α and AMPK. PMID:28973039

High-intensity high-volume swimming induces more robust signaling through PGC-1α and AMPK activation than sprint interval swimming in m. triceps brachii.

PubMed

Casuso, Rafael A; Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco J; Aragón-Vela, Jerónimo; Robles-Sanchez, Cándido; Nordsborg, Nikolai B; Hebberecht, Marina; Salmeron, Luis M; Huertas, Jesus R

2017-01-01

We aimed to test whether high-intensity high-volume training (HIHVT) swimming would induce more robust signaling than sprint interval training (SIT) swimming within the m. triceps brachii due to lower metabolic and oxidation. Nine well-trained swimmers performed the two training procedures on separate randomized days. Muscle biopsies from m. triceps brachii and blood samples were collected at three different time points: a) before the intervention (pre), b) immediately after the swimming procedures (post) and c) after 3 h of rest (3 h). Hydroperoxides, creatine kinase (CK), and lactate dehydrogenase (LDH) were quantified from blood samples, and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and the AMPKpTHR172/AMPK ratio were quantified by Western blot analysis. PGC-1α, sirtuin 3 (SIRT3), superoxide-dismutase 2 (SOD2), and vascular endothelial growth factor (VEGF) mRNA levels were also quantified. SIT induced a higher release of LDH (p < 0.01 at all time points) and CK (p < 0.01 at post) than HIHVT, but neither SIT nor HIHVT altered systemic hydroperoxides. Additionally, neither SIRT3 nor SOD2 mRNA levels increased, while PGC-1α transcription increased at 3 h after SIT (p < 0.01) and after HIHVT (p < 0.001). However, PGC-1α protein was higher after HIHVT than after SIT (p < 0.05). Moreover, the AMPKpTHR172/AMPK ratio increased at post after SIT (p < 0.05), whereas this effect was delayed after HIHVT as it increased after 3 h (p < 0.05). In addition, VEGF transcription was higher in response to HIHVT (p < 0.05). In conclusion, SIT induces higher muscular stress than HIHVT without increasing systemic oxidation. In addition, HIHVT may induce more robust oxidative adaptations through PGC-1α and AMPK.

Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury.

PubMed

Yang, Yunwen; Yu, Xiaowen; Zhang, Yue; Ding, Guixia; Zhu, Chunhua; Huang, Songming; Jia, Zhanjun; Zhang, Aihua

2018-04-16

Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active, small-molecule HIF PHD inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). The current study aimed to evaluate the effect of FG-4592 (Roxadustat) on cis -diamminedichloroplatinum (cisplatin)-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (blood urea nitrogen (BUN), serum creatinine (Scr), and cystatin C) and kidney morphology (periodic acid-Schiff (PAS) staining) in line with a robust blockade of renal tubular injury markers of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice. In vitro , FG-4592 treatment significantly up-regulated HIF-1α and protected the tubular cells against cisplatin-induced apoptosis. In summary, FG-4592 treatment remarkably ameliorated the cisplatin-induced kidney injury possibly through the stabilization of HIF. Thus, besides the role in treating CKD anemia, the clinical use of FG-4592 also could be extended to AKI. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical

Robust modular product family design

NASA Astrophysics Data System (ADS)

Jiang, Lan; Allada, Venkat

2001-10-01

This paper presents a modified Taguchi methodology to improve the robustness of modular product families against changes in customer requirements. The general research questions posed in this paper are: (1) How to effectively design a product family (PF) that is robust enough to accommodate future customer requirements. (2) How far into the future should designers look to design a robust product family? An example of a simplified vacuum product family is used to illustrate our methodology. In the example, customer requirements are selected as signal factors; future changes of customer requirements are selected as noise factors; an index called quality characteristic (QC) is set to evaluate the product vacuum family; and the module instance matrix (M) is selected as control factor. Initially a relation between the objective function (QC) and the control factor (M) is established, and then the feasible M space is systemically explored using a simplex method to determine the optimum M and the corresponding QC values. Next, various noise levels at different time points are introduced into the system. For each noise level, the optimal values of M and QC are computed and plotted on a QC-chart. The tunable time period of the control factor (the module matrix, M) is computed using the QC-chart. The tunable time period represents the maximum time for which a given control factor can be used to satisfy current and future customer needs. Finally, a robustness index is used to break up the tunable time period into suitable time periods that designers should consider while designing product families.

Hypoxia-inducible factor 1α is a critical downstream mediator for hypoxia-induced mitogenic factor (FIZZ1/RELMα)-induced pulmonary hypertension

PubMed Central

Johns, Roger A.; Takimoto, Eiki; Meuchel, Lucas W.; Elsaigh, Esra; Zhang, Ailan; Heller, Nicola M.; Semenza, Gregg L.; Yamaji-Kegan, Kazuyo

2017-01-01

Objective Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or RELMα) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/−) mice. HIMF-induced PH was significantly diminished in HIF-1α+/− mice and was accompanied by a dysregulated VEGF-A–VEGF receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β (RELMβ), significantly increased IL-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human RELMβ significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6–expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, VEGF-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology. PMID:26586659

SU-F-R-31: Identification of Robust Normal Lung CT Texture Features for the Prediction of Radiation-Induced Lung Disease

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

Choi, W; Riyahi, S; Lu, W

Purpose: Normal lung CT texture features have been used for the prediction of radiation-induced lung disease (radiation pneumonitis and radiation fibrosis). For these features to be clinically useful, they need to be relatively invariant (robust) to tumor size and not correlated with normal lung volume. Methods: The free-breathing CTs of 14 lung SBRT patients were studied. Different sizes of GTVs were simulated with spheres placed at the upper lobe and lower lobe respectively in the normal lung (contralateral to tumor). 27 texture features (9 from intensity histogram, 8 from grey-level co-occurrence matrix [GLCM] and 10 from grey-level run-length matrix [GLRM])more » were extracted from [normal lung-GTV]. To measure the variability of a feature F, the relative difference D=|Fref -Fsim|/Fref*100% was calculated, where Fref was for the entire normal lung and Fsim was for [normal lung-GTV]. A feature was considered as robust if the largest non-outlier (Q3+1.5*IQR) D was less than 5%, and considered as not correlated with normal lung volume when their Pearson correlation was lower than 0.50. Results: Only 11 features were robust. All first-order intensity-histogram features (mean, max, etc.) were robust, while most higher-order features (skewness, kurtosis, etc.) were unrobust. Only two of the GLCM and four of the GLRM features were robust. Larger GTV resulted greater feature variation, this was particularly true for unrobust features. All robust features were not correlated with normal lung volume while three unrobust features showed high correlation. Excessive variations were observed in two low grey-level run features and were later identified to be from one patient with local lung diseases (atelectasis) in the normal lung. There was no dependence on GTV location. Conclusion: We identified 11 robust normal lung CT texture features that can be further examined for the prediction of radiation-induced lung disease. Interestingly, low grey-level run features

Discovering mutated driver genes through a robust and sparse co-regularized matrix factorization framework with prior information from mRNA expression patterns and interaction network.

PubMed

Xi, Jianing; Wang, Minghui; Li, Ao

2018-06-05

Discovery of mutated driver genes is one of the primary objective for studying tumorigenesis. To discover some relatively low frequently mutated driver genes from somatic mutation data, many existing methods incorporate interaction network as prior information. However, the prior information of mRNA expression patterns are not exploited by these existing network-based methods, which is also proven to be highly informative of cancer progressions. To incorporate prior information from both interaction network and mRNA expressions, we propose a robust and sparse co-regularized nonnegative matrix factorization to discover driver genes from mutation data. Furthermore, our framework also conducts Frobenius norm regularization to overcome overfitting issue. Sparsity-inducing penalty is employed to obtain sparse scores in gene representations, of which the top scored genes are selected as driver candidates. Evaluation experiments by known benchmarking genes indicate that the performance of our method benefits from the two type of prior information. Our method also outperforms the existing network-based methods, and detect some driver genes that are not predicted by the competing methods. In summary, our proposed method can improve the performance of driver gene discovery by effectively incorporating prior information from interaction network and mRNA expression patterns into a robust and sparse co-regularized matrix factorization framework.

Disruption of the HPA-axis through corticosterone-release pellets induces robust depressive-like behavior and reduced BDNF levels in mice.

PubMed

Demuyser, Thomas; Bentea, Eduard; Deneyer, Lauren; Albertini, Giulia; Massie, Ann; Smolders, Ilse

2016-07-28

The corticosterone mouse model is widely used in preclinical research towards a better understanding of mechanisms of major depression. One particular administration procedure is the subcutaneous implantation of corticosterone slow-release pellets. In this report we want to provide basic evidence, regarding behavioral changes, neurotransmitter and -modulator levels and some other relevant biomolecules after hypothalamic-pituitary-adrenal-axis distortion. We show that three weeks of corticosterone pellet exposure robustly induces depressive-like but not anxiety-like behavior in mice, accompanied by a significant decrease in hippocampal brain-derived neurotrophic factor levels, at five weeks after the start of treatment. Furthermore there is an overall decrease in plasma corticosterone levels after three weeks of treatment that lasts up until the five weeks' time point. On the other hand, no differences are observed in total monoamine, glutamate or d-serine levels, nor in glucocorticoid receptor expression, in various depression-related brain areas. Altogether this characterization delivers vital information, supplementary to existing literature, regarding the phenotyping of pellet-induced hypothalamic-pituitary-adrenal-axis disruption in mice following three weeks of continuous corticosterone exposure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Robust Damage-Reporting Strategy for Polymeric Materials Enabled by Aggregation-Induced Emission.

PubMed

Robb, Maxwell J; Li, Wenle; Gergely, Ryan C R; Matthews, Christopher C; White, Scott R; Sottos, Nancy R; Moore, Jeffrey S

2016-09-28

Microscopic damage inevitably leads to failure in polymers and composite materials, but it is difficult to detect without the aid of specialized equipment. The ability to enhance the detection of small-scale damage prior to catastrophic material failure is important for improving the safety and reliability of critical engineering components, while simultaneously reducing life cycle costs associated with regular maintenance and inspection. Here, we demonstrate a simple, robust, and sensitive fluorescence-based approach for autonomous detection of damage in polymeric materials and composites enabled by aggregation-induced emission (AIE). This simple, yet powerful system relies on a single active component, and the general mechanism delivers outstanding performance in a wide variety of materials with diverse chemical and mechanical properties.

Fuzzy robust credibility-constrained programming for environmental management and planning.

PubMed

Zhang, Yimei; Hang, Guohe

2010-06-01

In this study, a fuzzy robust credibility-constrained programming (FRCCP) is developed and applied to the planning for waste management systems. It incorporates the concepts of credibility-based chance-constrained programming and robust programming within an optimization framework. The developed method can reflect uncertainties presented as possibility-density by fuzzy-membership functions. Fuzzy credibility constraints are transformed to the crisp equivalents with different credibility levels, and ordinary fuzzy inclusion constraints are determined by their robust deterministic constraints by setting a-cut levels. The FRCCP method can provide different system costs under different credibility levels (lambda). From the results of sensitivity analyses, the operation cost of the landfill is a critical parameter. For the management, any factors that would induce cost fluctuation during landfilling operation would deserve serious observation and analysis. By FRCCP, useful solutions can be obtained to provide decision-making support for long-term planning of solid waste management systems. It could be further enhanced through incorporating methods of inexact analysis into its framework. It can also be applied to other environmental management problems.

Hypoxia-Induced Mitogenic Factor Promotes Cardiac Hypertrophy via Calcium-Dependent and Hypoxia-Inducible Factor-1α Mechanisms.

PubMed

Kumar, Santosh; Wang, Gang; Liu, Wenjuan; Ding, Wenwen; Dong, Ming; Zheng, Na; Ye, Hongyu; Liu, Jie

2018-06-11

HIMF (hypoxia-induced mitogenic factor/found in inflammatory zone 1/resistin like α) is a secretory and cytokine-like protein and serves as a critical stimulator of hypoxia-induced pulmonary hypertension. With a role for HIMF in heart disease unknown, we explored the possible roles for HIMF in cardiac hypertrophy by overexpressing and knocking down HIMF in cardiomyocytes and characterizing HIMF gene ( himf ) knockout mice. We found that HIMF mRNA and protein levels were upregulated in phenylephrine-stimulated cardiomyocyte hypertrophy and our mouse model of transverse aortic constriction-induced cardiac hypertrophy, as well as in human hearts with dilated cardiomyopathy. Furthermore, HIMF overexpression could induce cardiomyocyte hypertrophy, as characterized by elevated protein expression of hypertrophic biomarkers (ANP [atrial natriuretic peptide] and β-MHC [myosin heavy chain-β]) and increased cell-surface area compared with controls. Conversely, HIMF knockdown prevented phenylephrine-induced cardiomyocyte hypertrophy and himf ablation in knockout mice significantly attenuated transverse aortic constriction-induced hypertrophic remodeling and cardiac dysfunction. HIMF overexpression increased the cytosolic Ca 2+ concentration and activated the CaN-NFAT (calcineurin-nuclear factor of activated T cell) and MAPK (mitogen-activated protein kinase) pathways; this effect could be prevented by reducing cytosolic Ca 2+ concentration with L-type Ca 2+ channel blocker nifedipine or inhibiting the CaSR (Ca 2+ sensing receptor) with Calhex 231. Furthermore, HIMF overexpression increased HIF-1α (hypoxia-inducible factor) expression in neonatal rat ventricular myocytes, and HIMF knockout inhibited HIF-1α upregulation in transverse aortic constriction mice. Knockdown of HIF-1α attenuated HIMF-induced cardiomyocyte hypertrophy. In conclusion, HIMF has a critical role in the development of cardiac hypertrophy, and targeting HIMF may represent a potential therapeutic

Robust Bayesian clustering.

PubMed

Archambeau, Cédric; Verleysen, Michel

2007-01-01

A new variational Bayesian learning algorithm for Student-t mixture models is introduced. This algorithm leads to (i) robust density estimation, (ii) robust clustering and (iii) robust automatic model selection. Gaussian mixture models are learning machines which are based on a divide-and-conquer approach. They are commonly used for density estimation and clustering tasks, but are sensitive to outliers. The Student-t distribution has heavier tails than the Gaussian distribution and is therefore less sensitive to any departure of the empirical distribution from Gaussianity. As a consequence, the Student-t distribution is suitable for constructing robust mixture models. In this work, we formalize the Bayesian Student-t mixture model as a latent variable model in a different way from Svensén and Bishop [Svensén, M., & Bishop, C. M. (2005). Robust Bayesian mixture modelling. Neurocomputing, 64, 235-252]. The main difference resides in the fact that it is not necessary to assume a factorized approximation of the posterior distribution on the latent indicator variables and the latent scale variables in order to obtain a tractable solution. Not neglecting the correlations between these unobserved random variables leads to a Bayesian model having an increased robustness. Furthermore, it is expected that the lower bound on the log-evidence is tighter. Based on this bound, the model complexity, i.e. the number of components in the mixture, can be inferred with a higher confidence.

A fast, robust and tunable synthetic gene oscillator.

PubMed

Stricker, Jesse; Cookson, Scott; Bennett, Matthew R; Mather, William H; Tsimring, Lev S; Hasty, Jeff

2008-11-27

One defining goal of synthetic biology is the development of engineering-based approaches that enable the construction of gene-regulatory networks according to 'design specifications' generated from computational modelling. This approach provides a systematic framework for exploring how a given regulatory network generates a particular phenotypic behaviour. Several fundamental gene circuits have been developed using this approach, including toggle switches and oscillators, and these have been applied in new contexts such as triggered biofilm development and cellular population control. Here we describe an engineered genetic oscillator in Escherichia coli that is fast, robust and persistent, with tunable oscillatory periods as fast as 13 min. The oscillator was designed using a previously modelled network architecture comprising linked positive and negative feedback loops. Using a microfluidic platform tailored for single-cell microscopy, we precisely control environmental conditions and monitor oscillations in individual cells through multiple cycles. Experiments reveal remarkable robustness and persistence of oscillations in the designed circuit; almost every cell exhibited large-amplitude fluorescence oscillations throughout observation runs. The oscillatory period can be tuned by altering inducer levels, temperature and the media source. Computational modelling demonstrates that the key design principle for constructing a robust oscillator is a time delay in the negative feedback loop, which can mechanistically arise from the cascade of cellular processes involved in forming a functional transcription factor. The positive feedback loop increases the robustness of the oscillations and allows for greater tunability. Examination of our refined model suggested the existence of a simplified oscillator design without positive feedback, and we construct an oscillator strain confirming this computational prediction.

Shock ignition targets: gain and robustness vs ignition threshold factor

NASA Astrophysics Data System (ADS)

Atzeni, Stefano; Antonelli, Luca; Schiavi, Angelo; Picone, Silvia; Volponi, Gian Marco; Marocchino, Alberto

2017-10-01

Shock ignition is a laser direct-drive inertial confinement fusion scheme, in which the stages of compression and hot spot formation are partly separated. The hot spot is created at the end of the implosion by a converging shock driven by a final ``spike'' of the laser pulse. Several shock-ignition target concepts have been proposed and relevant gain curves computed (see, e.g.). Here, we consider both pure-DT targets and more facility-relevant targets with plastic ablator. The investigation is conducted with 1D and 2D hydrodynamic simulations. We determine ignition threshold factors ITF's (and their dependence on laser pulse parameters) by means of 1D simulations. 2D simulations indicate that robustness to long-scale perturbations increases with ITF. Gain curves (gain vs laser energy), for different ITF's, are generated using 1D simulations. Work partially supported by Sapienza Project C26A15YTMA, Sapienza 2016 (n. 257584), Eurofusion Project AWP17-ENR-IFE-CEA-01.

ER stress-induced protein, VIGG, disturbs plant cation homeostasis, which is correlated with growth retardation and robustness to ER stress

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

Katoh, Hironori; Fujita, Keiko; Takuhara, Yuki

2011-02-18

Highlights: {yields} VIGG is an ER stress-induced protein in plant. {yields} We examine the characteristics of VIGG-overexpressing Arabidopsis plants. {yields} VIGG-overexpressing plants reveal growth retardation and robustness to ER stress. {yields} VIGG disturbs cation homeostasis in plant. -- Abstract: VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. Themore » overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42 days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation.« less

Endogenous growth factor stimulation of hemocyte proliferation induces resistance to Schistosoma mansoni challenge in the snail host.

PubMed

Pila, Emmanuel A; Gordy, Michelle A; Phillips, Valerie K; Kabore, Alethe L; Rudko, Sydney P; Hanington, Patrick C

2016-05-10

Digenean trematodes are a large, complex group of parasitic flatworms that infect an incredible diversity of organisms, including humans. Larval development of most digeneans takes place within a snail (Gastropoda). Compatibility between snails and digeneans is often very specific, such that suitable snail hosts define the geographical ranges of diseases caused by these worms. The immune cells (hemocytes) of a snail are sentinels that act as a crucial barrier to infection by larval digeneans. Hemocytes coordinate a robust and specific immunological response, participating directly in parasite killing by encapsulating and clearing the infection. Hemocyte proliferation and differentiation are influenced by unknown digenean-specific exogenous factors. However, we know nothing about the endogenous control of hemocyte development in any gastropod model. Here, we identify and functionally characterize a progranulin [Biomphalaria glabrata granulin (BgGRN)] from the snail B. glabrata, a natural host for the human blood fluke Schistosoma mansoni Granulins are growth factors that drive proliferation of immune cells in organisms, spanning the animal kingdom. We demonstrate that BgGRN induces proliferation of B. glabrata hemocytes, and specifically drives the production of an adherent hemocyte subset that participates centrally in the anti-digenean defense response. Additionally, we demonstrate that susceptible B. glabrata snails can be made resistant to infection with S. mansoni by first inducing hemocyte proliferation with BgGRN. This marks the functional characterization of an endogenous growth factor of a gastropod mollusc, and provides direct evidence of gain of resistance in a snail-digenean infection model using a defined factor to induce snail resistance to infection.

Helicobacter pylori induces vascular endothelial growth factor production in gastric epithelial cells through hypoxia-inducible factor-1α-dependent pathway.

PubMed

Kang, Min-Jung; Song, Eun-Jung; Kim, Bo-Yeon; Kim, Dong-Jae; Park, Jong-Hwan

2014-12-01

Although Helicobacter pylori have been known to induce vascular endothelial growth factor (VEGF) production in gastric epithelial cells, the precise mechanism for cellular signaling is incompletely understood. In this study, we investigated the role of bacterial virulence factor and host cellular signaling in VEGF production of H. pylori-infected gastric epithelial cells. We evaluated production of VEGF, activation of nuclear factor nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs) and hypoxia-inducible factor-1α (HIF-1α) stabilization in gastric epithelial cells infected with H. pylori WT or isogenic mutants deficient in type IV secretion system (T4SS). H. pylori induced VEGF production in gastric epithelial cells via both T4SS-dependent and T4SS-independent pathways, although T4SS-independent pathway seems to be the dominant signaling. The inhibitor assay implicated that activation of NF-κB and MAPKs is dispensable for H. pylori-induced VEGF production in gastric epithelial cells. H. pylori led to HIF-1α stabilization in gastric epithelial cells independently of T4SS, NF-κB, and MAPKs, which was essential for VEGF production in these cells. N-acetyl-cysteine (NAC), a reactive oxygen species (ROS) inhibitor, treatment impaired H. pylori-induced HIF-1α stabilization and VEGF production in gastric epithelial cells. We defined the important role of ROS-HIF-1α axis in VEGF production of H. pylori-infected gastric epithelial cells, and bacterial T4SS has a minor role in H. pylori-induced VEGF production of gastric epithelial cells. © 2014 John Wiley & Sons Ltd.

Vascular robustness: The missing parameter in cardiovascular risk prediction.

PubMed

Kraushaar, Lutz E; Dressel, Alexander; Maßmann, Alexander

2018-03-01

Undetected high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor scores is an acknowledged obstacle to CVD prevention. The vasculature's functional robustness against risk factor derailment may serve as a novel discriminator of mortality risk under similar risk factor loads. To test this assumption, we hypothesized that the expected inverse robustness-mortality association is verifiable as a significant trend along the age spectrum of risk factor-challenged cohorts. This is a retrospective cohort study of 372 adults (mean age 56.1 years, range 21-92; 45% female) with a variety of CV risk factors. An arterial model (VascAssist 2, iSYMED GmbH, Germany) was used to derive global parameters of arterial function from non-invasively acquired pulse pressure waves. Participants were stratified by health status: apparently healthy (AH; n = 221); with hypertension and/or hypercholesterolemia (CC; n = 61); with history of CV event(s) (CVE; n = 90). Multivariate linear regression was used to derive a robustness score which was calibrated against the CVD mortality hazard rate of a sub-cohort of the LURIC study (n = 1369; mean age 59.1 years, range 20-75; 37% female). Robustness correlated linearly with calendar age in CC (F(1, 59) = 10.42; p  < 0.01) and CVE (F(1, 88) = 40.34; p  < 0.0001) but not in the AH strata, supporting the hypothesis of preferential elimination of less robust individuals along the aging trajectory under risk factor challenges. Vascular robustness may serve as a biomarker of vulnerability to CVD risk factor challenges, prognosticating otherwise undetectable elevated risk for premature CVD mortality.

Background recovery via motion-based robust principal component analysis with matrix factorization

NASA Astrophysics Data System (ADS)

Pan, Peng; Wang, Yongli; Zhou, Mingyuan; Sun, Zhipeng; He, Guoping

2018-03-01

Background recovery is a key technique in video analysis, but it still suffers from many challenges, such as camouflage, lighting changes, and diverse types of image noise. Robust principal component analysis (RPCA), which aims to recover a low-rank matrix and a sparse matrix, is a general framework for background recovery. The nuclear norm is widely used as a convex surrogate for the rank function in RPCA, which requires computing the singular value decomposition (SVD), a task that is increasingly costly as matrix sizes and ranks increase. However, matrix factorization greatly reduces the dimension of the matrix for which the SVD must be computed. Motion information has been shown to improve low-rank matrix recovery in RPCA, but this method still finds it difficult to handle original video data sets because of its batch-mode formulation and implementation. Hence, in this paper, we propose a motion-assisted RPCA model with matrix factorization (FM-RPCA) for background recovery. Moreover, an efficient linear alternating direction method of multipliers with a matrix factorization (FL-ADM) algorithm is designed for solving the proposed FM-RPCA model. Experimental results illustrate that the method provides stable results and is more efficient than the current state-of-the-art algorithms.

Fingolimod induces neuroprotective factors in human astrocytes.

PubMed

Hoffmann, Franziska S; Hofereiter, Johann; Rübsamen, Heike; Melms, Johannes; Schwarz, Sigrid; Faber, Hans; Weber, Peter; Pütz, Benno; Loleit, Verena; Weber, Frank; Hohlfeld, Reinhard; Meinl, Edgar; Krumbholz, Markus

2015-09-30

Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.

Development of a robust modeling tool for radiation-induced segregation in austenitic stainless steels

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

Yang, Ying; Field, Kevin G; Allen, Todd R.

2015-09-01

Irradiation-assisted stress corrosion cracking (IASCC) of austenitic stainless steels in Light Water Reactor (LWR) components has been linked to changes in grain boundary composition due to irradiation induced segregation (RIS). This work developed a robust RIS modeling tool to account for thermodynamics and kinetics of the atom and defect transportation under combined thermal and radiation conditions. The diffusion flux equations were based on the Perks model formulated through the linear theory of the thermodynamics of irreversible processes. Both cross and non-cross phenomenological diffusion coefficients in the flux equations were considered and correlated to tracer diffusion coefficients through Manning’s relation. Themore » preferential atomvacancy coupling was described by the mobility model, whereas the preferential atom-interstitial coupling was described by the interstitial binding model. The composition dependence of the thermodynamic factor was modeled using the CALPHAD approach. Detailed analysis on the diffusion fluxes near and at grain boundaries of irradiated austenitic stainless steels suggested the dominant diffusion mechanism for chromium and iron is via vacancy, while that for nickel can swing from the vacancy to the interstitial dominant mechanism. The diffusion flux in the vicinity of a grain boundary was found to be greatly influenced by the composition gradient formed from the transient state, leading to the oscillatory behavior of alloy compositions in this region. This work confirms that both vacancy and interstitial diffusion, and segregation itself, have important roles in determining the microchemistry of Fe, Cr, and Ni at irradiated grain boundaries in austenitic stainless steels.« less

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques.

PubMed

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena; Warter, Lucile

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques

PubMed Central

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S.; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C.; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model’s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans. PMID:29694440

On the robustness of vocal development: an examination of infants with moderate-to-severe hearing loss and additional risk factors.

PubMed

Nathani, Suneeti; Oller, D Kimbrough; Neal, A Rebecca

2007-12-01

Onset of canonical babbling by 10 months of age is surprisingly robust in infancy, suggesting that there must be deep biological forces that keep the development of this key vocal capability on course. This study further evaluated the robustness of canonical babbling and other aspects of prelinguistic vocal development. Longitudinal observation was conducted on 4 infants who were at risk for abnormal vocal development because of bilateral moderate-to-severe sensorineural hearing loss and additional risk factors for developmental delay. Two of the infants were delayed in the onset of canonical babbling and showed greater fluctuation in canonical babbling ratios following its onset than did typically developing infants. On the same measures, the remaining 2 infants were within normal limits, although their age of onset for canonical babbling was later than the mean for typically developing infants. Volubility was not notably different from typically developing infants. Differences from typically developing infants were, however, observed in proportions of various prelinguistic syllable types produced across time. Results provided further evidence of robustness of canonical babbling and indicated the need for a large parametric study evaluating effects of varying degrees of hearing loss and other risk factors on vocal development.

Hypoxia-inducible factors promote alveolar development and regeneration.

PubMed

Vadivel, Arul; Alphonse, Rajesh S; Etches, Nicholas; van Haaften, Timothy; Collins, Jennifer J P; O'Reilly, Megan; Eaton, Farah; Thébaud, Bernard

2014-01-01

Understanding how alveoli and the underlying capillary network develop and how these mechanisms are disrupted in disease states is critical for developing effective therapies for lung regeneration. Recent evidence suggests that lung angiogenesis promotes lung development and repair. Vascular endothelial growth factor (VEGF) preserves lung angiogenesis and alveolarization in experimental O2-induced arrested alveolar growth in newborn rats, but combined VEGF+angiopoietin 1 treatment is necessary to correct VEGF-induced vessel leakiness. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple O2-sensitive genes, including those encoding for angiogenic growth factors, but their role during postnatal lung growth is incompletely understood. By inducing the expression of a range of angiogenic factors in a coordinated fashion, HIF may orchestrate efficient and safe angiogenesis superior to VEGF. We hypothesized that HIF inhibition impairs alveolarization and that HIF activation regenerates irreversible O2-induced arrested alveolar growth. HIF inhibition by intratracheal dominant-negative adenovirus (dnHIF-1α)-mediated gene transfer or chetomin decreased lung HIF-1α, HIF-2α, and VEGF expression and led to air space enlargement and arrested lung vascular growth. In experimental O2-induced arrested alveolar growth in newborn rats, the characteristic features of air space enlargement and loss of lung capillaries were associated with decreased lung HIF-1α and HIF-2α expression. Intratracheal administration of Ad.HIF-1α restored HIF-1α, endothelial nitric oxide synthase, VEGF, VEGFR2, and Tie2 expression and preserved and rescued alveolar growth and lung capillary formation in this model. HIFs promote normal alveolar development and may be useful targets for alveolar regeneration.

Vaccine-specific antibody secreting cells are a robust early marker of LAIV-induced B-cell response in ferrets.

PubMed

Cherukuri, Anu; Servat, Esteban; Woo, Jennifer

2012-01-05

Currently, a robust set of immune correlates for live attenuated influenza vaccine (LAIV) efficacy in humans has not been fully elucidated. The serum hemagglutination inhibition (HAI) assay has been historically used to measure humoral immune responses to injectable inactivated influenza vaccination. However, serum antibody titers do not reliably reflect the complete mechanism of action of LAIV, which is an intranasally delivered vaccine and is expected to induce local mucosal and cellular immune responses in addition to humoral immune responses. Therefore, we designed a study to evaluate potential immune correlates of LAIV vaccination in the ferret animal model of influenza infection. Ferrets were vaccinated with increasing doses of LAIV and four weeks later challenged with a homologous wild-type (wt) H1N1 strain. Humoral immune responses measured following LAIV vaccination included HAI, serum antibodies and antibody secreting cells (ASC); and the responses were found to correlate with the dose level of LAIV administered in this model. Protection from wt virus challenge was determined by measuring inhibition of wt viral replication in nasal washes and in lung tissue. Results demonstrated that LAIV doses ≥ 5.0 log(10) Plaque Forming Units (PFU) elicited vaccine-specific IgG and IgA ASC frequencies and induced complete protection in the lungs. Further, we developed a novel model utilizing seropositive older ferrets to demonstrate that in the background of previous wt influenza infection LAIV induces a robust vaccine-specific B-cell response even in the absence of serum antibody response, a result that suggests that effector B-cell responses generated by LAIV are not inhibited by prior viral exposure. Finally, we demonstrated that LAIV elicits strain-specific memory B-cell responses that are measurable in a background of wt influenza infections. Taken together, results from these studies identified the antigen-specific ASC frequency as a useful early biomarker of

Robust output tracking control of a laboratory helicopter for automatic landing

NASA Astrophysics Data System (ADS)

Liu, Hao; Lu, Geng; Zhong, Yisheng

2014-11-01

In this paper, robust output tracking control problem of a laboratory helicopter for automatic landing in high seas is investigated. The motion of the helicopter is required to synchronise with that of an oscillating platform, e.g. the deck of a vessel subject to wave-induced motions. A robust linear time-invariant output feedback controller consisting of a nominal controller and a robust compensator is designed. The robust compensator is introduced to restrain the influences of parametric uncertainties, nonlinearities and external disturbances. It is shown that robust stability and robust tracking property can be achieved simultaneously. Experimental results on the laboratory helicopter for automatic landing demonstrate the effectiveness of the designed control approach.

Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease.

PubMed

Das, Nupur; Xie, Liwei; Ramakrishnan, Sadeesh K; Campbell, Andrew; Rivella, Stefano; Shah, Yatrik M

2015-09-25

Sickle cell disease (SCD) is caused by genetic defects in the β-globin chain. SCD is a frequently inherited blood disorder, and sickle cell anemia is a common type of hemoglobinopathy. During anemia, the hypoxic response via the transcription factor hypoxia-inducible factor (HIF)-2α is highly activated in the intestine and is essential in iron absorption. Intestinal disruption of HIF-2α protects against tissue iron accumulation in iron overload anemias. However, the role of intestinal HIF-2α in regulating anemia in SCD is currently not known. Here we show that in mouse models of SCD, disruption of intestinal HIF-2α significantly decreased tissue iron accumulation. This was attributed to a decrease in intestinal iron absorptive genes, which were highly induced in a mouse model of SCD. Interestingly, disruption of intestinal HIF-2α led to a robust improvement in anemia with an increase in RBC, hemoglobin, and hematocrit. This was attributed to improvement in RBC survival, hemolysis, and insufficient erythropoiesis, which is evident from a significant decrease in serum bilirubin, reticulocyte counts, and serum erythropoietin following intestinal HIF-2α disruption. These data suggest that targeting intestinal HIF-2α has a significant therapeutic potential in SCD pathophysiology. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Robust quantum control using smooth pulses and topological winding

NASA Astrophysics Data System (ADS)

Barnes, Edwin; Wang, Xin

2015-03-01

Perhaps the greatest challenge in achieving control of microscopic quantum systems is the decoherence induced by the environment, a problem which pervades experimental quantum physics and is particularly severe in the context of solid state quantum computing and nanoscale quantum devices because of the inherently strong coupling to the surrounding material. We present an analytical approach to constructing intrinsically robust driving fields which automatically cancel the leading-order noise-induced errors in a qubit's evolution exactly. We address two of the most common types of non-Markovian noise that arise in qubits: slow fluctuations of the qubit energy splitting and fluctuations in the driving field itself. We demonstrate our method by constructing robust quantum gates for several types of spin qubits, including phosphorous donors in silicon and nitrogen-vacancy centers in diamond. Our results constitute an important step toward achieving robust generic control of quantum systems, bringing their novel applications closer to realization. Work supported by LPS-CMTC.

Electrostatic separation for recycling waste printed circuit board: a study on external factor and a robust design for optimization.

PubMed

Hou, Shibing; Wu, Jiang; Qin, Yufei; Xu, Zhenming

2010-07-01

Electrostatic separation is an effective and environmentally friendly method for recycling waste printed circuit board (PCB) by several kinds of electrostatic separators. However, some notable problems have been detected in its applications and cannot be efficiently resolved by optimizing the separation process. Instead of the separator itself, these problems are mainly caused by some external factors such as the nonconductive powder (NP) and the superficial moisture of feeding granule mixture. These problems finally lead to an inefficient separation. In the present research, the impacts of these external factors were investigated and a robust design was built to optimize the process and to weaken the adverse impact. A most robust parameter setting (25 kv, 80 rpm) was concluded from the experimental design. In addition, some theoretical methods, including cyclone separation, were presented to eliminate these problems substantially. This will contribute to efficient electrostatic separation of waste PCB and make remarkable progress for industrial applications.

Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities

PubMed Central

Fang, Xin; Sastry, Anand; Mih, Nathan; Kim, Donghyuk; Tan, Justin; Lloyd, Colton J.; Gao, Ye; Yang, Laurence; Palsson, Bernhard O.

2017-01-01

Transcriptional regulatory networks (TRNs) have been studied intensely for >25 y. Yet, even for the Escherichia coli TRN—probably the best characterized TRN—several questions remain. Here, we address three questions: (i) How complete is our knowledge of the E. coli TRN; (ii) how well can we predict gene expression using this TRN; and (iii) how robust is our understanding of the TRN? First, we reconstructed a high-confidence TRN (hiTRN) consisting of 147 transcription factors (TFs) regulating 1,538 transcription units (TUs) encoding 1,764 genes. The 3,797 high-confidence regulatory interactions were collected from published, validated chromatin immunoprecipitation (ChIP) data and RegulonDB. For 21 different TF knockouts, up to 63% of the differentially expressed genes in the hiTRN were traced to the knocked-out TF through regulatory cascades. Second, we trained supervised machine learning algorithms to predict the expression of 1,364 TUs given TF activities using 441 samples. The algorithms accurately predicted condition-specific expression for 86% (1,174 of 1,364) of the TUs, while 193 TUs (14%) were predicted better than random TRNs. Third, we identified 10 regulatory modules whose definitions were robust against changes to the TRN or expression compendium. Using surrogate variable analysis, we also identified three unmodeled factors that systematically influenced gene expression. Our computational workflow comprehensively characterizes the predictive capabilities and systems-level functions of an organism’s TRN from disparate data types. PMID:28874552

Robust dynamics in minimal hybrid models of genetic networks.

PubMed

Perkins, Theodore J; Wilds, Roy; Glass, Leon

2010-11-13

Many gene-regulatory networks necessarily display robust dynamics that are insensitive to noise and stable under evolution. We propose that a class of hybrid systems can be used to relate the structure of these networks to their dynamics and provide insight into the origin of robustness. In these systems, the genes are represented by logical functions, and the controlling transcription factor protein molecules are real variables, which are produced and destroyed. As the transcription factor concentrations cross thresholds, they control the production of other transcription factors. We discuss mathematical analysis of these systems and show how the concepts of robustness and minimality can be used to generate putative logical organizations based on observed symbolic sequences. We apply the methods to control of the cell cycle in yeast.

Robust design optimization method for centrifugal impellers under surface roughness uncertainties due to blade fouling

NASA Astrophysics Data System (ADS)

Ju, Yaping; Zhang, Chuhua

2016-03-01

Blade fouling has been proved to be a great threat to compressor performance in operating stage. The current researches on fouling-induced performance degradations of centrifugal compressors are based mainly on simplified roughness models without taking into account the realistic factors such as spatial non-uniformity and randomness of the fouling-induced surface roughness. Moreover, little attention has been paid to the robust design optimization of centrifugal compressor impellers with considerations of blade fouling. In this paper, a multi-objective robust design optimization method is developed for centrifugal impellers under surface roughness uncertainties due to blade fouling. A three-dimensional surface roughness map is proposed to describe the nonuniformity and randomness of realistic fouling accumulations on blades. To lower computational cost in robust design optimization, the support vector regression (SVR) metamodel is combined with the Monte Carlo simulation (MCS) method to conduct the uncertainty analysis of fouled impeller performance. The analyzed results show that the critical fouled region associated with impeller performance degradations lies at the leading edge of blade tip. The SVR metamodel has been proved to be an efficient and accurate means in the detection of impeller performance variations caused by roughness uncertainties. After design optimization, the robust optimal design is found to be more efficient and less sensitive to fouling uncertainties while maintaining good impeller performance in the clean condition. This research proposes a systematic design optimization method for centrifugal compressors with considerations of blade fouling, providing a practical guidance to the design of advanced centrifugal compressors.

Robust dynamics in minimal hybrid models of genetic networks

PubMed Central

Perkins, Theodore J.; Wilds, Roy; Glass, Leon

2010-01-01

Many gene-regulatory networks necessarily display robust dynamics that are insensitive to noise and stable under evolution. We propose that a class of hybrid systems can be used to relate the structure of these networks to their dynamics and provide insight into the origin of robustness. In these systems, the genes are represented by logical functions, and the controlling transcription factor protein molecules are real variables, which are produced and destroyed. As the transcription factor concentrations cross thresholds, they control the production of other transcription factors. We discuss mathematical analysis of these systems and show how the concepts of robustness and minimality can be used to generate putative logical organizations based on observed symbolic sequences. We apply the methods to control of the cell cycle in yeast. PMID:20921006

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Tradeoff on Phenotype Robustness in Biological Networks Part II: Ecological Networks

PubMed Central

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

In ecological networks, network robustness should be large enough to confer intrinsic robustness for tolerating intrinsic parameter fluctuations, as well as environmental robustness for resisting environmental disturbances, so that the phenotype stability of ecological networks can be maintained, thus guaranteeing phenotype robustness. However, it is difficult to analyze the network robustness of ecological systems because they are complex nonlinear partial differential stochastic systems. This paper develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance sensitivity in ecological networks. We found that the phenotype robustness criterion for ecological networks is that if intrinsic robustness + environmental robustness ≦ network robustness, then the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations and environmental disturbances. These results in robust ecological networks are similar to that in robust gene regulatory networks and evolutionary networks even they have different spatial-time scales. PMID:23515112

Emergence and robustness of target waves in a neuronal network

NASA Astrophysics Data System (ADS)

Xu, Ying; Jin, Wuyin; Ma, Jun

2015-08-01

Target waves in excitable media such as neuronal network can regulate the spatial distribution and orderliness as a continuous pacemaker. Three different schemes are used to develop stable target wave in the network, and the potential mechanism for emergence of target waves in the excitable media is investigated. For example, a local pacing driven by external periodical forcing can generate stable target wave in the excitable media, furthermore, heterogeneity and local feedback under self-feedback coupling are also effective to generate continuous target wave as well. To discern the difference of these target waves, a statistical synchronization factor is defined by using mean field theory and artificial defects are introduced into the network to block the target wave, thus the robustness of these target waves could be detected. However, these target waves developed from the above mentioned schemes show different robustness to the blocking from artificial defects. A regular network of Hindmarsh-Rose neurons is designed in a two-dimensional square array, target waves are induced by using three different ways, and then some artificial defects, which are associated with anatomical defects, are set in the network to detect the effect of defects blocking on the travelling waves. It confirms that the robustness of target waves to defects blocking depends on the intrinsic properties (ways to generate target wave) of target waves.

On the contributions of topological features to transcriptional regulatory network robustness

PubMed Central

2012-01-01

Background Because biological networks exhibit a high-degree of robustness, a systemic understanding of their architecture and function requires an appraisal of the network design principles that confer robustness. In this project, we conduct a computational study of the contribution of three degree-based topological properties (transcription factor-target ratio, degree distribution, cross-talk suppression) and their combinations on the robustness of transcriptional regulatory networks. We seek to quantify the relative degree of robustness conferred by each property (and combination) and also to determine the extent to which these properties alone can explain the robustness observed in transcriptional networks. Results To study individual properties and their combinations, we generated synthetic, random networks that retained one or more of the three properties with values derived from either the yeast or E. coli gene regulatory networks. Robustness of these networks were estimated through simulation. Our results indicate that the combination of the three properties we considered explains the majority of the structural robustness observed in the real transcriptional networks. Surprisingly, scale-free degree distribution is, overall, a minor contributor to robustness. Instead, most robustness is gained through topological features that limit the complexity of the overall network and increase the transcription factor subnetwork sparsity. Conclusions Our work demonstrates that (i) different types of robustness are implemented by different topological aspects of the network and (ii) size and sparsity of the transcription factor subnetwork play an important role for robustness induction. Our results are conserved across yeast and E Coli, which suggests that the design principles examined are present within an array of living systems. PMID:23194062

How robust is a robust policy? A comparative analysis of alternative robustness metrics for supporting robust decision analysis.

NASA Astrophysics Data System (ADS)

Kwakkel, Jan; Haasnoot, Marjolijn

2015-04-01

In response to climate and socio-economic change, in various policy domains there is increasingly a call for robust plans or policies. That is, plans or policies that performs well in a very large range of plausible futures. In the literature, a wide range of alternative robustness metrics can be found. The relative merit of these alternative conceptualizations of robustness has, however, received less attention. Evidently, different robustness metrics can result in different plans or policies being adopted. This paper investigates the consequences of several robustness metrics on decision making, illustrated here by the design of a flood risk management plan. A fictitious case, inspired by a river reach in the Netherlands is used. The performance of this system in terms of casualties, damages, and costs for flood and damage mitigation actions is explored using a time horizon of 100 years, and accounting for uncertainties pertaining to climate change and land use change. A set of candidate policy options is specified up front. This set of options includes dike raising, dike strengthening, creating more space for the river, and flood proof building and evacuation options. The overarching aim is to design an effective flood risk mitigation strategy that is designed from the outset to be adapted over time in response to how the future actually unfolds. To this end, the plan will be based on the dynamic adaptive policy pathway approach (Haasnoot, Kwakkel et al. 2013) being used in the Dutch Delta Program. The policy problem is formulated as a multi-objective robust optimization problem (Kwakkel, Haasnoot et al. 2014). We solve the multi-objective robust optimization problem using several alternative robustness metrics, including both satisficing robustness metrics and regret based robustness metrics. Satisficing robustness metrics focus on the performance of candidate plans across a large ensemble of plausible futures. Regret based robustness metrics compare the

Transcription Factors MYOCD, SRF, Mesp1 and SMARCD3 Enhance the Cardio-Inducing Effect of GATA4, TBX5, and MEF2C during Direct Cellular Reprogramming

PubMed Central

Christoforou, Nicolas; Chellappan, Malathi; Adler, Andrew F.; Kirkton, Robert D.; Wu, Tianyi; Addis, Russell C.; Bursac, Nenad; Leong, Kam W.

2013-01-01

Transient overexpression of defined combinations of master regulator genes can effectively induce cellular reprogramming: the acquisition of an alternative predicted phenotype from a differentiated cell lineage. This can be of particular importance in cardiac regenerative medicine wherein the heart lacks the capacity to heal itself, but simultaneously contains a large pool of fibroblasts. In this study we determined the cardio-inducing capacity of ten transcription factors to actuate cellular reprogramming of mouse embryonic fibroblasts into cardiomyocyte-like cells. Overexpression of transcription factors MYOCD and SRF alone or in conjunction with Mesp1 and SMARCD3 enhanced the basal but necessary cardio-inducing effect of the previously reported GATA4, TBX5, and MEF2C. In particular, combinations of five or seven transcription factors enhanced the activation of cardiac reporter vectors, and induced an upregulation of cardiac-specific genes. Global gene expression analysis also demonstrated a significantly greater cardio-inducing effect when the transcription factors MYOCD and SRF were used. Detection of cross-striated cells was highly dependent on the cell culture conditions and was enhanced by the addition of valproic acid and JAK inhibitor. Although we detected Ca2+ transient oscillations in the reprogrammed cells, we did not detect significant changes in resting membrane potential or spontaneously contracting cells. This study further elucidates the cardio-inducing effect of the transcriptional networks involved in cardiac cellular reprogramming, contributing to the ongoing rational design of a robust protocol required for cardiac regenerative therapies. PMID:23704920

Automated Robust Image Segmentation: Level Set Method Using Nonnegative Matrix Factorization with Application to Brain MRI.

PubMed

Dera, Dimah; Bouaynaya, Nidhal; Fathallah-Shaykh, Hassan M

2016-07-01

We address the problem of fully automated region discovery and robust image segmentation by devising a new deformable model based on the level set method (LSM) and the probabilistic nonnegative matrix factorization (NMF). We describe the use of NMF to calculate the number of distinct regions in the image and to derive the local distribution of the regions, which is incorporated into the energy functional of the LSM. The results demonstrate that our NMF-LSM method is superior to other approaches when applied to synthetic binary and gray-scale images and to clinical magnetic resonance images (MRI) of the human brain with and without a malignant brain tumor, glioblastoma multiforme. In particular, the NMF-LSM method is fully automated, highly accurate, less sensitive to the initial selection of the contour(s) or initial conditions, more robust to noise and model parameters, and able to detect as small distinct regions as desired. These advantages stem from the fact that the proposed method relies on histogram information instead of intensity values and does not introduce nuisance model parameters. These properties provide a general approach for automated robust region discovery and segmentation in heterogeneous images. Compared with the retrospective radiological diagnoses of two patients with non-enhancing grade 2 and 3 oligodendroglioma, the NMF-LSM detects earlier progression times and appears suitable for monitoring tumor response. The NMF-LSM method fills an important need of automated segmentation of clinical MRI.

Robust Differentiation of mRNA-Reprogrammed Human Induced Pluripotent Stem Cells Toward a Retinal Lineage.

PubMed

Sridhar, Akshayalakshmi; Ohlemacher, Sarah K; Langer, Kirstin B; Meyer, Jason S

2016-04-01

The derivation of human induced pluripotent stem cells (hiPSCs) from patient-specific sources has allowed for the development of novel approaches to studies of human development and disease. However, traditional methods of generating hiPSCs involve the risks of genomic integration and potential constitutive expression of pluripotency factors and often exhibit low reprogramming efficiencies. The recent description of cellular reprogramming using synthetic mRNA molecules might eliminate these shortcomings; however, the ability of mRNA-reprogrammed hiPSCs to effectively give rise to retinal cell lineages has yet to be demonstrated. Thus, efforts were undertaken to test the ability and efficiency of mRNA-reprogrammed hiPSCs to yield retinal cell types in a directed, stepwise manner. hiPSCs were generated from human fibroblasts via mRNA reprogramming, with parallel cultures of isogenic human fibroblasts reprogrammed via retroviral delivery of reprogramming factors. New lines of mRNA-reprogrammed hiPSCs were established and were subsequently differentiated into a retinal fate using established protocols in a directed, stepwise fashion. The efficiency of retinal differentiation from these lines was compared with retroviral-derived cell lines at various stages of development. On differentiation, mRNA-reprogrammed hiPSCs were capable of robust differentiation to a retinal fate, including the derivation of photoreceptors and retinal ganglion cells, at efficiencies often equal to or greater than their retroviral-derived hiPSC counterparts. Thus, given that hiPSCs derived through mRNA-based reprogramming strategies offer numerous advantages owing to the lack of genomic integration or constitutive expression of pluripotency genes, such methods likely represent a promising new approach for retinal stem cell research, in particular, those for translational applications. In the current report, the ability to derive mRNA-reprogrammed human induced pluripotent stem cells (hi

A Simple and Robust Method for Culturing Human-Induced Pluripotent Stem Cells in an Undifferentiated State Using Botulinum Hemagglutinin.

PubMed

Kim, Mee-Hae; Matsubara, Yoshifumi; Fujinaga, Yukako; Kino-Oka, Masahiro

2018-02-01

Clinical and industrial applications of human-induced pluripotent stem cells (hiPSCs) is hindered by the lack of robust culture strategies capable of sustaining a culture in an undifferentiated state. Here, a simple and robust hiPSC-culture-propagation strategy incorporating botulinum hemagglutinin (HA)-mediated selective removal of cells deviating from an undifferentiated state is developed. After HA treatment, cell-cell adhesion is disrupted, and deviated cells detached from the central region of the colony to subsequently form tight monolayer colonies following prolonged incubation. The authors find that the temporal and dose-dependent activity of HA regulated deviated-cell removal and recoverability after disruption of cell-cell adhesion in hiPSC colonies. The effects of HA are confirmed under all culture conditions examined, regardless of hiPSC line and feeder-dependent or -free culture conditions. After routine application of our HA-treatment paradigm for serial passages, hiPSCs maintains expression of pluripotent markers and readily forms embryoid bodies expressing markers for all three germ-cell layers. This method enables highly efficient culturing of hiPSCs and use of entire undifferentiated portions without having to pick deviated cells manually. This simple and readily reproducible culture strategy is a potentially useful tool for improving the robust and scalable maintenance of undifferentiated hiPSC cultures. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

MED GATA factors promote robust development of the C. elegans endoderm

PubMed Central

Maduro, Morris F.; Broitman-Maduro, Gina; Choi, Hailey; Carranza, Francisco; Wu, Allison Chia-Yi; Rifkin, Scott A.

2015-01-01

The MED-1,2 GATA factors contribute to specification of E, the progenitor of the C. elegans endoderm, through the genes end-1 and end-3, and in parallel with the maternal factors SKN-1, POP-1 and PAL-1. END-1,3 activate elt-2 and elt-7 to initiate a program of intestinal development, which is maintained by positive autoregulation. Here, we advance the understanding of MED-1,2 in E specification. We find that expression of end-1 and end-3 is greatly reduced in med-1,2(−) embryos. We generated strains in which MED sites have been mutated in end-1 and end-3. Without MED input, gut specification relies primarily on POP-1 and PAL-1. 25% of embryos fail to make intestine, while those that do display abnormal numbers of gut cells due to a delayed and stochastic acquisition of intestine fate. Surviving adults exhibit phenotypes consistent with a primary defect in the intestine. Our results establish that MED-1,2 provide robustness to endoderm specification through end-1 and end-3, and reveal that gut differentiation may be more directly linked to specification than previously appreciated. The results argue against an “all-or-none” description of cell specification, and suggest that activation of tissue-specific master regulators, even when expression of these is maintained by positive autoregulation, does not guarantee proper function of differentiated cells. PMID:25959238

Granulocyte colony-stimulating factor induces in vitro lymphangiogenesis

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

Lee, Ae Sin; Kim, Dal; Wagle, Susbin Raj

2013-07-12

Highlights: •G-CSF induces tube formation, migration and proliferation of lymphatic cells. •G-CSF increases phosphorylation of MAPK and Akt in lymphatic endothelial cells. •MAPK and Akt pathways are linked to G-CSF-induced in vitro lymphangiogenesis. •G-CSF increases sprouting of a lymphatic ring. •G-CSF produces peritoneal lymphangiogenesis. -- Abstract: Granulocyte-colony stimulating factor (G-CSF) is reported to induce differentiation in cells of the monocyte lineage and angiogenesis in vascular endothelial cells, but its effects on lymphangiogenesis is uncertain. Here we examined the effects and the mechanisms of G-CSF-induced lymphangiogenesis using human lymphatic endothelial cells (hLECs). Our results showed that G-CSF induced capillary-like tube formation,more » migration and proliferation of hLECs in a dose- and time-dependent manner and enhanced sprouting of thoracic duct. G-CSF increased phosphorylation of Akt and ERK1/2 in hLECs. Supporting the observations, specific inhibitors of phosphatidylinositol 3′-kinase and MAPK suppressed the G-CSF-induced in vitro lymphangiogenesis and sprouting. Intraperitoneal administration of G-CSF to mice also stimulated peritoneal lymphangiogenesis. These findings suggest that G-CSF is a lymphangiogenic factor.« less

The cardiovascular robustness hypothesis: Unmasking young adults' hidden risk for premature cardiovascular death.

PubMed

Kraushaar, Lutz E; Dressel, Alexander

2018-03-01

An undetected high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor levels is an acknowledged obstacle to CVD prevention. In this paper, we present the hypothesis that the vasculature's robustness against risk factor load will complement conventional risk factor models as a novel stratifier of risk. Figuratively speaking, mortality risk prediction without robustness scoring is akin to predicting the breaking risk of a lake's ice sheet considering load only while disregarding the sheet's bearing strength. Taking the cue from systems biology, which defines robustness as the ability to maintain function against internal and external challenges, we develop a robustness score from the physical parameters that comprehensively quantitate cardiovascular function. We derive the functional parameters using a recently introduced novel system, VascAssist 2 (iSYMED GmbH, Butzbach, Germany). VascAssist 2 (VA) applies the electronic-hydraulic analogy to a digital model of the arterial tree, replicating non-invasively acquired pule pressure waves by modulating the electronic equivalents of the physical parameters that describe in vivo arterial hemodynamics. As the latter is also subject to aging-associated degeneration which (a) progresses at inter-individually different rates, and which (b) affects the biomarker-mortality association, we express the robustness score as a correction factor to calendar age (CA), the dominant risk factor in all CVD risk factor models. We then propose a method for the validation of the score against known time-to-event data in reference populations. Our conceptualization of robustness implies that risk factor-challenged individuals with low robustness scores will face preferential elimination from the population resulting in a significant robustness-CA correlation in this strata absent in the unchallenged stratum. Hence, we also present an outline of a cross-sectional study design suitable to

Robust Bayesian Factor Analysis

ERIC Educational Resources Information Center

Hayashi, Kentaro; Yuan, Ke-Hai

2003-01-01

Bayesian factor analysis (BFA) assumes the normal distribution of the current sample conditional on the parameters. Practical data in social and behavioral sciences typically have significant skewness and kurtosis. If the normality assumption is not attainable, the posterior analysis will be inaccurate, although the BFA depends less on the current…

Robust synthetic biology design: stochastic game theory approach.

PubMed

Chen, Bor-Sen; Chang, Chia-Hung; Lee, Hsiao-Ching

2009-07-15

Synthetic biology is to engineer artificial biological systems to investigate natural biological phenomena and for a variety of applications. However, the development of synthetic gene networks is still difficult and most newly created gene networks are non-functioning due to uncertain initial conditions and disturbances of extra-cellular environments on the host cell. At present, how to design a robust synthetic gene network to work properly under these uncertain factors is the most important topic of synthetic biology. A robust regulation design is proposed for a stochastic synthetic gene network to achieve the prescribed steady states under these uncertain factors from the minimax regulation perspective. This minimax regulation design problem can be transformed to an equivalent stochastic game problem. Since it is not easy to solve the robust regulation design problem of synthetic gene networks by non-linear stochastic game method directly, the Takagi-Sugeno (T-S) fuzzy model is proposed to approximate the non-linear synthetic gene network via the linear matrix inequality (LMI) technique through the Robust Control Toolbox in Matlab. Finally, an in silico example is given to illustrate the design procedure and to confirm the efficiency and efficacy of the proposed robust gene design method. http://www.ee.nthu.edu.tw/bschen/SyntheticBioDesign_supplement.pdf.

Dexamethasone impairs hypoxia-inducible factor-1 function

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

Wagner, A.E.; Huck, G.; Stiehl, D.P.

2008-07-25

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription-factor composed of {alpha}- and {beta}-subunits. HIF-1 is not only necessary for the cellular adaptation to hypoxia, but it is also involved in inflammatory processes and wound healing. Glucocorticoids (GC) are therapeutically used to suppress inflammatory responses. Herein, we investigated whether GC modulate HIF-1 function using GC receptor (GR) possessing (HepG2) and GR deficient (Hep3B) human hepatoma cell cultures as model systems. Dexamethasone (DEX) treatment increased HIF-1{alpha} levels in the cytosol of HepG2 cells, while nuclear HIF-1{alpha} levels and HIF-1 DNA-binding was reduced. In addition, DEX dose-dependently lowered the hypoxia-induced luciferase activity in amore » reporter gene system. DEX suppressed the hypoxic stimulation of the expression of the HIF-1 target gene VEGF (vascular endothelial growth factor) in HepG2 cultures. DEX did not reduce hypoxically induced luciferase activity in HRB5 cells, a Hep3B derivative lacking GR. Transient expression of the GR in HRB5 cells restored the susceptibility to DEX. Our study discloses the inhibitory action of GC on HIF-1 dependent gene expression, which may be important with respect to the impaired wound healing in DEX-treated patients.« less

Biological robustness.

PubMed

Kitano, Hiroaki

2004-11-01

Robustness is a ubiquitously observed property of biological systems. It is considered to be a fundamental feature of complex evolvable systems. It is attained by several underlying principles that are universal to both biological organisms and sophisticated engineering systems. Robustness facilitates evolvability and robust traits are often selected by evolution. Such a mutually beneficial process is made possible by specific architectural features observed in robust systems. But there are trade-offs between robustness, fragility, performance and resource demands, which explain system behaviour, including the patterns of failure. Insights into inherent properties of robust systems will provide us with a better understanding of complex diseases and a guiding principle for therapy design.

Robust Entrainment of Circadian Oscillators Requires Specific Phase Response Curves

PubMed Central

Pfeuty, Benjamin; Thommen, Quentin; Lefranc, Marc

2011-01-01

The circadian clocks keeping time in many living organisms rely on self-sustained biochemical oscillations entrained by external cues, such as light, to the 24-h cycle induced by Earth's rotation. However, environmental cues are unreliable due to the variability of habitats, weather conditions, or cue-sensing mechanisms among individuals. A tempting hypothesis is that circadian clocks have evolved so as to be robust to fluctuations in the signal that entrains them. To support this hypothesis, we analyze the synchronization behavior of weakly and periodically forced oscillators in terms of their phase response curve (PRC), which measures phase changes induced by a perturbation applied at different times of the cycle. We establish a general relationship between the robustness of key entrainment properties, such as stability and oscillator phase, on the one hand, and the shape of the PRC as characterized by a specific curvature or the existence of a dead zone, on the other hand. The criteria obtained are applied to computational models of circadian clocks and account for the disparate robustness properties of various forcing schemes. Finally, the analysis of PRCs measured experimentally in several organisms strongly suggests a case of convergent evolution toward an optimal strategy for maintaining a clock that is accurate and robust to environmental fluctuations. PMID:21641300

Growth factor involvement in tension-induced skeletal muscle growth

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman H.

1993-01-01

Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

PubMed

Hua, Lun; Zhuo, Yong; Jiang, Dandan; Li, Jing; Huang, Xiaohua; Zhu, Yingguo; Li, Zhen; Yan, Lijun; Jin, Chao; Jiang, Xuemei; Che, Lianqiang; Fang, Zhengfeng; Lin, Yan; Xu, Shengyu; Li, Jian; Feng, Bin; Wu, De

2018-05-02

Both ovarian E2 and hepatic fibroblast growth factor 21 (FGF21) are critical for energy homeostasis and white adipose tissue browning. Estrogen receptor α (ERα) is abundantly expressed in liver. However, whether FGF21 has a role in E2-induced white adipose tissue browning remains uncertain. In this study, we showed that hepatic Fgf21 expression and secretion during estrus cycle changed with the tetradian oscillatory secretion of circulation E2 in adult, female mice, with their peak expressions and secretions at the proestrus. In addition, exogenous E2 robustly stimulated liver Fgf21 expression and elevated serum FGF21 concentrations, which induced browning gene expression and reduced the tissue weight in subcutaneous white adipose in mice with ovariectomies. The inhibitor of mammalian target of rapamycin (mTOR) and of ERα blocked the induction effect of E2 on the expression of Fgf21 in primary hepatocytes, which revealed that E2 might stimulate FGF21 expression via the ERα-mTOR pathway. Furthermore, FGF21 liver-specific deficiency abolished E2-induced white adipose browning in mice with ovariectomies. This study indicates that ovarian E2 increased liver FGF21 expression directly, which in turn, functioned as an endocrine signal to influence inguinal white adipose tissue browning.-Hua, L., Zhuo, Y., Jiang, D., Li, Jin., Huang, X., Zhu, Y., Li, Z., Yan, L., Jin, C., Jiang, X., Che, L., Fang, Z., Lin, Y., Xu, S. Li, Jia., Feng, B., Wu, D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

Robust dynamic mitigation of instabilities

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

Kawata, S.; Karino, T.

2015-04-15

A dynamic mitigation mechanism for instability growth was proposed and discussed in the paper [S. Kawata, Phys. Plasmas 19, 024503 (2012)]. In the present paper, the robustness of the dynamic instability mitigation mechanism is discussed further. The results presented here show that the mechanism of the dynamic instability mitigation is rather robust against changes in the phase, the amplitude, and the wavelength of the wobbling perturbation applied. Generally, instability would emerge from the perturbation of the physical quantity. Normally, the perturbation phase is unknown so that the instability growth rate is discussed. However, if the perturbation phase is known, themore » instability growth can be controlled by a superposition of perturbations imposed actively: If the perturbation is induced by, for example, a driving beam axis oscillation or wobbling, the perturbation phase could be controlled, and the instability growth is mitigated by the superposition of the growing perturbations.« less

Heat shock factor 1 suppresses the HIV-induced inflammatory response by inhibiting nuclear factor-κB.

PubMed

Pan, Xiaoyan; Lin, Jian; Zeng, Xiaoyun; Li, Wenjuan; Wu, Wenjiao; Lu, Wan Zhen; Liu, Jing; Liu, Shuwen

2018-05-01

The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4 + T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS. Copyright © 2018 Elsevier Inc. All rights reserved.

Robust design optimization using the price of robustness, robust least squares and regularization methods

NASA Astrophysics Data System (ADS)

Bukhari, Hassan J.

2017-12-01

In this paper a framework for robust optimization of mechanical design problems and process systems that have parametric uncertainty is presented using three different approaches. Robust optimization problems are formulated so that the optimal solution is robust which means it is minimally sensitive to any perturbations in parameters. The first method uses the price of robustness approach which assumes the uncertain parameters to be symmetric and bounded. The robustness for the design can be controlled by limiting the parameters that can perturb.The second method uses the robust least squares method to determine the optimal parameters when data itself is subjected to perturbations instead of the parameters. The last method manages uncertainty by restricting the perturbation on parameters to improve sensitivity similar to Tikhonov regularization. The methods are implemented on two sets of problems; one linear and the other non-linear. This methodology will be compared with a prior method using multiple Monte Carlo simulation runs which shows that the approach being presented in this paper results in better performance.

Myostatin is a novel tumoral factor that induces cancer cachexia

PubMed Central

Lokireddy, Sudarsanareddy; Wijesoma, Isuru Wijerupage; Bonala, Sabeera; Wei, Meng; Sze, Siu Kwan; McFarlane, Craig; Kambadur, Ravi; Sharma, Mridula

2012-01-01

Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice. PMID:22621320

Multi-damage identification based on joint approximate diagonalisation and robust distance measure

NASA Astrophysics Data System (ADS)

Cao, S.; Ouyang, H.

2017-05-01

Mode shapes or operational deflection shapes are highly sensitive to damage and can be used for multi-damage identification. Nevertheless, one drawback of this kind of methods is that the extracted spatial shape features tend to be compromised by noise, which degrades their damage identification accuracy, especially for incipient damage. To overcome this, joint approximate diagonalisation (JAD) also known as simultaneous diagonalisation is investigated to estimate mode shapes (MS’s) statistically. The major advantage of JAD method is that it efficiently provides the common Eigen-structure of a set of power spectral density matrices. In this paper, a new criterion in terms of coefficient of variation (CV) is utilised to numerically demonstrate the better noise robustness and accuracy of JAD method over traditional frequency domain decomposition method (FDD). Another original contribution is that a new robust damage index (DI) is proposed, which is comprised of local MS distortions of several modes weighted by their associated vibration participation factors. The advantage of doing this is to include fair contributions from changes of all modes concerned. Moreover, the proposed DI provides a measure of damage-induced changes in ‘modal vibration energy’ in terms of the selected mode shapes. Finally, an experimental study is presented to verify the efficiency and noise robustness of JAD method and the proposed DI. The results show that the proposed DI is effective and robust under random vibration situations, which indicates that it has the potential to be applied to practical engineering structures with ambient excitations.

The significance of developmental robustness for species diversity.

PubMed

Melzer, Rainer; Theißen, Günter

2016-04-01

The origin of new species and of new forms is one of the fundamental characteristics of evolution. However, the mechanisms that govern the diversity and disparity of lineages remain poorly understood. Particularly unclear are the reasons why some taxa are vastly more species-rich than others and the manner in which species diversity and morphological disparity are interrelated. Evolutionary innovations and ecological opportunities are usually cited as among the major factors promoting the evolution of species diversity. In many cases it is likely that these factors are positively reinforcing, with evolutionary innovations creating ecological opportunities that in turn foster the origin of new innovations. However, we propose that a third factor, developmental robustness, is very often essential for this reinforcement to be effective. Evolutionary innovations need to be stably and robustly integrated into the developmental genetic programme of an organism to be a suitable substrate for selection to 'explore' ecological opportunities and morphological 'design' space (morphospace). In particular, we propose that developmental robustness of the bauplan is often a prerequisite for the exploration of morphospace and to enable the evolution of further novelties built upon this bauplan Thus, while robustness may reduce the morphological disparity at one level, it may be the basis for increased morphological disparity and for evolutionary innovations at another level, thus fostering species diversity. © The Author 2016. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha.

PubMed Central

Montrucchio, G.; Lupia, E.; de Martino, A.; Battaglia, E.; Arese, M.; Tizzani, A.; Bussolino, F.; Camussi, G.

1997-01-01

We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells and in the in vivo angiogenic response elicited by platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF). The NO synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothelial cells induced in vitro by PAF and by TNF. The motogenic activity of TNF was also inhibited by WEB 2170, a specific PAF-receptor antagonist. In contrast, chemotaxis induced by bFGF was not prevented by L-NAME or by WEB 2170. Angiogenesis was studied in vivo in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model, the angiogenesis induced by PAF and TNF was inhibited by WEB 2170 and L-NAME but not by D-NAME. In contrast, angiogenesis induced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not bFGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced by TNF, which is dependent on the production of PAF. In contrast, the angiogenic effect of bFGF appears to be both PAF and NO independent. Images Figure 3 Figure 4 PMID:9250168

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-offs on Phenotype Robustness in Biological Networks. Part III: Synthetic Gene Networks in Synthetic Biology

PubMed Central

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties that are observed in biological systems at many different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be large enough to confer: intrinsic robustness for tolerating intrinsic parameter fluctuations; genetic robustness for buffering genetic variations; and environmental robustness for resisting environmental disturbances. Network robustness is needed so phenotype stability of biological network can be maintained, guaranteeing phenotype robustness. Synthetic biology is foreseen to have important applications in biotechnology and medicine; it is expected to contribute significantly to a better understanding of functioning of complex biological systems. This paper presents a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation for synthetic gene networks in synthetic biology. Further, from the unifying mathematical framework, we found that the phenotype robustness criterion for synthetic gene networks is the following: if intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness, then the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in synthetic biology can also be investigated through corresponding phenotype robustness criteria from the systematic point of view. Finally, a robust synthetic design that involves network evolution algorithms with desired behavior under intrinsic parameter fluctuations, genetic variations, and environmental

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-offs on Phenotype Robustness in Biological Networks. Part III: Synthetic Gene Networks in Synthetic Biology.

PubMed

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties that are observed in biological systems at many different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be large enough to confer: intrinsic robustness for tolerating intrinsic parameter fluctuations; genetic robustness for buffering genetic variations; and environmental robustness for resisting environmental disturbances. Network robustness is needed so phenotype stability of biological network can be maintained, guaranteeing phenotype robustness. Synthetic biology is foreseen to have important applications in biotechnology and medicine; it is expected to contribute significantly to a better understanding of functioning of complex biological systems. This paper presents a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation for synthetic gene networks in synthetic biology. Further, from the unifying mathematical framework, we found that the phenotype robustness criterion for synthetic gene networks is the following: if intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness, then the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in synthetic biology can also be investigated through corresponding phenotype robustness criteria from the systematic point of view. Finally, a robust synthetic design that involves network evolution algorithms with desired behavior under intrinsic parameter fluctuations, genetic variations, and environmental

Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1.

PubMed

Abán, C; Martinez, N; Carou, C; Albamonte, I; Toro, A; Seyahian, A; Franchi, A; Leguizamón, G; Trigubo, D; Damiano, A; Farina, M

2016-10-01

During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α). We found that HIF-1α stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1α stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1α may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process.

Design optimization for cost and quality: The robust design approach

NASA Technical Reports Server (NTRS)

Unal, Resit

1990-01-01

Designing reliable, low cost, and operable space systems has become the key to future space operations. Designing high quality space systems at low cost is an economic and technological challenge to the designer. A systematic and efficient way to meet this challenge is a new method of design optimization for performance, quality, and cost, called Robust Design. Robust Design is an approach for design optimization. It consists of: making system performance insensitive to material and subsystem variation, thus allowing the use of less costly materials and components; making designs less sensitive to the variations in the operating environment, thus improving reliability and reducing operating costs; and using a new structured development process so that engineering time is used most productively. The objective in Robust Design is to select the best combination of controllable design parameters so that the system is most robust to uncontrollable noise factors. The robust design methodology uses a mathematical tool called an orthogonal array, from design of experiments theory, to study a large number of decision variables with a significantly small number of experiments. Robust design also uses a statistical measure of performance, called a signal-to-noise ratio, from electrical control theory, to evaluate the level of performance and the effect of noise factors. The purpose is to investigate the Robust Design methodology for improving quality and cost, demonstrate its application by the use of an example, and suggest its use as an integral part of space system design process.

Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

PubMed

Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

2017-05-01

Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

Bilinear Factor Matrix Norm Minimization for Robust PCA: Algorithms and Applications.

PubMed

Shang, Fanhua; Cheng, James; Liu, Yuanyuan; Luo, Zhi-Quan; Lin, Zhouchen

2017-09-04

The heavy-tailed distributions of corrupted outliers and singular values of all channels in low-level vision have proven effective priors for many applications such as background modeling, photometric stereo and image alignment. And they can be well modeled by a hyper-Laplacian. However, the use of such distributions generally leads to challenging non-convex, non-smooth and non-Lipschitz problems, and makes existing algorithms very slow for large-scale applications. Together with the analytic solutions to Lp-norm minimization with two specific values of p, i.e., p=1/2 and p=2/3, we propose two novel bilinear factor matrix norm minimization models for robust principal component analysis. We first define the double nuclear norm and Frobenius/nuclear hybrid norm penalties, and then prove that they are in essence the Schatten-1/2 and 2/3 quasi-norms, respectively, which lead to much more tractable and scalable Lipschitz optimization problems. Our experimental analysis shows that both our methods yield more accurate solutions than original Schatten quasi-norm minimization, even when the number of observations is very limited. Finally, we apply our penalties to various low-level vision problems, e.g. moving object detection, image alignment and inpainting, and show that our methods usually outperform the state-of-the-art methods.

Roles of tumour necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14 pathway in lupus nephritis.

PubMed

Chen, Jingyun; Wei, Linlin; Xia, Yumin

2017-02-01

As one of the manifestations of patients with systemic lupus erythematosus, lupus nephritis (LN) has high morbidity and mortality. Although the explicit mechanism of LN remains to be fully elucidated, there is increasing evidence to support the notion that tumour necrosis factor-related weak inducer of apoptosis (TWEAK), acting via its sole receptor, fibroblast growth factor-inducible 14 (Fn14), plays a pivotal role in such pathologic process. TWEAK/Fn14 interactions occur prominently in kidneys of LN, inducing inflammatory responses, angiogenesis, mesangial proliferation, filtration barrier injuries, renal fibrosis, etc. This review will specify the important roles of TWEAK/Fn14 pathway in the pathogenesis of LN with experimental data from cellular and animal models. Additionally, the raised levels of urinary and serum soluble TWEAK correlate with renal disease activity in patients with LN. The neutralizing antibodies targeting TWEAK or other approaches inhibiting TWEAK/Fn14 signals can attenuate renal damage in the murine lupus models. Therefore, to focus on TWEAK/Fn14 signalling may be promising in both clinical evaluation and the treatment of patients with LN. © 2016 Asian Pacific Society of Nephrology.

Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium.

PubMed

Kawanami, Daiji; Mahabeleshwar, Ganapati H; Lin, Zhiyong; Atkins, G Brandon; Hamik, Anne; Haldar, Saptarsi M; Maemura, Koji; Lamanna, Joseph C; Jain, Mukesh K

2009-07-31

Hypoxia-inducible factor 1 (HIF-1) is a central regulator of the hypoxic response in many cell types. In endothelial cells, HIF-1 induces the expression of key proangiogenic factors to promote angiogenesis. Recent studies have identified Kruppel-like factor 2 (KLF2) as a potent inhibitor of angiogenesis. However, the role of KLF2 in regulating HIF-1 expression and function has not been evaluated. KLF2 expression was induced acutely by hypoxia in endothelial cells. Adenoviral overexpression of KLF2 inhibited hypoxia-induced expression of HIF-1alpha and its target genes such as interleukin 8, angiopoietin-2, and vascular endothelial growth factor in endothelial cells. Conversely, knockdown of KLF2 increased expression of HIF-1alpha and its targets. Furthermore, KLF2 inhibited hypoxia-induced endothelial tube formation, whereas endothelial cells from mice with haploinsufficiency of KLF2 showed increased tube formation in response to hypoxia. Consistent with this ex vivo observation, KLF2 heterozygous mice showed increased microvessel density in the brain. Mechanistically, KLF2 promoted HIF-1alpha degradation in a von Hippel-Lindau protein-independent but proteasome-dependent manner. Finally, KLF2 disrupted the interaction between HIF-1alpha and its chaperone Hsp90, suggesting that KLF2 promotes degradation of HIF-1alpha by affecting its folding and maturation. These observations identify KLF2 as a novel inhibitor of HIF-1alpha expression and function. Therefore, KLF2 may be a target for modulating the angiogenic response in disease states.

Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

PubMed Central

Geiger, Tamar; Levitzki, Alexander

2007-01-01

Infection of keratinocytes with high risk human Papilloma virus causes immortalization, and when followed by further mutations, leads to cervical cancer and other anogenital tumors. Here we monitor the progressive loss of robustness in an in vitro model of the early stages of transformation that comprises normal keratinocytes and progressive passages of HPV16 immortalized cells. As transformation progresses, the cells acquire higher proliferation rates and gain the ability to grow in soft agar. Concurrently, the cells lose robustness, becoming more sensitive to serum starvation and DNA damage by Cisplatin. Loss of robustness in the course of transformation correlates with significant reductions in the activities of the anti-apoptotic proteins PKB/Akt, Erk, Jnk and p38 both under normal growth conditions and upon stress. In parallel, loss of robustness is manifested by the shrinkage of the number of growth factors that can rescue starving cells from apoptosis, with the emergence of dependence solely on IGF1. Treatment with IGF1 activates PKB/Akt and Jnk and through them inhibits p53, rescuing the cells from starvation. We conclude that transformation in this model induces higher susceptibility of cells to stress due to reduced anti-apoptotic signaling and hyper-activation of p53 upon stress. PMID:17622350

Lactobacillus rhamnosus GG Treatment Potentiates Intestinal Hypoxia-Inducible Factor, Promotes Intestinal Integrity and Ameliorates Alcohol-Induced Liver Injury

PubMed Central

Wang, Yuhua; Kirpich, Irina; Liu, Yanlong; Ma, Zhenhua; Barve, Shirish; McClain, Craig J.; Feng, Wenke

2012-01-01

Gut-derived endotoxin is a critical factor in the development and progression of alcoholic liver disease (ALD). Probiotics can treat alcohol-induced liver injury associated with gut leakiness and endotoxemia in animal models, as well as in human ALD; however, the mechanism or mechanisms of their beneficial action are not well defined. We hypothesized that alcohol impairs the adaptive response-induced hypoxia-inducible factor (HIF) and that probiotic supplementation could attenuate this impairment, restoring barrier function in a mouse model of ALD by increasing HIF-responsive proteins (eg, intestinal trefoil factor) and reversing established ALD. C57BJ/6N mice were fed the Lieber DeCarli diet containing 5% alcohol for 8 weeks. Animals received Lactobacillus rhamnosus GG (LGG) supplementation in the last 2 weeks. LGG supplementation significantly reduced alcohol-induced endotoxemia and hepatic steatosis and improved liver function. LGG restored alcohol-induced reduction of HIF-2α and intestinal trefoil factor levels. In vitro studies using the Caco-2 cell culture model showed that the addition of LGG supernatant prevented alcohol-induced epithelial monolayer barrier dysfunction. Furthermore, gene silencing of HIF-1α/2α abolished the LGG effects, indicating that the protective effect of LGG is HIF-dependent. The present study provides a mechanistic insight for utilization of probiotics for the treatment of ALD, and suggests a critical role for intestinal hypoxia and decreased trefoil factor in the development of ALD. PMID:22093263

Robust power spectral estimation for EEG data.

PubMed

Melman, Tamar; Victor, Jonathan D

2016-08-01

Typical electroencephalogram (EEG) recordings often contain substantial artifact. These artifacts, often large and intermittent, can interfere with quantification of the EEG via its power spectrum. To reduce the impact of artifact, EEG records are typically cleaned by a preprocessing stage that removes individual segments or components of the recording. However, such preprocessing can introduce bias, discard available signal, and be labor-intensive. With this motivation, we present a method that uses robust statistics to reduce dependence on preprocessing by minimizing the effect of large intermittent outliers on the spectral estimates. Using the multitaper method (Thomson, 1982) as a starting point, we replaced the final step of the standard power spectrum calculation with a quantile-based estimator, and the Jackknife approach to confidence intervals with a Bayesian approach. The method is implemented in provided MATLAB modules, which extend the widely used Chronux toolbox. Using both simulated and human data, we show that in the presence of large intermittent outliers, the robust method produces improved estimates of the power spectrum, and that the Bayesian confidence intervals yield close-to-veridical coverage factors. The robust method, as compared to the standard method, is less affected by artifact: inclusion of outliers produces fewer changes in the shape of the power spectrum as well as in the coverage factor. In the presence of large intermittent outliers, the robust method can reduce dependence on data preprocessing as compared to standard methods of spectral estimation. Copyright © 2016 Elsevier B.V. All rights reserved.

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-off on Phenotype Robustness in Biological Networks Part I: Gene Regulatory Networks in Systems and Evolutionary Biology

PubMed Central

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties observed in biological systems at different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be enough to confer intrinsic robustness in order to tolerate intrinsic parameter fluctuations, genetic robustness for buffering genetic variations, and environmental robustness for resisting environmental disturbances. With this, the phenotypic stability of biological network can be maintained, thus guaranteeing phenotype robustness. This paper presents a survey on biological systems and then develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation in systems and evolutionary biology. Further, from the unifying mathematical framework, it was discovered that the phenotype robustness criterion for biological networks at different levels relies upon intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness. When this is true, the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in systems and evolutionary biology can also be investigated through their corresponding phenotype robustness criterion from the systematic point of view. PMID:23515240

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-off on Phenotype Robustness in Biological Networks Part I: Gene Regulatory Networks in Systems and Evolutionary Biology.

PubMed

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties observed in biological systems at different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be enough to confer intrinsic robustness in order to tolerate intrinsic parameter fluctuations, genetic robustness for buffering genetic variations, and environmental robustness for resisting environmental disturbances. With this, the phenotypic stability of biological network can be maintained, thus guaranteeing phenotype robustness. This paper presents a survey on biological systems and then develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation in systems and evolutionary biology. Further, from the unifying mathematical framework, it was discovered that the phenotype robustness criterion for biological networks at different levels relies upon intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness. When this is true, the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in systems and evolutionary biology can also be investigated through their corresponding phenotype robustness criterion from the systematic point of view.

Kelch-like ECH-associated Protein 1-dependent Nuclear Factor-E2-related Factor 2 Activation in Relation to Antioxidation Induced by Sevoflurane Preconditioning.

PubMed

Cai, Min; Tong, Li; Dong, Beibei; Hou, Wugang; Shi, Likai; Dong, Hailong

2017-03-01

The authors have reported that antioxidative effects play a crucial role in the volatile anesthetic-induced neuroprotection. Accumulated evidence shows that endogenous antioxidation could be up-regulated by nuclear factor-E2-related factor 2 through multiple pathways. However, whether nuclear factor-E2-related factor 2 activation is modulated by sevoflurane preconditioning and, if so, what is the signaling cascade underlying upstream of this activation are still unknown. Sevoflurane preconditioning in mice was performed with sevoflurane (2.5%) 1 h per day for five consecutive days. Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. Expression of nuclear factor-E2-related factor 2, kelch-like ECH-associated protein 1, manganese superoxide dismutase, thioredoxin-1, and nicotinamide adenine dinucleotide phosphate quinolone oxidoreductase-1 was detected (n = 6). The antioxidant activities and oxidative product expression were also examined. To determine the role of kelch-like ECH-associated protein 1 inhibition-dependent nuclear factor-E2-related factor 2 activation in sevoflurane preconditioning-induced neuroprotection, the kelch-like ECH-associated protein 1-nuclear factor-E2-related factor 2 signal was modulated by nuclear factor-E2-related factor 2 knockout, kelch-like ECH-associated protein 1 overexpression lentivirus, and kelch-like ECH-associated protein 1 deficiency small interfering RNA (n = 8). The infarct volume, neurologic scores, and cellular apoptosis were assessed. Sevoflurane preconditioning elicited neuroprotection and increased nuclear factor-E2-related factor 2 nuclear translocation, which in turn up-regulated endogenous antioxidation and reduced oxidative injury. Sevoflurane preconditioning reduced kelch-like ECH-associated protein 1 expression. Nuclear factor-E2-related factor 2 ablation abolished neuroprotection and reversed sevoflurane preconditioning by mediating the up-regulation of antioxidants. Kelch

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

PubMed

Morar-Mitrica, Sorina; Adams, Monica L; Crotts, George; Wurth, Christine; Ihnat, Peter M; Tabish, Tanvir; Antochshuk, Valentyn; DiLuzio, Willow; Dix, Daniel B; Fernandez, Jason E; Gupta, Kapil; Fleming, Michael S; He, Bing; Kranz, James K; Liu, Dingjiang; Narasimhan, Chakravarthy; Routhier, Eric; Taylor, Katherine D; Truong, Nobel; Stokes, Elaine S E

2018-02-01

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Hydrogen Rich Water Attenuates Renal Injury and Fibrosis by Regulation Transforming Growth Factor-β Induced Sirt1.

PubMed

Xing, Zhaoyu; Pan, Wanma; Zhang, Jing; Xu, Xianlin; Zhang, Xuemei; He, Xiaozhou; Fan, Min

2017-01-01

The current research was designed to study the role of hydrogen in renal fibrosis and the renal epithelial to mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1). Hydrogen rich water (HW) was used to treat animal and cell models. Unilateral ureteral obstruction (UUO) was performed on Balb/c mice to create a model of renal fibrosis. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TGF-β1 for 36 h to induce EMT. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured to test renal function, in addition, kidney histology and immunohistochemical staining of alpha-smooth muscle actin (α-SMA) positive cells was performed to examine the morphological changes. The treatment with UUO induced a robust fibrosis of renal interstitium, shrink of glomerulus and partial fracture of basement membrane. Renal function was also impaired in the experimental group with UUO, with an increase of Scr and BUN in serum. After that, Western-blot was performed to examine the expression of α-SMA, fibronectin, E-cadherin, Smad2 and Sirtuin-1 (Sirt1). The treatment with HW attenuated the development of fibrosis and deterioration of renal function in UUO model. In HK-2 cells, the pretreatment of HW abolished EMT induced by TGF-β1. The down-regulation the expression of Sirt1 induced by TGF-β1 which was dampened by the treatment with HW. Sirtinol, a Sirt1 inhibitor, reversed the effect of HW on EMT induced by TGF-β1. HW can inhibit the development of fibrosis in kidney and prevents HK-2 cells from undergoing EMT which is mediated through Sirt1, a downstream molecule of TGF-β1.

A Robustness Testing Campaign for IMA-SP Partitioning Kernels

NASA Astrophysics Data System (ADS)

Grixti, Stephen; Lopez Trecastro, Jorge; Sammut, Nicholas; Zammit-Mangion, David

2015-09-01

With time and space partitioned architectures becoming increasingly appealing to the European space sector, the dependability of partitioning kernel technology is a key factor to its applicability in European Space Agency projects. This paper explores the potential of the data type fault model, which injects faults through the Application Program Interface, in partitioning kernel robustness testing. This fault injection methodology has been tailored to investigate its relevance in uncovering vulnerabilities within partitioning kernels and potentially contributing towards fault removal campaigns within this domain. This is demonstrated through a robustness testing case study of the XtratuM partitioning kernel for SPARC LEON3 processors. The robustness campaign exposed a number of vulnerabilities in XtratuM, exhibiting the potential benefits of using such a methodology for the robustness assessment of partitioning kernels.

Characteristics of adipose tissue macrophages and macrophage-derived insulin-like growth factor-1 in virus-induced obesity.

PubMed

Park, S; Park, H-L; Lee, S-Y; Nam, J-H

2016-03-01

Various pathogens are implicated in the induction of obesity. Previous studies have confirmed that human adenovirus 36 (Ad36) is associated with increased adiposity, improved glycemic control and induction of inflammation. The Ad36-induced inflammation is reflected in the infiltration of macrophages into adipose tissue. However, the characteristics and role of adipose tissue macrophages (ATMs) and macrophage-secreted factors in virus-induced obesity (VIO) are unclear. Although insulin-like growth factor-1 (IGF-1) is involved in obesity metabolism, the contribution of IGF secreted by macrophages in VIO has not been studied. Four-week-old male mice were studied 1 week and 12 weeks after Ad36 infection for determining the characteristics of ATMs in VIO and diet-induced obesity (DIO). In addition, macrophage-specific IGF-1-deficient (MIKO) mice were used to study the involvement of IGF-1 in VIO. In the early stage of VIO (1 week after Ad36 infection), the M1 ATM sub-population increased, which increased the M1/M2 ratio, whereas DIO did not cause this change. In the late stage of VIO (12 weeks after Ad36 infection), the M1/M2 ratio did not change because the M1 and M2 ATM sub-populations increased to a similar extent, despite an increase in adiposity. By contrast, DIO increased the M1/M2 ratio. In addition, VIO in wild-type mice upregulated angiogenesis in adipose tissue and improved glycemic control. However, MIKO mice showed no increase in adiposity, angiogenesis, infiltration of macrophages into adipose tissue, or improvement in glycemic control after Ad36 infection. These data suggest that IGF-1 secreted by macrophages may contribute to hyperplasia and hypertrophy in adipose tissue by increasing angiogenesis, which helps to maintain the 'adipose tissue robustness'.

Robustness of the p53 network and biological hackers.

PubMed

Dartnell, Lewis; Simeonidis, Evangelos; Hubank, Michael; Tsoka, Sophia; Bogle, I David L; Papageorgiou, Lazaros G

2005-06-06

The p53 protein interaction network is crucial in regulating the metazoan cell cycle and apoptosis. Here, the robustness of the p53 network is studied by analyzing its degeneration under two modes of attack. Linear Programming is used to calculate average path lengths among proteins and the network diameter as measures of functionality. The p53 network is found to be robust to random loss of nodes, but vulnerable to a targeted attack against its hubs, as a result of its architecture. The significance of the results is considered with respect to mutational knockouts of proteins and the directed attacks mounted by tumour inducing viruses.

Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver.

PubMed

Amenya, Hesbon Z; Tohyama, Chiharu; Ohsako, Seiichiroh

2016-10-07

The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.

Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver

NASA Astrophysics Data System (ADS)

Amenya, Hesbon Z.; Tohyama, Chiharu; Ohsako, Seiichiroh

2016-10-01

The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.

Robust power spectral estimation for EEG data

PubMed Central

Melman, Tamar; Victor, Jonathan D.

2016-01-01

Background Typical electroencephalogram (EEG) recordings often contain substantial artifact. These artifacts, often large and intermittent, can interfere with quantification of the EEG via its power spectrum. To reduce the impact of artifact, EEG records are typically cleaned by a preprocessing stage that removes individual segments or components of the recording. However, such preprocessing can introduce bias, discard available signal, and be labor-intensive. With this motivation, we present a method that uses robust statistics to reduce dependence on preprocessing by minimizing the effect of large intermittent outliers on the spectral estimates. New method Using the multitaper method[1] as a starting point, we replaced the final step of the standard power spectrum calculation with a quantile-based estimator, and the Jackknife approach to confidence intervals with a Bayesian approach. The method is implemented in provided MATLAB modules, which extend the widely used Chronux toolbox. Results Using both simulated and human data, we show that in the presence of large intermittent outliers, the robust method produces improved estimates of the power spectrum, and that the Bayesian confidence intervals yield close-to-veridical coverage factors. Comparison to existing method The robust method, as compared to the standard method, is less affected by artifact: inclusion of outliers produces fewer changes in the shape of the power spectrum as well as in the coverage factor. Conclusion In the presence of large intermittent outliers, the robust method can reduce dependence on data preprocessing as compared to standard methods of spectral estimation. PMID:27102041

Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

PubMed

Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

2016-04-01

Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. © 2016 American Heart Association, Inc.

Hypoxia-Inducible Factors Link Iron Homeostasis and Erythropoiesis

PubMed Central

Shah, Yatrik M.; Xie, Liwei

2014-01-01

Iron is required for efficient oxygen transport, and hypoxia signaling links erythropoiesis with iron homeostasis. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low O2. One component of this pathway, hypoxia-inducible factor (HIF), is a transcription factor that is highly active in hypoxic cells. The first HIF target gene characterized was EPO, which encodes erythropoietin—a glycoprotein hormone that controls erythropoiesis. The past decade has led to fundamental advances in our understanding of how hypoxia regulates iron levels to support erythropoiesis and maintain systemic iron homeostasis. We review the cell-type specific effects of hypoxia and HIFs in adaptive response to changes in oxygen and iron availability, as well as potential uses of HIF modulators for patients with iron-related disorders. PMID:24389303

Ruscogenin inhibits lipopolysaccharide-induced acute lung injury in mice: involvement of tissue factor, inducible NO synthase and nuclear factor (NF)-κB.

PubMed

Sun, Qi; Chen, Ling; Gao, Mengyu; Jiang, Wenwen; Shao, Fangxian; Li, Jingjing; Wang, Jun; Kou, Junping; Yu, Boyang

2012-01-01

Acute lung injury is still a significant clinical problem with a high mortality rate and there are few effective therapies in clinic. Here, we studied the inhibitory effect of ruscogenin, an anti-inflammatory and anti-thrombotic natural product, on lipopolysaccharide (LPS)-induced acute lung injury in mice basing on our previous studies. The results showed that a single oral administration of ruscogenin significantly decreased lung wet to dry weight (W/D) ratio at doses of 0.3, 1.0 and 3.0 mg/kg 1 h prior to LPS challenge (30 mg/kg, intravenous injection). Histopathological changes such as pulmonary edema, coagulation and infiltration of inflammatory cells were also attenuated by ruscogenin. In addition, ruscogenin markedly decreased LPS-induced myeloperoxidase (MPO) activity and nitrate/nitrite content, and also downregulated expression of tissue factor (TF), inducible NO synthase (iNOS) and nuclear factor (NF)-κB p-p65 (Ser 536) in the lung tissue at three doses. Furthermore, ruscogenin reduced plasma TF procoagulant activity and nitrate/nitrite content in LPS-induced ALI mice. These findings confirmed that ruscogenin significantly attenuate LPS-induced acute lung injury via inhibiting expressions of TF and iNOS and NF-κB p65 activation, indicating it as a potential therapeutic agent for ALI or sepsis. Copyright © 2011 Elsevier B.V. All rights reserved.

Views of Health System Experts on Macro Factors of Induced Demand

PubMed Central

Khorasani, Elahe; Keyvanara, Mahmoud; Karimi, Saeed; Jazi, Marzie Jafarian

2014-01-01

Background: The probability and severity of effects of induced demand are because of the interaction between a range of factors that can affect physicians and patients behavior. It is also affected by the laws of the markets and organizational arrangements for medical services. This article studies major factors that affect the phenomenon of induced demand with the use of experts’ experiences of the Isfahan University of Medical Sciences. Methods: The research is applied a qualitative method. Semi-structured interview was used for data generation. Participants in this study were people who had been informed in this regard and had to be experienced and were known as experts. Purposive sampling was done for data saturation. Seventeen people were interviewed and criteria such as data “reliability of information” and stability were considered. The anonymity of the interviewees was preserved. The data are transcribed, categorized and then used the thematic analysis. Results: In this study, thematic analysis was conducted, and 77 sub-themes and 3 themes were extracted respectively. The three main themes include infrastructural factors, social factors, and organizational structural factors affecting induced demand. Each of these also has some sub-themes. Conclusions: Results of this research present a framework for analyzing the major causes of induced demand. The causes identified here include complexity of medicine, information mismatch between service providers and consumers, clinical uncertainty, false beliefs, advertisements, insufficient supervision, scarcity of clinical guidelines, weakness of education system, and ignorance of medical ethics. These findings help policymakers to investigate the induced demand phenomenon clear-sighted. PMID:25400888

Membrane Resonance Enables Stable and Robust Gamma Oscillations

PubMed Central

Moca, Vasile V.; Nikolić, Danko; Singer, Wolf; Mureşan, Raul C.

2014-01-01

Neuronal mechanisms underlying beta/gamma oscillations (20–80 Hz) are not completely understood. Here, we show that in vivo beta/gamma oscillations in the cat visual cortex sometimes exhibit remarkably stable frequency even when inputs fluctuate dramatically. Enhanced frequency stability is associated with stronger oscillations measured in individual units and larger power in the local field potential. Simulations of neuronal circuitry demonstrate that membrane properties of inhibitory interneurons strongly determine the characteristics of emergent oscillations. Exploration of networks containing either integrator or resonator inhibitory interneurons revealed that: (i) Resonance, as opposed to integration, promotes robust oscillations with large power and stable frequency via a mechanism called RING (Resonance INduced Gamma); resonance favors synchronization by reducing phase delays between interneurons and imposes bounds on oscillation cycle duration; (ii) Stability of frequency and robustness of the oscillation also depend on the relative timing of excitatory and inhibitory volleys within the oscillation cycle; (iii) RING can reproduce characteristics of both Pyramidal INterneuron Gamma (PING) and INterneuron Gamma (ING), transcending such classifications; (iv) In RING, robust gamma oscillations are promoted by slow but are impaired by fast inputs. Results suggest that interneuronal membrane resonance can be an important ingredient for generation of robust gamma oscillations having stable frequency. PMID:23042733

Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae.

PubMed

Muzaffar, Suhail; Chattoo, Bharat B

2017-03-01

Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.

Research on robust optimization of emergency logistics network considering the time dependence characteristic

NASA Astrophysics Data System (ADS)

WANG, Qingrong; ZHU, Changfeng; LI, Ying; ZHANG, Zhengkun

2017-06-01

Considering the time dependence of emergency logistic network and complexity of the environment that the network exists in, in this paper the time dependent network optimization theory and robust discrete optimization theory are combined, and the emergency logistics dynamic network optimization model with characteristics of robustness is built to maximize the timeliness of emergency logistics. On this basis, considering the complexity of dynamic network and the time dependence of edge weight, an improved ant colony algorithm is proposed to realize the coupling of the optimization algorithm and the network time dependence and robustness. Finally, a case study has been carried out in order to testify validity of this robustness optimization model and its algorithm, and the value of different regulation factors was analyzed considering the importance of the value of the control factor in solving the optimal path. Analysis results show that this model and its algorithm above-mentioned have good timeliness and strong robustness.

Tumor necrosis factor-{alpha} enhances IL-15-induced natural killer cell differentiation

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

Lee, Jiwon; Lee, Suk Hyung; Korea University of Science and Technology, Yusong, Daejeon 305-333

2009-09-04

The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-{alpha} (TNF-{alpha}) is a positive regulator of NK cell differentiation. TNF-{alpha} augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-{alpha} alone also induced NK cell maturation as well as IL-15. TNF-{alpha} also increased IFN-{gamma} production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-{alpha} and IL-15. In addition, TNF-{alpha} increased nuclear factor-kappamore » B (NF-{kappa}B) activity in NK cells and inhibition of NF-{kappa}B impeded TNF-{alpha}-enhanced NK cell maturation. Overall, these data suggest that TNF-{alpha} significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-{kappa}B activity.« less

Model robustness as a confirmatory virtue: The case of climate science.

PubMed

Lloyd, Elisabeth A

2015-02-01

I propose a distinct type of robustness, which I suggest can support a confirmatory role in scientific reasoning, contrary to the usual philosophical claims. In model robustness, repeated production of the empirically successful model prediction or retrodiction against a background of independently-supported and varying model constructions, within a group of models containing a shared causal factor, may suggest how confident we can be in the causal factor and predictions/retrodictions, especially once supported by a variety of evidence framework. I present climate models of greenhouse gas global warming of the 20th Century as an example, and emphasize climate scientists' discussions of robust models and causal aspects. The account is intended as applicable to a broad array of sciences that use complex modeling techniques. Copyright © 2014 Elsevier Ltd. All rights reserved.

Engineering Robustness of Microbial Cell Factories.

PubMed

Gong, Zhiwei; Nielsen, Jens; Zhou, Yongjin J

2017-10-01

Metabolic engineering and synthetic biology offer great prospects in developing microbial cell factories capable of converting renewable feedstocks into fuels, chemicals, food ingredients, and pharmaceuticals. However, prohibitively low production rate and mass concentration remain the major hurdles in industrial processes even though the biosynthetic pathways are comprehensively optimized. These limitations are caused by a variety of factors unamenable for host cell survival, such as harsh industrial conditions, fermentation inhibitors from biomass hydrolysates, and toxic compounds including metabolic intermediates and valuable target products. Therefore, engineered microbes with robust phenotypes is essential for achieving higher yield and productivity. In this review, the recent advances in engineering robustness and tolerance of cell factories is described to cope with these issues and briefly introduce novel strategies with great potential to enhance the robustness of cell factories, including metabolic pathway balancing, transporter engineering, and adaptive laboratory evolution. This review also highlights the integration of advanced systems and synthetic biology principles toward engineering the harmony of overall cell function, more than the specific pathways or enzymes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Familial factors responsible for persistent crying-induced asthma: a case report.

PubMed

Weinstein, A G

1987-10-01

Crying behavior of the asthmatic child may induce wheezing symptoms. This may be a clinical problem for families with asthmatic children who exhibit frequent and persistent crying behavior. This case report identifies behaviors by the child and parents that may be responsible for continual crying. Child factors include (1) "spoiled" personality, (2) poor self-image, (3) biologic sensitivity to foods, medication, and environmental allergens producing irritability. Parental factors include poor disciplinary practices secondary to (1) disrupted home life, (2) guilt, and (3) overprotective behavior. Identification of these factors may be helpful in establishing clinical management strategies to reduce crying-induced asthma.

Robust, Decoupled, Flight Control Design with Rate Saturating Actuators

NASA Technical Reports Server (NTRS)

Snell, S. A.; Hess, R. A.

1997-01-01

Techniques for the design of control systems for manually controlled, high-performance aircraft must provide the following: (1) multi-input, multi-output (MIMO) solutions, (2) acceptable handling qualities including no tendencies for pilot-induced oscillations, (3) a tractable approach for compensator design, (4) performance and stability robustness in the presence of significant plant uncertainty, and (5) performance and stability robustness in the presence actuator saturation (particularly rate saturation). A design technique built upon Quantitative Feedback Theory is offered as a candidate methodology which can provide flight control systems meeting these requirements, and do so over a considerable part of the flight envelope. An example utilizing a simplified model of a supermaneuverable fighter aircraft demonstrates the proposed design methodology.

Defining robustness protocols: a method to include and evaluate robustness in clinical plans

NASA Astrophysics Data System (ADS)

McGowan, S. E.; Albertini, F.; Thomas, S. J.; Lomax, A. J.

2015-04-01

We aim to define a site-specific robustness protocol to be used during the clinical plan evaluation process. Plan robustness of 16 skull base IMPT plans to systematic range and random set-up errors have been retrospectively and systematically analysed. This was determined by calculating the error-bar dose distribution (ebDD) for all the plans and by defining some metrics used to define protocols aiding the plan assessment. Additionally, an example of how to clinically use the defined robustness database is given whereby a plan with sub-optimal brainstem robustness was identified. The advantage of using different beam arrangements to improve the plan robustness was analysed. Using the ebDD it was found range errors had a smaller effect on dose distribution than the corresponding set-up error in a single fraction, and that organs at risk were most robust to the range errors, whereas the target was more robust to set-up errors. A database was created to aid planners in terms of plan robustness aims in these volumes. This resulted in the definition of site-specific robustness protocols. The use of robustness constraints allowed for the identification of a specific patient that may have benefited from a treatment of greater individuality. A new beam arrangement showed to be preferential when balancing conformality and robustness for this case. The ebDD and error-bar volume histogram proved effective in analysing plan robustness. The process of retrospective analysis could be used to establish site-specific robustness planning protocols in proton therapy. These protocols allow the planner to determine plans that, although delivering a dosimetrically adequate dose distribution, have resulted in sub-optimal robustness to these uncertainties. For these cases the use of different beam start conditions may improve the plan robustness to set-up and range uncertainties.

Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer.

PubMed

Yamada, Tadaaki; Takeuchi, Shinji; Kita, Kenji; Bando, Hideaki; Nakamura, Takahiro; Matsumoto, Kunio; Yano, Seiji

2012-02-01

Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by coculture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status.

A Design Tool for Robust Composite Structures

DTIC Science & Technology

2010-06-01

a a UNIVERSITY OF ^?CAiVI BRIDGE FINAL REPORT A Design Tool for Robust Composite Structures Frank Zok Materials Department University of ...organic fibers, especially Dyneema®. The principal objectives of the present study were to ascertain the fundamental mechanical properties of Dyneema...composites increases by a factor of 2 and the ductility by almost a factor of 3 over the strain rate range 10-3 s-1 to 104 s- 1. One consequence is

[Importance of age and other risk factors in NSAID-induced gastropathy].

PubMed

Lee, Hang Lak; Han, Dong Soo; Kim, Jin Bae; Kim, Jong Pyo; Jeon, Yong Chul; Sohn, Joo Hyun; Hahm, Joon Soo

2004-11-01

It is clinically important to analyze the risk factors of NSAID-induced gastropathy because there could be no symptoms. Age is the most important risk factor according to previous reports. The aim of this study was to find risk factors of NSAID-induced gastropathy and to confirm the association between NSAID-induced gastropathy and age. We retrospectively assessed 300 patients who conducted an upper gastroscopy during the course of chronic NSAID treatment. Median age of patients group is 51.4 +/- 12.2 years. In multivariate analysis, age and ulcer history are two significant risk factors. Median age is 46.7 +/- 10.7 years for the patients with nonspecific gastroscopic finding, 53.0 +/- 12.5 for those with erosion, 57.6 +/- 10.0 for those with ulcer, and 63.2 +/- 8.9 for those with hemorrhage. The proportion of ulcer patients is as follows: 6% in the patients of under 40 years old, 14.9% in patients of the 40s, 20% in patients of the 50s, 30.9% in patients of the 60s, 33.3% in patients over 70 years. The proportion of nonspecific findings is 62.2% in patients of the 40s, 37.8% in patients of the 50s, and 29% in patients over 60 years. Age is the most important risk factor of the NSAID-induced gastrointestinal mucosal injury. A larger randomized prospective control study will be required in the future for more conclusive results.

Persisting mild hypothermia suppresses hypoxia-inducible factor-1alpha protein synthesis and hypoxia-inducible factor-1-mediated gene expression.

PubMed

Tanaka, Tomoharu; Wakamatsu, Takuhiko; Daijo, Hiroki; Oda, Seiko; Kai, Shinichi; Adachi, Takehiko; Kizaka-Kondoh, Shinae; Fukuda, Kazuhiko; Hirota, Kiichi

2010-03-01

The transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in regulating gene expression in response to hypoxia-ischemia. Ischemia causes the tissue not only to be hypoxic but also to be hypothermic because of the hypoperfusion under certain circumstances. On the other hand, the induced hypothermia is one of the most common therapeutic modalities to extend tolerance to hypoxia. Although hypoxia elicits a variety of cellular and systemic responses at different organizational levels in the body, little is known about how hypoxia-induced responses are affected by low temperature. We examined the influence of mild hypothermic conditions (28-32 degrees C) on HIF-1 in both in vitro and in vivo settings. In vitro experiments adopting cultured cells elucidated that hypoxia-induced HIF-1 activation was resistant to 4-h exposure to the low temperature. In contrast, exposure to the low temperature as long as 24 h suppressed HIF-1 activation and the subsequent upregulation of HIF-1 target genes such as VEGF or GLUT-1. HIF-1alpha protein stability in the cell was not affected by hypothermic treatment. Furthermore, intracellular ATP content was reduced under 1% O(2) conditions but was not largely affected by hypothermic treatment. The evidence indicates that reduction of oxygen consumption is not largely involved in suppression of HIF-1. In addition, we demonstrated that HIF-1 DNA-binding activity and HIF-1-dependent gene expressions induced under 10% O(2) atmosphere in mouse brain were not influenced by treatment under 3-h hypothermic temperature but were inhibited under 5-h treatment. On the other hand, we indicated that warming ischemic legs of mice for 24 h preserved HIF-1 activity. In this report we describe for the first time that persisting low temperature significantly reduced HIF-1alpha neosynthesis under hypoxic conditions, leading to a decrease in gene expression for adaptation to hypoxia in both in vitro and in vivo settings.

Robustness for slope stability modelling under deep uncertainty

NASA Astrophysics Data System (ADS)

Almeida, Susana; Holcombe, Liz; Pianosi, Francesca; Wagener, Thorsten

2015-04-01

Landslides can have large negative societal and economic impacts, such as loss of life and damage to infrastructure. However, the ability of slope stability assessment to guide management is limited by high levels of uncertainty in model predictions. Many of these uncertainties cannot be easily quantified, such as those linked to climate change and other future socio-economic conditions, restricting the usefulness of traditional decision analysis tools. Deep uncertainty can be managed more effectively by developing robust, but not necessarily optimal, policies that are expected to perform adequately under a wide range of future conditions. Robust strategies are particularly valuable when the consequences of taking a wrong decision are high as is often the case of when managing natural hazard risks such as landslides. In our work a physically based numerical model of hydrologically induced slope instability (the Combined Hydrology and Stability Model - CHASM) is applied together with robust decision making to evaluate the most important uncertainties (storm events, groundwater conditions, surface cover, slope geometry, material strata and geotechnical properties) affecting slope stability. Specifically, impacts of climate change on long-term slope stability are incorporated, accounting for the deep uncertainty in future climate projections. Our findings highlight the potential of robust decision making to aid decision support for landslide hazard reduction and risk management under conditions of deep uncertainty.

A novel vaccine containing EphA2 epitope and LIGHT plasmid induces robust cellular immunity against glioma U251 cells.

PubMed

Chen, Hongjie; Yuan, Bangqing; Zheng, Zhaocong; Liu, Zheng; Wang, Shousen; Liu, Yong

2011-01-01

EphA2 is a receptor tyrosine kinase and can be acted as an attractive antigen for glioma vaccines. In addition, LIGHT plays an important role on enhancing T cell proliferation and cytokine production. To improve the CTL mediated immune response against glioma cells, we prepared the novel vaccine containing EphA2(883-891) peptide (TLADFDPRV) and LIGHT plasmid and utilized it to immunize the HLA-A2 transgenic HHD mice. In addition, trimera mice were immunized with the novel vaccine to elicit the antitumor immune response. The results demonstrated that the novel vaccine could induce robust cellular immunity against glioma U251 cells without lysing autologous lymphocytes. Moreover, the novel vaccine could significantly inhibit the tumor growth and prolong the life span of tumor bearing mice. These findings suggested that the novel vaccine containing EphA2 epitope and LIGHT plasmid could induce anti-tumor immunity against U251 cells expressing EphA2, and provided a promising strategy for glioma immunotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.

A Histologically Distinctive Interstitial Pneumonia Induced by Overexpression of the Interleukin 6, Transforming Growth Factor β1, or Platelet-Derived Growth Factor B Gene

NASA Astrophysics Data System (ADS)

Yoshida, Mitsuhiro; Sakuma, Junko; Hayashi, Seiji; Abe, Kin'ya; Saito, Izumu; Harada, Shizuko; Sakatani, Mitsunoir; Yamamoto, Satoru; Matsumoto, Norinao; Kaneda, Yasufumi; Kishmoto, Tadamitsu

1995-10-01

Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor β1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor β1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

Mechanisms for Robust Cognition.

PubMed

Walsh, Matthew M; Gluck, Kevin A

2015-08-01

To function well in an unpredictable environment using unreliable components, a system must have a high degree of robustness. Robustness is fundamental to biological systems and is an objective in the design of engineered systems such as airplane engines and buildings. Cognitive systems, like biological and engineered systems, exist within variable environments. This raises the question, how do cognitive systems achieve similarly high degrees of robustness? The aim of this study was to identify a set of mechanisms that enhance robustness in cognitive systems. We identify three mechanisms that enhance robustness in biological and engineered systems: system control, redundancy, and adaptability. After surveying the psychological literature for evidence of these mechanisms, we provide simulations illustrating how each contributes to robust cognition in a different psychological domain: psychomotor vigilance, semantic memory, and strategy selection. These simulations highlight features of a mathematical approach for quantifying robustness, and they provide concrete examples of mechanisms for robust cognition. © 2014 Cognitive Science Society, Inc.

PLACENTAL GROWTH FACTOR ADMINISTRATION ABOLISHES PLACENTAL ISCHEMIA-INDUCED HYPERTENSION

PubMed Central

Spradley, Frank T.; Tan, Adelene Y.; Joo, Woo S.; Daniels, Garrett; Kussie, Paul; Karumanchi, S. Ananth; Granger, Joey P.

2016-01-01

Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia as placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and VEGF are both natural ligands for sFlt-1, VEGF also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to four groups: normal pregnant (NP) or RUPP ± infusion of rhPlGF (180 μg/kg/day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than NP rats. Infusion of rhPlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that rhPlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

Computer Vision-Based Structural Displacement Measurement Robust to Light-Induced Image Degradation for In-Service Bridges

PubMed Central

Lee, Junhwa; Lee, Kyoung-Chan; Cho, Soojin

2017-01-01

The displacement responses of a civil engineering structure can provide important information regarding structural behaviors that help in assessing safety and serviceability. A displacement measurement using conventional devices, such as the linear variable differential transformer (LVDT), is challenging owing to issues related to inconvenient sensor installation that often requires additional temporary structures. A promising alternative is offered by computer vision, which typically provides a low-cost and non-contact displacement measurement that converts the movement of an object, mostly an attached marker, in the captured images into structural displacement. However, there is limited research on addressing light-induced measurement error caused by the inevitable sunlight in field-testing conditions. This study presents a computer vision-based displacement measurement approach tailored to a field-testing environment with enhanced robustness to strong sunlight. An image-processing algorithm with an adaptive region-of-interest (ROI) is proposed to reliably determine a marker’s location even when the marker is indistinct due to unfavorable light. The performance of the proposed system is experimentally validated in both laboratory-scale and field experiments. PMID:29019950

Extrinsic grouping factors in motion-induced blindness

PubMed Central

2018-01-01

We investigated how various grouping factors altered subjective disappearances of the individual targets in the motion-induced blindness display. The latter relies on a moving mask to render highly salient static targets temporarily subjectively invisible. Specifically, we employed two extrinsic grouping factors, the connectedness and the common region, and examined whether their presence would make targets more resilient against the suppression. In addition, we investigated whether the presence of an illusory Kanizsa triangle would affect the suppression of the inducing Pac-Man elements. We quantified the perceptual dynamics using the proportion of the disappearance time (this indicates whether targets became more resilient against the suppression), and the proportion of simultaneous disappearance and reappearance events (characterizes the tendency for the targets to disappear or reappear as a group). We report that a single mask that encompassed all targets (a common region grouping) significantly increased the proportion of simultaneous disappearance and reappearance events, but had no effect on the proportion of the disappearance time. In contrast, a line that connected two targets significantly decreased the total invisibility time, but had no impact on the simultaneity of the disappearance and reappearance events. We found no statistically significant effect of the presence of the illusory Kanizsa triangle on either measure. Finally, we found no interaction either between the common region and the connectedness or between the common region and the presence of the illusory Kanizsa triangle. Our results indicate that extrinsic grouping factors might influence the perception differently than the intrinsic ones and highlight the importance of using several measures to characterize the perceptual dynamics, as various grouping factors might affect it differentially. PMID:29381747

Regulation of erythropoiesis by hypoxia-inducible factors

PubMed Central

Haase, Volker H.

2012-01-01

A classic physiologic response to systemic hypoxia is the increase in red blood cell production. Hypoxia-inducible factors (HIFs) orchestrate this response by inducing cell-type specific gene expression changes that result in increased erythropoietin (EPO) production in kidney and liver, in enhanced iron uptake and utilization and in adjustments of the bone marrow microenvironment that facilitate erythroid progenitor maturation and proliferation. In particular HIF-2 has emerged as the transcription factor that regulates EPO synthesis in the kidney and liver and plays a critical role in the regulation of intestinal iron uptake. Its key function in the hypoxic regulation of erythropoiesis is underscored by genetic studies in human populations that live at high-altitude and by mutational analysis of patients with familial erythrocytosis. This review provides a perspective on recent insights into HIF-controlled erythropoiesis and iron metabolism, and examines cell types that have EPO-producing capability. Furthermore, the review summarizes clinical syndromes associated with mutations in the O2-sensing pathway and the genetic changes that occur in high altitude natives. The therapeutic potential of pharmacologic HIF activation for the treatment of anemia is discussed. PMID:23291219

Robust Fault Detection Using Robust Z1 Estimation and Fuzzy Logic

NASA Technical Reports Server (NTRS)

Curry, Tramone; Collins, Emmanuel G., Jr.; Selekwa, Majura; Guo, Ten-Huei (Technical Monitor)

2001-01-01

This research considers the application of robust Z(sub 1), estimation in conjunction with fuzzy logic to robust fault detection for an aircraft fight control system. It begins with the development of robust Z(sub 1) estimators based on multiplier theory and then develops a fixed threshold approach to fault detection (FD). It then considers the use of fuzzy logic for robust residual evaluation and FD. Due to modeling errors and unmeasurable disturbances, it is difficult to distinguish between the effects of an actual fault and those caused by uncertainty and disturbance. Hence, it is the aim of a robust FD system to be sensitive to faults while remaining insensitive to uncertainty and disturbances. While fixed thresholds only allow a decision on whether a fault has or has not occurred, it is more valuable to have the residual evaluation lead to a conclusion related to the degree of, or probability of, a fault. Fuzzy logic is a viable means of determining the degree of a fault and allows the introduction of human observations that may not be incorporated in the rigorous threshold theory. Hence, fuzzy logic can provide a more reliable and informative fault detection process. Using an aircraft flight control system, the results of FD using robust Z(sub 1) estimation with a fixed threshold are demonstrated. FD that combines robust Z(sub 1) estimation and fuzzy logic is also demonstrated. It is seen that combining the robust estimator with fuzzy logic proves to be advantageous in increasing the sensitivity to smaller faults while remaining insensitive to uncertainty and disturbances.

Marmoset induced pluripotent stem cells: Robust neural differentiation following pretreatment with dimethyl sulfoxide.

PubMed

Qiu, Zhifang; Mishra, Anuja; Li, Miao; Farnsworth, Steven L; Guerra, Bernadette; Lanford, Robert E; Hornsby, Peter J

2015-07-01

The marmoset is an important nonhuman primate model for regenerative medicine. For experimental autologous cell therapy based on induced pluripotent (iPS) cells in the marmoset, cells must be able to undergo robust and reliable directed differentiation that will not require customization for each specific iPS cell clone. When marmoset iPS cells were aggregated in a hanging drop format for 3 days, followed by exposure to dual SMAD inhibitors and retinoic acid in monolayer culture for 3 days, we found substantial variability in the response of different iPS cell clones. However, when clones were pretreated with 0.05-2% dimethyl sulfoxide (DMSO) for 24 hours, all clones showed a very similar maximal response to the directed differentiation scheme. Peak responses were observed at 0.5% DMSO in two clones and at 1% DMSO in a third clone. When patterns of gene expression were examined by microarray analysis, hierarchical clustering showed very similar responses in all 3 clones when they were pretreated with optimal DMSO concentrations. The change in phenotype following exposure to DMSO and the 6 day hanging drop/monolayer treatment was confirmed by immunocytochemistry. Analysis of DNA content in DMSO-exposed cells indicated that it is unlikely that DMSO acts by causing cells to exit from the cell cycle. This approach should be generally valuable in the directed neural differentiation of pluripotent cells for experimental cell therapy. Copyright © 2015. Published by Elsevier B.V.

Design principles for robust vesiculation in clathrin-mediated endocytosis

PubMed Central

Hassinger, Julian E.; Oster, George; Drubin, David G.; Rangamani, Padmini

2017-01-01

A critical step in cellular-trafficking pathways is the budding of membranes by protein coats, which recent experiments have demonstrated can be inhibited by elevated membrane tension. The robustness of processes like clathrin-mediated endocytosis (CME) across a diverse range of organisms and mechanical environments suggests that the protein machinery in this process has evolved to take advantage of some set of physical design principles to ensure robust vesiculation against opposing forces like membrane tension. Using a theoretical model for membrane mechanics and membrane protein interaction, we have systematically investigated the influence of membrane rigidity, curvature induced by the protein coat, area covered by the protein coat, membrane tension, and force from actin polymerization on bud formation. Under low tension, the membrane smoothly evolves from a flat to budded morphology as the coat area or spontaneous curvature increases, whereas the membrane remains essentially flat at high tensions. At intermediate, physiologically relevant, tensions, the membrane undergoes a “snap-through instability” in which small changes in the coat area, spontaneous curvature or membrane tension cause the membrane to “snap” from an open, U-shape to a closed bud. This instability can be smoothed out by increasing the bending rigidity of the coat, allowing for successful budding at higher membrane tensions. Additionally, applied force from actin polymerization can bypass the instability by inducing a smooth transition from an open to a closed bud. Finally, a combination of increased coat rigidity and force from actin polymerization enables robust vesiculation even at high membrane tensions. PMID:28126722

Robust short-term memory without synaptic learning.

PubMed

Johnson, Samuel; Marro, J; Torres, Joaquín J

2013-01-01

Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings.

Non-negative Tensor Factorization for Robust Exploratory Big-Data Analytics

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

Alexandrov, Boian; Vesselinov, Velimir Valentinov; Djidjev, Hristo Nikolov

Currently, large multidimensional datasets are being accumulated in almost every field. Data are: (1) collected by distributed sensor networks in real-time all over the globe, (2) produced by large-scale experimental measurements or engineering activities, (3) generated by high-performance simulations, and (4) gathered by electronic communications and socialnetwork activities, etc. Simultaneous analysis of these ultra-large heterogeneous multidimensional datasets is often critical for scientific discoveries, decision-making, emergency response, and national and global security. The importance of such analyses mandates the development of the next-generation of robust machine learning (ML) methods and tools for bigdata exploratory analysis.

Prognostic factors for risk stratification of adult cancer patients with chemotherapy-induced febrile neutropenia: a systematic review and meta-analysis.

PubMed

Lee, Yee Mei; Lang, Dora; Lockwood, Craig

(thrombocytopenia, presence of central venous catheter, and duration and severity of neutropenia) have not previously been included in prognostic models. This review has found these factors may improve the performance of current models by adding or replacing some of the factors. The role of risk stratification of chemotherapy-induced febrile neutropenia patients continues to evolve as the practice of risk-based therapy has been demonstrated to be beneficial to patients, clinicians and health care organisations. Further research to identify new factors /markers is needed to develop a new model which is reliable and accurate for these patients, regardless of cancer types. A robust and well-validated prognostic model is the key to enhance patient safety in the risk-based management of cancer patients with chemotherapy-induced febrile neutropenia.

Architecture-Dependent Robustness and Bistability in a Class of Genetic Circuits

PubMed Central

Zhang, Jiajun; Yuan, Zhanjiang; Li, Han-Xiong; Zhou, Tianshou

2010-01-01

Understanding the relationship between genotype and phenotype is a challenge in systems biology. An interesting yet related issue is why a particular circuit topology is present in a cell when the same function can supposedly be obtained from an alternative architecture. Here we analyzed two topologically equivalent genetic circuits of coupled positive and negative feedback loops, named NAT and ALT circuits, respectively. The computational search for the oscillation volume of the entire biologically reasonable parameter region through large-scale random samplings shows that the NAT circuit exhibits a distinctly larger fraction of the oscillatory region than the ALT circuit. Such a global robustness difference between two circuits is supplemented by analyzing local robustness, including robustness to parameter perturbations and to molecular noise. In addition, detailed dynamical analysis shows that the molecular noise of both circuits can induce transient switching of the different mechanism between a stable steady state and a stable limit cycle. Our investigation on robustness and dynamics through examples provides insights into the relationship between network architecture and its function. PMID:20712986

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.

PubMed

Wiraswati, Hesti Lina; Hangen, Emilie; Sanz, Ana Belén; Lam, Ngoc-Vy; Reinhardt, Camille; Sauvat, Allan; Mogha, Ariane; Ortiz, Alberto; Kroemer, Guido; Modjtahedi, Nazanine

2016-11-22

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.

Expression of hypoxia-induced factor-1 alpha in early-stage and in metastatic oral squamous cell carcinoma.

PubMed

Ribeiro, Maisa; Teixeira, Sarah R; Azevedo, Monarko N; Fraga, Ailton C; Gontijo, Antônio Pm; Vêncio, Eneida F

2017-04-01

To investigate hypoxia-induced factor-1 alpha expression in distinct oral squamous cell carcinoma subtypes and topographies and correlate with clinicopathological data. Hypoxia-induced factor-1 alpha expression was assessed by immunohistochemistry in 93 cases of OSCC. Clinical and histopathological data were reviewed from medical records. Hypoxia-induced factor-1 alpha status was distinct according to tumor location, subtype and topography affect. In superficial oral squamous cell carcinomas, most tumor cells overexpressed hypoxia-induced factor-1 alpha, whereas hypoxia-induced factor-1 alpha was restricted to the intratumoral region in conventional squamous cell carcinomas. All basaloid squamous cell carcinomas exhibited downregulation of hypoxia-induced factor-1 alpha. Interestingly, metastatic lymph nodes (91.7%, p = 0.001) and the intratumoral regions of corresponding primary tumors (58.3%, p = 0.142) showed hypoxia-induced factor-1 alpha-positive tumor cells. Overall survival was poor in patients with metastatic lymph nodes. Hypoxia-induced factor-1 alpha has distinct expression patterns in different oral squamous cell carcinoma subtypes and topographies, suggesting that low oxygen tension promotes the growth pattern of superficial and conventional squamous cell carcinoma, but not basaloid squamous cell carcinoma. Indeed, a hypoxic environment may facilitate regional metastasis, making it a useful diagnostic and prognostic marker in primary tumors.

Robustness Analysis and Optimally Robust Control Design via Sum-of-Squares

NASA Technical Reports Server (NTRS)

Dorobantu, Andrei; Crespo, Luis G.; Seiler, Peter J.

2012-01-01

A control analysis and design framework is proposed for systems subject to parametric uncertainty. The underlying strategies are based on sum-of-squares (SOS) polynomial analysis and nonlinear optimization to design an optimally robust controller. The approach determines a maximum uncertainty range for which the closed-loop system satisfies a set of stability and performance requirements. These requirements, de ned as inequality constraints on several metrics, are restricted to polynomial functions of the uncertainty. To quantify robustness, SOS analysis is used to prove that the closed-loop system complies with the requirements for a given uncertainty range. The maximum uncertainty range, calculated by assessing a sequence of increasingly larger ranges, serves as a robustness metric for the closed-loop system. To optimize the control design, nonlinear optimization is used to enlarge the maximum uncertainty range by tuning the controller gains. Hence, the resulting controller is optimally robust to parametric uncertainty. This approach balances the robustness margins corresponding to each requirement in order to maximize the aggregate system robustness. The proposed framework is applied to a simple linear short-period aircraft model with uncertain aerodynamic coefficients.

CHEMOSENSITIZATION BY A NON-APOPTOGENIC HEAT SHOCK PROTEIN 70-BINDING APOPTOSIS INDUCING FACTOR MUTANT

EPA Science Inventory

Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis inducing factor mutant

Abstract
HSP70 inhibits apoptosis by neutralizing the caspase activator Apaf-1 and by interacting with apoptosis inducing factor (AIF), a mitochondrial flavoprotein wh...

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2.

PubMed

Koth, Laura L; Rodriguez, Madeleine W; Bernstein, Xin Liu; Chan, Salina; Huang, Xiaozhu; Charo, Israel F; Rollins, Barrett J; Erle, David J

2004-09-15

Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.

Factors associated with repeat induced abortion in Kenya.

PubMed

Maina, Beatrice W; Mutua, Michael M; Sidze, Estelle M

2015-10-12

Over six million induced abortions were reported in Africa in 2008 with over two million induced abortions occurring in Eastern Africa. Although a significant proportion of women in the region procure more than one abortion during their reproductive period, there is a dearth of research on factors associated with repeat abortion. Data for this study come from the Magnitude and Incidence of Unsafe Abortion Study conducted by the African Population and Health Research Center in Kenya in 2012. The study used a nationally-representative sample of 350 facilities (level II to level VI) that offer post-abortion services for complications following induced and spontaneous abortions. A prospective morbidity survey tool was used by health providers in 328 facilities to collect information on socio-demographic charateristics, reproductive health history and contraceptive use at conception for all patients presenting for post-abortion services. Our analysis is based on data recorded on 769 women who were classified as having had an induced abortion. About 16 % of women seeking post abortion services for an induced abortion reported to have had a previous induced abortion. Being separated or divorced or widowed, having no education, having unwanted pregnancy, having 1-2 prior births and using traditional methods of contraception were associated with a higher likelihood of a repeat induced abortion. The findings point to the need to address the reasons why women with first time induced abortion do not have the necessary information to prevent unintended pregnancies and further induced abortions. Possible explanations linked to the quality of post-abortion family planning and coverage of long-acting methods should be explored.

Robust kernel representation with statistical local features for face recognition.

PubMed

Yang, Meng; Zhang, Lei; Shiu, Simon Chi-Keung; Zhang, David

2013-06-01

Factors such as misalignment, pose variation, and occlusion make robust face recognition a difficult problem. It is known that statistical features such as local binary pattern are effective for local feature extraction, whereas the recently proposed sparse or collaborative representation-based classification has shown interesting results in robust face recognition. In this paper, we propose a novel robust kernel representation model with statistical local features (SLF) for robust face recognition. Initially, multipartition max pooling is used to enhance the invariance of SLF to image registration error. Then, a kernel-based representation model is proposed to fully exploit the discrimination information embedded in the SLF, and robust regression is adopted to effectively handle the occlusion in face images. Extensive experiments are conducted on benchmark face databases, including extended Yale B, AR (A. Martinez and R. Benavente), multiple pose, illumination, and expression (multi-PIE), facial recognition technology (FERET), face recognition grand challenge (FRGC), and labeled faces in the wild (LFW), which have different variations of lighting, expression, pose, and occlusions, demonstrating the promising performance of the proposed method.

A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis*

PubMed Central

Mahabeleshwar, Ganapati H.; Qureshi, Muhammad Awais; Takami, Yoichi; Sharma, Nikunj; Lingrel, Jerry B.; Jain, Mukesh K.

2012-01-01

Although Gram-positive infections account for the majority of cases of sepsis, the molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components of Gram-positive bacteria contribute to the development of sepsis. Experimental observations derived from cultured primary macrophages and the cell line indicate that Gram-positive bacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA and protein expression. Inoculation of live or heat-inactivated Gram-positive bacteria with macrophages induced HIF-1 transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1α attenuated Gram-positive bacterial endotoxin-induced cellular motility and proinflammatory gene expression in macrophages. Conversely, Gram-positive bacteria and their endotoxins reduced expression of the myeloid anti-inflammatory transcription factor Krüppel-like transcription factor 2 (KLF2). Sustained expression of KLF2 reduced and deficiency of KLF2 enhanced Gram-positive endotoxins induced HIF-1α mRNA and protein expression in macrophages. More importantly, KLF2 attenuated Gram-positive endotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistent with these results, mice deficient in myeloid HIF-1α were protected from Gram-positive endotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficient mice were susceptible to Gram-positive sepsis induced mortality and clinical symptoms. Collectively, these observations identify HIF-1α and KLF2 as critical regulators of Gram-positive endotoxin-mediated sepsis. PMID:22110137

Bovine trophectoderm cell lines induced from bovine fibroblasts with reprogramming factors

USDA-ARS?s Scientific Manuscript database

Bovine trophectoderm (TE) cells were induced [induced bovine trophectoderm-like (iBT)] from bovine fetal liver-derived fibroblasts, and other bovine fetal fibroblasts, after viral-vector transduction with either four or six reprogramming factors (RF), including POU5F1, KLF4, SOX2, C-MYC, SV40 large ...

Oxidative stress-induced miR-27a targets the redox gene nuclear factor erythroid 2-related factor 2 in diabetic embryopathy.

PubMed

Zhao, Yang; Dong, Daoyin; Reece, E Albert; Wang, Ashley R; Yang, Peixin

2018-01-01

Maternal diabetes induces neural tube defects, and oxidative stress is a causal factor for maternal diabetes-induced neural tube defects. The redox gene nuclear factor erythroid 2-related factor 2 is the master regulator of the cellular antioxidant system. In this study, we aimed to determine whether maternal diabetes inhibits nuclear factor erythroid 2-related factor 2 expression and nuclear factor erythroid 2-related factor 2-controlled antioxidant genes through the redox-sensitive miR-27a. We used a well-established type 1 diabetic embryopathy mouse model induced by streptozotocin for our in vivo studies. Embryos at embryonic day 8.5 were harvested for analysis of nuclear factor erythroid 2-related factor 2, nuclear factor erythroid 2-related factor 2-controlled antioxidant genes, and miR-27a expression. To determine if mitigating oxidative stress inhibits the increase of miR-27a and the decrease of nuclear factor erythroid 2-related factor 2 expression, we induced diabetic embryopathy in superoxide dismutase 2 (mitochondrial-associated antioxidant gene)-overexpressing mice. This model exhibits reduced mitochondria reactive oxygen species even in the presence of hyperglycemia. To investigate the causal relationship between miR-27a and nuclear factor erythroid 2-related factor 2 in vitro, we examined C17.2 neural stem cells under normal and high-glucose conditions. We observed that the messenger RNA and protein levels of nuclear factor erythroid 2-related factor 2 were significantly decreased in embryos on embryonic day 8.5 from diabetic dams compared to those from nondiabetic dams. High-glucose also significantly decreased nuclear factor erythroid 2-related factor 2 expression in a dose- and time-dependent manner in cultured neural stem cells. Our data revealed that miR-27a was up-regulated in embryos on embryonic day 8.5 exposed to diabetes, and that high glucose increased miR-27a levels in a dose- and time-dependent manner in cultured neural stem cells. In

Factors affecting drug-induced liver injury: antithyroid drugs as instances

PubMed Central

Niknahad, Hossein; Jamshidzadeh, Akram; Abdoli, Narges

2014-01-01

Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed. PMID:25320726

Resonant Interneurons Can Increase Robustness of Gamma Oscillations.

PubMed

Tikidji-Hamburyan, Ruben A; Martínez, Joan José; White, John A; Canavier, Carmen C

2015-11-25

Gamma oscillations are believed to play a critical role in in information processing, encoding, and retrieval. Inhibitory interneuronal network gamma (ING) oscillations may arise from a coupled oscillator mechanism in which individual neurons oscillate or from a population oscillator in which individual neurons fire sparsely and stochastically. All ING mechanisms, including the one proposed herein, rely on alternating waves of inhibition and windows of opportunity for spiking. The coupled oscillator model implemented with Wang-Buzsáki model neurons is not sufficiently robust to heterogeneity in excitatory drive, and therefore intrinsic frequency, to account for in vitro models of ING. Similarly, in a tightly synchronized regime, the stochastic population oscillator model is often characterized by sparse firing, whereas interneurons both in vivo and in vitro do not fire sparsely during gamma, but rather on average every other cycle. We substituted so-called resonator neural models, which exhibit class 2 excitability and postinhibitory rebound (PIR), for the integrators that are typically used. This results in much greater robustness to heterogeneity that actually increases as the average participation in spikes per cycle approximates physiological levels. Moreover, dynamic clamp experiments that show autapse-induced firing in entorhinal cortical interneurons support the idea that PIR can serve as a network gamma mechanism. Furthermore, parvalbumin-positive (PV(+)) cells were much more likely to display both PIR and autapse-induced firing than GAD2(+) cells, supporting the view that PV(+) fast-firing basket cells are more likely to exhibit class 2 excitability than other types of inhibitory interneurons. Gamma oscillations are believed to play a critical role in information processing, encoding, and retrieval. Networks of inhibitory interneurons are thought to be essential for these oscillations. We show that one class of interneurons with an abrupt onset of firing

The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis.

PubMed

Salnikow, Konstantin; Davidson, Todd; Zhang, Qunwei; Chen, Lung Chi; Su, Weichen; Costa, Max

2003-07-01

Nickel is a potent environmental pollutant in industrial countries. Because nickel compounds are carcinogenic, exposure to nickel represents a serious hazard to human health. The understanding of how nickel exerts its toxic and carcinogenic effects at a molecular level may be important in risk assessment, as well as in the treatment and prevention of occupational diseases. Previously, using human and rodent cells in vitro, we showed that hypoxia-inducible signaling pathway was activated by carcinogenic nickel compounds. Acute exposure to nickel resulted in the accumulation of hypoxia-inducible transcription factor (HIF)-1, which strongly activated hypoxia-inducible genes, including the recently discovered tumor marker NDRG1 (Cap43). To further identify HIF-1-dependent nickel-inducible genes and to understand the role of the HIF-dependent signaling pathway in nickel-induced transformation, we used the Affymetrix GeneChip to compare the gene expression profiles in wild-type cells or in cells from HIF-1 alpha knockout mouse embryos exposed to nickel chloride. As expected, when we examined 12,000 genes for expression changes, we found that genes coding for glycolytic enzymes and glucose transporters, known to be regulated by HIF-1 transcription factor, were induced by nickel only in HIF-1 alpha-proficient cells. In addition, we found a number of other hypoxia-inducible genes up-regulated by nickel in a HIF-dependent manner including BCL-2-binding protein Nip3, EGLN1, hypoxia-inducible gene 1 (HIG1), and prolyl 4-hydroxylase. Additionally, we found a number of genes induced by nickel in a HIF-independent manner, suggesting that Ni activated other signaling pathways besides HIF-1. Finally, we found that in HIF-1 alpha knockout cells, nickel strongly induced the expression of the whole group of genes that were not expressed in the presence of HIF-1. Because the majority of modulated genes were induced or suppressed by nickel in a HIF-1-dependent manner, we elucidated the

Identification of jasmonic acid and its methyl ester as gum-inducing factors in tulips.

PubMed

Skrzypek, Edyta; Miyamoto, Kensuke; Saniewski, Marian; Ueda, Junichi

2005-02-01

The purpose of this study was to identify endogenous factors that induce gummosis and to show their role in gummosis in tulip (Tulipa gesneriana L. cv. Apeldoorn) stems. Using procedures to detect endogenous factors that induce gum in the stem of tulips, jasmonic acid (JA) and methyl jasmonate (JA-Me) were successfully identified using gas-liquid chromatography-mass spectrometry. Total amounts of JA and JA-Me designated as jasmonates in tulip stems were also estimated at about 70-80 ng/g fresh weight, using deuterium-labeled jasmonates as internal standards. The application of JA and JA-Me as lanolin pastes substantially induced gums in tulip stems with ethylene production. The application of ethephon, an ethylene-generating compound, however, induced no gummosis although it slightly affected jasmonate content in tulip stems. These results strongly suggest that JA and JA-Me are endogenous factors that induce gummosis in tulip stems.

Robust control of burst suppression for medical coma

NASA Astrophysics Data System (ADS)

Westover, M. Brandon; Kim, Seong-Eun; Ching, ShiNung; Purdon, Patrick L.; Brown, Emery N.

2015-08-01

Objective. Medical coma is an anesthetic-induced state of brain inactivation, manifest in the electroencephalogram by burst suppression. Feedback control can be used to regulate burst suppression, however, previous designs have not been robust. Robust control design is critical under real-world operating conditions, subject to substantial pharmacokinetic and pharmacodynamic parameter uncertainty and unpredictable external disturbances. We sought to develop a robust closed-loop anesthesia delivery (CLAD) system to control medical coma. Approach. We developed a robust CLAD system to control the burst suppression probability (BSP). We developed a novel BSP tracking algorithm based on realistic models of propofol pharmacokinetics and pharmacodynamics. We also developed a practical method for estimating patient-specific pharmacodynamics parameters. Finally, we synthesized a robust proportional integral controller. Using a factorial design spanning patient age, mass, height, and gender, we tested whether the system performed within clinically acceptable limits. Throughout all experiments we subjected the system to disturbances, simulating treatment of refractory status epilepticus in a real-world intensive care unit environment. Main results. In 5400 simulations, CLAD behavior remained within specifications. Transient behavior after a step in target BSP from 0.2 to 0.8 exhibited a rise time (the median (min, max)) of 1.4 [1.1, 1.9] min; settling time, 7.8 [4.2, 9.0] min; and percent overshoot of 9.6 [2.3, 10.8]%. Under steady state conditions the CLAD system exhibited a median error of 0.1 [-0.5, 0.9]%; inaccuracy of 1.8 [0.9, 3.4]%; oscillation index of 1.8 [0.9, 3.4]%; and maximum instantaneous propofol dose of 4.3 [2.1, 10.5] mg kg-1. The maximum hourly propofol dose was 4.3 [2.1, 10.3] mg kg-1 h-1. Performance fell within clinically acceptable limits for all measures. Significance. A CLAD system designed using robust control theory achieves clinically acceptable

Robust control of burst suppression for medical coma

PubMed Central

Westover, M Brandon; Kim, Seong-Eun; Ching, ShiNung; Purdon, Patrick L; Brown, Emery N

2015-01-01

Objective Medical coma is an anesthetic-induced state of brain inactivation, manifest in the electroencephalogram by burst suppression. Feedback control can be used to regulate burst suppression, however, previous designs have not been robust. Robust control design is critical under real-world operating conditions, subject to substantial pharmacokinetic and pharmacodynamic parameter uncertainty and unpredictable external disturbances. We sought to develop a robust closed-loop anesthesia delivery (CLAD) system to control medical coma. Approach We developed a robust CLAD system to control the burst suppression probability (BSP). We developed a novel BSP tracking algorithm based on realistic models of propofol pharmacokinetics and pharmacodynamics. We also developed a practical method for estimating patient-specific pharmacodynamics parameters. Finally, we synthesized a robust proportional integral controller. Using a factorial design spanning patient age, mass, height, and gender, we tested whether the system performed within clinically acceptable limits. Throughout all experiments we subjected the system to disturbances, simulating treatment of refractory status epilepticus in a real-world intensive care unit environment. Main results In 5400 simulations, CLAD behavior remained within specifications. Transient behavior after a step in target BSP from 0.2 to 0.8 exhibited a rise time (the median (min, max)) of 1.4 [1.1, 1.9] min; settling time, 7.8 [4.2, 9.0] min; and percent overshoot of 9.6 [2.3, 10.8]%. Under steady state conditions the CLAD system exhibited a median error of 0.1 [−0.5, 0.9]%; inaccuracy of 1.8 [0.9, 3.4]%; oscillation index of 1.8 [0.9, 3.4]%; and maximum instantaneous propofol dose of 4.3 [2.1, 10.5] mg kg−1. The maximum hourly propofol dose was 4.3 [2.1, 10.3] mg kg−1 h−1. Performance fell within clinically acceptable limits for all measures. Significance A CLAD system designed using robust control theory achieves clinically acceptable

Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism.

PubMed

Contreras, Maya; Ansari, Bilal; Curley, Gerard; Higgins, Brendan D; Hassett, Patrick; O'Toole, Daniel; Laffey, John G

2012-09-01

Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-κB, a key transcriptional regulator in inflammation, injury, and repair. Prospective randomized animal study. University research laboratory. Adult male Sprague-Dawley rats. In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; FICO2 0.00) or (hypercapnic acidosis; FICO2 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-κB pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-κB pathway in hypercapnic acidosis-mediated protection from stretch injury was then determined. Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-κB inhibitor IκBα and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-κB activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. Hypercapnic acidosis attenuated ventilation-induced lung injury independent of injury severity and decreased mechanical stretch-induced

Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

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

Dumortier, Jerome; Streblow, Daniel N.; Moses, Ashlee V.

2008-07-01

Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH),more » suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.« less

A kriging metamodel-assisted robust optimization method based on a reverse model

NASA Astrophysics Data System (ADS)

Zhou, Hui; Zhou, Qi; Liu, Congwei; Zhou, Taotao

2018-02-01

The goal of robust optimization methods is to obtain a solution that is both optimum and relatively insensitive to uncertainty factors. Most existing robust optimization approaches use outer-inner nested optimization structures where a large amount of computational effort is required because the robustness of each candidate solution delivered from the outer level should be evaluated in the inner level. In this article, a kriging metamodel-assisted robust optimization method based on a reverse model (K-RMRO) is first proposed, in which the nested optimization structure is reduced into a single-loop optimization structure to ease the computational burden. Ignoring the interpolation uncertainties from kriging, K-RMRO may yield non-robust optima. Hence, an improved kriging-assisted robust optimization method based on a reverse model (IK-RMRO) is presented to take the interpolation uncertainty of kriging metamodel into consideration. In IK-RMRO, an objective switching criterion is introduced to determine whether the inner level robust optimization or the kriging metamodel replacement should be used to evaluate the robustness of design alternatives. The proposed criterion is developed according to whether or not the robust status of the individual can be changed because of the interpolation uncertainties from the kriging metamodel. Numerical and engineering cases are used to demonstrate the applicability and efficiency of the proposed approach.

Exploring the segregating and mineralization-inducing capacities of cationic hydrophilic polymers for preparation of robust, multifunctional mesoporous hybrid microcapsules.

PubMed

Shi, Jiafu; Zhang, Wenyan; Wang, Xiaoli; Jiang, Zhongyi; Zhang, Shaohua; Zhang, Xiaoman; Zhang, Chunhong; Song, Xiaokai; Ai, Qinghong

2013-06-12

A facile approach to preparing mesoporous hybrid microcapsules is developed by exploring the segregating and mineralization-inducing capacities of cationic hydrophilic polymer. The preparation process contains four steps: segregation of cationic hydrophilic polymer during template formation, cross-linking of the segregated polymer, biomimetic mineralization within cross-linked polymer network, and removal of template to simultaneously generate capsule lumen and mesopores on the capsule wall. Poly(allylamine hydrochloride) (PAH) is chosen as the model polymer, its hydrophilicity renders the segregating capacity and spontaneous enrichment in the near-surface region of CaCO3 microspheres; its biopolyamine-mimic structure renders the mineralization-inducing capacity to produce titania from the water-soluble titanium(IV) precursor. Meanwhile, CaCO3 microspheres serve the dual templating functions in the formation of hollow lumen and mesoporous wall. The thickness of capsule wall can be controlled by changing the polymer segregating and cross-linking conditions, while the pore size on the capsule wall can be tuned by changing the template synthesizing conditions. The robust hybrid microcapsules exhibit desirable efficiency in enzymatic catalysis, wastewater treatment and drug delivery. This approach may open facile, generic, and efficient pathway to designing and preparing a variety of hybrid microcapsules with high and tunable permeability, good stability and multiple functionalities for a broad range of applications.

Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells in Phenotypic Screening: A Transforming Growth Factor-β Type 1 Receptor Kinase Inhibitor Induces Efficient Cardiac Differentiation.

PubMed

Drowley, Lauren; Koonce, Chad; Peel, Samantha; Jonebring, Anna; Plowright, Alleyn T; Kattman, Steven J; Andersson, Henrik; Anson, Blake; Swanson, Bradley J; Wang, Qing-Dong; Brolen, Gabriella

2016-02-01

Several progenitor cell populations have been reported to exist in hearts that play a role in cardiac turnover and/or repair. Despite the presence of cardiac stem and progenitor cells within the myocardium, functional repair of the heart after injury is inadequate. Identification of the signaling pathways involved in the expansion and differentiation of cardiac progenitor cells (CPCs) will broaden insight into the fundamental mechanisms playing a role in cardiac homeostasis and disease and might provide strategies for in vivo regenerative therapies. To understand and exploit cardiac ontogeny for drug discovery efforts, we developed an in vitro human induced pluripotent stem cell-derived CPC model system using a highly enriched population of KDR(pos)/CKIT(neg)/NKX2.5(pos) CPCs. Using this model system, these CPCs were capable of generating highly enriched cultures of cardiomyocytes under directed differentiation conditions. In order to facilitate the identification of pathways and targets involved in proliferation and differentiation of resident CPCs, we developed phenotypic screening assays. Screening paradigms for therapeutic applications require a robust, scalable, and consistent methodology. In the present study, we have demonstrated the suitability of these cells for medium to high-throughput screens to assess both proliferation and multilineage differentiation. Using this CPC model system and a small directed compound set, we identified activin-like kinase 5 (transforming growth factor-β type 1 receptor kinase) inhibitors as novel and potent inducers of human CPC differentiation to cardiomyocytes. Significance: Cardiac disease is a leading cause of morbidity and mortality, with no treatment available that can result in functional repair. This study demonstrates how differentiation of induced pluripotent stem cells can be used to identify and isolate cell populations of interest that can translate to the adult human heart. Two separate examples of phenotypic

Hypoxia inducible factor 1 (HIF-1) and cardioprotection

PubMed Central

Tekin, Demet; Dursun, Ali D; Xi, Lei

2010-01-01

Since its discovery in early 1990s, hypoxia inducible factor 1 (HIF-1) has been increasingly recognized for its key role in transcriptional control of more than a hundred genes that regulate a wide-spectrum of cellular functional events, including angiogenesis, vasomotor control, glucose and energy metabolism, erythropoiesis, iron homeostasis, pH regulation, cell proliferation and viability. Evidence accumulated during the past 7 years suggests a critical role for HIF-1α in mediating cardioprotection. The purpose of our present article is to provide an updated overview on this important regulator of gene expression in the cellular stress-responsive and adaptive process. We have particularly emphasized the involvement of HIF-1 in the induction of cardioprotective molecules, such as inducible nitric oxide synthase (iNOS), hemeoxygenase 1 (HO-1), and erythropoietin (EPO), which in turn alleviate myocardial damages caused by harmful events such as ischemia-reperfusion injury. Despite these advances, further in-depth studies are needed to elucidate the possible coordination or interaction between HIF-1α and other key transcription factors in regulating protein expression that leads to cardioprotection. PMID:20711226

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

PubMed Central

Nordquist, Lina; Friederich-Persson, Malou; Fasching, Angelica; Liss, Per; Shoji, Kumi; Nangaku, Masaomi; Hansell, Peter

2015-01-01

Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy. PMID:25183809

Robust infrared targets tracking with covariance matrix representation

NASA Astrophysics Data System (ADS)

Cheng, Jian

2009-07-01

Robust infrared target tracking is an important and challenging research topic in many military and security applications, such as infrared imaging guidance, infrared reconnaissance, scene surveillance, etc. To effectively tackle the nonlinear and non-Gaussian state estimation problems, particle filtering is introduced to construct the theory framework of infrared target tracking. Under this framework, the observation probabilistic model is one of main factors for infrared targets tracking performance. In order to improve the tracking performance, covariance matrices are introduced to represent infrared targets with the multi-features. The observation probabilistic model can be constructed by computing the distance between the reference target's and the target samples' covariance matrix. Because the covariance matrix provides a natural tool for integrating multiple features, and is scale and illumination independent, target representation with covariance matrices can hold strong discriminating ability and robustness. Two experimental results demonstrate the proposed method is effective and robust for different infrared target tracking, such as the sensor ego-motion scene, and the sea-clutter scene.

Tumor necrosis factor α (TNF-α) receptor-II is required for TNF-α–induced leukocyte-endothelial interaction in vivo

PubMed Central

Chandrasekharan, Unni M.; Siemionow, Maria; Unsal, Murat; Yang, Lin; Poptic, Earl; Bohn, Justin; Ozer, Kagan; Zhou, Zhongmin; Howe, Philip H.; Penn, Marc

2007-01-01

Tumor necrosis factor-α (TNF-α) binds to 2 distinct cell-surface receptors: TNF-α receptor-I (TNFR-I: p55) and TNF-α receptor-II (TNFR-II: p75). TNF-α induces leukocyte adhesion molecules on endothelial cells (ECs), which mediate 3 defined steps of the inflammatory response; namely, leukocyte rolling, firm adhesion, and transmigration. In this study, we have investigated the role of p75 in TNF-α–induced leukocyte adhesion molecules using cultured ECs derived from wild-type (WT), p75-null (p75−/−), or p55-null (p55−/−) mice. We observed that p75 was essential for TNF-α–induced E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) expression. We also investigated the putative role of p75 in inflammation in vivo using an intravital microscopic approach with a mouse cremaster muscle model. TNF-α–stimulated leukocyte rolling, firm adhesion to ECs, and transmigration were dramatically reduced in p75−/− mice. Transplanted WT cremaster in p75−/− mice showed a robust leukocyte rolling and firm adhesion upon TNF-α activation, suggesting that the impairment in EC-leukocyte interaction in p75−/− mice is due to EC dysfunction. These results demonstrate, for the first time, that endothelial p75 is essential for TNF-α–induced leukocyte–endothelial-cell interaction. Our findings may contribute to the identification of novel p75-targeted therapeutic approaches for inflammatory diseases. PMID:17068152

Robust demarcation of basal cell carcinoma by dependent component analysis-based segmentation of multi-spectral fluorescence images.

PubMed

Kopriva, Ivica; Persin, Antun; Puizina-Ivić, Neira; Mirić, Lina

2010-07-02

This study was designed to demonstrate robust performance of the novel dependent component analysis (DCA)-based approach to demarcation of the basal cell carcinoma (BCC) through unsupervised decomposition of the red-green-blue (RGB) fluorescent image of the BCC. Robustness to intensity fluctuation is due to the scale invariance property of DCA algorithms, which exploit spectral and spatial diversities between the BCC and the surrounding tissue. Used filtering-based DCA approach represents an extension of the independent component analysis (ICA) and is necessary in order to account for statistical dependence that is induced by spectral similarity between the BCC and surrounding tissue. This generates weak edges what represents a challenge for other segmentation methods as well. By comparative performance analysis with state-of-the-art image segmentation methods such as active contours (level set), K-means clustering, non-negative matrix factorization, ICA and ratio imaging we experimentally demonstrate good performance of DCA-based BCC demarcation in two demanding scenarios where intensity of the fluorescent image has been varied almost two orders of magnitude. Copyright 2010 Elsevier B.V. All rights reserved.

Social factors modulate restraint stress induced hyperthermia in mice.

PubMed

Watanabe, Shigeru

2015-10-22

Stress-induced hyperthermia (SIH) was examined in three different social conditions in mice by thermographic measurement of the body surface temperature. Placing animals in cylindrical holders induced restraint stress. I examined the effect of the social factors in SIH using the thermograph (body surface temperature). Mice restrained in the holders alone showed SIH. Mice restrained in the holders at the same time as other similarly restrained cage mates (social equality condition) showed less hyperthermia. Interestingly, restrained mice with free moving cage mates (social inequality condition) showed the highest hyperthermia. These results are consistent with a previous experiment measuring the memory-enhancing effects of stress and the stress-induced elevation of corticosterone, and suggest that social inequality enhances stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice

PubMed Central

Wong, Jennifer C.; Dutton, Stacey B. B.; Collins, Stephen D.; Schachter, Steven; Escayg, Andrew

2016-01-01

De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15–20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a+/−) and GEFS+ (Scn1aRH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Scn1aRH/+ mutants. Finally, we determined that muscarinic and GABAA receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy. PMID:27799911

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione

PubMed Central

Wiraswati, Hesti Lina; Hangen, Emilie; Sanz, Ana Belén; Lam, Ngoc-Vy; Reinhardt, Camille; Sauvat, Allan; Mogha, Ariane; Ortiz, Alberto

2016-01-01

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion. PMID:27738311

Reducing regional vulnerabilities and multi-city robustness conflicts using many-objective optimization under deep uncertainty

NASA Astrophysics Data System (ADS)

Reed, Patrick; Trindade, Bernardo; Jonathan, Herman; Harrison, Zeff; Gregory, Characklis

2016-04-01

Emerging water scarcity concerns in southeastern US are associated with several deeply uncertain factors, including rapid population growth, limited coordination across adjacent municipalities and the increasing risks for sustained regional droughts. Managing these uncertainties will require that regional water utilities identify regionally coordinated, scarcity-mitigating strategies that trigger the appropriate actions needed to avoid water shortages and financial instabilities. This research focuses on the Research Triangle area of North Carolina, seeking to engage the water utilities within Raleigh, Durham, Cary and Chapel Hill in cooperative and robust regional water portfolio planning. Prior analysis of this region through the year 2025 has identified significant regional vulnerabilities to volumetric shortfalls and financial losses. Moreover, efforts to maximize the individual robustness of any of the mentioned utilities also have the potential to strongly degrade the robustness of the others. This research advances a multi-stakeholder Many-Objective Robust Decision Making (MORDM) framework to better account for deeply uncertain factors when identifying cooperative management strategies. Results show that the sampling of deeply uncertain factors in the computational search phase of MORDM can aid in the discovery of management actions that substantially improve the robustness of individual utilities as well as the overall region to water scarcity. Cooperative water transfers, financial risk mitigation tools, and coordinated regional demand management must be explored jointly to decrease robustness conflicts between the utilities. The insights from this work have general merit for regions where adjacent municipalities can benefit from cooperative regional water portfolio planning.

Reducing regional vulnerabilities and multi-city robustness conflicts using many-objective optimization under deep uncertainty

NASA Astrophysics Data System (ADS)

Trindade, B. C.; Reed, P. M.; Herman, J. D.; Zeff, H. B.; Characklis, G. W.

2015-12-01

Emerging water scarcity concerns in southeastern US are associated with several deeply uncertain factors, including rapid population growth, limited coordination across adjacent municipalities and the increasing risks for sustained regional droughts. Managing these uncertainties will require that regional water utilities identify regionally coordinated, scarcity-mitigating strategies that trigger the appropriate actions needed to avoid water shortages and financial instabilities. This research focuses on the Research Triangle area of North Carolina, seeking to engage the water utilities within Raleigh, Durham, Cary and Chapel Hill in cooperative and robust regional water portfolio planning. Prior analysis of this region through the year 2025 has identified significant regional vulnerabilities to volumetric shortfalls and financial losses. Moreover, efforts to maximize the individual robustness of any of the mentioned utilities also have the potential to strongly degrade the robustness of the others. This research advances a multi-stakeholder Many-Objective Robust Decision Making (MORDM) framework to better account for deeply uncertain factors when identifying cooperative management strategies. Results show that the sampling of deeply uncertain factors in the computational search phase of MORDM can aid in the discovery of management actions that substantially improve the robustness of individual utilities as well as of the overall region to water scarcity. Cooperative water transfers, financial risk mitigation tools, and coordinated regional demand management should be explored jointly to decrease robustness conflicts between the utilities. The insights from this work have general merit for regions where adjacent municipalities can benefit from cooperative regional water portfolio planning.

Effect of interaction strength on robustness of controlling edge dynamics in complex networks

NASA Astrophysics Data System (ADS)

Pang, Shao-Peng; Hao, Fei

2018-05-01

Robustness plays a critical role in the controllability of complex networks to withstand failures and perturbations. Recent advances in the edge controllability show that the interaction strength among edges plays a more important role than network structure. Therefore, we focus on the effect of interaction strength on the robustness of edge controllability. Using three categories of all edges to quantify the robustness, we develop a universal framework to evaluate and analyze the robustness in complex networks with arbitrary structures and interaction strengths. Applying our framework to a large number of model and real-world networks, we find that the interaction strength is a dominant factor for the robustness in undirected networks. Meanwhile, the strongest robustness and the optimal edge controllability in undirected networks can be achieved simultaneously. Different from the case of undirected networks, the robustness in directed networks is determined jointly by the interaction strength and the network's degree distribution. Moreover, a stronger robustness is usually associated with a larger number of driver nodes required to maintain full control in directed networks. This prompts us to provide an optimization method by adjusting the interaction strength to optimize the robustness of edge controllability.

The Effects of Abiotic Factors on Induced Volatile Emissions in Corn Plants1

PubMed Central

Gouinguené, Sandrine P.; Turlings, Ted C.J.

2002-01-01

Many plants respond to herbivory by releasing a specific blend of volatiles that is attractive to natural enemies of the herbivores. In corn (Zea mays), this induced odor blend is mainly composed of terpenoids and indole. The induced signal varies with plant species and genotype, but little is known about the variation due to abiotic factors. Here, we tested the effect of soil humidity, air humidity, temperature, light, and fertilization rate on the emission of induced volatiles in young corn plants. Each factor was tested separately under constant conditions for the other factors. Plants released more when standing in dry soil than in wet soil, whereas for air humidity, the optimal release was found at around 60% relative humidity. Temperatures between 22°C and 27°C led to a higher emission than lower or higher temperatures. Light intensity had a dramatic effect. The emission of volatiles did not occur in the dark and increased steadily with an increase in the light intensity. An experiment with an unnatural light-dark cycle showed that the release was fully photophase dependent. Fertilization also had a strong positive effect; the emission of volatiles was minimal when plants were grown under low nutrition, even when results were corrected for plant biomass. Changes in all abiotic factors caused small but significant changes in the relative ratios among the different compounds (quality) in the induced odor blends, except for air humidity. Hence, climatic conditions and nutrient availability can be important factors in determining the intensity and variability in the release of induced plant volatiles. PMID:12114583

Promiscuous survivin peptide induces robust CD4+ T-cell responses in the majority of vaccinated cancer patients.

PubMed

Widenmeyer, Melanie; Griesemann, Heinrich; Stevanović, Stefan; Feyerabend, Susan; Klein, Reinhild; Attig, Sebastian; Hennenlotter, Jörg; Wernet, Dorothee; Kuprash, Dmitri V; Sazykin, Alexei Y; Pascolo, Steve; Stenzl, Arnulf; Gouttefangeas, Cécile; Rammensee, Hans-Georg

2012-07-01

CD4(+) T cells have been shown to be crucial for the induction and maintenance of cytotoxic T cell responses and to be also capable of mediating direct tumor rejection. Therefore, the anticancer therapeutic efficacy of peptide-based vaccines may be improved by addition of HLA class II epitopes to stimulate T helper cells. Survivin is an apoptosis inhibiting protein frequently overexpressed in tumors. Here we describe the first immunological evaluation of a survivin-derived CD4(+) T cell epitope in a multipeptide immunotherapy trial for prostate carcinoma patients. The survivin peptide is promiscuously presented by several human HLA-DRB1 molecules and, most importantly, is naturally processed by dendritic cells. In vaccinated patients, it was able to induce frequent, robust and multifunctional CD4(+) T cell responses, as monitored by IFN-γ ELISPOT and intracellular cytokine staining. Thus, this HLA-DR restricted epitope is broadly immunogenic and should be valuable for stimulating T helper cells in patients suffering from a wide range of tumors. Copyright © 2011 UICC.

From Cellulose Nanospheres, Nanorods to Nanofibers: Various Aspect Ratio Induced Nucleation/Reinforcing Effects on Polylactic Acid for Robust-Barrier Food Packaging.

PubMed

Yu, Hou-Yong; Zhang, Heng; Song, Mei-Li; Zhou, Ying; Yao, Juming; Ni, Qing-Qing

2017-12-20

The traditional approach toward improving the crystallization rate as well as the mechanical and barrier properties of poly(lactic acid) (PLA) is the incorporation of nanocelluloses (NCs). Unfortunately, little study has been focused on the influence of the differences in NC morphology and dimensions on the PLA property enhancement. Here, by HCOOH/HCl hydrolysis of lyocell fibers, microcrystalline cellulose (MCC), and ginger fibers, we unveil the preparation of cellulose nanospheres (CNS), rod-like cellulose nanocrystals (CNC), and cellulose nanofibers (CNF) with different aspect ratios, respectively. All the NC surfaces were chemically modified by Fischer esterification with hydrophobic formate groups to improve the NC dispersion in the PLA matrix. This study systematically compared CNS, CNC, and CNF as reinforcing agents to induce different kinds of heterogeneous nucleation and reinforce the effects on the properties of PLA. The incorporation of three NCs can greatly improve the PLA crystallization ability, thermal stability, and mechanical strength of nanocomposites. At the same NC loading level, the PLA/CNS showed the highest crystallinity (19.8 ± 0.4%) with a smaller spherulite size (33 ± 1.5 μm), indicating that CNS, with its high specific surface area, can induce a stronger heterogeneous nucleation effect on the PLA crystallization than CNC or CNF. Instead, compared to PLA, the PLA/CNF nanocomposites gave the largest Young's modulus increase of 350 %, due to the larger aspect ratio/rigidity of CNF and their interlocking or percolation network caused by filler-matrix interfacial bonds. Furthermore, taking these factors of hydrogen bonding interaction, increased crystallinity, and interfacial tortuosity into account, the PLA/CNC nanocomposite films showed the best barrier property against water vapor and lowest migration levels in two liquid food simulates (well below 60 mg kg -1 for required overall migration in packaging) than CNS- and CNF-based films

Distribution path robust optimization of electric vehicle with multiple distribution centers

PubMed Central

Hao, Wei; He, Ruichun; Jia, Xiaoyan; Pan, Fuquan; Fan, Jing; Xiong, Ruiqi

2018-01-01

To identify electrical vehicle (EV) distribution paths with high robustness, insensitivity to uncertainty factors, and detailed road-by-road schemes, optimization of the distribution path problem of EV with multiple distribution centers and considering the charging facilities is necessary. With the minimum transport time as the goal, a robust optimization model of EV distribution path with adjustable robustness is established based on Bertsimas’ theory of robust discrete optimization. An enhanced three-segment genetic algorithm is also developed to solve the model, such that the optimal distribution scheme initially contains all road-by-road path data using the three-segment mixed coding and decoding method. During genetic manipulation, different interlacing and mutation operations are carried out on different chromosomes, while, during population evolution, the infeasible solution is naturally avoided. A part of the road network of Xifeng District in Qingyang City is taken as an example to test the model and the algorithm in this study, and the concrete transportation paths are utilized in the final distribution scheme. Therefore, more robust EV distribution paths with multiple distribution centers can be obtained using the robust optimization model. PMID:29518169

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2

PubMed Central

Koth, Laura L; Rodriguez, Madeleine W; Bernstein, Xin Liu; Chan, Salina; Huang, Xiaozhu; Charo, Israel F; Rollins, Barrett J; Erle, David J

2004-01-01

Background Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. Methods To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. Results We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. Conclusion We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2. PMID:15377395

Robust extraction of basis functions for simultaneous and proportional myoelectric control via sparse non-negative matrix factorization

NASA Astrophysics Data System (ADS)

Lin, Chuang; Wang, Binghui; Jiang, Ning; Farina, Dario

2018-04-01

Objective. This paper proposes a novel simultaneous and proportional multiple degree of freedom (DOF) myoelectric control method for active prostheses. Approach. The approach is based on non-negative matrix factorization (NMF) of surface EMG signals with the inclusion of sparseness constraints. By applying a sparseness constraint to the control signal matrix, it is possible to extract the basis information from arbitrary movements (quasi-unsupervised approach) for multiple DOFs concurrently. Main Results. In online testing based on target hitting, able-bodied subjects reached a greater throughput (TP) when using sparse NMF (SNMF) than with classic NMF or with linear regression (LR). Accordingly, the completion time (CT) was shorter for SNMF than NMF or LR. The same observations were made in two patients with unilateral limb deficiencies. Significance. The addition of sparseness constraints to NMF allows for a quasi-unsupervised approach to myoelectric control with superior results with respect to previous methods for the simultaneous and proportional control of multi-DOF. The proposed factorization algorithm allows robust simultaneous and proportional control, is superior to previous supervised algorithms, and, because of minimal supervision, paves the way to online adaptation in myoelectric control.

Seminal Plasma Induces Ovulation in Llamas in the Absence of a Copulatory Stimulus: Role of Nerve Growth Factor as an Ovulation-Inducing Factor

PubMed Central

Berland, Marco A.; Ulloa-Leal, Cesar; Barría, Miguel; Wright, Hollis; Dissen, Gregory A.; Silva, Mauricio E.; Ojeda, Sergio R.

2016-01-01

Llamas are considered to be reflex ovulators. However, semen from these animals is reported to be rich in ovulation-inducing factor(s), one of which has been identified as nerve growth factor (NGF). These findings suggest that ovulation in llamas may be elicited by chemical signals contained in semen instead of being mediated by neural signals. The present study examines this notion. Llamas displaying a preovulatory follicle were assigned to four groups: group 1 received an intrauterine infusion (IUI) of PBS; group 2 received an IUI of seminal plasma; group 3 was mated to a male whose urethra had been surgically diverted (urethrostomized male); and group 4 was mated to an intact male. Ovulation (detected by ultrasonography) occurred only in llamas mated to an intact male or given an IUI of seminal plasma and was preceded by a surge in plasma LH levels initiated within an hour after coitus or IUI. In both ovulatory groups, circulating β-NGF levels increased within 15 minutes after treatment, reaching values that were greater and more sustained in llamas mated with an intact male. These results demonstrate that llamas can be induced to ovulate by seminal plasma in the absence of copulation and that copulation alone cannot elicit ovulation in the absence of seminal plasma. In addition, our results implicate β-NGF as an important mediator of seminal plasma-induced ovulation in llamas because ovulation does not occur if β-NGF levels do not increase in the bloodstream, a change that occurs promptly after copulation with an intact male or IUI of seminal plasma. PMID:27355492

Seminal Plasma Induces Ovulation in Llamas in the Absence of a Copulatory Stimulus: Role of Nerve Growth Factor as an Ovulation-Inducing Factor.

PubMed

Berland, Marco A; Ulloa-Leal, Cesar; Barría, Miguel; Wright, Hollis; Dissen, Gregory A; Silva, Mauricio E; Ojeda, Sergio R; Ratto, Marcelo H

2016-08-01

Llamas are considered to be reflex ovulators. However, semen from these animals is reported to be rich in ovulation-inducing factor(s), one of which has been identified as nerve growth factor (NGF). These findings suggest that ovulation in llamas may be elicited by chemical signals contained in semen instead of being mediated by neural signals. The present study examines this notion. Llamas displaying a preovulatory follicle were assigned to four groups: group 1 received an intrauterine infusion (IUI) of PBS; group 2 received an IUI of seminal plasma; group 3 was mated to a male whose urethra had been surgically diverted (urethrostomized male); and group 4 was mated to an intact male. Ovulation (detected by ultrasonography) occurred only in llamas mated to an intact male or given an IUI of seminal plasma and was preceded by a surge in plasma LH levels initiated within an hour after coitus or IUI. In both ovulatory groups, circulating β-NGF levels increased within 15 minutes after treatment, reaching values that were greater and more sustained in llamas mated with an intact male. These results demonstrate that llamas can be induced to ovulate by seminal plasma in the absence of copulation and that copulation alone cannot elicit ovulation in the absence of seminal plasma. In addition, our results implicate β-NGF as an important mediator of seminal plasma-induced ovulation in llamas because ovulation does not occur if β-NGF levels do not increase in the bloodstream, a change that occurs promptly after copulation with an intact male or IUI of seminal plasma.

Robustness surfaces of complex networks

NASA Astrophysics Data System (ADS)

Manzano, Marc; Sahneh, Faryad; Scoglio, Caterina; Calle, Eusebi; Marzo, Jose Luis

2014-09-01

Despite the robustness of complex networks has been extensively studied in the last decade, there still lacks a unifying framework able to embrace all the proposed metrics. In the literature there are two open issues related to this gap: (a) how to dimension several metrics to allow their summation and (b) how to weight each of the metrics. In this work we propose a solution for the two aforementioned problems by defining the R*-value and introducing the concept of robustness surface (Ω). The rationale of our proposal is to make use of Principal Component Analysis (PCA). We firstly adjust to 1 the initial robustness of a network. Secondly, we find the most informative robustness metric under a specific failure scenario. Then, we repeat the process for several percentage of failures and different realizations of the failure process. Lastly, we join these values to form the robustness surface, which allows the visual assessment of network robustness variability. Results show that a network presents different robustness surfaces (i.e., dissimilar shapes) depending on the failure scenario and the set of metrics. In addition, the robustness surface allows the robustness of different networks to be compared.

Robustness surfaces of complex networks

PubMed Central

Manzano, Marc; Sahneh, Faryad; Scoglio, Caterina; Calle, Eusebi; Marzo, Jose Luis

2014-01-01

Despite the robustness of complex networks has been extensively studied in the last decade, there still lacks a unifying framework able to embrace all the proposed metrics. In the literature there are two open issues related to this gap: (a) how to dimension several metrics to allow their summation and (b) how to weight each of the metrics. In this work we propose a solution for the two aforementioned problems by defining the R*-value and introducing the concept of robustness surface (Ω). The rationale of our proposal is to make use of Principal Component Analysis (PCA). We firstly adjust to 1 the initial robustness of a network. Secondly, we find the most informative robustness metric under a specific failure scenario. Then, we repeat the process for several percentage of failures and different realizations of the failure process. Lastly, we join these values to form the robustness surface, which allows the visual assessment of network robustness variability. Results show that a network presents different robustness surfaces (i.e., dissimilar shapes) depending on the failure scenario and the set of metrics. In addition, the robustness surface allows the robustness of different networks to be compared. PMID:25178402

Robustness surfaces of complex networks.

PubMed

Manzano, Marc; Sahneh, Faryad; Scoglio, Caterina; Calle, Eusebi; Marzo, Jose Luis

2014-09-02

Despite the robustness of complex networks has been extensively studied in the last decade, there still lacks a unifying framework able to embrace all the proposed metrics. In the literature there are two open issues related to this gap: (a) how to dimension several metrics to allow their summation and (b) how to weight each of the metrics. In this work we propose a solution for the two aforementioned problems by defining the R*-value and introducing the concept of robustness surface (Ω). The rationale of our proposal is to make use of Principal Component Analysis (PCA). We firstly adjust to 1 the initial robustness of a network. Secondly, we find the most informative robustness metric under a specific failure scenario. Then, we repeat the process for several percentage of failures and different realizations of the failure process. Lastly, we join these values to form the robustness surface, which allows the visual assessment of network robustness variability. Results show that a network presents different robustness surfaces (i.e., dissimilar shapes) depending on the failure scenario and the set of metrics. In addition, the robustness surface allows the robustness of different networks to be compared.

Quercetin Reduces Tumor Necrosis Factor Alpha-Induced Muscle Atrophy by Upregulation of Heme Oxygenase-1.

PubMed

Kim, Yeji; Kim, Chu-Sook; Joe, Yeonsoo; Chung, Hun Taeg; Ha, Tae Youl; Yu, Rina

2018-06-01

The inflammatory cytokine tumor necrosis factor α (TNFα), upregulated in the obese condition, promotes protein degradation and is implicated in obesity-related skeletal muscle atrophy and age-related sarcopenia. Quercetin, a flavonoid, elicits antioxidative and anti-inflammatory activities. In this study, we investigated the effect of quercetin on TNFα-induced skeletal muscle atrophy as well as its potential mechanism of action. In this study, we observed that quercetin suppressed expression of TNFα-induced atrophic factors such as MAFbx/atrogin-1 and MuRF1 in myotubes, and it enhanced heme oxygenase-1 (HO-1) protein level accompanied by increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in myotubes. The HO-1 inhibitor ZnPP suppressed the inhibitory actions of quercetin on TNFα-induced atrophic responses and degradation of IκB-α in myotubes. Moreover, quercetin supplementation to high-fat diet-fed obese mice inhibited obesity-induced atrophic responses in skeletal muscle, accompanied by upregulation of HO-1 and inactivation of nuclear factor-kappa B (NF-κB), and the quercetin actions were attenuated in Nrf2-deficient mice. These findings suggest that quercetin protects against TNFα-induced muscle atrophy under obese conditions through Nrf2-mediated HO-1 induction accompanied by inactivation of NF-κB. Quercetin may be used as a dietary supplement to protect against obesity-induced skeletal muscle atrophy.

Robust pupil center detection using a curvature algorithm

NASA Technical Reports Server (NTRS)

Zhu, D.; Moore, S. T.; Raphan, T.; Wall, C. C. (Principal Investigator)

1999-01-01

Determining the pupil center is fundamental for calculating eye orientation in video-based systems. Existing techniques are error prone and not robust because eyelids, eyelashes, corneal reflections or shadows in many instances occlude the pupil. We have developed a new algorithm which utilizes curvature characteristics of the pupil boundary to eliminate these artifacts. Pupil center is computed based solely on points related to the pupil boundary. For each boundary point, a curvature value is computed. Occlusion of the boundary induces characteristic peaks in the curvature function. Curvature values for normal pupil sizes were determined and a threshold was found which together with heuristics discriminated normal from abnormal curvature. Remaining boundary points were fit with an ellipse using a least squares error criterion. The center of the ellipse is an estimate of the pupil center. This technique is robust and accurately estimates pupil center with less than 40% of the pupil boundary points visible.

Hunter-gatherer postcranial robusticity relative to patterns of mobility, climatic adaptation, and selection for tissue economy.

PubMed

Stock, J T

2006-10-01

Human skeletal robusticity is influenced by a number of factors, including habitual behavior, climate, and physique. Conflicting evidence as to the relative importance of these factors complicates our ability to interpret variation in robusticity in the past. It remains unclear how the pattern of robusticity in the skeleton relates to adaptive constraints on skeletal morphology. This study investigates variation in robusticity in claviculae, humeri, ulnae, femora, and tibiae among human foragers, relative to climate and habitual behavior. Cross-sectional geometric properties of the diaphyses are compared among hunter-gatherers from southern Africa (n = 83), the Andaman Islands (n = 32), Tierra del Fuego (n = 34), and the Great Lakes region (n = 15). The robusticity of both proximal and distal limb segments correlates negatively with climate and positively with patterns of terrestrial and marine mobility among these groups. However, the relative correspondence between robusticity and these factors varies throughout the body. In the lower limb, partial correlations between polar second moment of area (J(0.73)) and climate decrease from proximal to distal section locations, while this relationship increases from proximal to distal in the upper limb. Patterns of correlation between robusticity and mobility, either terrestrial or marine, generally increase from proximal to distal in the lower and upper limbs, respectively. This suggests that there may be a stronger relationship between observed patterns of diaphyseal hypertrophy and behavioral differences between populations in distal elements. Despite this trend, strength circularity indices at the femoral midshaft show the strongest correspondence with terrestrial mobility, particularly among males.

Robust model predictive control for multi-step short range spacecraft rendezvous

NASA Astrophysics Data System (ADS)

Zhu, Shuyi; Sun, Ran; Wang, Jiaolong; Wang, Jihe; Shao, Xiaowei

2018-07-01

This work presents a robust model predictive control (MPC) approach for the multi-step short range spacecraft rendezvous problem. During the specific short range phase concerned, the chaser is supposed to be initially outside the line-of-sight (LOS) cone. Therefore, the rendezvous process naturally includes two steps: the first step is to transfer the chaser into the LOS cone and the second step is to transfer the chaser into the aimed region with its motion confined within the LOS cone. A novel MPC framework named after Mixed MPC (M-MPC) is proposed, which is the combination of the Variable-Horizon MPC (VH-MPC) framework and the Fixed-Instant MPC (FI-MPC) framework. The M-MPC framework enables the optimization for the two steps to be implemented jointly rather than to be separated factitiously, and its computation workload is acceptable for the usually low-power processors onboard spacecraft. Then considering that disturbances including modeling error, sensor noise and thrust uncertainty may induce undesired constraint violations, a robust technique is developed and it is attached to the above M-MPC framework to form a robust M-MPC approach. The robust technique is based on the chance-constrained idea, which ensures that constraints can be satisfied with a prescribed probability. It improves the robust technique proposed by Gavilan et al., because it eliminates the unnecessary conservativeness by explicitly incorporating known statistical properties of the navigation uncertainty. The efficacy of the robust M-MPC approach is shown in a simulation study.

Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis

PubMed Central

Li, Ling; Qu, Ye; Jin, Xin; Guo, Xiao Qin; Wang, Yue; Qi, Lin; Yang, Jing; Zhang, Peng; Li, Ling Zhi

2016-01-01

Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling. PMID:27558909

Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells.

PubMed

Zhang, Chuanzhao; Zhi, Wanqing Iris; Lu, Haiquan; Samanta, Debangshu; Chen, Ivan; Gabrielson, Edward; Semenza, Gregg L

2016-10-04

Exposure of breast cancer cells to hypoxia increases the percentage of breast cancer stem cells (BCSCs), which are required for tumor initiation and metastasis, and this response is dependent on the activity of hypoxia-inducible factors (HIFs). We previously reported that exposure of breast cancer cells to hypoxia induces the ALKBH5-mediated demethylation of N6-methyladenosine (m6A) in NANOG mRNA leading to increased expression of NANOG, which is a pluripotency factor that promotes BCSC specification. Here we report that exposure of breast cancer cells to hypoxia also induces ZNF217-dependent inhibition of m6A methylation of mRNAs encoding NANOG and KLF4, which is another pluripotency factor that mediates BCSC specification. Although hypoxia induced the BCSC phenotype in all breast-cancer cell lines analyzed, it did so through variable induction of pluripotency factors and ALKBH5 or ZNF217. However, in every breast cancer line, the hypoxic induction of pluripotency factor and ALKBH5 or ZNF217 expression was HIF-dependent. Immunohistochemistry revealed that expression of HIF-1α and ALKBH5 was concordant in all human breast cancer biopsies analyzed. ALKBH5 knockdown in MDA-MB-231 breast cancer cells significantly decreased metastasis from breast to lungs in immunodeficient mice. Thus, HIFs stimulate pluripotency factor expression and BCSC specification by negative regulation of RNA methylation.

Autocrine motility factor (neuroleukin, phosphohexose isomerase) induces cell movement through 12-lipoxygenase-dependent tyrosine phosphorylation and serine dephosphorylation events.

PubMed

Timár, J; Tóth, S; Tóvári, J; Paku, S; Raz, A

1999-01-01

Autocrine motility factor (AMF) is one of the motility cytokines regulating tumor cell migration, therefore identification of the signaling pathway coupled with it has critical importance. Previous studies revealed several elements of this pathway predominated by lipoxygenase-PKC activations but the role for tyrosine kinases remained questionable. Motility cytokines frequently have mitogenic effect as well, producing activation of overlapping signaling pathways therefore we have used B16a melanoma cells as models where AMF has exclusive motility effect. Our studies revealed that in B16a cells AMF initiated rapid (1-5 min) activation of the protein tyrosine kinase (PTK) cascade inducing phosphorylation of 179, 125, 95 and 40/37 kD proteins which was mediated by upstream cyclo- and lipoxygenases. The phosphorylated proteins were localized to the cortical actin-stress fiber attachment zones in situ by confocal microscopy. On the other hand, AMF receptor activation induced significant decrease in overall serine-phosphorylation level of cellular proteins accompanied by serine phosphorylation of 200, 90, 78 and 65 kd proteins. The decrease in serine phosphorylation was independent of PTKs, PKC as well as cyclo- and lipoxygenases. However, AMF induced robust translocation of PKCalpha to the stress fibers and cortical actin suggesting a critical role for this kinase in the generation of the motility signal. Based on the significant decrease in serine phosphorylation after AMF stimulus in B16a cells we postulated the involvement of putative serine/threonine phosphatase(s) upstream lipoxygenase and activation of the protein tyrosine kinase cascade downstream cyclo- and lipoxygenase(s) in the previously identified autocrine motility signal.

Linear, multivariable robust control with a mu perspective

NASA Technical Reports Server (NTRS)

Packard, Andy; Doyle, John; Balas, Gary

1993-01-01

The structured singular value is a linear algebra tool developed to study a particular class of matrix perturbation problems arising in robust feedback control of multivariable systems. These perturbations are called linear fractional, and are a natural way to model many types of uncertainty in linear systems, including state-space parameter uncertainty, multiplicative and additive unmodeled dynamics uncertainty, and coprime factor and gap metric uncertainty. The structured singular value theory provides a natural extension of classical SISO robustness measures and concepts to MIMO systems. The structured singular value analysis, coupled with approximate synthesis methods, make it possible to study the tradeoff between performance and uncertainty that occurs in all feedback systems. In MIMO systems, the complexity of the spatial interactions in the loop gains make it difficult to heuristically quantify the tradeoffs that must occur. This paper examines the role played by the structured singular value (and its computable bounds) in answering these questions, as well as its role in the general robust, multivariable control analysis and design problem.

Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy.

PubMed

Reza, Musarrat Maisha; Subramaniyam, Nathiya; Sim, Chu Ming; Ge, Xiaojia; Sathiakumar, Durgalakshmi; McFarlane, Craig; Sharma, Mridula; Kambadur, Ravi

2017-10-24

Exercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice.

Robust Multimodal Dictionary Learning

PubMed Central

Cao, Tian; Jojic, Vladimir; Modla, Shannon; Powell, Debbie; Czymmek, Kirk; Niethammer, Marc

2014-01-01

We propose a robust multimodal dictionary learning method for multimodal images. Joint dictionary learning for both modalities may be impaired by lack of correspondence between image modalities in training data, for example due to areas of low quality in one of the modalities. Dictionaries learned with such non-corresponding data will induce uncertainty about image representation. In this paper, we propose a probabilistic model that accounts for image areas that are poorly corresponding between the image modalities. We cast the problem of learning a dictionary in presence of problematic image patches as a likelihood maximization problem and solve it with a variant of the EM algorithm. Our algorithm iterates identification of poorly corresponding patches and re-finements of the dictionary. We tested our method on synthetic and real data. We show improvements in image prediction quality and alignment accuracy when using the method for multimodal image registration. PMID:24505674

Oral Application of Magnesium-L-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling.

PubMed

Xu, Ting; Li, Dai; Zhou, Xin; Ouyang, Han-Dong; Zhou, Li-Jun; Zhou, Hang; Zhang, Hong-Mei; Wei, Xu-Hong; Liu, Guosong; Liu, Xian-Guo

2017-06-01

Antineoplastic agents, including vincristine, often induce neuropathic pain and magnesium deficiency clinically, but the causal link between them has not been determined. No drug is available for treating this form of neuropathic pain. Injection of vincristine (0.1 mg · kg · day, intraperitoneally, for 10 days) was used to induce nociceptive sensitization, which was accessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Magnesium-L- threonate was administered through drinking water (604 mg · kg · day). Extracellular and intracellular free Mg were measured by Calmagite chromometry and flow cytometry. Molecular biologic and electrophysiologic experiments were performed to expose the underlying mechanisms. Vincristine injection induced allodynia and hyperalgesia (n = 12), activated tumor necrosis factor-α/nuclear factor-κB signaling, and reduced free Mg in cerebrospinal fluid by 21.7 ± 6.3% (mean ± SD; n = 13) and in dorsal root ganglion neurons by 27 ± 6% (n = 11). Reducing Mg activated tumor necrosis factor-α/nuclear factor-κB signaling in cultured dorsal root ganglion neurons. Oral application of magnesium-L-threonate prevented magnesium deficiency and attenuated both activation of tumor necrosis factor-α/nuclear factor-κB signaling and nociceptive sensitization (n = 12). Mechanistically, vincristine induced long-term potentiation at C-fiber synapses, up-regulated N-methyl-D-aspartate receptor type 2B subunit of N-methyl-D-aspartate receptor, and led to peptidergic C-fiber sprouting in spinal dorsal horn (n = 6 each). The vincristine-induced pathologic plasticity was blocked by intrathecal injection of nuclear factor-κB inhibitor (n = 6), mimicked by tumor necrosis factor-α, and substantially prevented by oral magnesium-L-threonate (n = 5). Vincristine may activate tumor necrosis factor-α/nuclear factor-κB pathway by reduction of intracellular magnesium, leading to spinal pathologic plasticity and

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

PubMed Central

Dumas, Eric K.; Gross, Timothy; Larabee, Jason; Pate, Lance; Cuthbertson, Hannah; Charlton, Sue; Hallis, Bassam; Engler, Renata J. M.; Collins, Limone C.; Spooner, Christina E.; Chen, Hua; Ballard, Jimmy; James, Judith A.

2017-01-01

ABSTRACT Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of Bacillus anthracis that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with Bacillus anthracis spores or ET. This study compared humoral responses to ET in recipients of AVP (n = 33) versus anthrax vaccine adsorbed (AVA; n = 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 ± 58.6) of EF antibodies than AVA (4.2% and 7.8 ± 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG-positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines. PMID:28877928

Factors Associated with Incidence of Induced Abortion in Hamedan, Iran.

PubMed

Hosseini, Hatam; Erfani, Amir; Nojomi, Marzieh

2017-05-01

There is limited reliable information on abortion in Iran, where abortion is illegal and many women of reproductive age seek clandestine abortion to end their unintended pregnancy. This study aims to examine the determinants of induced abortion in the city of Hamedan, Iran. The study utilizes recent data from the 2015 Hamedan Survey of Fertility, conducted in a representative sample of 3,000 married women aged 15-49 years in the city of Hamedan, Iran. Binary logistic regression models are used to examine factors associated with the incidence of abortion. Overall, 3.8% of respondents reported having had an induced abortion in their life. Multivariate results showed that the incidence of abortion was strongly associated with women's education, type of contraceptive and family income level, after controlling for confounding factors. Women using long-acting contraceptive methods, those educated under high school diploma or postsecondary education, and those with high level of income were more likely to report having an induced abortion. The high incidence of abortion among less or more educated women and those with high income level signifies unmet family planning needs among these women, which must be addressed by focused reproductive health and family planning programs.

Shikonin suppresses proliferation and induces cell cycle arrest through the inhibition of hypoxia-inducible factor-1α signaling.

PubMed

Li, Ming Yue; Mi, Chunliu; Wang, Ke Si; Wang, Zhe; Zuo, Hong Xiang; Piao, Lian Xun; Xu, Guang Hua; Li, Xuezheng; Ma, Juan; Jin, Xuejun

2017-08-25

Hypoxia enhances the development of solid tumors. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor of tumor regulation. HIF-1α regulates several target genes involved in many aspects of cancer progression, including angiogenesis, metastasis, and cell proliferation, as well as imparting resistance to cancer treatment. In this study, we assessed shikonin, which derives from the traditional medical herb Lithospermum erythrorhizon, for its anti-cancer effects in hypoxia-induced human colon cancer cell lines. Shikonin showed potent inhibitory activity against hypoxia-induced HIF-1α activation in various human cancer cell lines and efficient scavenging activity of hypoxia-induced reactive oxygen species in tumor cells. Further analysis revealed that shikonin inhibited HIF-1α protein synthesis without affecting the expression of HIF-1α mRNA or degrading HIF-1α protein. It was subsequently shown to attenuate the activation of downstream mTOR/p70S6K/4E-BP1/eIF4E kinase. Shikonin also dose-dependently caused the cell cycle arrest of activated HCT116 cells and inhibited the proliferation of HCT116 and SW620 cells. Moreover, it significantly inhibited tumor growth in a xenograft modal. These findings suggest that shikonin could be considered for use as a potential drug in human colon cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

A bi-objective model for robust yard allocation scheduling for outbound containers

NASA Astrophysics Data System (ADS)

Liu, Changchun; Zhang, Canrong; Zheng, Li

2017-01-01

This article examines the yard allocation problem for outbound containers, with consideration of uncertainty factors, mainly including the arrival and operation time of calling vessels. Based on the time buffer inserting method, a bi-objective model is constructed to minimize the total operational cost and to maximize the robustness of fighting against the uncertainty. Due to the NP-hardness of the constructed model, a two-stage heuristic is developed to solve the problem. In the first stage, initial solutions are obtained by a greedy algorithm that looks n-steps ahead with the uncertainty factors set as their respective expected values; in the second stage, based on the solutions obtained in the first stage and with consideration of uncertainty factors, a neighbourhood search heuristic is employed to generate robust solutions that can fight better against the fluctuation of uncertainty factors. Finally, extensive numerical experiments are conducted to test the performance of the proposed method.

STATs MEDIATE FIBROBLAST GROWTH FACTOR INDUCED VASCULAR ENDOTHELIAL MORPHOGENESIS

PubMed Central

Yang, Xinhai; Qiao, Dianhua; Meyer, Kristy; Friedl, Andreas

2009-01-01

The fibroblast growth factors (FGFs) play diverse roles in development, wound healing and angiogenesis. The intracellular signal transduction pathways which mediate these pleiotropic activities remain incompletely understood. We show here that the proangiogenic factors FGF2 and FGF8b can activate signal transducers and activators of transcription (STATs) in mouse microvascular endothelial cells. Both FGF2 and FGF8b activate STAT5 and to a lesser extent STAT1, but not STAT3. The FGF2-dependent activation of endothelial STAT5 was confirmed in vivo with the matrigel plug angiogenesis assay. In tissue samples of human gliomas, a tumor type where FGF-induced angiogenesis is important, STAT5 is detected in tumor vessel endothelial cell nuclei, consistent with STAT5 activation. By forced expression of constitutively active or dominant-negative mutant STAT5A in mouse brain endothelial cells, we further show that STAT5 activation is both necessary and sufficient for FGF-induced cell migration, invasion and tube formation, which are key events in vascular endothelial morphogenesis and angiogenesis. In contrast, STAT5 is not required for brain endothelial cell mitogenesis. The cytoplasmic tyrosine kinases Src and Janus kinase 2 (Jak2) both appear to be involved in the activation of STAT5, as their inhibition reduces FGF2 and FGF8b induced STAT5 phosphorylation and endothelial cell tube formation. Constitutively active STAT5A partially restores tube formation in the presence of Src or Jak2 inhibitors. These observations demonstrate that FGFs utilize distinct signaling pathways to induce angiogenic phenotypes. Together, our findings implicate the FGF-Jak2/Src-STAT5 cascade as a critical angiogenic FGF signaling pathway. PMID:19176400

Turning science on robust cattle into improved genetic selection decisions.

PubMed

Amer, P R

2012-04-01

More robust cattle have the potential to increase farm profitability, improve animal welfare, reduce the contribution of ruminant livestock to greenhouse gas emissions and decrease the risk of food shortages in the face of increased variability in the farm environment. Breeding is a powerful tool for changing the robustness of cattle; however, insufficient recording of breeding goal traits and selection of animals at younger ages tend to favour genetic change in productivity traits relative to robustness traits. This paper has extended a previously proposed theory of artificial evolution to demonstrate, using deterministic simulation, how choice of breeding scheme design can be used as a tool to manipulate the direction of genetic progress, whereas the breeding goal remains focussed on the factors motivating individual farm decision makers. Particular focus was placed on the transition from progeny testing or mass selection to genomic selection breeding strategies. Transition to genomic selection from a breeding strategy where candidates are selected before records from progeny being available was shown to be highly likely to favour genetic progress in robustness traits relative to productivity traits. This was shown even with modest numbers of animals available for training and when heritability for robustness traits was only slightly lower than that for productivity traits. When transitioning from progeny testing to a genomic selection strategy without progeny testing, it was shown that there is a significant risk that robustness traits could become less influential in selection relative to productivity traits. Augmentations of training populations using genotyped cows and support for industry-wide improvements in phenotypic recording of robustness traits were put forward as investment opportunities for stakeholders wishing to facilitate the application of science on robust cattle into improved genetic selection schemes.

Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance.

PubMed

Qing, Zhou; Xiao-Hui, Wu; Xi-Mei, Wu; Chao-Chun, Zou

2018-06-15

Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo -/- ) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo -/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo -/- mice. In HepG2 cells, vitamin C reversed the TNF-α-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3β pathway. Furthermore, vitamin C inhibited the TNF-α-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-κB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

Beyond optimality: Multistakeholder robustness tradeoffs for regional water portfolio planning under deep uncertainty

NASA Astrophysics Data System (ADS)

Herman, Jonathan D.; Zeff, Harrison B.; Reed, Patrick M.; Characklis, Gregory W.

2014-10-01

While optimality is a foundational mathematical concept in water resources planning and management, "optimal" solutions may be vulnerable to failure if deeply uncertain future conditions deviate from those assumed during optimization. These vulnerabilities may produce severely asymmetric impacts across a region, making it vital to evaluate the robustness of management strategies as well as their impacts for regional stakeholders. In this study, we contribute a multistakeholder many-objective robust decision making (MORDM) framework that blends many-objective search and uncertainty analysis tools to discover key tradeoffs between water supply alternatives and their robustness to deep uncertainties (e.g., population pressures, climate change, and financial risks). The proposed framework is demonstrated for four interconnected water utilities representing major stakeholders in the "Research Triangle" region of North Carolina, U.S. The utilities supply well over one million customers and have the ability to collectively manage drought via transfer agreements and shared infrastructure. We show that water portfolios for this region that compose optimal tradeoffs (i.e., Pareto-approximate solutions) under expected future conditions may suffer significantly degraded performance with only modest changes in deeply uncertain hydrologic and economic factors. We then use the Patient Rule Induction Method (PRIM) to identify which uncertain factors drive the individual and collective vulnerabilities for the four cooperating utilities. Our framework identifies key stakeholder dependencies and robustness tradeoffs associated with cooperative regional planning, which are critical to understanding the tensions between individual versus regional water supply goals. Cooperative demand management was found to be the key factor controlling the robustness of regional water supply planning, dominating other hydroclimatic and economic uncertainties through the 2025 planning horizon. Results

Cultural adaptation and validation of the Health Literacy Questionnaire (HLQ): robust nine-dimension Danish language confirmatory factor model.

PubMed

Maindal, Helle Terkildsen; Kayser, Lars; Norgaard, Ole; Bo, Anne; Elsworth, Gerald R; Osborne, Richard H

2016-01-01

Health literacy is an important construct in population health and healthcare requiring rigorous measurement. The Health Literacy Questionnaire (HLQ), with nine scales, measures a broad perception of health literacy. This study aimed to adapt the HLQ to the Danish setting, and to examine the factor structure, homogeneity, reliability and discriminant validity. The HLQ was adapted using forward-backward translation, consensus conference and cognitive interviews (n = 15). Psychometric properties were examined based on data collected by face-to-face interview (n = 481). Tests included difficulty level, composite scale reliability and confirmatory factor analysis (CFA). Cognitive testing revealed that only minor re-wording was required. The easiest scale to respond to positively was 'Social support for health', and the hardest were 'Navigating the healthcare system' and 'Appraisal of health information'. CFA of the individual scales showed acceptably high loadings (range 0.49-0.93). CFA fit statistics after including correlated residuals were good for seven scales, acceptable for one. Composite reliability and Cronbach's α were >0.8 for all but one scale. A nine-factor CFA model was fitted to items with no cross-loadings or correlated residuals allowed. Given this restricted model, the fit was satisfactory. The HLQ appears robust for its intended application of assessing health literacy in a range of settings. Further work is required to demonstrate sensitivity to measure changes.

SU-F-R-40: Robustness Test of Computed Tomography Textures of Lung Tissues to Varying Scanning Protocols Using a Realistic Phantom Environment

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

Lee, S; Markel, D; Hegyi, G

2016-06-15

Purpose: The reliability of computed tomography (CT) textures is an important element of radiomics analysis. This study investigates the dependency of lung CT textures on different breathing phases and changes in CT image acquisition protocols in a realistic phantom setting. Methods: We investigated 11 CT texture features for radiation-induced lung disease from 3 categories (first-order, grey level co-ocurrence matrix (GLCM), and Law’s filter). A biomechanical swine lung phantom was scanned at two breathing phases (inhale/exhale) and two scanning protocols set for PET/CT and diagnostic CT scanning. Lung volumes acquired from the CT images were divided into 2-dimensional sub-regions with amore » grid spacing of 31 mm. The distribution of the evaluated texture features from these sub-regions were compared between the two scanning protocols and two breathing phases. The significance of each factor on feature values were tested at 95% significance level using analysis of covariance (ANCOVA) model with interaction terms included. Robustness of a feature to a scanning factor was defined as non-significant dependence on the factor. Results: Three GLCM textures (variance, sum entropy, difference entropy) were robust to breathing changes. Two GLCM (variance, sum entropy) and 3 Law’s filter textures (S5L5, E5L5, W5L5) were robust to scanner changes. Moreover, the two GLCM textures (variance, sum entropy) were consistent across all 4 scanning conditions. First-order features, especially Hounsfield unit intensity features, presented the most drastic variation up to 39%. Conclusion: Amongst the studied features, GLCM and Law’s filter texture features were more robust than first-order features. However, the majority of the features were modified by either breathing phase or scanner changes, suggesting a need for calibration when retrospectively comparing scans obtained at different conditions. Further investigation is necessary to identify the sensitivity of individual

Apoptosis inducing factor gene depletion inhibits zearalenone-induced cell death in a goat Leydig cell line.

PubMed

Yang, Diqi; Jiang, Tingting; Lin, Pengfei; Chen, Huatao; Wang, Lei; Wang, Nan; Zhao, Fan; Tang, Keqiong; Zhou, Dong; Wang, Aihua; Jin, Yaping

2017-01-01

Zearalenone (ZEA) is a contaminant of human food and animal feedstuffs that causes health hazards. However, the signal pathways underlying ZEA toxicity remain elusive. The aims of this study were to determine which pathways are involved in ZEA-induced cell death and investigate the effect of apoptosis inducing factor (AIF) on cell death during ZEA treatment in the immortalized goat Leydig cell line hTERT-GLC. This study showed that ZEA-induced cell death in hTERT-GLCs works via endoplasmic reticulum (ER) stress, the caspase-dependent pathway, the caspase-independent pathway and autophagy. Recombinant lentiviral vectors were constructed to silence AIF expression in hTERT-GLCs. Flow cytometry results showed that knockdown of AIF diminished ZEA-induced cell apoptosis in hTERT-GLCs. Furthermore, we found AIF depletion down-regulated phosphoIRE1α, GRP78, CHOP and promoted the switch of LC3-I to LC3-II. Therefore, ZEA induces cytotoxicity in hTERT-GLCs via different pathways, while AIF-mediated signaling plays a critical role in ZEA-induced cell death in hTERT-GLCs. Copyright © 2016 Elsevier Inc. All rights reserved.

Induced abortion and associated factors in health facilities of Guraghe zone, southern Ethiopia.

PubMed

Tesfaye, Gezahegn; Hambisa, Mitiku Teshome; Semahegn, Agumasie

2014-01-01

Unsafe abortion is one of the major medical and public health problems in developing countries including Ethiopia. However, there is a lack of up-to-date and reliable information on induced abortion distribution and its determinant factors in the country. This study was intended to assess induced abortion and associated factors in health facilities of Guraghe zone, Southern Ethiopia. Institution based cross-sectional study was conducted in eight health facilities in Guraghe zone. Client exit interview was conducted on 400 patients using a structured questionnaire. Bivariate and multivariate logistic regression analysis was performed to identify factors associated with induced abortion. Out of 400 women, 75.5% responded that the current pregnancy that ended in abortion is unwanted. However, only 12.3% of the respondents have admitted interference to the current pregnancy. Having more than four pregnancies (AOR = 4.28, CI: (1.24-14.71)), age of 30-34 years (AOR = 0.15, CI: (0.04-0.55)), primary education (AOR = 0.26, CI: (0.13-0.88)), and wanted pregnancy (AOR = 0.44, CI: (0.14-0.65)) were found to have association with induced abortion. The study revealed high level of induced abortion which is underpinned by high magnitude of unwanted pregnancy. There is requirement for widespread expansion of increased access to high quality family planning service and post-abortion care.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioblastoma cell chemotaxis via Lyn activation

PubMed Central

Tran, Nhan L.

2014-01-01

The long-term survival of patients with glioblastoma is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the Rho guanosine triphosphatase family member Rac1. Here, we demonstrate that TWEAK acts as a chemotactic factor for glioma cells, a potential process for driving cell invasion into the surrounding brain tissue. TWEAK exposure induced the activation of Src family kinases (SFKs), and pharmacologic suppression of SFK activity inhibited TWEAK-induced chemotactic migration. We employed a multiplexed Luminex assay and identified Lyn as a candidate SFK activated by TWEAK. Depletion of Lyn suppressed TWEAK-induced chemotaxis and Rac1 activity. Furthermore, Lyn gene expression levels increase with primary glioma tumor grade and inversely correlate with patient survival. These results show that TWEAK-induced glioma cell chemotaxis is dependent upon Lyn kinase function and, thus, provides opportunities for therapeutic targeting of this deadly disease. PMID:23975833

Placental Induced Growth Factor (PIGf) in Coronary Artery Disease

NASA Technical Reports Server (NTRS)

Sundaresan, Alamelu; Carabello, Blaise; Mehta, Satish; Schlegel, Todd; Pellis, Neal; Ott, Mark; Pierson, Duane

2010-01-01

Our previous studies on normal human lymphocytes have shown a five-fold increase (p less than 0.001) in angiogenic inducers such as Placental Induced Growth Factor (PIGf) in physiologically stressful environments such as modeled microgravity, a space analog. This suggests de-regulation of cardiovascular signalling pathways indicated by upregulation of PIGf. In the current study, we measured PIGf in the plasma of 33 patients with and without coronary artery disease (CAD) to investigate whether such disease is associated with increased levels of PIGf. A control consisting of 31 sex matched apparently healthy subjects was also included in the study. We observed that the levels of PIGf in CAD patients were significantly increased compared to those in healthy control subjects (p less than 0.001) and usually increased beyond the clinical threshold level (greater than 27ng/L). The mechanisms leading to up-regulation of angiogenic factors and the adaptation of organisms to stressful environments such as isolation, high altitude, hypoxia, ischemia, microgravity, increased radiation, etc are presently unknown and require further investigation in spaceflight and these other physiologically stressed environments.

Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

PubMed

Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P; Curry, William T; Esaki, Shin-ichi; Kasper, Ekkehard M; Chi, Andrew S; Louis, David N; Martuza, Robert L; Rabkin, Samuel D; Wakimoto, Hiroaki

2015-07-01

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Modulating factors in the expression of radiation-induced oncogenic transformation.

PubMed Central

Hall, E J; Hei, T K

1990-01-01

Many assays for oncogenic transformation have been developed ranging from those in established rodent cell lines where morphological alteration is scored, to those in human cells growing in nude mice where tumor invasiveness is scored. In general, systems that are most quantitative are also the least relevant in terms of human carcinogenesis and human risk estimation. The development of cell culture systems has made it possible to assess at the cellular level the oncogenic potential of a variety of chemical, physical and viral agents. Cell culture systems afford the opportunity to identify factors and conditions that may prevent or enhance cellular transformation by radiation and chemicals. Permissive and protective factors in radiation-induced transformation include thyroid hormone and the tumor promoter TPA that increase the transformation incidence for a given dose of radiation, and retinoids, selenium, vitamin E, and 5-aminobenzamide that inhibit the expression of transformation. Densely ionizing alpha-particles, similar to those emitted by radon daughters, are highly effective in inducing transformations and appear to interact in a supra-additive fashion with asbestos fibers. The activation of a known dominant oncogene has not yet been demonstrated in radiation-induced oncogenic transformation. The most likely mechanism for radiation activation of an oncogene would be via the production of a chromosomal translocation. Radiation also efficiently induces deletions and may thus lead to the loss of a suppressor gene. Images FIGURE 4. PMID:2272310

Cyclooxygenase-2 is an obligatory factor in methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Kuhn, Donald M

2005-05-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. The mechanisms underlying its neurotoxicity are not fully understood, but considerable evidence points to oxidative stress as a probable mechanism. A recent microarray analysis of gene expression changes caused by methamphetamine revealed that cyclooxygenase-2 (COX-2) was induced along with its transcription factor CCAAT/enhancer-binding protein (Thomas DM, Francescutti-Verbeem DM, Liu X, and Kuhn DM, 2004). We report presently that methamphetamine increases striatal expression of COX-2 protein. Cyclooxygenase-1 (COX-1) expression was not changed. Mice bearing a null mutation of the gene for COX-2 were resistant to methamphetamine-induced neurotoxicity. COX-1 knockouts, like wild-type mice, showed extensive dopamine nerve terminal damage. Selective inhibitors of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole (SC-560)], COX-2 [N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398), rofecoxib], or COX-3 (antipyrine) or a nonselective inhibitor of the COX-1/2 isoforms (ketoprofen) did not protect mice from neurotoxicity. Finally, methamphetamine did not change striatal prostaglandin E(2) content. Taken together, these data suggest that COX-2 is an obligatory factor in methamphetamine-induced neurotoxicity. The functional aspect of COX-2 that contributes to drug-induced neurotoxicity does not appear to be its prostaglandin synthetic capacity. Instead, the peroxidase activity associated with COX-2, which can lead to the formation of reactive oxygen species and dopamine quinones, can account for its role.

The complexity and robustness of metro networks

NASA Astrophysics Data System (ADS)

Derrible, Sybil; Kennedy, Christopher

2010-09-01

Transportation systems, being real-life examples of networks, are particularly interesting to analyze from the viewpoint of the new and rapidly emerging field of network science. Two particular concepts seem to be particularly relevant: scale-free patterns and small-worlds. By looking at 33 metro systems in the world, this paper adapts network science methodologies to the transportation literature, and offers one application to the robustness of metros; here, metro refers to urban rail transit with exclusive right-of-way, whether it is underground, at grade or elevated. We find that most metros are indeed scale-free (with scaling factors ranging from 2.10 to 5.52) and small-worlds; they show atypical behaviors, however, with increasing size. In particular, the presence of transfer-hubs (stations hosting more than three lines) results in relatively large scaling factors. The analysis provides insights/recommendations for increasing the robustness of metro networks. Smaller networks should focus on creating transfer stations, thus generating cycles to offer alternative routes. For larger networks, few stations seem to detain a certain monopole on transferring, it is therefore important to create additional transfers, possibly at the periphery of city centers; the Tokyo system seems to remarkably incorporate these properties.

Robust permanence for ecological equations with internal and external feedbacks.

PubMed

Patel, Swati; Schreiber, Sebastian J

2018-07-01

Species experience both internal feedbacks with endogenous factors such as trait evolution and external feedbacks with exogenous factors such as weather. These feedbacks can play an important role in determining whether populations persist or communities of species coexist. To provide a general mathematical framework for studying these effects, we develop a theorem for coexistence for ecological models accounting for internal and external feedbacks. Specifically, we use average Lyapunov functions and Morse decompositions to develop sufficient and necessary conditions for robust permanence, a form of coexistence robust to large perturbations of the population densities and small structural perturbations of the models. We illustrate how our results can be applied to verify permanence in non-autonomous models, structured population models, including those with frequency-dependent feedbacks, and models of eco-evolutionary dynamics. In these applications, we discuss how our results relate to previous results for models with particular types of feedbacks.

Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors.

PubMed

Campos, Carlos; Rocha, Nuno Barbosa F; Lattari, Eduardo; Paes, Flávia; Nardi, António E; Machado, Sérgio

2016-06-01

Age-related neurodegenerative disorders, like Alzheimer's or Parkinson's disease, are becoming a major issue to public health care. Currently, there is no effective pharmacological treatment to address cognitive impairment in these patients. Here, we aim to explore the role of exercise-induced trophic factor enhancement in the prevention or delay of cognitive decline in patients with neurodegenerative diseases. There is a significant amount of evidence from animal and human studies that links neurodegenerative related cognitive deficits with changes on brain and peripheral trophic factor levels. Several trials with elderly individuals and patients with neurodegenerative diseases report exercise induced cognitive improvements and changes on trophic factor levels including BDNF, IGF-I, among others. Further studies with healthy aging and clinical populations are needed to understand how diverse exercise interventions produce different variations in trophic factor signaling. Genetic profiles and potential confounders regarding trophic factors should also be addressed in future trials.

c-Jun and Hypoxia-Inducible Factor 1 Functionally Cooperate in Hypoxia-Induced Gene Transcription

PubMed Central

Alfranca, Arántzazu; Gutiérrez, M. Dolores; Vara, Alicia; Aragonés, Julián; Vidal, Felipe; Landázuri, Manuel O.

2002-01-01

Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1α subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1α are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-Jun at Ser63 in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser63 and Ser73 impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis. PMID:11739718

Swarm: robust and fast clustering method for amplicon-based studies.

PubMed

Mahé, Frédéric; Rognes, Torbjørn; Quince, Christopher; de Vargas, Colomban; Dunthorn, Micah

2014-01-01

Popular de novo amplicon clustering methods suffer from two fundamental flaws: arbitrary global clustering thresholds, and input-order dependency induced by centroid selection. Swarm was developed to address these issues by first clustering nearly identical amplicons iteratively using a local threshold, and then by using clusters' internal structure and amplicon abundances to refine its results. This fast, scalable, and input-order independent approach reduces the influence of clustering parameters and produces robust operational taxonomic units.

Reducing regional drought vulnerabilities and multi-city robustness conflicts using many-objective optimization under deep uncertainty

NASA Astrophysics Data System (ADS)

Trindade, B. C.; Reed, P. M.; Herman, J. D.; Zeff, H. B.; Characklis, G. W.

2017-06-01

Emerging water scarcity concerns in many urban regions are associated with several deeply uncertain factors, including rapid population growth, limited coordination across adjacent municipalities and the increasing risks for sustained regional droughts. Managing these uncertainties will require that regional water utilities identify coordinated, scarcity-mitigating strategies that trigger the appropriate actions needed to avoid water shortages and financial instabilities. This research focuses on the Research Triangle area of North Carolina, seeking to engage the water utilities within Raleigh, Durham, Cary and Chapel Hill in cooperative and robust regional water portfolio planning. Prior analysis of this region through the year 2025 has identified significant regional vulnerabilities to volumetric shortfalls and financial losses. Moreover, efforts to maximize the individual robustness of any of the mentioned utilities also have the potential to strongly degrade the robustness of the others. This research advances a multi-stakeholder Many-Objective Robust Decision Making (MORDM) framework to better account for deeply uncertain factors when identifying cooperative drought management strategies. Our results show that appropriately designing adaptive risk-of-failure action triggers required stressing them with a comprehensive sample of deeply uncertain factors in the computational search phase of MORDM. Search under the new ensemble of states-of-the-world is shown to fundamentally change perceived performance tradeoffs and substantially improve the robustness of individual utilities as well as the overall region to water scarcity. Search under deep uncertainty enhanced the discovery of how cooperative water transfers, financial risk mitigation tools, and coordinated regional demand management must be employed jointly to improve regional robustness and decrease robustness conflicts between the utilities. Insights from this work have general merit for regions where

Gallium induces the production of virulence factors in Pseudomonas aeruginosa.

PubMed

García-Contreras, Rodolfo; Pérez-Eretza, Berenice; Lira-Silva, Elizabeth; Jasso-Chávez, Ricardo; Coria-Jiménez, Rafael; Rangel-Vega, Adrián; Maeda, Toshinari; Wood, Thomas K

2014-02-01

The novel antimicrobial gallium is a nonredox iron III analogue with bacteriostatic and bactericidal properties, effective for the treatment of Pseudomonas aeruginosa in vitro and in vivo in mouse and rabbit infection models. It interferes with iron metabolism, transport, and presumably its homeostasis. As gallium exerts its antimicrobial effects by competing with iron, we hypothesized that it ultimately will lead cells to an iron deficiency status. As iron deficiency promotes the expression of virulence factors in vitro and promotes the pathogenicity of P. aeruginosa in animal models, it is anticipated that treatment with gallium will also promote the production of virulence factors. To test this hypothesis, the reference strain PA14 and two clinical isolates from patients with cystic fibrosis were exposed to gallium, and their production of pyocyanin, rhamnolipids, elastase, alkaline protease, alginate, pyoverdine, and biofilm was determined. Gallium treatment induced the production of all the virulence factors tested in the three strains except for pyoverdine. In addition, as the Ga-induced virulence factors are quorum sensing controlled, co-administration of Ga and the quorum quencher brominated furanone C-30 was assayed, and it was found that C-30 alleviated growth inhibition from gallium. Hence, adding both C-30 and gallium may be more effective in the treatment of P. aeruginosa infections. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Robust image watermarking using DWT and SVD for copyright protection

NASA Astrophysics Data System (ADS)

Harjito, Bambang; Suryani, Esti

2017-02-01

The Objective of this paper is proposed a robust combined Discrete Wavelet Transform (DWT) and Singular Value Decomposition (SVD). The RGB image is called a cover medium, and watermark image is converted into gray scale. Then, they are transformed using DWT so that they can be split into several subbands, namely sub-band LL2, LH2, HL2. The watermark image embeds into the cover medium on sub-band LL2. This scheme aims to obtain the higher robustness level than the previous method which performs of SVD matrix factorization image for copyright protection. The experiment results show that the proposed method has robustness against several image processing attacks such as Gaussian, Poisson and Salt and Pepper Noise. In these attacks, noise has average Normalized Correlation (NC) values of 0.574863 0.889784, 0.889782 respectively. The watermark image can be detected and extracted.

Robust Linear Models for Cis-eQTL Analysis.

PubMed

Rantalainen, Mattias; Lindgren, Cecilia M; Holmes, Christopher C

2015-01-01

Expression Quantitative Trait Loci (eQTL) analysis enables characterisation of functional genetic variation influencing expression levels of individual genes. In outbread populations, including humans, eQTLs are commonly analysed using the conventional linear model, adjusting for relevant covariates, assuming an allelic dosage model and a Gaussian error term. However, gene expression data generally have noise that induces heavy-tailed errors relative to the Gaussian distribution and often include atypical observations, or outliers. Such departures from modelling assumptions can lead to an increased rate of type II errors (false negatives), and to some extent also type I errors (false positives). Careful model checking can reduce the risk of type-I errors but often not type II errors, since it is generally too time-consuming to carefully check all models with a non-significant effect in large-scale and genome-wide studies. Here we propose the application of a robust linear model for eQTL analysis to reduce adverse effects of deviations from the assumption of Gaussian residuals. We present results from a simulation study as well as results from the analysis of real eQTL data sets. Our findings suggest that in many situations robust models have the potential to provide more reliable eQTL results compared to conventional linear models, particularly in respect to reducing type II errors due to non-Gaussian noise. Post-genomic data, such as that generated in genome-wide eQTL studies, are often noisy and frequently contain atypical observations. Robust statistical models have the potential to provide more reliable results and increased statistical power under non-Gaussian conditions. The results presented here suggest that robust models should be considered routinely alongside other commonly used methodologies for eQTL analysis.

Contributory factors in herb-induced fatal aconite poisoning.

PubMed

Chan, Thomas Y K

2012-11-30

Detailed investigations of all reported cases of herb-induced aconite poisoning are necessary to identify the major contributory causes so that preventive measures can be formulated. In the present review of 12 fatal cases that were published in the medical journals during 1992 and 2011, the available clinical data and forensic toxicological analyses indicated that poor post-harvest processing of aconite roots, use of greater than the recommended doses and inadequate boiling of processed aconite roots during decoction preparation were important contributory factors in herb-induced aconite poisoning. Under such circumstances, the actual amount of Aconitum alkaloids ingested was much larger than intended. Good manufacturing practice to ensure adequate processing of aconite roots, use of the recommended doses, clear instructions for the patients and their compliance during decoction preparation are important preventive measures. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Towards robust optimal design of storm water systems

NASA Astrophysics Data System (ADS)

Marquez Calvo, Oscar; Solomatine, Dimitri

2015-04-01

In this study the focus is on the design of a storm water or a combined sewer system. Such a system should be capable to handle properly most of the storm to minimize the damages caused by flooding due to the lack of capacity of the system to cope with rain water at peak times. This problem is a multi-objective optimization problem: we have to take into account the minimization of the construction costs, the minimization of damage costs due to flooding, and possibly other criteria. One of the most important factors influencing the design of storm water systems is the expected amount of water to deal with. It is common that this infrastructure is developed with the capacity to cope with events that occur once in, say 10 or 20 years - so-called design rainfall events. However, rainfall is a random variable and such uncertainty typically is not taken explicitly into account in optimization. Rainfall design data is based on historical information of rainfalls, but many times this data is based on unreliable measures; or in not enough historical information; or as we know, the patterns of rainfall are changing regardless of historical information. There are also other sources of uncertainty influencing design, for example, leakages in the pipes and accumulation of sediments in pipes. In the context of storm water or combined sewer systems design or rehabilitation, robust optimization technique should be able to find the best design (or rehabilitation plan) within the available budget but taking into account uncertainty in those variables that were used to design the system. In this work we consider various approaches to robust optimization proposed by various authors (Gabrel, Murat, Thiele 2013; Beyer, Sendhoff 2007) and test a novel method ROPAR (Solomatine 2012) to analyze robustness. References Beyer, H.G., & Sendhoff, B. (2007). Robust optimization - A comprehensive survey. Comput. Methods Appl. Mech. Engrg., 3190-3218. Gabrel, V.; Murat, C., Thiele, A. (2014

The structural robustness of geographical networks against regional failure and their pre-optimization

NASA Astrophysics Data System (ADS)

Li, Yixiao; Zhang, Lin; Huang, Chaogeng; Shen, Bin

2016-06-01

Failures of real-world infrastructure networks due to natural disasters often originate in a certain region, but this feature has seldom been considered in theoretical models. In this article, we introduce a possible failure pattern of geographical networks-;regional failure;-by which nodes and edges within a region malfunction. Based on a previous spatial network model (Louf et al., 2013), we study the robustness of geographical networks against regional failure, which is measured by the fraction of nodes that remain in the largest connected component, via simulations. A small-area failure results in a large reduction of their robustness measure. Furthermore, we investigate two pre-deployed mechanisms to enhance their robustness: One is to extend the cost-benefit growth mechanism of the original network model by adding more than one link in a growth step, and the other is to strengthen the interconnection of hubs in generated networks. We measure the robustness-enhancing effects of both mechanisms on the basis of their costs, i.e., the amount of excessive links and the induced geographical length. The latter mechanism is better than the former one if a normal level of costs is considered. When costs exceed a certain level, the former has an advantage. Because the costs of excessive links affect the investment decision of real-world infrastructure networks, it is practical to enhance their robustness by adding more links between hubs. These results might help design robust geographical networks economically.

Epidermal growth factor receptor signaling mediates aldosterone-induced profibrotic responses in kidney

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

Sheng, Lili; Yang, Min; Ding, Wei

Aldosterone has been recognized as a risk factor for the development of chronic kidney disease (CKD). Studies have indicated that enhanced activation of epidermal growth factor receptor (EGFR) is associated with the development and progression of renal fibrosis. But if EGFR is involved in aldosterone-induced renal fibrosis is less investigated. In the present study, we examined the effect of erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of aldosterone-induced renal profibrotic responses in a murine model underwent uninephrectomy. Erlotinib-treated rats exhibited relieved structural lesion comparing with rats treated with aldosterone alone, as characterized by glomerular hypertrophy, mesangialmore » cell proliferation and expansion. Also, erlotinib inhibited the expression of TGF-β, α-SMA and mesangial matrix proteins such as collagen Ⅳ and fibronectin. In cultured mesangial cells, inhibition of EGFR also abrogated aldosterone-induced expression of extracellular matrix proteins, cell proliferation and migration. We also demonstrated that aldosterone induced the phosphorylation of EGFR through generation of ROS. And the activation of EGFR resulted in the phosphorylation of ERK1/2, leading to the activation of profibrotic pathways. Taken together, we concluded that aldosterone-mediated tissue fibrosis relies on ROS induced EGFR/ERK activation, highlighting EGFR as a potential therapeutic target for modulating renal fibrosis. - Highlights: • EGFR was involved in aldosterone-induced renal profibrotic responses. • Aldosterone-induced EGFR activation was mediated by MR-dependent ROS generation. • EGFR activated the MAPK/ERK1/2 signaling to promote renal fibrosis.« less

Activating transcription factor 4 regulates stearate-induced vascular calcification.

PubMed

Masuda, Masashi; Ting, Tabitha C; Levi, Moshe; Saunders, Sommer J; Miyazaki-Anzai, Shinobu; Miyazaki, Makoto

2012-08-01

Previously, we reported that stearate, a saturated fatty acid, promotes osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC). In this study, we examined the molecular mechanisms by which stearate promotes vascular calcification. ATF4 is a pivotal transcription factor in osteoblastogenesis and endoplasmic reticulum (ER) stress. Increased stearate by either supplementation of exogenous stearic acid or inhibition of stearoyl-CoA desaturase (SCD) by CAY10566 induced ATF4 mRNA, phosphorylated ATF4 protein, and total ATF4 protein. Induction occurred through activation of the PERK-eIF2α pathway, along with increased osteoblastic differentiation and mineralization of VSMCs. Either stearate or the SCD inhibitor but not oleate or other fatty acid treatments also increased ER stress as determined by the expression of p-eIF2α, CHOP, and the spliced form of XBP-1, which were directly correlated with ER stearate levels. ATF4 knockdown by lentiviral ATF4 shRNA blocked osteoblastic differentiation and mineralization induced by stearate and SCD inhibition. Conversely, treatment of VSMCs with an adenovirus containing ATF4 induced vascular calcification. Our results demonstrated that activation of ATF4 mediates vascular calcification induced by stearate.

Activating transcription factor 4 regulates stearate-induced vascular calcification

PubMed Central

Masuda, Masashi; Ting, Tabitha C.; Levi, Moshe; Saunders, Sommer J.; Miyazaki-Anzai, Shinobu; Miyazaki, Makoto

2012-01-01

Previously, we reported that stearate, a saturated fatty acid, promotes osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMC). In this study, we examined the molecular mechanisms by which stearate promotes vascular calcification. ATF4 is a pivotal transcription factor in osteoblastogenesis and endoplasmic reticulum (ER) stress. Increased stearate by either supplementation of exogenous stearic acid or inhibition of stearoyl-CoA desaturase (SCD) by CAY10566 induced ATF4 mRNA, phosphorylated ATF4 protein, and total ATF4 protein. Induction occurred through activation of the PERK-eIF2α pathway, along with increased osteoblastic differentiation and mineralization of VSMCs. Either stearate or the SCD inhibitor but not oleate or other fatty acid treatments also increased ER stress as determined by the expression of p-eIF2α, CHOP, and the spliced form of XBP-1, which were directly correlated with ER stearate levels. ATF4 knockdown by lentiviral ATF4 shRNA blocked osteoblastic differentiation and mineralization induced by stearate and SCD inhibition. Conversely, treatment of VSMCs with an adenovirus containing ATF4 induced vascular calcification. Our results demonstrated that activation of ATF4 mediates vascular calcification induced by stearate. PMID:22628618

Directing traffic on DNA-How transcription factors relieve or induce transcriptional interference.

PubMed

Hao, Nan; Palmer, Adam C; Dodd, Ian B; Shearwin, Keith E

2017-03-15

Transcriptional interference (TI) is increasingly recognized as a widespread mechanism of gene control, particularly given the pervasive nature of transcription, both sense and antisense, across all kingdoms of life. Here, we discuss how transcription factor binding kinetics strongly influence the ability of a transcription factor to relieve or induce TI.

Alcohol induces synaptotagmin 1 expression in neurons via activation of heat shock factor 1.

PubMed

Varodayan, F P; Pignataro, L; Harrison, N L

2011-10-13

Many synapses within the central nervous system are sensitive to ethanol. Although alcohol is known to affect the probability of neurotransmitter release in specific brain regions, the effects of alcohol on the underlying synaptic vesicle fusion machinery have been little studied. To identify a potential pathway by which ethanol can regulate neurotransmitter release, we investigated the effects of acute alcohol exposure (1-24 h) on the expression of the gene encoding synaptotagmin 1 (Syt1), a synaptic protein that binds calcium to directly trigger vesicle fusion. Syt1 was identified in a microarray screen as a gene that may be sensitive to alcohol and heat shock. We found that Syt1 mRNA and protein expression are rapidly and robustly up-regulated by ethanol in mouse cortical neurons, and that the distribution of Syt1 protein along neuronal processes is also altered. Syt1 mRNA up-regulation is dependent on the activation of the transcription factor heat shock factor 1 (HSF1). The transfection of a constitutively active Hsf1 construct into neurons stimulates Syt1 transcription, while transfection of Hsf1 small interfering RNA (siRNA) or a constitutively inactive Hsf1 construct into neurons attenuates the induction of Syt1 by ethanol. This suggests that the activation of HSF1 can induce Syt1 expression and that this may be a mechanism by which alcohol regulates neurotransmitter release during brief exposures. Further analysis revealed that a subset of the genes encoding the core synaptic vesicle fusion (soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor; SNARE) proteins share this property of induction by ethanol, suggesting that alcohol may trigger a specific coordinated adaptation in synaptic function. This molecular mechanism could explain some of the changes in synaptic function that occur following alcohol administration and may be an important step in the process of neuronal adaptation to alcohol. Copyright © 2011 IBRO. Published by

Computing factors of safety against wind-induced tree stem damage.

PubMed

Niklas, K J

2000-04-01

The drag forces, bending moments and stresses acting on stems differing in size and location within the mechanical infrastructure of a large wild cherry (Prunus serotina Ehrh.) tree are estimated and used to calculate the factor of safety against wind-induced mechanical failure based on the mean breaking stress of intact stems and samples of wood drawn from this tree. The drag forces acting on stems are calculated based on stem projected areas and field measurements of wind speed taken within the canopy and along the length of the trunk. The bending moments and stresses resulting from these forces are shown to increase basipetally in a nearly log-log linear fashion toward the base of the tree. The factor of safety, however, varies in a sinusoidal manner such that the most distal stems have the highest factors of safety, whereas stems of intermediate location and portions of the trunk near ground level have equivalent and much lower factors of safety. This pattern of variation is interpreted to indicate that, as a course of normal growth and development, trees similar to the one examined in this study maintain a cadre of stems prone to wind-induced mechanical damage that can reduce the probability of catastrophic tree failure by reducing the drag forces acting on older portions of the tree. Comparisons among real and hypothetical stems with different taper experiencing different vertical wind speed profiles show that geometrically self-similar stems have larger factors of safety than stems tapering according to elastic or stress self-similarity, and that safety factors are less significantly influenced by the 'geometry' of the wind-profile.

Induced Abortion and Associated Factors in Health Facilities of Guraghe Zone, Southern Ethiopia

PubMed Central

Hambisa, Mitiku Teshome; Semahegn, Agumasie

2014-01-01

Unsafe abortion is one of the major medical and public health problems in developing countries including Ethiopia. However, there is a lack of up-to-date and reliable information on induced abortion distribution and its determinant factors in the country. This study was intended to assess induced abortion and associated factors in health facilities of Guraghe zone, Southern Ethiopia. Institution based cross-sectional study was conducted in eight health facilities in Guraghe zone. Client exit interview was conducted on 400 patients using a structured questionnaire. Bivariate and multivariate logistic regression analysis was performed to identify factors associated with induced abortion. Out of 400 women, 75.5% responded that the current pregnancy that ended in abortion is unwanted. However, only 12.3% of the respondents have admitted interference to the current pregnancy. Having more than four pregnancies (AOR = 4.28, CI: (1.24–14.71)), age of 30–34 years (AOR = 0.15, CI: (0.04–0.55)), primary education (AOR = 0.26, CI: (0.13–0.88)), and wanted pregnancy (AOR = 0.44, CI: (0.14–0.65)) were found to have association with induced abortion. The study revealed high level of induced abortion which is underpinned by high magnitude of unwanted pregnancy. There is requirement for widespread expansion of increased access to high quality family planning service and post-abortion care. PMID:24800079

Robustness. [in space systems

NASA Technical Reports Server (NTRS)

Ryan, Robert

1993-01-01

The concept of rubustness includes design simplicity, component and path redundancy, desensitization to the parameter and environment variations, control of parameter variations, and punctual operations. These characteristics must be traded with functional concepts, materials, and fabrication approach against the criteria of performance, cost, and reliability. The paper describes the robustness design process, which includes the following seven major coherent steps: translation of vision into requirements, definition of the robustness characteristics desired, criteria formulation of required robustness, concept selection, detail design, manufacturing and verification, operations.

Growth Factors and Tension-Induced Skeletal Muscle Growth

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman H.

1994-01-01

The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we

RSRE: RNA structural robustness evaluator

PubMed Central

Shu, Wenjie; Zheng, Zhiqiang; Wang, Shengqi

2007-01-01

Biological robustness, defined as the ability to maintain stable functioning in the face of various perturbations, is an important and fundamental topic in current biology, and has become a focus of numerous studies in recent years. Although structural robustness has been explored in several types of RNA molecules, the origins of robustness are still controversial. Computational analysis results are needed to make up for the lack of evidence of robustness in natural biological systems. The RNA structural robustness evaluator (RSRE) web server presented here provides a freely available online tool to quantitatively evaluate the structural robustness of RNA based on the widely accepted definition of neutrality. Several classical structure comparison methods are employed; five randomization methods are implemented to generate control sequences; sub-optimal predicted structures can be optionally utilized to mitigate the uncertainty of secondary structure prediction. With a user-friendly interface, the web application is easy to use. Intuitive illustrations are provided along with the original computational results to facilitate analysis. The RSRE will be helpful in the wide exploration of RNA structural robustness and will catalyze our understanding of RNA evolution. The RSRE web server is freely available at http://biosrv1.bmi.ac.cn/RSRE/ or http://biotech.bmi.ac.cn/RSRE/. PMID:17567615

Motion-robust intensity-modulated proton therapy for distal esophageal cancer.

PubMed

Yu, Jen; Zhang, Xiaodong; Liao, Li; Li, Heng; Zhu, Ronald; Park, Peter C; Sahoo, Narayan; Gillin, Michael; Li, Yupeng; Chang, Joe Y; Komaki, Ritsuko; Lin, Steven H

2016-03-01

To develop methods for evaluation and mitigation of dosimetric impact due to respiratory and diaphragmatic motion during free breathing in treatment of distal esophageal cancers using intensity-modulated proton therapy (IMPT). This was a retrospective study on 11 patients with distal esophageal cancer. For each patient, four-dimensional computed tomography (4D CT) data were acquired, and a nominal dose was calculated on the average phase of the 4D CT. The changes of water equivalent thickness (ΔWET) to cover the treatment volume from the peak of inspiration to the valley of expiration were calculated for a full range of beam angle rotation. Two IMPT plans were calculated: one at beam angles corresponding to small ΔWET and one at beam angles corresponding to large ΔWET. Four patients were selected for the calculation of 4D-robustness-optimized IMPT plans due to large motion-induced dose errors generated in conventional IMPT. To quantitatively evaluate motion-induced dose deviation, the authors calculated the lowest dose received by 95% (D95) of the internal clinical target volume for the nominal dose, the D95 calculated on the maximum inhale and exhale phases of 4D CT DCT0 andDCT50 , the 4D composite dose, and the 4D dynamic dose for a single fraction. The dose deviation increased with the average ΔWET of the implemented beams, ΔWETave. When ΔWETave was less than 5 mm, the dose error was less than 1 cobalt gray equivalent based on DCT0 and DCT50 . The dose deviation determined on the basis of DCT0 and DCT50 was proportionally larger than that determined on the basis of the 4D composite dose. The 4D-robustness-optimized IMPT plans notably reduced the overall dose deviation of multiple fractions and the dose deviation caused by the interplay effect in a single fraction. In IMPT for distal esophageal cancer, ΔWET analysis can be used to select the beam angles that are least affected by respiratory and diaphragmatic motion. To further reduce dose deviation, the 4

Robust Magnetotelluric Impedance Estimation

NASA Astrophysics Data System (ADS)

Sutarno, D.

2010-12-01

Robust magnetotelluric (MT) response function estimators are now in standard use by the induction community. Properly devised and applied, these have ability to reduce the influence of unusual data (outliers). The estimators always yield impedance estimates which are better than the conventional least square (LS) estimation because the `real' MT data almost never satisfy the statistical assumptions of Gaussian distribution and stationary upon which normal spectral analysis is based. This paper discuses the development and application of robust estimation procedures which can be classified as M-estimators to MT data. Starting with the description of the estimators, special attention is addressed to the recent development of a bounded-influence robust estimation, including utilization of the Hilbert Transform (HT) operation on causal MT impedance functions. The resulting robust performances are illustrated using synthetic as well as real MT data.

Mechanically induced intercellular calcium communication in confined endothelial structures.

PubMed

Junkin, Michael; Lu, Yi; Long, Juexuan; Deymier, Pierre A; Hoying, James B; Wong, Pak Kin

2013-03-01

Calcium signaling in the diverse vascular structures is regulated by a wide range of mechanical and biochemical factors to maintain essential physiological functions of the vasculature. To properly transmit information, the intercellular calcium communication mechanism must be robust against various conditions in the cellular microenvironment. Using plasma lithography geometric confinement, we investigate mechanically induced calcium wave propagation in networks of human umbilical vein endothelial cells organized. Endothelial cell networks with confined architectures were stimulated at the single cell level, including using capacitive force probes. Calcium wave propagation in the network was observed using fluorescence calcium imaging. We show that mechanically induced calcium signaling in the endothelial networks is dynamically regulated against a wide range of probing forces and repeated stimulations. The calcium wave is able to propagate consistently in various dimensions from monolayers to individual cell chains, and in different topologies from linear patterns to cell junctions. Our results reveal that calcium signaling provides a robust mechanism for cell-cell communication in networks of endothelial cells despite the diversity of the microenvironmental inputs and complexity of vascular structures. Copyright © 2012 Elsevier Ltd. All rights reserved.

Swarm: robust and fast clustering method for amplicon-based studies

PubMed Central

Rognes, Torbjørn; Quince, Christopher; de Vargas, Colomban; Dunthorn, Micah

2014-01-01

Popular de novo amplicon clustering methods suffer from two fundamental flaws: arbitrary global clustering thresholds, and input-order dependency induced by centroid selection. Swarm was developed to address these issues by first clustering nearly identical amplicons iteratively using a local threshold, and then by using clusters’ internal structure and amplicon abundances to refine its results. This fast, scalable, and input-order independent approach reduces the influence of clustering parameters and produces robust operational taxonomic units. PMID:25276506

Robustness Elasticity in Complex Networks

PubMed Central

Matisziw, Timothy C.; Grubesic, Tony H.; Guo, Junyu

2012-01-01

Network robustness refers to a network’s resilience to stress or damage. Given that most networks are inherently dynamic, with changing topology, loads, and operational states, their robustness is also likely subject to change. However, in most analyses of network structure, it is assumed that interaction among nodes has no effect on robustness. To investigate the hypothesis that network robustness is not sensitive or elastic to the level of interaction (or flow) among network nodes, this paper explores the impacts of network disruption, namely arc deletion, over a temporal sequence of observed nodal interactions for a large Internet backbone system. In particular, a mathematical programming approach is used to identify exact bounds on robustness to arc deletion for each epoch of nodal interaction. Elasticity of the identified bounds relative to the magnitude of arc deletion is assessed. Results indicate that system robustness can be highly elastic to spatial and temporal variations in nodal interactions within complex systems. Further, the presence of this elasticity provides evidence that a failure to account for nodal interaction can confound characterizations of complex networked systems. PMID:22808060

Decreased contraction induced by endothelium-derived contracting factor in prolonged treatment of rat renal artery with endoplasmic reticulum stress inducer.

PubMed

Ando, Makoto; Matsumoto, Takayuki; Taguchi, Kumiko; Kobayashi, Tsuneo

2018-05-04

Recent evidence suggests that endoplasmic reticulum (ER) stress is involved in the regulation of various physiological functions, including those of the vascular system. However, the relationship between ER stress and vascular function is poorly understood. The endothelial cells control the vascular tone by releasing endothelium-derived relaxing factors and contracting factors (EDCFs). We hypothesized that tunicamycin, an inducer of ER stress, modifies endothelium-dependent contraction and prostaglandins (PGs), a major class of EDCFs, induced contractions in the rat renal artery in rats. An organ-culture technique was used to purely investigate the effects of ER stress on the vascular tissue. We observed that tunicamycin treatment (20 μg/mL for 23 ± 1 h) did not affect acetylcholine (ACh)-induced relaxation and decreased EDCF-mediated contractions under nitric oxide synthase (NOS) inhibition induced by ACh, ATP, or A23187 (a calcium ionophore) in the renal arteries. Under NOS inhibition, U46619 (a thromboxane A 2 mimetic)- and beraprost (a prostacyclin analog)-induced contractions were also decreased in the renal arteries of the tunicamycin-treated group (vs. vehicle), while PGE 2 - and PGF 2α -induced contractions were similar between the groups. Tunicamycin treatment slightly enhanced the contractions induced by phenylephrine, an α 1 adrenoceptor ligand. Isotonic high-K + -induced contractions were similar between the vehicle- and tunicamycin-treated groups. Another ER stress inducer, thapsigargin (4 μmol/L for 23 ± 1 h), also caused substantial reduction of ACh-induced EDCF-mediated contraction (vs. vehicle-treated group). In the cultured renal arteries, tunicamycin and thapsigargin increased the expression of binding immunoglobulin protein (BiP), an ER stress marker. In conclusion, ER stress induction directly affects renal arterial function, especially in reducing EDCF-mediated contractions.

Treatment of clozapine- and molindone-induced agranulocytosis with granulocyte colony-stimulating factor.

PubMed

Geibig, C B; Marks, L W

1993-10-01

To report a case of clozapine- and molindone-induced agranulocytosis and to discuss treatment using filgrastim, a granulocyte colony-stimulating factor. A 64-year-old woman who had been on long-term clozapine therapy for schizophrenia was hospitalized with presumed drug-induced agranulocytosis. She had also been on short-term molindone therapy. A bone marrow biopsy and the initial white blood cell (WBC) count were consistent with drug-induced agranulocytosis. Following seven days of treatment with subcutaneous filgrastim 300 micrograms/d, her absolute neutrophil count was above 500 x 10(6)/L. Reports in the literature discussing antipsychotic drug-induced agranulocytosis are reviewed. A relationship between treatment with filgrastim and WBC response is postulated. Filgrastim may be useful in ameliorating the effects of clozapine- and molindone-induced agranulocytosis.

The comparison of robust partial least squares regression with robust principal component regression on a real

NASA Astrophysics Data System (ADS)

Polat, Esra; Gunay, Suleyman

2013-10-01

One of the problems encountered in Multiple Linear Regression (MLR) is multicollinearity, which causes the overestimation of the regression parameters and increase of the variance of these parameters. Hence, in case of multicollinearity presents, biased estimation procedures such as classical Principal Component Regression (CPCR) and Partial Least Squares Regression (PLSR) are then performed. SIMPLS algorithm is the leading PLSR algorithm because of its speed, efficiency and results are easier to interpret. However, both of the CPCR and SIMPLS yield very unreliable results when the data set contains outlying observations. Therefore, Hubert and Vanden Branden (2003) have been presented a robust PCR (RPCR) method and a robust PLSR (RPLSR) method called RSIMPLS. In RPCR, firstly, a robust Principal Component Analysis (PCA) method for high-dimensional data on the independent variables is applied, then, the dependent variables are regressed on the scores using a robust regression method. RSIMPLS has been constructed from a robust covariance matrix for high-dimensional data and robust linear regression. The purpose of this study is to show the usage of RPCR and RSIMPLS methods on an econometric data set, hence, making a comparison of two methods on an inflation model of Turkey. The considered methods have been compared in terms of predictive ability and goodness of fit by using a robust Root Mean Squared Error of Cross-validation (R-RMSECV), a robust R2 value and Robust Component Selection (RCS) statistic.

V3 spinal neurons establish a robust and balanced locomotor rhythm during walking.

PubMed

Zhang, Ying; Narayan, Sujatha; Geiman, Eric; Lanuza, Guillermo M; Velasquez, Tomoko; Shanks, Bayle; Akay, Turgay; Dyck, Jason; Pearson, Keir; Gosgnach, Simon; Fan, Chen-Ming; Goulding, Martyn

2008-10-09

A robust and well-organized rhythm is a key feature of many neuronal networks, including those that regulate essential behaviors such as circadian rhythmogenesis, breathing, and locomotion. Here we show that excitatory V3-derived neurons are necessary for a robust and organized locomotor rhythm during walking. When V3-mediated neurotransmission is selectively blocked by the expression of the tetanus toxin light chain subunit (TeNT), the regularity and robustness of the locomotor rhythm is severely perturbed. A similar degeneration in the locomotor rhythm occurs when the excitability of V3-derived neurons is reduced acutely by ligand-induced activation of the allatostatin receptor. The V3-derived neurons additionally function to balance the locomotor output between both halves of the spinal cord, thereby ensuring a symmetrical pattern of locomotor activity during walking. We propose that the V3 neurons establish a regular and balanced motor rhythm by distributing excitatory drive between both halves of the spinal cord.

Pin1 promotes transforming growth factor-beta-induced migration and invasion.

PubMed

Matsuura, Isao; Chiang, Keng-Nan; Lai, Chen-Yu; He, Dongming; Wang, Guannan; Ramkumar, Romila; Uchida, Takafumi; Ryo, Akihide; Lu, Kunping; Liu, Fang

2010-01-15

Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-beta responses. TGF-beta binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their C terminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-beta-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-beta, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-beta-induced growth-inhibitory responses and a number of TGF-beta/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-beta-mediated migration and invasion. Accordingly, TGF-beta induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-beta-induced migration and invasion of cancer cells.

Designing robust control laws using genetic algorithms

NASA Technical Reports Server (NTRS)

Marrison, Chris

1994-01-01

The purpose of this research is to create a method of finding practical, robust control laws. The robustness of a controller is judged by Stochastic Robustness metrics and the level of robustness is optimized by searching for design parameters that minimize a robustness cost function.

Robust information propagation through noisy neural circuits

PubMed Central

Pouget, Alexandre

2017-01-01

Sensory neurons give highly variable responses to stimulation, which can limit the amount of stimulus information available to downstream circuits. Much work has investigated the factors that affect the amount of information encoded in these population responses, leading to insights about the role of covariability among neurons, tuning curve shape, etc. However, the informativeness of neural responses is not the only relevant feature of population codes; of potentially equal importance is how robustly that information propagates to downstream structures. For instance, to quantify the retina’s performance, one must consider not only the informativeness of the optic nerve responses, but also the amount of information that survives the spike-generating nonlinearity and noise corruption in the next stage of processing, the lateral geniculate nucleus. Our study identifies the set of covariance structures for the upstream cells that optimize the ability of information to propagate through noisy, nonlinear circuits. Within this optimal family are covariances with “differential correlations”, which are known to reduce the information encoded in neural population activities. Thus, covariance structures that maximize information in neural population codes, and those that maximize the ability of this information to propagate, can be very different. Moreover, redundancy is neither necessary nor sufficient to make population codes robust against corruption by noise: redundant codes can be very fragile, and synergistic codes can—in some cases—optimize robustness against noise. PMID:28419098

Robust Control Systems.

DTIC Science & Technology

1981-12-01

time control system algorithms that will perform adequately (i.e., at least maintain closed-loop system stability) when ucertain parameters in the...system design models vary significantly. Such a control algorithm is said to have stability robustness-or more simply is said to be "robust". This...cas6s above, the performance is analyzed using a covariance analysis. The development of all the controllers and the performance analysis algorithms is

Robust method for TALEN-edited correction of pF508del in patient-specific induced pluripotent stem cells.

PubMed

Camarasa, María Vicenta; Gálvez, Víctor Miguel

2016-02-09

Cystic fibrosis is one of the most frequent inherited rare diseases, caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. Apart from symptomatic treatments, therapeutic protocols for curing the disease have not yet been established. The regeneration of genetically corrected, disease-free epithelia in cystic fibrosis patients is envisioned by designing a stem cell/genetic therapy in which patient-derived pluripotent stem cells are genetically corrected, from which target tissues are derived. In this framework, we present an efficient method for seamless correction of pF508del mutation in patient-specific induced pluripotent stem cells by gene edited homologous recombination. Gene edition has been performed by transcription activator-like effector nucleases and a homologous recombination donor vector which contains a PiggyBac transposon-based double selectable marker cassette.This new method has been designed to partially avoid xenobiotics from the culture system, improve cell culture efficiency and genome stability by using a robust culture system method, and optimize timings. Overall, once the pluripotent cells have been amplified for the first nucleofection, the procedure can be completed in 69 days, and can be easily adapted to edit and change any gene of interest.

Cold adaptation shapes the robustness of metabolic networks in Drosophila melanogaster

PubMed Central

Williams, CM; Watanabe, M; Guarracino, MR; Ferraro, MB; Edison, AS; Morgan, TJ; Boroujerdi, AFB; Hahn, DA

2015-01-01

When ectotherms are exposed to low temperatures, they enter a cold-induced coma (chill coma) that prevents resource acquisition, mating, oviposition, and escape from predation. There is substantial variation in time taken to recover from chill coma both within and among species, and this variation is correlated with habitat temperatures such that insects from cold environments recover more quickly. This suggests an adaptive response, but the mechanisms underlying variation in recovery times are unknown, making it difficult to decisively test adaptive hypotheses. We use replicated lines of Drosophila melanogaster selected in the laboratory for fast (hardy) or slow (susceptible) chill-coma recovery times to investigate modifications to metabolic profiles associated with cold adaptation. We measured metabolite concentrations of flies before, during, and after cold exposure using NMR spectroscopy to test the hypotheses that hardy flies maintain metabolic homeostasis better during cold exposure and recovery, and that their metabolic networks are more robust to cold-induced perturbations. The metabolites of cold-hardy flies were less cold responsive and their metabolic networks during cold exposure were more robust, supporting our hypotheses. Metabolites involved in membrane lipid synthesis, tryptophan metabolism, oxidative stress, energy balance, and proline metabolism were altered by selection on cold tolerance. We discuss the potential significance of these alterations. PMID:25308124

Robust impact of social anxiety in relation to coping motives and expectancies, barriers to quitting, and cessation-related problems.

PubMed

Buckner, Julia D; Zvolensky, Michael J; Jeffries, Emily R; Schmidt, Norman B

2014-08-01

Although social anxiety is related to smoking and nicotine dependence, few researchers have sought to identify factors that contribute to these relations. The current study examined whether social anxiety was associated with cognitive vulnerability factors related to smoking: perceived barriers for quitting, cessation-related problems, negative-affect-reduction-outcome expectancies, and negative-affect-reduction motives. Further, we tested whether social anxiety was robustly related to these factors after controlling for cigarettes smoked per day, gender, alcohol-use frequency, lifetime cannabis-use status, panic attack frequency, anxiety sensitivity, and negative affectivity. The sample consisted of 580 (38.6% female) treatment-seeking smokers. Social anxiety was associated with perceived barriers for quitting, cessation-related problems, negative-affect-reduction-outcome expectancies, and negative-affect-reduction motives. After controlling for covariates, social anxiety was robustly related to perceived barriers for quitting, cessation-related problems, and negative-affect-reduction-outcome expectancies. Social anxiety was robustly related to negative-affect-reduction motives among men, but not women. Results indicate that social anxiety is robustly related to cognitive vulnerability factors associated with poorer cessation outcomes, suggesting that social anxiety may be an important therapeutic target during smoking cessation.

Targeting Hypoxia-Inducible Factor-1α/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis.

PubMed

Goodwin, Justin; Choi, Hyunsung; Hsieh, Meng-Hsiung; Neugent, Michael L; Ahn, Jung-Mo; Hayenga, Heather N; Singh, Pankaj K; Shackelford, David B; Lee, In-Kyu; Shulaev, Vladimir; Dhar, Shanta; Takeda, Norihiko; Kim, Jung-Whan

2018-02-01

Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-β-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.

HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation

PubMed Central

Kim, Hyeon Ju; Chuang, De-Maw

2014-01-01

White matter injury is an important component of stroke pathology, but its pathophysiology and potential treatment remain relatively elusive and underexplored. We previously reported that after permanent middle cerebral artery occlusion (pMCAO), sodium butyrate (SB) and trichostatin A (TSA) induced neurogenesis via histone deacetylase (HDAC) inhibition in multiple ischemic brain regions in rats; these effects-which depended on activation of brain-derived neurotrophic factor (BDNF)-TrkB signaling-contributed to behavioral improvement. The present study found that SB or TSA robustly protected against ischemia-induced loss of oligodendrocytes detected by confocal microscopy of myelin basic protein (MBP) immunostaining in the ipsilateral subventricular zone (SVZ), striatum, corpus callosum, and frontal cortex seven days post-pMCAO. Co-localization of 5-bromo-2’-deoxyuridine (BrdU)+ and MBP+ cells after SB treatment suggested the occurrence of oligodendrogenesis. SB also strongly upregulated vascular endothelial growth factor (VEGF), which plays a major role in neurogenesis, angiogenesis, and functional recovery after stroke. These SB-induced effects were markedly suppressed by blocking the TrkB signaling pathway with K252a. pMCAO-induced activation of microglia (OX42+) and macrophages/monocytes (ED1+)-which has been linked to white matter injury-was robustly suppressed by SB in a K252a-sensitive manner. In addition, SB treatment largely blocked caspase-3+ and OX42+ cells in ipsilateral brain regions. Our results suggest that HDAC inhibitor-mediated protection against ischemia-induced oligodendrocyte loss may involve multiple mechanisms including oligodendrogenesis, VEGF upregulation, anti-inflammation, and caspase-3 downregulation. Taken together, the results suggest that post-insult treatment with HDAC inhibitors is a rational strategy to mitigate white matter injury following ischemic stroke. PMID:24936215

Robust odd-parity superconductivity in the doped topological insulator NbxBi2Se3

NASA Astrophysics Data System (ADS)

Smylie, M. P.; Willa, K.; Claus, H.; Snezhko, A.; Martin, I.; Kwok, W.-K.; Qiu, Y.; Hor, Y. S.; Bokari, E.; Niraula, P.; Kayani, A.; Mishra, V.; Welp, U.

2017-09-01

We present resistivity and magnetization measurements on proton-irradiated crystals demonstrating that the superconducting state in the doped topological insulator NbxBi2Se3 (x =0.25 ) is surprisingly robust against disorder-induced electron scattering. The superconducting transition temperature Tc decreases without indication of saturation with increasing defect concentration, and the corresponding scattering rates far surpass expectations based on conventional theory. The low-temperature variation of the London penetration depth Δ λ (T ) follows a power law [Δ λ (T ) ˜T2] indicating the presence of symmetry-protected point nodes. Our results are consistent with the proposed robust nematic Eu pairing state in this material.

Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

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

Yang, Bin; Li, Wei; Zheng, Qichang

Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negativemore » effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.« less

Robust Fixed-Structure Controller Synthesis

NASA Technical Reports Server (NTRS)

Corrado, Joseph R.; Haddad, Wassim M.; Gupta, Kajal (Technical Monitor)

2000-01-01

The ability to develop an integrated control system design methodology for robust high performance controllers satisfying multiple design criteria and real world hardware constraints constitutes a challenging task. The increasingly stringent performance specifications required for controlling such systems necessitates a trade-off between controller complexity and robustness. The principle challenge of the minimal complexity robust control design is to arrive at a tractable control design formulation in spite of the extreme complexity of such systems. Hence, design of minimal complexitY robust controllers for systems in the face of modeling errors has been a major preoccupation of system and control theorists and practitioners for the past several decades.

Robustness of spatial micronetworks

NASA Astrophysics Data System (ADS)

McAndrew, Thomas C.; Danforth, Christopher M.; Bagrow, James P.

2015-04-01

Power lines, roadways, pipelines, and other physical infrastructure are critical to modern society. These structures may be viewed as spatial networks where geographic distances play a role in the functionality and construction cost of links. Traditionally, studies of network robustness have primarily considered the connectedness of large, random networks. Yet for spatial infrastructure, physical distances must also play a role in network robustness. Understanding the robustness of small spatial networks is particularly important with the increasing interest in microgrids, i.e., small-area distributed power grids that are well suited to using renewable energy resources. We study the random failures of links in small networks where functionality depends on both spatial distance and topological connectedness. By introducing a percolation model where the failure of each link is proportional to its spatial length, we find that when failures depend on spatial distances, networks are more fragile than expected. Accounting for spatial effects in both construction and robustness is important for designing efficient microgrids and other network infrastructure.

Elicitors and co-factors in food-induced anaphylaxis in adults

PubMed Central

2013-01-01

Food-induced anaphylaxis (FIA) in adults is often insufficiently diagnosed. One reason is related to the presence of co-factors like exercise, alcohol, additives and non-steroidal anti-inflammatory drugs. The objective of this analysis was to retrospectively investigate the role of co-factors in patients with FIA. 93 adult patients with suspected FIA underwent double-blind, placebo-controlled food challenges with suspected allergens and co-factors. The elicitors of anaphylaxis were identified in 44/93 patients. 27 patients reacted to food allergens upon challenge, 15 patients reacted only when a co-factor was co-exposed with the allergen. The most common identified allergens were celery (n = 7), soy, wheat (n = 4 each) and lupine (n = 3). Among the co-factors food additives (n = 8) and physical exercise (n = 6) were most frequent. In 10 patients more than one co-factor and/or more than one food allergen was necessary to elicit a positive reaction. The implementation of co-factors into the challenge protocol increases the identification rate of elicitors in adult food anaphylactic patients. PMID:24262093

Ikkepsilon regulates viral-induced interferon regulatory factor-3 activation via a redox-sensitive pathway

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

Indukuri, Hemalatha; Castro, Shawn M.; Liao, S.-M.

2006-09-15

Respiratory syncytial virus (RSV)-induced chemokine gene expression occurs through the activation of a subset of transcription factors, including Interferon Regulatory Factor (IRF)-3. In this study, we have investigated the signaling pathway leading to RSV-induced IRF-3 activation and whether it is mediated by intracellular reactive oxygen species (ROS) generation. Our results show that RSV infection induces expression and catalytic activity of IKK{epsilon}, a noncanonical IKK-like kinase. Expression of a kinase-inactive IKK{epsilon} blocks RSV-induced IRF-3 serine phosphorylation, nuclear translocation and DNA-binding, leading to inhibition of RANTES gene transcription, mRNA expression and protein synthesis. Treatment of alveolar epithelial cells with antioxidants or withmore » NAD(P)H oxidase inhibitors abrogates RSV-induced chemokine secretion, IRF-3 phosphorylation and IKK{epsilon} induction, indicating that ROS generation plays a fundamental role in the signaling pathway leading to IRF-3 activation, therefore, identifying a novel molecular target for the development of strategies aimed to modify the inflammatory response associated with RSV infection of the lung.« less

Local factors modify the dose dependence of 56Fe-induced atherosclerosis.

NASA Astrophysics Data System (ADS)

Kucik, Dennis; Gupta, Kiran; Wu, Xing; Yu, Tao; Chang, Polly; Kabarowski, Janusz; Yu, Shaohua

2012-07-01

Radiation exposure from a number of terrestrial sources is associated with an increased risk of cardiovascular disease, but evidence establishing whether high-LET radiation has similar effects has been lacking. We recently demonstrated that 600 MeV/n 56Fe induces atherosclerosis as well. Ten-week old male apolipoprotein-E deficient mice, a well-characterized atherosclerosis animal model, were exposed to 0 (control) 2, or 5Gy 56Fe targeted to the chest and neck. In these mice, 56Fe-induced atherosclerosis was similar in character to that induced by X-rays in the same mouse model and to that resulting from therapeutic radiation in cancer patients. Atherosclerosis was exacerbated by 56Fe only in targeted areas, however, suggesting a direct effect of the radiation on the arteries themselves. This is in contrast to some other risk factors, such as high cholesterol or tobacco use, which have systemic effects. The radiation dose required to accelerate development of atherosclerotic plaques, however, differed depending on the vessel that was irradiated and even the location within the vessel. For example, atherosclerosis in the aortic arch was accelerated only by the highest dose (5 Gy), while the carotid arteries and the aortic root showed effects at 2 Gy (a dose four- to eight-fold lower than the dose of X-rays that produces similar effects in this model). Since shear stress is disrupted in the area of the aortic root, it is likely that at least part of the site-specificity is due to additive or synergistic effects of radiation and local hydrodynamics. Other factors, such as local oxidative stress or gene expression may also have been involved. Since the pro-atherogenic effects of 56Fe depend on additional local factors, this suggests that radiation exposure, when unavoidable, might be mitigated by modification of factors unrelated to the radiation itself.

Receptor Signaling Directs Global Recruitment of Pre-existing Transcription Factors to Inducible Elements.

PubMed

Cockerill, Peter N

2016-12-01

Gene expression programs are largely regulated by the tissue-specific expression of lineage-defining transcription factors or by the inducible expression of transcription factors in response to specific stimuli. Here I will review our own work over the last 20 years to show how specific activation signals also lead to the wide-spread re-distribution of pre-existing constitutive transcription factors to sites undergoing chromatin reorganization. I will summarize studies showing that activation of kinase signaling pathways creates open chromatin regions that recruit pre-existing factors which were previously unable to bind to closed chromatin. As models I will draw upon genes activated or primed by receptor signaling in memory T cells, and genes activated by cytokine receptor mutations in acute myeloid leukemia. I also summarize a hit-and-run model of stable epigenetic reprograming in memory T cells, mediated by transient Activator Protein 1 (AP-1) binding, which enables the accelerated activation of inducible enhancers.

Tumor necrosis factor alpha induces gamma-glutamyltransferase expression via nuclear factor-kappaB in cooperation with Sp1.

PubMed

Reuter, Simone; Schnekenburger, Michael; Cristofanon, Silvia; Buck, Isabelle; Teiten, Marie-Hélène; Daubeuf, Sandrine; Eifes, Serge; Dicato, Mario; Aggarwal, Bharat B; Visvikis, Athanase; Diederich, Marc

2009-02-01

Gamma-glutamyltransferase (GGT) cleaves the gamma-glutamyl moiety of glutathione (GSH), an endogenous antioxidant, and is involved in mercapturic acid metabolism and in cancer drug resistance when overexpressed. Moreover, GGT converts leukotriene (LT) C4 into LTD4 implicated in various inflammatory pathologies. So far the effect of inflammatory stimuli on regulation of GGT expression and activity remained to be addressed. We found that the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) induced GGT promoter transactivation, mRNA and protein synthesis, as well as enzymatic activity. Remicade, a clinically used anti-TNFalpha antibody, small interfering RNA (siRNA) against p50 and p65 nuclear factor-kappaB (NF-kappaB) isoforms, curcumin, a well characterized natural NF-kappaB inhibitor, as well as a dominant negative inhibitor of kappaB alpha (IkappaBalpha), prevented GGT activation at various levels, illustrating the involvement of this signaling pathway in TNFalpha-induced stimulation. Over-expression of receptor of TNFalpha-1 (TNFR1), TNFR-associated factor-2 (TRAF2), TNFR-1 associated death domain (TRADD), dominant negative (DN) IkappaBalpha or NF-kappaB p65 further confirmed GGT promoter activation via NF-kappaB. Linker insertion mutagenesis of 536 bp of the proximal GGT promoter revealed NF-kappaB and Sp1 binding sites at -110 and -78 relative to the transcription start site, responsible for basal GGT transcription. Mutation of the NF-kappaB site located at -110 additionally inhibited TNFalpha-induced promoter induction. Chromatin immunoprecipitation (ChIP) assays confirmed mutagenesis results and further demonstrated that TNFalpha treatment induced in vivo binding of both NF-kappaB and Sp1, explaining increased GGT expression, and led to RNA polymerase II recruitment under inflammatory conditions.

Optimizing the robustness of electrical power systems against cascading failures.

PubMed

Zhang, Yingrui; Yağan, Osman

2016-06-21

Electrical power systems are one of the most important infrastructures that support our society. However, their vulnerabilities have raised great concern recently due to several large-scale blackouts around the world. In this paper, we investigate the robustness of power systems against cascading failures initiated by a random attack. This is done under a simple yet useful model based on global and equal redistribution of load upon failures. We provide a comprehensive understanding of system robustness under this model by (i) deriving an expression for the final system size as a function of the size of initial attacks; (ii) deriving the critical attack size after which system breaks down completely; (iii) showing that complete system breakdown takes place through a first-order (i.e., discontinuous) transition in terms of the attack size; and (iv) establishing the optimal load-capacity distribution that maximizes robustness. In particular, we show that robustness is maximized when the difference between the capacity and initial load is the same for all lines; i.e., when all lines have the same redundant space regardless of their initial load. This is in contrast with the intuitive and commonly used setting where capacity of a line is a fixed factor of its initial load.

Robust multi-model control of an autonomous wind power system

NASA Astrophysics Data System (ADS)

Cutululis, Nicolas Antonio; Ceanga, Emil; Hansen, Anca Daniela; Sørensen, Poul

2006-09-01

This article presents a robust multi-model control structure for a wind power system that uses a variable speed wind turbine (VSWT) driving a permanent magnet synchronous generator (PMSG) connected to a local grid. The control problem consists in maximizing the energy captured from the wind for varying wind speeds. The VSWT-PMSG linearized model analysis reveals the resonant nature of its dynamic at points on the optimal regimes characteristic (ORC). The natural frequency of the system and the damping factor are strongly dependent on the operating point on the ORC. Under these circumstances a robust multi-model control structure is designed. The simulation results prove the viability of the proposed control structure. Copyright

Multilevel robustness

NASA Astrophysics Data System (ADS)

Girard, Henri-Louis; Khan, Sami; Varanasi, Kripa K.

2018-03-01

A combination of hard, soft and nanoscale organic components results in robust superhydrophobic surfaces that can withstand mechanical abrasion and chemical oxidation, and exhibit excellent substrate adhesion.

Robustness of Thirty Meter Telescope primary mirror control

NASA Astrophysics Data System (ADS)

Macmynowski, Douglas G.; Thompson, Peter M.; Shelton, Chris; Roberts, Lewis C., Jr.

2010-07-01

The primary mirror control system for the Thirty Meter Telescope (TMT) maintains the alignment of the 492 segments in the presence of both quasi-static (gravity and thermal) and dynamic disturbances due to unsteady wind loads. The latter results in a desired control bandwidth of 1Hz at high spatial frequencies. The achievable bandwidth is limited by robustness to (i) uncertain telescope structural dynamics (control-structure interaction) and (ii) small perturbations in the ill-conditioned influence matrix that relates segment edge sensor response to actuator commands. Both of these effects are considered herein using models of TMT. The former is explored through multivariable sensitivity analysis on a reduced-order Zernike-basis representation of the structural dynamics. The interaction matrix ("A-matrix") uncertainty has been analyzed theoretically elsewhere, and is examined here for realistic amplitude perturbations due to segment and sensor installation errors, and gravity and thermal induced segment motion. The primary influence of A-matrix uncertainty is on the control of "focusmode"; this is the least observable mode, measurable only through the edge-sensor (gap-dependent) sensitivity to the dihedral angle between segments. Accurately estimating focus-mode will require updating the A-matrix as a function of the measured gap. A-matrix uncertainty also results in a higher gain-margin requirement for focus-mode, and hence the A-matrix and CSI robustness need to be understood simultaneously. Based on the robustness analysis, the desired 1 Hz bandwidth is achievable in the presence of uncertainty for all except the lowest spatial-frequency response patterns of the primary mirror.

Fibroblast Growth Factor 23–Induced Hypophosphatemia in Acute Leukemia

PubMed Central

Reinert, Rachel B; Bixby, Dale; Koenig, Ronald J

2018-01-01

Abstract Fibroblast growth factor 23 (FGF23)–induced hypophosphatemia is a rare paraneoplastic syndrome of phosphate wasting that, if unrecognized, may cause tumor-induced osteomalacia. It is classically associated with benign mesenchymal tumors but occasionally has been found in patients with other malignancies. Hypophosphatemia has been associated with acute leukemia but has not previously been reported to be due to inappropriate FGF23 secretion. Here, we describe FGF23-induced severe hypophosphatemia and renal phosphate wasting associated with a mixed-phenotype Philadelphia chromosome-like acute leukemia in a previously healthy 22-year-old man. He was found to have low serum 1,25-dihydroxyvitamin D and extremely high FGF23 levels, as well as inappropriate urinary phosphorus excretion. The hypophosphatemia improved with calcitriol and oral phosphate treatment but normalized only during chemotherapy-induced ablation of the blasts. FGF23 levels declined with a reduction in peripheral blast counts. Using real-time reverse transcription polymerase chain reaction, we found that the leukemia cells were the source of FGF23. To our knowledge, this is the first description of FGF23-induced hypophosphatemia associated with acute leukemia. We recommend that the FGF23 paraneoplastic syndrome be considered as a possible etiology of hypophosphatemia in patients with acute leukemia. PMID:29696242

Mechanisms for Robust Cognition

ERIC Educational Resources Information Center

Walsh, Matthew M.; Gluck, Kevin A.

2015-01-01

To function well in an unpredictable environment using unreliable components, a system must have a high degree of robustness. Robustness is fundamental to biological systems and is an objective in the design of engineered systems such as airplane engines and buildings. Cognitive systems, like biological and engineered systems, exist within…

The Kmif (Kveim-induced macrophage migration inhibition factor) test in sarcoidosis

PubMed Central

Williams, W. Jones; Pioli, E.; Jones, D. J.; Dighero, M.

1972-01-01

Circulating lymphocytes from 30 patients with sarcoidosis when stimulated in vitro with Kveim-induced macrophage migration factor, the Kmif test, produced a guinea-pig macrophage migration inhibition factor in 21 of 30 cases (70%). In those patients not on steroids the results showed a good correlation with the cutaneous Kveim test. One positive test was found in 16 normal subjects. Our results suggest that the Kmif test may prove a useful rapid alternative to the Kveim test. PMID:4675181

Ovulation-inducing factor: a protein component of llama seminal plasma

PubMed Central

2010-01-01

Background Previously, we documented the presence of ovulation-inducing factor (OIF) in the seminal plasma of llamas and alpacas. The purpose of the study was to define the biochemical characteristics of the molecule(s) in seminal plasma responsible for inducing ovulation. Methods In Experiment 1, llama seminal plasma was centrifuged using filtration devices with nominal molecular mass cut-offs of 30, 10 and 5 kDa. Female llamas (n = 9 per group) were treated i.m. with whole seminal plasma (positive control), phosphate-buffered saline (negative control), or the fraction of seminal plasma equal or higher than 30 kDa, 10 to 30 kDa, 5 to 10 kDa, or < 5 kDa. In Experiment 2, female llamas (n = 7 per group) were given an i.m. dose of seminal plasma treated previously by: 1) enzymatic digestion with proteinase-K, 2) incubation with charcoal-dextran, 3) heating to 65°C, or 4) untreated (control). In Experiment 3, female llamas (n = 10 per group) were given an i.m. dose of pronase-treated or non-treated (control) seminal plasma. In all experiments, llamas were examined by transrectal ultrasonography to detect ovulation and CL formation. Ovulation rate was compared among groups by Fisher's exact test and follicle and CL diameters were compared among groups by analyses of variance or student's t-tests. Results In Experiment 1, all llamas in the equal or higher than 30 kDa and positive control groups ovulated (9/9 in each), but none ovulated in the other groups (P < 0.001). In Experiment 2, ovulations were detected in all llamas in each treatment group; i.e., respective treatments of seminal plasma failed to inactivate the ovulation-inducing factor. In Experiment 3, ovulations were detected in 0/10 llamas given pronase-treated seminal plasma and in 9/10 controls (P < 0.01). Conclusions We conclude that ovulation-inducing factor (OIF) in llama seminal plasma is a protein molecule that is resistant to heat and enzymatic digestion with proteinase K, and has a molecular mass of

Glutathione regulation of redox-sensitive signals in tumor necrosis factor-{alpha}-induced vascular endothelial dysfunction

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

Tsou, T.-C.; Yeh, S.C.; Tsai, F.-Y.

2007-06-01

We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-{alpha})-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-{alpha} induces various biological effects on vascular cells, TNF-{alpha} dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-{alpha} concentrations, we adopted the lower TNF-{alpha} (0.2 ng/ml) to rule out the possible involvement of other TNF-{alpha}-induced biological effects. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-{alpha}-induced adhesion molecule expression and monocyte-endothelial monolayermore » binding. BSO attenuated the TNF-{alpha}-induced nuclear factor-kappaB (NF-{kappa}B) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-{alpha}. Inhibition of ERK, JNK, or NF-{kappa}B attenuates TNF-{alpha}-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-{alpha} induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-{kappa}B in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-{alpha}. Although AP-1 activation by the lower TNF-{alpha} was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-{alpha}-induced adhesion molecule expression.« less

Technetium-99 conjugated with methylene diphosphonate inhibits receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis.

PubMed

Gong, Wei; Dou, Huan; Liu, Xianqin; Sun, Lingyun; Hou, Yayi

2012-10-01

1. In the present study, we investigated the effects of technetium-99 conjugated with methylene diphosphonate ((99)Tc-MDP), an agent used in radionuclide therapy, on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and explored the underlying mechanisms. 2. The murine macrophage cell line RAW264.7 and bone marrow-derived-macrophages from C57BL/6 mice (BMM) were used as models for osteoclastogenesis in vitro. The expression of some key factors in RANKL (50 ng/mL)-induced osteoclastogenesis in RAW264.7 cells was investigated by flow cytometry and real-time reverse transcription-polymerase chain reaction (RT-PCR). To detect multinucleated osteoclast formation, RAW264.7 cells were induced with RANKL for 4 days, whereas BMM were induced by 50 ng/mL RANKL and 20 ng/mL macrophage colony-stimulating factor for 7 days, before being stained with tartrate-resistant acid phosphatase. 3. Osteoclastogenesis was evaluated using the osteoclast markers CD51, matrix metalloproteinase (MMP)-9 and cathepsin K. At 0.01 μg/mL, (99)Tc-MDP significantly inhibited RANKL-induced osteoclastogenesis without any cytotoxicity. In addition, (99)Tc-MDP abolished the appearance of multinucleated osteoclasts. 4. Real-time RT-PCR analysis of transcription factor expression revealed that (99)Tc-MDP inhibited the expression of c-Fos and nuclear factor of activated T cells. In addition, (99)Tc-MDP inhibited the expression of the inflammatory factors interleukin (IL)-6, tumour necrosis factor-α and IL-1β. Finally, (99)Tc-MDP inhibited the activation of mitogen-activated protein kinases in RAW264.7 cells following RANKL stimulation. 5. In conclusion, (99)Tc-MDP possesses anti-osteoclastogenic activity against RANKL-induced osteoclast formation. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

Platelet-Released Growth Factors Induce Differentiation of Primary Keratinocytes

PubMed Central

Tohidnezhad, Mersedeh; Lammel, Justus; Lippross, Sebastian; Behrendt, Peter; Klüter, Tim; Pufe, Thomas; Jahr, Holger; Cremer, Jochen; Rademacher, Franziska; Gläser, Regine; Harder, Jürgen

2017-01-01

Autologous thrombocyte concentrate lysates, for example, platelet-released growth factors, (PRGFs) or their clinically related formulations (e.g., Vivostat PRF®) came recently into the physicians' focus as they revealed promising effects in regenerative and reparative medicine such as the support of healing of chronic wounds. To elucidate the underlying mechanisms, we analyzed the influence of PRGF and Vivostat PRF on human keratinocyte differentiation in vitro and on epidermal differentiation status of skin wounds in vivo. Therefore, we investigated the expression of early (keratin 1 and keratin 10) and late (transglutaminase-1 and involucrin) differentiation markers. PRGF treatment of primary human keratinocytes decreased keratin 1 and keratin 10 gene expression but induced involucrin and transglutaminase-1 gene expression in an epidermal growth factor receptor- (EGFR-) dependent manner. In concordance with these results, microscopic analyses revealed that PRGF-treated human keratinocytes displayed morphological features typical of keratinocytes undergoing terminal differentiation. In vivo treatment of artificial human wounds with Vivostat PRF revealed a significant induction of involucrin and transglutaminase-1 gene expression. Together, our results indicate that PRGF and Vivostat PRF induce terminal differentiation of primary human keratinocytes. This potential mechanism may contribute to the observed beneficial effects in the treatment of hard-to-heal wounds with autologous thrombocyte concentrate lysates in vivo. PMID:28808357

Exercise Protects against PCB-Induced Inflammation and Associated Cardiovascular Risk Factors

PubMed Central

Murphy, Margaret O.; Petriello, Michael C.; Han, Sung Gu; Sunkara, Manjula; Morris, Andrew J; Esser, Karyn; Hennig, Bernhard

2015-01-01

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that contribute to the initiation of cardiovascular disease. Exercise has been shown to reduce the risk of cardiovascular disease; however, whether exercise can modulate PCB-induced vascular endothelial dysfunction and associated cardiovascular risk factors is unknown. We examined the effects of exercise on coplanar PCB- induced cardiovascular risk factors including oxidative stress, inflammation, impaired glucose tolerance, hypercholesteremia, and endothelium-dependent relaxation. Male ApoE−/− mice were divided into sedentary and exercise groups (voluntary wheel running) over a 12 week period. Half of each group was exposed to vehicle or PCB 77 at weeks 1, 2, 9, and 10. For ex vivo studies, male C57BL/6 mice exercised via voluntary wheel training for 5 weeks and then were administered with vehicle or PCB 77 24 hours before vascular reactivity studies were performed. Exposure to coplanar PCB increased risk factors associated with cardiovascular disease, including oxidative stress and systemic inflammation, glucose intolerance, and hypercholesteremia. The 12 week exercise intervention significantly reduced these pro-atherogenic parameters. Exercise also upregulated antioxidant enzymes including phase II detoxification enzymes. Sedentary animals exposed to PCB 77 exhibited endothelial dysfunction as demonstrated by significant impairment of endothelium-dependent relaxation, which was prevented by exercise. Lifestyle modifications such as aerobic exercise could be utilized as a therapeutic approach for the prevention of adverse cardiovascular health effects induced by environmental pollutants such as PCBs. Keywords: exercise, polychlorinated biphenyl, endothelial function, antioxidant response, cardiovascular disease, inflammation, oxidative stress PMID:25586614

Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity.

PubMed

Dilshara, Matharage Gayani; Kang, Chang-Hee; Choi, Yung Hyun; Kim, Gi-Young

2015-10-01

We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-α-stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-α-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-α significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-α-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-α-induced invasion of LNCaP cells. Compared to untreated controls, TNF-α-stimulated LNCaP cells showed a significant increase in nuclear factor-κB (NF-κB) luciferase activity. However, mangiferin treatment markedly decreased TNF-α-induced NF-κB luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-κB subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-κB-mediated MMP-9 expression.

Robust finger vein ROI localization based on flexible segmentation.

PubMed

Lu, Yu; Xie, Shan Juan; Yoon, Sook; Yang, Jucheng; Park, Dong Sun

2013-10-24

Finger veins have been proved to be an effective biometric for personal identification in the recent years. However, finger vein images are easily affected by influences such as image translation, orientation, scale, scattering, finger structure, complicated background, uneven illumination, and collection posture. All these factors may contribute to inaccurate region of interest (ROI) definition, and so degrade the performance of finger vein identification system. To improve this problem, in this paper, we propose a finger vein ROI localization method that has high effectiveness and robustness against the above factors. The proposed method consists of a set of steps to localize ROIs accurately, namely segmentation, orientation correction, and ROI detection. Accurate finger region segmentation and correct calculated orientation can support each other to produce higher accuracy in localizing ROIs. Extensive experiments have been performed on the finger vein image database, MMCBNU_6000, to verify the robustness of the proposed method. The proposed method shows the segmentation accuracy of 100%. Furthermore, the average processing time of the proposed method is 22 ms for an acquired image, which satisfies the criterion of a real-time finger vein identification system.

Robust Finger Vein ROI Localization Based on Flexible Segmentation

PubMed Central

Lu, Yu; Xie, Shan Juan; Yoon, Sook; Yang, Jucheng; Park, Dong Sun

2013-01-01

Finger veins have been proved to be an effective biometric for personal identification in the recent years. However, finger vein images are easily affected by influences such as image translation, orientation, scale, scattering, finger structure, complicated background, uneven illumination, and collection posture. All these factors may contribute to inaccurate region of interest (ROI) definition, and so degrade the performance of finger vein identification system. To improve this problem, in this paper, we propose a finger vein ROI localization method that has high effectiveness and robustness against the above factors. The proposed method consists of a set of steps to localize ROIs accurately, namely segmentation, orientation correction, and ROI detection. Accurate finger region segmentation and correct calculated orientation can support each other to produce higher accuracy in localizing ROIs. Extensive experiments have been performed on the finger vein image database, MMCBNU_6000, to verify the robustness of the proposed method. The proposed method shows the segmentation accuracy of 100%. Furthermore, the average processing time of the proposed method is 22 ms for an acquired image, which satisfies the criterion of a real-time finger vein identification system. PMID:24284769

Sphingosine-1-phosphate mediates epidermal growth factor-induced muscle satellite cell activation

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

Nagata, Yosuke, E-mail: cynagata@mail.ecc.u-tokyo.ac.jp; Ohashi, Kazuya; Wada, Eiji

2014-08-01

Skeletal muscle can regenerate repeatedly due to the presence of resident stem cells, called satellite cells. Because satellite cells are usually quiescent, they must be activated before participating in muscle regeneration in response to stimuli such as injury, overloading, and stretch. Although satellite cell activation is a crucial step in muscle regeneration, little is known of the molecular mechanisms controlling this process. Recent work showed that the bioactive lipid sphingosine-1-phosphate (S1P) plays crucial roles in the activation, proliferation, and differentiation of muscle satellite cells. We investigated the role of growth factors in S1P-mediated satellite cell activation. We found that epidermalmore » growth factor (EGF) in combination with insulin induced proliferation of quiescent undifferentiated mouse myoblast C2C12 cells, which are also known as reserve cells, in serum-free conditions. Sphingosine kinase activity increased when reserve cells were stimulated with EGF. Treatment of reserve cells with the D-erythro-N,N-dimethylsphingosine, Sphingosine Kinase Inhibitor, or siRNA duplexes specific for sphingosine kinase 1, suppressed EGF-induced C2C12 activation. We also present the evidence showing the S1P receptor S1P2 is involved in EGF-induced reserve cell activation. Moreover, we demonstrated a combination of insulin and EGF promoted activation of satellite cells on single myofibers in a manner dependent on SPHK and S1P2. Taken together, our observations show that EGF-induced satellite cell activation is mediated by S1P and its receptor. - Highlights: • EGF in combination with insulin induces proliferation of quiescent C2C12 cells. • Sphingosine kinase activity increases when reserve cells are stimulated with EGF. • EGF-induced activation of reserve cells is dependent on sphingosine kinase and ERK. • The S1P receptor S1P2 is involved in EGF-induced reserve cell activation. • EGF-induced reserve cell activation is mediated by S1P and

Phenomenology of the sound-induced flash illusion.

PubMed

Abadi, Richard V; Murphy, Jonathan S

2014-07-01

Past studies, using pairings of auditory tones and visual flashes, which were static and coincident in space but variable in time, demonstrated errors in judging the temporal patterning of the visual flashes-the sound-induced flash illusion. These errors took one of the two forms: under-reporting (sound-induced fusion) or over-reporting (sound-induced fission) of the flash numbers. Our study had three objectives: to examine the robustness of both illusions and to consider the effects of stimulus set and response bias. To this end, we used an extended range of fixed spatial location flash-tone pairings, examined stimuli that were variable in space and time and measured confidence in judging flash numbers. Our results indicated that the sound-induced flash illusion is a robust percept, a finding underpinned by the confidence measures. Sound-induced fusion was found to be more robust than sound-induced fission and a most likely outcome when high numbers of flashes were incorporated within an incongruent flash-tone pairing. Conversely, sound-induced fission was the most likely outcome for the flash-tone pairing which contained two flashes. Fission was also shown to be strongly driven by stimuli confounds such as categorical boundary conditions (e.g. flash-tone pairings with ≤2 flashes) and compressed response options. These findings suggest whilst both fission and fusion are associated with 'auditory driving', the differences in the occurrence and strength of the two illusions not only reflect the separate neuronal mechanisms underlying audio and visual signal processing, but also the test conditions that have been used to investigate the sound-induced flash illusion.

Robust control of accelerators

NASA Astrophysics Data System (ADS)

Joel, W.; Johnson, D.; Chaouki, Abdallah T.

1991-07-01

The problem of controlling the variations in the rf power system can be effectively cast as an application of modern control theory. Two components of this theory are obtaining a model and a feedback structure. The model inaccuracies influence the choice of a particular controller structure. Because of the modelling uncertainty, one has to design either a variable, adaptive controller or a fixed, robust controller to achieve the desired objective. The adaptive control scheme usually results in very complex hardware; and, therefore, shall not be pursued in this research. In contrast, the robust control method leads to simpler hardware. However, robust control requires a more accurate mathematical model of the physical process than is required by adaptive control. Our research at the Los Alamos National Laboratory (LANL) and the University of New Mexico (UNM) has led to the development and implementation of a new robust rf power feedback system. In this article, we report on our research progress. In section 1, the robust control problem for the rf power system and the philosophy adopted for the beginning phase of our research is presented. In section 2, the results of our proof-of-principle experiments are presented. In section 3, we describe the actual controller configuration that is used in LANL FEL physics experiments. The novelty of our approach is that the control hardware is implemented directly in rf. without demodulating, compensating, and then remodulating.

Berberine Induces Caspase-Independent Cell Death in Colon Tumor Cells through Activation of Apoptosis-Inducing Factor

PubMed Central

Wang, Lihong; Liu, Liping; Shi, Yan; Cao, Hanwei; Chaturvedi, Rupesh; Calcutt, M. Wade; Hu, Tianhui; Ren, Xiubao; Wilson, Keith T.; Polk, D. Brent; Yan, Fang

2012-01-01

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc min mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth. PMID:22574158

Three-phase power factor controller with induced EMF sensing

NASA Technical Reports Server (NTRS)

Nola, F. J. (Inventor)

1984-01-01

A power factor controller for an ac induction motor is provided which is of the type comprising thyristor switches connected in series with the motor, phase detectors for sensing the motor current and voltage and providing an output proportional to the phase difference between the motor voltage and current, and a control circuit, responsive to the output of the phase detector and to a power factor command signal, for controlling switching of the thyristor. The invention involves sensing the induced emf produced by the motor during the time interval when the thyristor is off and for producing a corresponding feedback signal for controlling switching of the thyristor. The sensed emf is also used to enhance soft starting of the motor.

Hypoxic preconditioning protects photoreceptors against light damage independently of hypoxia inducible transcription factors in rods.

PubMed

Kast, Brigitte; Schori, Christian; Grimm, Christian

2016-05-01

Hypoxic preconditioning protects photoreceptors against light-induced degeneration preserving retinal morphology and function. Although hypoxia inducible transcription factors 1 and 2 (HIF1, HIF2) are the main regulators of the hypoxic response, photoreceptor protection does not depend on HIF1 in rods. Here we used rod-specific Hif2a single and Hif1a;Hif2a double knockout mice to investigate the potential involvement of HIF2 in rods for protection after hypoxic preconditioning. To identify potential HIF2 target genes in rods we determined the retinal transcriptome of hypoxic control and rod-specific Hif2a knockouts by RNA sequencing. We show that rods do not need HIF2 for hypoxia-induced increased survival after light exposure. The transcriptomic analysis revealed a number of genes that are potentially regulated by HIF2 in rods; among those were Htra1, Timp3 and Hmox1, candidates that are interesting due to their connection to human degenerative diseases of the retina. We conclude that neither HIF1 nor HIF2 are required in photoreceptors for protection by hypoxic preconditioning. We hypothesize that HIF transcription factors may be needed in other cells to produce protective factors acting in a paracrine fashion on photoreceptor cells. Alternatively, hypoxic preconditioning induces a rod-intrinsic response that is independent of HIF transcription factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Role for the epidermal growth factor receptor in chemotherapy-induced alopecia.

PubMed

Bichsel, Kyle J; Gogia, Navdeep; Malouff, Timothy; Pena, Zachary; Forney, Eric; Hammiller, Brianna; Watson, Patrice; Hansen, Laura A

2013-01-01

Treatment of cancer patients with chemotherapeutics like cyclophosphamide often causes alopecia as a result of premature and aberrant catagen. Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia. To test this hypothesis, skin-targeted Egfr mutant mice were generated by crossing floxed Egfr and Keratin 14 promoter-driven Cre recombinase mice. Cyclophosphamide treatment of control mice resulted in alopecia while Egfr mutant skin was resistant to cyclophosphamide-induced alopecia. Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles. Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide. Treatment of control mice with the EGFR inhibitors erlotinib or gefitinib similarly suppressed alopecia and catagen progression by cyclophosphamide. Secondary analysis of clinical trials utilizing EGFR-targeted therapies and alopecia-inducing chemotherapy also revealed evidence for involvement of EGFR in chemotherapy-induced alopecia. Taken together, our results demonstrated the involvement of EGFR signaling in chemotherapy-induced alopecia, which will help in the design of novel therapeutic regimens to minimize chemotherapy-induced alopecia.

Multiobjective robust design of the double wishbone suspension system based on particle swarm optimization.

PubMed

Cheng, Xianfu; Lin, Yuqun

2014-01-01

The performance of the suspension system is one of the most important factors in the vehicle design. For the double wishbone suspension system, the conventional deterministic optimization does not consider any deviations of design parameters, so design sensitivity analysis and robust optimization design are proposed. In this study, the design parameters of the robust optimization are the positions of the key points, and the random factors are the uncertainties in manufacturing. A simplified model of the double wishbone suspension is established by software ADAMS. The sensitivity analysis is utilized to determine main design variables. Then, the simulation experiment is arranged and the Latin hypercube design is adopted to find the initial points. The Kriging model is employed for fitting the mean and variance of the quality characteristics according to the simulation results. Further, a particle swarm optimization method based on simple PSO is applied and the tradeoff between the mean and deviation of performance is made to solve the robust optimization problem of the double wishbone suspension system.

Robust High-Capacity Audio Watermarking Based on FFT Amplitude Modification

NASA Astrophysics Data System (ADS)

Fallahpour, Mehdi; Megías, David

This paper proposes a novel robust audio watermarking algorithm to embed data and extract it in a bit-exact manner based on changing the magnitudes of the FFT spectrum. The key point is selecting a frequency band for embedding based on the comparison between the original and the MP3 compressed/decompressed signal and on a suitable scaling factor. The experimental results show that the method has a very high capacity (about 5kbps), without significant perceptual distortion (ODG about -0.25) and provides robustness against common audio signal processing such as added noise, filtering and MPEG compression (MP3). Furthermore, the proposed method has a larger capacity (number of embedded bits to number of host bits rate) than recent image data hiding methods.

Robust odd-parity superconductivity in the doped topological insulator Nb x Bi 2 Se 3

DOE PAGES

Smylie, M. P.; Willa, K.; Claus, H.; ...

2017-09-15

We present resistivity and magnetization measurements on proton-irradiated crystals demonstrating that the superconducting state in the doped topological insulator Nb xBi 2Se 3 (x = 0.25) is surprisingly robust against disorder-induced electron scattering. The superconducting transition temperature Tc decreases without indication of saturation with increasing defect concentration, and the corresponding scattering rates far surpass expectations based on conventional theory. The low-temperature variation of the London penetration depth Δλ(T) follows a power law [Δλ(T)~T 2] indicating the presence of symmetry-protected point nodes. Lastly, our results are consistent with the proposed robust nematic E u pairing state in this material.

Robust Group Sparse Beamforming for Multicast Green Cloud-RAN With Imperfect CSI

NASA Astrophysics Data System (ADS)

Shi, Yuanming; Zhang, Jun; Letaief, Khaled B.

2015-09-01

In this paper, we investigate the network power minimization problem for the multicast cloud radio access network (Cloud-RAN) with imperfect channel state information (CSI). The key observation is that network power minimization can be achieved by adaptively selecting active remote radio heads (RRHs) via controlling the group-sparsity structure of the beamforming vector. However, this yields a non-convex combinatorial optimization problem, for which we propose a three-stage robust group sparse beamforming algorithm. In the first stage, a quadratic variational formulation of the weighted mixed l1/l2-norm is proposed to induce the group-sparsity structure in the aggregated beamforming vector, which indicates those RRHs that can be switched off. A perturbed alternating optimization algorithm is then proposed to solve the resultant non-convex group-sparsity inducing optimization problem by exploiting its convex substructures. In the second stage, we propose a PhaseLift technique based algorithm to solve the feasibility problem with a given active RRH set, which helps determine the active RRHs. Finally, the semidefinite relaxation (SDR) technique is adopted to determine the robust multicast beamformers. Simulation results will demonstrate the convergence of the perturbed alternating optimization algorithm, as well as, the effectiveness of the proposed algorithm to minimize the network power consumption for multicast Cloud-RAN.

Moisture-Induced Alumina Scale Spallation: The Hydrogen Factor

NASA Technical Reports Server (NTRS)

Smialek, James L.

2010-01-01

For some time the oxidation community has been concerned with interfacial spallation of protective alumina scales, not just upon immediate cool down, but as a time-delayed phenomenon. Moisture-induced delayed spallation (MIDS) and desktop spallation (DTS) of thermal barrier coatings (TBCs) refer to this process. It is most apparent for relatively adherent alumina scales that have survived initial cool down in a dry environment, have built up considerable thickness and strain energy, and have been somewhat damaged, such as by cyclic oxidation cracking. Indeed, a "sensitive zone" can be described that maximizes the observed effect as a function of all the relevant factors. Moisture has been postulated to serve as a source of interfacial hydrogen embrittlement. Hydrogen is derived from reaction with aluminum in the alloy at an exposed interface. The purpose of this monograph is to trace the close analogy of this phenomenon to other hydrogen-induced effects, such as embrittlement of aluminides and blistering of alloys and anodic alumina films. A formalized, top-down, logic-tree structure is presented as a guide to this discussion. A theoretical basis for interfacial weakening by hydrogen is first cited, as are demonstrations of hydrogen detection as a reaction product or interfacial species. Further support is provided by critical experiments that recreate the moisture effect, but by isolating hydrogen from other potential causative factors. These experiments include tests in H 2-containing atmospheres or cathodic hydrogen charging. Accordingly, they strongly indicate that interfacial hydrogen, derived from moisture, is the key chemical species accounting for delayed alumina scale spallation.

A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population

PubMed Central

WATANABE, YUSAKU; YOSHIMURA, KIYOSHI; YOSHIKAWA, KOICHI; TSUNEDOMI, RYOICHI; SHINDO, YOSHITARO; MATSUKUMA, SOU; MAEDA, NORIKO; KANEKIYO, SHINSUKE; SUZUKI, NOBUAKI; KURAMASU, ATSUO; SONODA, KOUHEI; TAMADA, KOJI; KOBAYASHI, SEI; SAYA, HIDEYUKI; HAZAMA, SHOICHI; OKA, MASAAKI

2014-01-01

Cancer stem cells (CSCs) have been studied for their self-renewal capacity and pluripotency, as well as their resistance to anticancer therapy and their ability to metastasize to distant organs. CSCs are difficult to study because their population is quite low in tumor specimens. To overcome this problem, we established a culture method to induce a pancreatic cancer stem-like cell (P-CSLC)-enriched population from human pancreatic cancer cell lines. Human pancreatic cancer cell lines established at our department were cultured in CSC-inducing media containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), neural cell survivor factor-1 (NSF-1), and N-acetylcysteine. Sphere cells were obtained and then transferred to a laminin-coated dish and cultured for approximately two months. The surface markers, gene expression, aldehyde dehydrogenase (ALDH) activity, cell cycle, and tumorigenicity of these induced cells were examined for their stem cell-like characteristics. The population of these induced cells expanded within a few months. The ratio of CD24high, CD44high, epithelial specific antigen (ESA) high, and CD44variant (CD44v) high cells in the induced cells was greatly enriched. The induced cells stayed in the G0/G1 phase and demonstrated mesenchymal and stemness properties. The induced cells had high tumorigenic potential. Thus, we established a culture method to induce a P-CSLCenriched population from human pancreatic cancer cell lines. The CSLC population was enriched approximately 100-fold with this method. Our culture method may contribute to the precise analysis of CSCs and thus support the establishment of CSC-targeting therapy. PMID:25118635

Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage

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

Yang, Bei; Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang 110001; Fu, Jingqi

2012-11-01

Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs{sup 3+}) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic β-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA andmore » pancreatic islets isolated from Nrf2-knockout (Nrf2−/−) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs{sup 3+} exposure. As a result, Nrf2-KD MIN6 cells and Nrf2−/− islets were more susceptible to iAs{sup 3+} and monomethylarsonous acid (MMA{sup 3+})-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs{sup 3+}-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N‐acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs{sup 3+}. The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic β-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic β-cell dysfunction induced by environmental arsenic exposure. -- Highlights: ► Lack of Nrf2 reduced expression of antioxidant genes induced by iAs{sup 3+} in β-cells. ► Deficiency of Nrf2 in �

Coronary Serum Obtained After Myocardial Infarction Induces Angiogenesis and Microvascular Obstruction Repair. Role of Hypoxia-inducible Factor-1A.

PubMed

Ríos-Navarro, César; Hueso, Luisa; Miñana, Gema; Núñez, Julio; Ruiz-Saurí, Amparo; Sanz, María Jesús; Cànoves, Joaquin; Chorro, Francisco J; Piqueras, Laura; Bodí, Vicente

2018-06-01

Microvascular obstruction (MVO) exerts deleterious effects following acute myocardial infarction (AMI). We investigated coronary angiogenesis induced by coronary serum and the role of hypoxia-inducible factor-1A (HIF-1A) in MVO repair. Myocardial infarction was induced in swine by transitory 90-minute coronary occlusion. The pigs were divided into a control group and 4 AMI groups: no reperfusion, 1minute, 1 week and 1 month after reperfusion. Microvascular obstruction and microvessel density were quantified. The proangiogenic effect of coronary serum drawn from coronary sinus on endothelial cells was evaluated using an in vitro tubulogenesis assay. Circulating and myocardial HIF-1A levels and the effect of in vitro blockade of HIF-1A was assessed. Compared with control myocardium, microvessel density decreased at 90-minute ischemia, and MVO first occurred at 1minute after reperfusion. Both peaked at 1 week and almost completely resolved at 1 month. Coronary serum exerted a neoangiogenic effect on coronary endothelial cells in vitro, peaking at ischemia and 1minute postreperfusion (32 ± 4 and 41 ± 9 tubes vs control: 3 ± 3 tubes; P < .01). Hypoxia-inducible factor-1A increased in serum during ischemia (5-minute ischemia: 273 ± 52 pg/mL vs control: 148 ± 48 pg/mL; P < .01) being present on microvessels of all AMI groups (no reperfusion: 67% ± 5% vs control: 15% ± 17%; P < .01). In vitro blockade of HIF-1A reduced the angiogenic response induced by serum. Coronary serum represents a potent neoangiogenic stimulus even before reperfusion; HIF-1A might be crucial. Coronary neoangiogenesis induced by coronary serum can contribute to understanding the pathophysiology of AMI. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Robust control for uncertain structures

NASA Technical Reports Server (NTRS)

Douglas, Joel; Athans, Michael

1991-01-01

Viewgraphs on robust control for uncertain structures are presented. Topics covered include: robust linear quadratic regulator (RLQR) formulas; mismatched LQR design; RLQR design; interpretations of RLQR design; disturbance rejection; and performance comparisons: RLQR vs. mismatched LQR.

Surfactant functionalization induces robust, differential adhesion of tumor cells and blood cells to charged nanotube-coated biomaterials under flow.

PubMed

Mitchell, Michael J; Castellanos, Carlos A; King, Michael R

2015-07-01

The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion. Copyright © 2015 Elsevier Ltd. All rights reserved.

Surfactant Functionalization Induces Robust, Differential Adhesion of Tumor Cells and Blood Cells to Charged Nanotube-Coated Biomaterials Under Flow

PubMed Central

Mitchell, Michael J.; Castellanos, Carlos A.; King, Michael R.

2015-01-01

The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion. PMID:25934290

Predictive factor and antihypertensive usage of tyrosine kinase inhibitor-induced hypertension in kidney cancer patients

PubMed Central

IZUMI, KOUJI; ITAI, SHINGO; TAKAHASHI, YOSHIKO; MAOLAKE, AERKEN; NAMIKI, MIKIO

2014-01-01

Hypertension (HT) is the common adverse event associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKI). The present study was performed to identify the predictive factors of TKI-induced HT and to determine the classes of antihypertensive agents (AHTA) that demonstrate optimal efficacy against this type of HT. The charts of 50 cases of patients that had received VEGFR-TKI treatment were retrospectively examined. The association between patient background and TKI-induced HT, and the effect of administering AHTA were analyzed. High systolic blood pressure at baseline was identified to be a predictive factor for HT. In addition, there was no difference observed between calcium channel blockers (CCBs) and angiotensin receptor II blockers (ARBs) as first-line AHTA for the control of HT. The findings of the present study may aid with predicting the onset of TKI-induced HT, as well as for its management via the primary use of either CCBs or ARBs. PMID:24959266

Factors inducing falling in schizophrenia patients

PubMed Central

Tsuji, Yoko; Akezaki, Yoshiteru; Mori, Kohei; Yuri, Yoshimi; Katsumura, Hitomi; Hara, Tomihiro; Usui, Yuki; Fujino, Yoritaka; Nomura, Takuo; Hirao, Fumio

2017-01-01

[Purpose] The purpose of this study is to investigate the factors causing falling among patients with schizophrenia hospitalized in psychiatric hospitals. [Subjects and Methods] The study subjects were divided into either those having experienced a fall within the past one year (Fall group, 12 patients) and those not having experienced a fall (Non-fall group, 7 patients), and we examined differences between the two groups. Assessment items measured included muscle strength, balance ability, flexibility, body composition assessment, Global Assessment of Functioning scale (GAF), the antipsychotic drug intake, and Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS). [Results] As a result, significant differences were observed in regard to One leg standing time with eyes open, Time Up and Go Test (TUGT), and DIEPSS Sialorrhea between the Fall group and the Non-fall group. [Conclusion] These results suggest that a decrease in balance ability was significantly correlated with falling in schizophrenia patients. PMID:28356628

Robust estimation approach for blind denoising.

PubMed

Rabie, Tamer

2005-11-01

This work develops a new robust statistical framework for blind image denoising. Robust statistics addresses the problem of estimation when the idealized assumptions about a system are occasionally violated. The contaminating noise in an image is considered as a violation of the assumption of spatial coherence of the image intensities and is treated as an outlier random variable. A denoised image is estimated by fitting a spatially coherent stationary image model to the available noisy data using a robust estimator-based regression method within an optimal-size adaptive window. The robust formulation aims at eliminating the noise outliers while preserving the edge structures in the restored image. Several examples demonstrating the effectiveness of this robust denoising technique are reported and a comparison with other standard denoising filters is presented.

Towards designing robust coupled networks

NASA Astrophysics Data System (ADS)

Schneider, Christian M.; Yazdani, Nuri; Araújo, Nuno A. M.; Havlin, Shlomo; Herrmann, Hans J.

2013-06-01

Natural and technological interdependent systems have been shown to be highly vulnerable due to cascading failures and an abrupt collapse of global connectivity under initial failure. Mitigating the risk by partial disconnection endangers their functionality. Here we propose a systematic strategy of selecting a minimum number of autonomous nodes that guarantee a smooth transition in robustness. Our method which is based on betweenness is tested on various examples including the famous 2003 electrical blackout of Italy. We show that, with this strategy, the necessary number of autonomous nodes can be reduced by a factor of five compared to a random choice. We also find that the transition to abrupt collapse follows tricritical scaling characterized by a set of exponents which is independent on the protection strategy.

MutY DNA Glycosylase Protects Cells From Tumor Necrosis Factor Alpha-Induced Necroptosis.

PubMed

Tran, An Hue Vy; Han, Se Hee; Kim, Joon; Grasso, Francesca; Kim, In San; Han, Ye Sun

2017-07-01

Numerous studies have implied that mutY DNA glycosylase (MYH) is involved in the repair of post-replicative mispairs and plays a critical role in the base excision repair pathway. Recent in vitro studies have shown that MYH interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD), a key effector protein of tumor necrosis factor receptor-1 (TNFR1) signaling. The association between MYH and TRADD is reversed during tumor necrosis factor alpha (TNF-α)- and camptothecin (CPT)-induced apoptosis, and enhanced during TNF-α-induced survival. After investigating the role of MYH interacts with various proteins following TNF-α stimulation, here, we focus on MYH and TRADD interaction functions in necroptosis and its effects to related proteins. We report that the level of the MYH and TRADD complex was also reduced during necroptosis induced by TNF-α and zVAD-fmk. In particular, we also found that MYH is a biologically important necrosis suppressor. Under combined TNF-α and zVAD-fmk treatment, MYH-deficient cells were induced to enter the necroptosis pathway but primary mouse embryonic fibroblasts (MEFs) were not. Necroptosis in the absence of MYH proceeds via the inactivation of caspase-8, followed by an increase in the formation of the kinase receptor- interacting protein 1 (RIP1)-RIP3 complex. Our results suggested that MYH, which interacts with TRADD, inhibits TNF-α necroptotic signaling. Therefore, MYH inactivation is essential for necroptosis via the downregulation of caspase-8. J. Cell. Biochem. 118: 1827-1838, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Advanced Glycation End-Products Induce Connective Tissue Growth Factor-Mediated Renal Fibrosis Predominantly through Transforming Growth Factor β-Independent Pathway

PubMed Central

Zhou, Guihua; Li, Cai; Cai, Lu

2004-01-01

Advanced glycation end-products (AGEs) play a critical role in diabetic nephropathy by stimulating extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) is a potent inducer of ECM synthesis and increases in the diabetic kidneys. To determine the critical role of CTGF in AGE-induced ECM accumulation leading to diabetic nephropathy, rats were given AGEs by intravenous injection for 6 weeks. AGE treatment induced a significant renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) accumulation in glomeruli, and a mild renal dysfunction, as shown by increases in urinary volume and protein content. AGE treatment also caused significant increases in renal CTGF and transforming growth factor (TGF)-β1 mRNA and protein expression. Direct exposure of rat mesangial cells to AGEs in vitro significantly induced increases in fibronectin and Col IV production, which could be completely prevented by pretreatment with anti-CTGF antibody. AGE treatment also significantly increased both TGF-β1 and CTGF mRNA expression; however, inhibition of TGF-β1 mRNA expression by shRNA or neutralization of TGF-β1 protein by anti-TGF-β1 antibody did not significantly prevent AGE-increased expression of CTGF mRNA and protein. These results suggest that AGE-induced CTGF expression, predominantly through a TGF-β1-independent pathway, plays a critical role in renal ECM accumulation leading to diabetic nephropathy. PMID:15579446

Non-Hermitian bidirectional robust transport

NASA Astrophysics Data System (ADS)

Longhi, Stefano

2017-01-01

Transport of quantum or classical waves in open systems is known to be strongly affected by non-Hermitian terms that arise from an effective description of system-environment interaction. A simple and paradigmatic example of non-Hermitian transport, originally introduced by Hatano and Nelson two decades ago [N. Hatano and D. R. Nelson, Phys. Rev. Lett. 77, 570 (1996), 10.1103/PhysRevLett.77.570], is the hopping dynamics of a quantum particle on a one-dimensional tight-binding lattice in the presence of an imaginary vectorial potential. The imaginary gauge field can prevent Anderson localization via non-Hermitian delocalization, opening up a mobility region and realizing robust transport immune to disorder and backscattering. Like for robust transport of topologically protected edge states in quantum Hall and topological insulator systems, non-Hermitian robust transport in the Hatano-Nelson model is unidirectional. However, there is not any physical impediment to observe robust bidirectional non-Hermitian transport. Here it is shown that in a quasi-one-dimensional zigzag lattice, with non-Hermitian (imaginary) hopping amplitudes and a synthetic gauge field, robust transport immune to backscattering can occur bidirectionally along the lattice.

Robust control of combustion instabilities

NASA Astrophysics Data System (ADS)

Hong, Boe-Shong

Several interactive dynamical subsystems, each of which has its own time-scale and physical significance, are decomposed to build a feedback-controlled combustion- fluid robust dynamics. On the fast-time scale, the phenomenon of combustion instability is corresponding to the internal feedback of two subsystems: acoustic dynamics and flame dynamics, which are parametrically dependent on the slow-time-scale mean-flow dynamics controlled for global performance by a mean-flow controller. This dissertation constructs such a control system, through modeling, analysis and synthesis, to deal with model uncertainties, environmental noises and time- varying mean-flow operation. Conservation law is decomposed as fast-time acoustic dynamics and slow-time mean-flow dynamics, served for synthesizing LPV (linear parameter varying)- L2-gain robust control law, in which a robust observer is embedded for estimating and controlling the internal status, while achieving trade- offs among robustness, performances and operation. The robust controller is formulated as two LPV-type Linear Matrix Inequalities (LMIs), whose numerical solver is developed by finite-element method. Some important issues related to physical understanding and engineering application are discussed in simulated results of the control system.

Robustness, Death of Spiral Wave in the Network of Neurons under Partial Ion Channel Block

NASA Astrophysics Data System (ADS)

Ma, Jun; Huang, Long; Wang, Chun-Ni; Pu, Zhong-Sheng

2013-02-01

The development of spiral wave in a two-dimensional square array due to partial ion channel block (Potassium, Sodium) is investigated, the dynamics of the node is described by Hodgkin—Huxley neuron and these neurons are coupled with nearest neighbor connection. The parameter ratio xNa (and xK), which defines the ratio of working ion channel number of sodium (potassium) to the total ion channel number of sodium (and potassium), is used to measure the shift conductance induced by channel block. The distribution of statistical variable R in the two-parameter phase space (parameter ratio vs. poisoning area) is extensively calculated to mark the parameter region for transition of spiral wave induced by partial ion channel block, the area with smaller factors of synchronization R is associated the parameter region that spiral wave keeps alive and robust to the channel poisoning. Spiral wave keeps alive when the poisoned area (potassium or sodium) and degree of intoxication are small, distinct transition (death, several spiral waves coexist or multi-arm spiral wave emergence) occurs under moderate ratio xNa (and xK) when the size of blocked area exceeds certain thresholds. Breakup of spiral wave occurs and multi-arm of spiral waves are observed when the channel noise is considered.

Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity

PubMed Central

Dilshara, Matharage Gayani; Kang, Chang-Hee; Choi, Yung Hyun; Kim, Gi-Young

2015-01-01

We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-α-stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-α-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-α significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-α-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-α-induced invasion of LNCaP cells. Compared to untreated controls, TNF-α-stimulated LNCaP cells showed a significant increase in nuclear factor-κB (NF-κB) luciferase activity. However, mangiferin treatment markedly decreased TNF-α-induced NF-κB luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-κB subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-κB-mediated MMP-9 expression. [BMB Reports 2015; 48(10): 559-564] PMID:25739392

Effect of the Camelid's Seminal Plasma Ovulation-Inducing Factor/β-NGF: A Kisspeptin Target Hypothesis.

PubMed

El Allali, Khalid; El Bousmaki, Najlae; Ainani, Hassan; Simonneaux, Valérie

2017-01-01

Female mammals are classified into spontaneous and induced ovulators based on the mechanism eliciting ovulation. Ovulation in spontaneous species (e.g., human, sheep, cattle, horse, pigs, and most rodents) occurs at regular intervals and depends upon the circulating estradiol. However, in induced ovulators (e.g., rabbits, ferrets, cats, and camelids), ovulation is associated with coitus. In the later, various factors have been proposed to trigger ovulation, including auditory, visual, olfactory, and mechanic stimuli. However, other studies have identified a biochemical component in the semen of induced ovulators responsible for the induction of ovulation and named accordingly ovulation-inducing factor (OIF). In camelids, intramuscular or intrauterine administration of seminal plasma (SP) was shown to induce the preovulatory luteinizing hormone (LH) surge followed by ovulation and subsequent formation of corpus luteum. Recently, this OIF has been identified from SP as a neurotrophin, the β subunit of nerve growth factor (β-NGF). β-NGF is well known as promoting neuron survival and growth, but in this case, it appears to induce ovulation through an endocrine mode of action. Indeed, β-NGF may be absorbed through the endometrium to be conveyed, via the blood stream, to the central structures regulating the LH preovulatory surge. In this review, we provide a summary of the most relevant results obtained in the field, and we propose a working hypothesis for the central action of β-NGF based on our recent demonstration of the presence of neurons expressing kisspeptin, a potent stimulator of GnRH/LH, in the camel hypothalamus.

More About Robustness of Coherence

NASA Astrophysics Data System (ADS)

Li, Pi-Yu; Liu, Feng; Xu, Yan-Qin; La, Dong-Sheng

2018-07-01

Quantum coherence is an important physical resource in quantum computation and quantum information processing. In this paper, the distribution of the robustness of coherence in multipartite quantum system is considered. It is shown that the additivity of the robustness of coherence is not always valid for general quantum state, but the robustness of coherence is decreasing under partial trace for any bipartite quantum system. The ordering states with the coherence measures RoC, the l 1 norm of coherence C_{l1} and the relative entropy of coherence C r are also discussed.

Myopathy induced by statin-ezetimibe combination: Evaluation of potential risk factors.

PubMed

Brahmachari, Ballari; Chatterjee, Suparna

2015-01-01

Although both atorvastatin and ezetimibe may cause myopathy, statin-induced myopathy is less likely at low doses, and ezetimibe is only rarely reported to induce myopathy. Also, ezetimibe is not usually known to potentiate statin-induced myopathy. We report a case of myalgia with elevated serum creatinine phosphokinase in a patient after 2 months of therapy with fixed dose combination of atorvastatin and ezetimibe (10 mg each). At the time of the event, patient was undertaking moderate physical exertion in the form of brisk walking for 30-40 min a day and was detected to have low serum Vitamin D levels. The adverse event resolved after stopping atorvastatin-ezetimibe combination therapy. Potential risk factors, such as physical exertion and Vitamin D deficiency, co-existent in dyslipidemic patients, may exacerbate myopathy potential of these drugs, and precipitate muscular symptoms even at a low-dose.

The Organization of Controller Motifs Leading to Robust Plant Iron Homeostasis

PubMed Central

Agafonov, Oleg; Selstø, Christina Helen; Thorsen, Kristian; Xu, Xiang Ming; Drengstig, Tormod; Ruoff, Peter

2016-01-01

Iron is an essential element needed by all organisms for growth and development. Because iron becomes toxic at higher concentrations iron is under homeostatic control. Plants face also the problem that iron in the soil is tightly bound to oxygen and difficult to access. Plants have therefore developed special mechanisms for iron uptake and regulation. During the last years key components of plant iron regulation have been identified. How these components integrate and maintain robust iron homeostasis is presently not well understood. Here we use a computational approach to identify mechanisms for robust iron homeostasis in non-graminaceous plants. In comparison with experimental results certain control arrangements can be eliminated, among them that iron homeostasis is solely based on an iron-dependent degradation of the transporter IRT1. Recent IRT1 overexpression experiments suggested that IRT1-degradation is iron-independent. This suggestion appears to be misleading. We show that iron signaling pathways under IRT1 overexpression conditions become saturated, leading to a breakdown in iron regulation and to the observed iron-independent degradation of IRT1. A model, which complies with experimental data places the regulation of cytosolic iron at the transcript level of the transcription factor FIT. Including the experimental observation that FIT induces inhibition of IRT1 turnover we found a significant improvement in the system’s response time, suggesting a functional role for the FIT-mediated inhibition of IRT1 degradation. By combining iron uptake with storage and remobilization mechanisms a model is obtained which in a concerted manner integrates iron uptake, storage and remobilization. In agreement with experiments the model does not store iron during its high-affinity uptake. As an iron biofortification approach we discuss the possibility how iron can be accumulated even during high-affinity uptake. PMID:26800438

Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production via down-regulation of MyD88 expression.

PubMed

Noman, Abu Shadat M; Koide, Naoki; Hassan, Ferdaus; I-E-Khuda, Imtiaz; Dagvadorj, Jargalsaikhan; Tumurkhuu, Gantsetseg; Islam, Shamima; Naiki, Yoshikazu; Yoshida, Tomoaki; Yokochi, Takashi

2009-02-01

The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-alpha production. Thalidomide prevented the activation of nuclear factor (NF)-KB by down-regulating phosphorylation of inhibitory KB factor (IKB), and IKB kinase (IKK)-alpha and IKK-beta Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-alpha production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam(3)Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-alpha production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.

Factors influencing fluoxetine-induced sexual dysfunction in female rats

PubMed Central

Adams, Sarah; Heckard, Danyeal; Hassell, James; Uphouse, Lynda

2012-01-01

Treatment with selective serotonin reuptake inhibitors, such as fluoxetine, produces sexual side effects with low sexual desire being the most prevalent effect in females. In few studies have preclinical models for such antidepressant-induced sexual dysfunction been fruitful. In the current manuscript, the effects of fluoxetine on multiple measures of female sexual motivation and sexual receptivity were examined. Ovariectomized, Fischer rats were primed with 10 μg estradiol benzoate and 500 μg progesterone. Partner preference, active investigation of the male, and measures of sexual behavior were examined after injection with 15 mg/kg fluoxetine. Factors (pretesting for sexual behavior, size of the test arena, non-contact time with a male) that differ among experiments designed to study antidepressant-induced female rat sexual dysfunction were studied. The male preference ratio was not affected by fluoxetine treatment but active investigation of the male was reduced; lordosis behavior was inhibited and pretesting for sexual receptivity amplified fluoxetine's inhibition; size of the testing arena or non-contact experience with the male had no effect. Regardless of test condition, when given the opportunity to escape from the male, fluoxetine-treated females displayed escape behavior. Measures of male preference and active investigation, but not lordosis behavior, appeared to be affected by fluoxetine's impact on activity. The collective data provided a behavioral profile of fluoxetine-induced sexual dysfunction. These findings reinforce the value of multiple measures when attempting to model antidepressant-induced female sexual dysfunction. PMID:22835821

A robust ordering strategy for retailers facing a free shipping option.

PubMed

Meng, Qing-chun; Wan, Xiao-le; Rong, Xiao-xia

2015-01-01

Free shipping with conditions has become one of the most effective marketing tools available. An increasing number of companies, especially e-businesses, prefer to offer free shipping with some predetermined condition, such as a minimum purchase amount by the customer. However, in practice, the demands of buyers are uncertain; they are often affected by many factors, such as the weather and season. We begin by modeling the centralized ordering problem in which the supplier offers a free shipping service and retailers face stochastic demands. As these random data are considered, only partial information such as the known mean, support, and deviation is needed. The model is then analyzed via a robust optimization method, and the two types of equivalent sets of uncertainty constraints that are obtained provide good mathematical properties with consideration of the robustness of solutions. Subsequently, a numerical example is used to compare the results achieved from a robust optimization method and the linear decision rules. Additionally, the robustness of the optimal solution is discussed, as it is affected by the minimum quantity parameters. The increasing cost-threshold relationship is divided into three periods. In addition, the case study shows that the proposed method achieves better stability as well as computational complexity.

A Robust Ordering Strategy for Retailers Facing a Free Shipping Option

PubMed Central

Meng, Qing-chun; Wan, Xiao-le; Rong, Xiao-xia

2015-01-01

Free shipping with conditions has become one of the most effective marketing tools available. An increasing number of companies, especially e-businesses, prefer to offer free shipping with some predetermined condition, such as a minimum purchase amount by the customer. However, in practice, the demands of buyers are uncertain; they are often affected by many factors, such as the weather and season. We begin by modeling the centralized ordering problem in which the supplier offers a free shipping service and retailers face stochastic demands. As these random data are considered, only partial information such as the known mean, support, and deviation is needed. The model is then analyzed via a robust optimization method, and the two types of equivalent sets of uncertainty constraints that are obtained provide good mathematical properties with consideration of the robustness of solutions. Subsequently, a numerical example is used to compare the results achieved from a robust optimization method and the linear decision rules. Additionally, the robustness of the optimal solution is discussed, as it is affected by the minimum quantity parameters. The increasing cost-threshold relationship is divided into three periods. In addition, the case study shows that the proposed method achieves better stability as well as computational complexity. PMID:25993533

Smad7 Protein Induces Interferon Regulatory Factor 1-dependent Transcriptional Activation of Caspase 8 to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis

PubMed Central

Hong, Suntaek; Kim, Hye-Youn; Kim, Jooyoung; Ha, Huyen Trang; Kim, Young-Mi; Bae, Eunjin; Kim, Tae Hyung; Lee, Kang Choon; Kim, Seong-Jin

2013-01-01

Smad7 has been known as a negative regulator for the transforming growth factor-β (TGF-β) signaling pathway through feedback regulation. However, Smad7 has been suspected to have other biological roles through the regulation of gene transcription. By screening differentially regulated genes, we found that the caspase 8 gene was highly up-regulated in Smad7-expressing cells. Smad7 was able to activate the caspase 8 promoter through recruitment of the interferon regulatory factor 1 (IRF1) transcription factor to the interferon-stimulated response element (ISRE) site. Interaction of Smad7 on the caspase 8 promoter was confirmed with electrophoretic mobility shift assay and chromatin immunoprecipitation experiment. Interestingly, Smad7 did not directly interact with the ISRE site, but it increased the binding activity of IRF1 with ISRE. These results support that Smad7 recruits IRF1 protein on the caspase 8 promoter and functions as a transcriptional coactivator. To confirm the biological significance of caspase 8 up-regulation, we tested tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cell death assay in breast cancer cells. Smad7 in apoptosis-resistant MCF7 cells markedly sensitized the cells to TRAIL-induced cell death by restoring the caspase cascade. Furthermore, restoration of caspase 8-mediated apoptosis pathway repressed the tumor growth in the xenograft model. In conclusion, we suggest a novel role for Smad7 as a transcriptional coactivator for caspase 8 through the interaction with IRF1 in regulation of the cell death pathway. PMID:23255602

Robustness and structure of complex networks

NASA Astrophysics Data System (ADS)

Shao, Shuai

This dissertation covers the two major parts of my PhD research on statistical physics and complex networks: i) modeling a new type of attack -- localized attack, and investigating robustness of complex networks under this type of attack; ii) discovering the clustering structure in complex networks and its influence on the robustness of coupled networks. Complex networks appear in every aspect of our daily life and are widely studied in Physics, Mathematics, Biology, and Computer Science. One important property of complex networks is their robustness under attacks, which depends crucially on the nature of attacks and the structure of the networks themselves. Previous studies have focused on two types of attack: random attack and targeted attack, which, however, are insufficient to describe many real-world damages. Here we propose a new type of attack -- localized attack, and study the robustness of complex networks under this type of attack, both analytically and via simulation. On the other hand, we also study the clustering structure in the network, and its influence on the robustness of a complex network system. In the first part, we propose a theoretical framework to study the robustness of complex networks under localized attack based on percolation theory and generating function method. We investigate the percolation properties, including the critical threshold of the phase transition pc and the size of the giant component Pinfinity. We compare localized attack with random attack and find that while random regular (RR) networks are more robust against localized attack, Erdoḧs-Renyi (ER) networks are equally robust under both types of attacks. As for scale-free (SF) networks, their robustness depends crucially on the degree exponent lambda. The simulation results show perfect agreement with theoretical predictions. We also test our model on two real-world networks: a peer-to-peer computer network and an airline network, and find that the real-world networks

Improving poor fill factors for solar cells via light-induced plating

NASA Astrophysics Data System (ADS)

Zhao, Xing; Rui, Jia; Wuchang, Ding; Yanlong, Meng; Zhi, Jin; Xinyu, Liu

2012-09-01

Silicon solar cells are prepared following the conventional fabrication processes, except for the metallization firing process. The cells are divided into two groups with higher and lower fill factors, respectively. After light-induced plating (LIP), the fill factors of the solar cells in both groups with different initial values reach the same level. Scanning electron microscope (SEM) images are taken under the bulk silver electrodes, which prove that the improvement for cells with a poor factor after LIP should benefit from sufficient exploitation of the high density silver crystals formed during the firing process. Moreover, the application of LIP to cells with poor electrode contact performance, such as nanowire cells and radial junction solar cells, is proposed.

Robust numerical electromagnetic eigenfunction expansion algorithms

NASA Astrophysics Data System (ADS)

Sainath, Kamalesh

-region-dependent integration order (Chapter 3), (3) Integration partition-extrapolation-based (Chapter 3) and Gauss-Laguerre Quadrature (GLQ)-based (Chapter 4) evaluations of the deformed, semi-infinite-length integration contour tails, (4) Robust in-situ-based (i.e., at the spectral-domain integrand level) direct/homogeneous-medium field contribution subtraction and analytical curbing of the source current spatial spectrum function's ill behavior (Chapter 5), and (5) Analytical re-casting of the direct-field expressions when the source is embedded within a NBAM, short for non-birefringent anisotropic medium (Chapter 6). The benefits of these contributions are, respectively, (1) Avoiding computationally intensive critical-point location and tracking (computation time savings), (2) Sensor and material-robust curbing of the integrand's oscillatory and slow decay behavior, as well as preventing undesirable critical-point migration within the complex plane (computation speed, precision, and instability-avoidance benefits), (3) sensor and material-robust reduction (or, for GLQ, elimination) of integral truncation error, (4) robustly stable modeling of scattered fields and/or fields radiated from current sources modeled as spatially distributed (10 to 1000-fold compute-speed acceleration also realized for distributed-source computations), and (5) numerically stable modeling of fields radiated from sources within NBAM layers. Having addressed these limitations, are PWE algorithms applicable to modeling EM waves in tilted planar-layered geometries too? This question is explored in Chapter 7 using a Transformation Optics-based approach, allowing one to model wave propagation through layered media that (in the sensor's vicinity) possess tilted planar interfaces. The technique leads to spurious wave scattering however, whose induced computation accuracy degradation requires analysis. Mathematical exhibition, and exhaustive simulation-based study and analysis of the limitations of, this novel tilted

Inducing articular cartilage phenotype in costochondral cells

PubMed Central

2013-01-01

Introduction Costochondral cells may be isolated with minimal donor site morbidity and are unaffected by pathologies of the diarthrodial joints. Identification of optimal exogenous stimuli will allow abundant and robust hyaline articular cartilage to be formed from this cell source. Methods In a three factor, two level full factorial design, the effects of hydrostatic pressure (HP), transforming growth factor β1 (TGF-β1), and chondroitinase ABC (C-ABC), and all resulting combinations, were assessed in third passage expanded, redifferentiated costochondral cells. After 4 wks, the new cartilage was assessed for matrix content, superficial zone protein (SZP), and mechanical properties. Results Hyaline articular cartilage was generated, demonstrating the presence of type II collagen and SZP, and the absence of type I collagen. TGF-β1 upregulated collagen synthesis by 175% and glycosaminoglycan synthesis by 75%, resulting in a nearly 200% increase in tensile and compressive moduli. C-ABC significantly increased collagen content, and fibril density and diameter, leading to a 125% increase in tensile modulus. Hydrostatic pressure increased fibril diameter by 30% and tensile modulus by 45%. Combining TGF-β1 with C-ABC synergistically increased collagen content by 300% and tensile strength by 320%, over control. No significant differences were observed between C-ABC/TGF-β1 dual treatment and HP/C-ABC/TGF-β1. Conclusions Employing biochemical, biophysical, and mechanical stimuli generated robust hyaline articular cartilage with a tensile modulus of 2 MPa and a compressive instantaneous modulus of 650 kPa. Using expanded, redifferentiated costochondral cells in the self-assembling process allows for recapitulation of robust mechanical properties, and induced SZP expression, key characteristics of functional articular cartilage. PMID:24330640

Robustness Recipes for Minimax Robust Optimization in Intensity Modulated Proton Therapy for Oropharyngeal Cancer Patients

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

Voort, Sebastian van der; Section of Nuclear Energy and Radiation Applications, Department of Radiation, Science and Technology, Delft University of Technology, Delft; Water, Steven van de

Purpose: We aimed to derive a “robustness recipe” giving the range robustness (RR) and setup robustness (SR) settings (ie, the error values) that ensure adequate clinical target volume (CTV) coverage in oropharyngeal cancer patients for given gaussian distributions of systematic setup, random setup, and range errors (characterized by standard deviations of Σ, σ, and ρ, respectively) when used in minimax worst-case robust intensity modulated proton therapy (IMPT) optimization. Methods and Materials: For the analysis, contoured computed tomography (CT) scans of 9 unilateral and 9 bilateral patients were used. An IMPT plan was considered robust if, for at least 98% of themore » simulated fractionated treatments, 98% of the CTV received 95% or more of the prescribed dose. For fast assessment of the CTV coverage for given error distributions (ie, different values of Σ, σ, and ρ), polynomial chaos methods were used. Separate recipes were derived for the unilateral and bilateral cases using one patient from each group, and all 18 patients were included in the validation of the recipes. Results: Treatment plans for bilateral cases are intrinsically more robust than those for unilateral cases. The required RR only depends on the ρ, and SR can be fitted by second-order polynomials in Σ and σ. The formulas for the derived robustness recipes are as follows: Unilateral patients need SR = −0.15Σ{sup 2} + 0.27σ{sup 2} + 1.85Σ − 0.06σ + 1.22 and RR=3% for ρ = 1% and ρ = 2%; bilateral patients need SR = −0.07Σ{sup 2} + 0.19σ{sup 2} + 1.34Σ − 0.07σ + 1.17 and RR=3% and 4% for ρ = 1% and 2%, respectively. For the recipe validation, 2 plans were generated for each of the 18 patients corresponding to Σ = σ = 1.5 mm and ρ = 0% and 2%. Thirty-four plans had adequate CTV coverage in 98% or more of the simulated fractionated treatments; the remaining 2 had adequate coverage in 97.8% and 97.9%. Conclusions: Robustness recipes were derived

Inhibitory Effect of Memantine on Streptozotocin-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Neurotrophic Factor Decline in Astrocytes.

PubMed

Rajasekar, N; Nath, Chandishwar; Hanif, Kashif; Shukla, Rakesh

2016-12-01

Our earlier studies showed that insulin receptor (IR) dysfunction along with neuroinflammation and amyloidogenesis played a major role in streptozotocin (STZ)-induced toxicity in astrocytes. N-methyl-D-aspartate (NMDA) receptor antagonist-memantine shows beneficial effects in Alzheimer's disease (AD) pathology. However, the protective molecular and cellular mechanism of memantine in astrocytes is not properly understood. Therefore, the present study was undertaken to investigate the effect of memantine on insulin receptors, neurotrophic factors, neuroinflammation, and amyloidogenesis in STZ-treated astrocytes. STZ (100 μM) treatment for 24 h in astrocytes resulted significant decrease in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and insulin-degrading enzyme (IDE) expression in astrocytes. Treatment with memantine (1-10 μM) improved STZ-induced neurotrophic factor decline (BDNF, GDNF) along with IR dysfunction as evidenced by a significant increase in IR protein expression, phosphorylation of IRS-1, Akt, and GSK-3 α/β in astrocytes. Further, memantine attenuated STZ-induced amyloid precursor protein (APP), β-site APP-cleaving enzyme-1 and amyloid-β 1-42 expression and restored IDE expression in astrocytes. In addition, memantine also displays protective effects against STZ-induced astrocyte activation showed by reduction of inflammatory markers, nuclear factor kappa-B translocation, glial fibrillary acidic protein, cyclooxygenase-2, tumor necrosis factor-α level, and oxidative-nitrostative stress. The results suggest that besides the NMDA receptor antagonisic activity, effect on astroglial IR and neurotrophic factor may also be an important factor in the beneficial effect of memantine in AD pathology. Graphical Abstract Novel neuroprotective mechanisms of memenatine in streptozotocin-induced toxicity in astrocytes.

BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

PubMed Central

Shen, Jia; James, Aaron W.; Zara, Janette N.; Asatrian, Greg; Khadarian, Kevork; Zhang, James B.; Ho, Stephanie; Kim, Hyun Ju

2013-01-01

Bone-morphogenetic protein 2 (BMP2) is currently the only Food and Drug Administration-approved osteoinductive growth factor used in clinical settings for bone regeneration and repair. However, the use of BMP2 is encumbered by numerous clinical complications, including postoperative inflammation and life-threatening cervical swelling. Thus, methods to prevent BMP2-induced inflammation would have far-reaching clinical implications toward improving current BMP2-based methods for bone regeneration. For the first time, we investigate the potential role of the growth factor Nel-like molecule-1 (NELL-1) in inhibiting BMP2-induced inflammation. Adult rats underwent a femoral bone onlay procedure, treated with either BMP2 protein (4 mg/mL), NELL-1 protein (4 mg/mL), or both proteins combined. Animals were evaluated at 3, 7, and 14 days postoperatively by histology, histomorphometry, immunohistochemistry, and real-time PCR for markers of inflammation (TNFα, IL6). The relative levels of TNFα and IL6 in serum were also detected by ELISA. The mechanism for NELL-1's anti-inflammatory effect was further assessed through examining inflammatory markers and generation of reactive oxygen species (ROS) in the mouse embryonic fibroblast NIH3T3 cells. BMP2 significantly induced local inflammation, including an early and pronounced polymorphonuclear cell infiltration accompanied by increased expression of TNFα and IL6. Treatment with NELL-1 alone elicited no significant inflammatory response. However, NELL-1 significantly attenuated BMP2-induced inflammation by all markers and at all timepoints. These local findings were also confirmed using systemic serum inflammatory biomarkers (TNFα, IL6). In each case, NELL-1 fully reversed BMP2-induced systemic inflammation. Lastly, our findings were recapitulated in vitro, where NELL-1 suppressed BMP2 induced expression of inflammatory markers, as well as NF-κB transcriptional activity and generation of ROS. BMP2-induced inflammation is a

Microgravity inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression in macrophage cells.

PubMed

Wang, Chongzhen; Luo, Haiying; Zhu, Linnan; Yang, Fan; Chu, Zhulang; Tian, Hongling; Feng, Meifu; Zhao, Yong; Shang, Peng

2014-01-01

Microgravity environments in space can cause major abnormalities in human physiology, including decreased immunity. The underlying mechanisms of microgravity-induced inflammatory defects in macrophages are unclear. RAW264.7 cells and primary mouse macrophages were used in the present study. Lipopolysaccharide (LPS)-induced cytokine expression in mouse macrophages was detected under either simulated microgravity or 1g control. Freshly isolated primary mouse macrophages and RAW264.7 cells were cultured in a standard simulated microgravity situation using a rotary cell culture system (RCCS-1) and 1g control conditions. The cytokine expression was determined by real-time PCR and ELISA assays. Western blots were used to investigate the related intracellular signals. LPS-induced tumor necrosis factor-α (TNF-α) expression, but not interleukin-1β expression, in mouse macrophages was significantly suppressed under simulated microgravity. The molecular mechanism studies showed that LPS-induced intracellular signal transduction including phosphorylation of IKK and JNK and nuclear translocation of NF-κB in macrophages was identical under normal gravity and simulated microgravity. Furthermore, TNF-α mRNA stability did not decrease under simulated microgravity. Finally, we found that heat shock factor-1 (HSF1), a known repressor of TNF-α promoter, was markedly activated under simulated microgravity. Short-term treatment with microgravity caused significantly decreased TNF-α production. Microgravity-activated HSF1 may contribute to the decreased TNF-α expression in macrophages directly caused by microgravity, while the LPS-induced NF-κB pathway is resistant to microgravity.

Integration of the Response Surface Methodology with the Compromise Decision Support Problem in Developing a General Robust Design Procedure

NASA Technical Reports Server (NTRS)

Chen, Wei; Tsui, Kwok-Leung; Allen, Janet K.; Mistree, Farrokh

1994-01-01

In this paper we introduce a comprehensive and rigorous robust design procedure to overcome some limitations of the current approaches. A comprehensive approach is general enough to model the two major types of robust design applications, namely, robust design associated with the minimization of the deviation of performance caused by the deviation of noise factors (uncontrollable parameters), and robust design due to the minimization of the deviation of performance caused by the deviation of control factors (design variables). We achieve mathematical rigor by using, as a foundation, principles from the design of experiments and optimization. Specifically, we integrate the Response Surface Method (RSM) with the compromise Decision Support Problem (DSP). Our approach is especially useful for design problems where there are no closed-form solutions and system performance is computationally expensive to evaluate. The design of a solar powered irrigation system is used as an example. Our focus in this paper is on illustrating our approach rather than on the results per se.

Robust continuous clustering

PubMed Central

Shah, Sohil Atul

2017-01-01

Clustering is a fundamental procedure in the analysis of scientific data. It is used ubiquitously across the sciences. Despite decades of research, existing clustering algorithms have limited effectiveness in high dimensions and often require tuning parameters for different domains and datasets. We present a clustering algorithm that achieves high accuracy across multiple domains and scales efficiently to high dimensions and large datasets. The presented algorithm optimizes a smooth continuous objective, which is based on robust statistics and allows heavily mixed clusters to be untangled. The continuous nature of the objective also allows clustering to be integrated as a module in end-to-end feature learning pipelines. We demonstrate this by extending the algorithm to perform joint clustering and dimensionality reduction by efficiently optimizing a continuous global objective. The presented approach is evaluated on large datasets of faces, hand-written digits, objects, newswire articles, sensor readings from the Space Shuttle, and protein expression levels. Our method achieves high accuracy across all datasets, outperforming the best prior algorithm by a factor of 3 in average rank. PMID:28851838

Robust geostatistical analysis of spatial data

NASA Astrophysics Data System (ADS)

Papritz, Andreas; Künsch, Hans Rudolf; Schwierz, Cornelia; Stahel, Werner A.

2013-04-01

Most of the geostatistical software tools rely on non-robust algorithms. This is unfortunate, because outlying observations are rather the rule than the exception, in particular in environmental data sets. Outliers affect the modelling of the large-scale spatial trend, the estimation of the spatial dependence of the residual variation and the predictions by kriging. Identifying outliers manually is cumbersome and requires expertise because one needs parameter estimates to decide which observation is a potential outlier. Moreover, inference after the rejection of some observations is problematic. A better approach is to use robust algorithms that prevent automatically that outlying observations have undue influence. Former studies on robust geostatistics focused on robust estimation of the sample variogram and ordinary kriging without external drift. Furthermore, Richardson and Welsh (1995) proposed a robustified version of (restricted) maximum likelihood ([RE]ML) estimation for the variance components of a linear mixed model, which was later used by Marchant and Lark (2007) for robust REML estimation of the variogram. We propose here a novel method for robust REML estimation of the variogram of a Gaussian random field that is possibly contaminated by independent errors from a long-tailed distribution. It is based on robustification of estimating equations for the Gaussian REML estimation (Welsh and Richardson, 1997). Besides robust estimates of the parameters of the external drift and of the variogram, the method also provides standard errors for the estimated parameters, robustified kriging predictions at both sampled and non-sampled locations and kriging variances. Apart from presenting our modelling framework, we shall present selected simulation results by which we explored the properties of the new method. This will be complemented by an analysis a data set on heavy metal contamination of the soil in the vicinity of a metal smelter. Marchant, B.P. and Lark, R

Robust detection-isolation-accommodation for sensor failures

NASA Technical Reports Server (NTRS)

Weiss, J. L.; Pattipati, K. R.; Willsky, A. S.; Eterno, J. S.; Crawford, J. T.

1985-01-01

The results of a one year study to: (1) develop a theory for Robust Failure Detection and Identification (FDI) in the presence of model uncertainty, (2) develop a design methodology which utilizes the robust FDI ththeory, (3) apply the methodology to a sensor FDI problem for the F-100 jet engine, and (4) demonstrate the application of the theory to the evaluation of alternative FDI schemes are presented. Theoretical results in statistical discrimination are used to evaluate the robustness of residual signals (or parity relations) in terms of their usefulness for FDI. Furthermore, optimally robust parity relations are derived through the optimization of robustness metrics. The result is viewed as decentralization of the FDI process. A general structure for decentralized FDI is proposed and robustness metrics are used for determining various parameters of the algorithm.

LPS-inducible factor(s) from activated macrophages mediates cytolysis of Naegleria fowleri amoebae

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

Cleary, S.F.; Marciano-Cabral, F.

1986-03-01

Soluble cytolytic factors of macrophage origin have previously been described with respect to their tumoricidal activity. The purpose of this study was to investigate the mechanism and possible factor(s) responsible for cytolysis of the amoeba Naegleria fowleri by activated peritoneal macrophages from B6C3F1 mice. Macrophages or conditioned medium (CM) from macrophage cultures were incubated with /sup 3/H-Uridine labeled amoebae. Percent specific release of label served as an index of cytolysis. Bacille Calmette-Guerin (BCG) and Corynebacterium parvum macrophages demonstrated significant cytolysis of amoebae at 24 h with an effector to target ratio of 10:1. Treatment of macrophages with inhibitors of RNAmore » or protein synthesis blocked amoebicidal activity. Interposition of a 1 ..mu..m pore membrane between macrophages and amoebae inhibited killing. Inhibition in the presence of the membrane was overcome by stimulating the macrophages with LPS. CM from SPS-stimulated, but not unstimulated, cultures of activated macrophages was cytotoxic for amoebae. The activity was heat sensitive and was recovered from ammonium sulfate precipitation of the CM. Results indicate that amoebicidal activity is mediated by a protein(s) of macrophage origin induced by target cell contact or stimulation with LPS.« less

Inducer analysis/pump model development

NASA Astrophysics Data System (ADS)

Cheng, Gary C.

1994-03-01

Current design of high performance turbopumps for rocket engines requires effective and robust analytical tools to provide design information in a productive manner. The main goal of this study was to develop a robust and effective computational fluid dynamics (CFD) pump model for general turbopump design and analysis applications. A finite difference Navier-Stokes flow solver, FDNS, which includes an extended k-epsilon turbulence model and appropriate moving zonal interface boundary conditions, was developed to analyze turbulent flows in turbomachinery devices. In the present study, three key components of the turbopump, the inducer, impeller, and diffuser, were investigated by the proposed pump model, and the numerical results were benchmarked by the experimental data provided by Rocketdyne. For the numerical calculation of inducer flows with tip clearance, the turbulence model and grid spacing are very important. Meanwhile, the development of the cross-stream secondary flow, generated by curved blade passage and the flow through tip leakage, has a strong effect on the inducer flow. Hence, the prediction of the inducer performance critically depends on whether the numerical scheme of the pump model can simulate the secondary flow pattern accurately or not. The impeller and diffuser, however, are dominated by pressure-driven flows such that the effects of turbulence model and grid spacing (except near leading and trailing edges of blades) are less sensitive. The present CFD pump model has been proved to be an efficient and robust analytical tool for pump design due to its very compact numerical structure (requiring small memory), fast turnaround computing time, and versatility for different geometries.

Inducer analysis/pump model development

NASA Technical Reports Server (NTRS)

Cheng, Gary C.

1994-01-01

Current design of high performance turbopumps for rocket engines requires effective and robust analytical tools to provide design information in a productive manner. The main goal of this study was to develop a robust and effective computational fluid dynamics (CFD) pump model for general turbopump design and analysis applications. A finite difference Navier-Stokes flow solver, FDNS, which includes an extended k-epsilon turbulence model and appropriate moving zonal interface boundary conditions, was developed to analyze turbulent flows in turbomachinery devices. In the present study, three key components of the turbopump, the inducer, impeller, and diffuser, were investigated by the proposed pump model, and the numerical results were benchmarked by the experimental data provided by Rocketdyne. For the numerical calculation of inducer flows with tip clearance, the turbulence model and grid spacing are very important. Meanwhile, the development of the cross-stream secondary flow, generated by curved blade passage and the flow through tip leakage, has a strong effect on the inducer flow. Hence, the prediction of the inducer performance critically depends on whether the numerical scheme of the pump model can simulate the secondary flow pattern accurately or not. The impeller and diffuser, however, are dominated by pressure-driven flows such that the effects of turbulence model and grid spacing (except near leading and trailing edges of blades) are less sensitive. The present CFD pump model has been proved to be an efficient and robust analytical tool for pump design due to its very compact numerical structure (requiring small memory), fast turnaround computing time, and versatility for different geometries.

Monocarboxylate transporter 1 contributes to growth factor-induced tumor cell migration independent of transporter activity

PubMed Central

Gray, Alana L.; Coleman, David T.; Shi, Runhua; Cardelli, James A.

2016-01-01

Tumor progression to metastatic disease contributes to the vast majority of incurable cancer. Understanding the processes leading to advanced stage cancer is important for the development of future therapeutic strategies. Here, we establish a connection between tumor cell migration, a prerequisite to metastasis, and monocarboxylate transporter 1 (MCT1). MCT1 transporter activity is known to regulate aspects of tumor progression and, as such, is a clinically relevant target for treating cancer. Knockdown of MCT1 expression caused decreased hepatocyte growth factor (HGF)-induced as well as epidermal growth factor (EGF)-induced tumor cell scattering and wound healing. Western blot analysis suggested that MCT1 knockdown (KD) hinders signaling through the HGF receptor (c-Met) but not the EGF receptor. Exogenous, membrane-permeable MCT1 substrates were not able to rescue motility in MCT1 KD cells, nor was pharmacologic inhibition of MCT1 able to recapitulate decreased cell motility as seen with MCT1 KD cells, indicating transporter activity of MCT1 was dispensable for EGF- and HGF-induced motility. These results indicate MCT1 expression, independent of transporter activity, is required for growth factor-induced tumor cell motility. The findings presented herein suggest a novel function for MCT1 in tumor progression independent of its role as a monocarboxylate transporter. PMID:27127175

Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha.

PubMed

Leibovich, S J; Polverini, P J; Shepard, H M; Wiseman, D M; Shively, V; Nuseir, N

Macrophages are important in the induction of new blood vessel growth during wound repair, inflammation and tumour growth. We show here that tumour necrosis factor-alpha (TNF-alpha), a secretory product of activated macrophages that is believed to mediate tumour cytotoxicity, is a potent inducer of new blood vessel growth (angiogenesis). In vivo, TNF-alpha induces capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membrane at very low doses. In vitro, TNF-alpha stimulates chemotaxis of bovine adrenal capillary endothelial cells and induces cultures of these cells grown on type-1 collagen gels to form capillary-tube-like structures. The angiogenic activity produced by activated murine peritoneal macrophages is completely neutralized by a polyclonal antibody to TNF-alpha, suggesting immunological features are common to TNF-alpha and the protein responsible for macrophage-derived angiogenic activity. In inflammation and wound repair, TNF-alpha could augment repair by stimulating new blood vessel growth; in tumours, TNF-alpha might both stimulate tumour development by promoting vessel growth and participate in tumour destruction by direct cytotoxicity.

Modeling Shear Induced Von Willebrand Factor Binding to Collagen

NASA Astrophysics Data System (ADS)

Dong, Chuqiao; Wei, Wei; Morabito, Michael; Webb, Edmund; Oztekin, Alparslan; Zhang, Xiaohui; Cheng, Xuanhong

2017-11-01

Von Willebrand factor (vWF) is a blood glycoprotein that binds with platelets and collagen on injured vessel surfaces to form clots. VWF bioactivity is shear flow induced: at low shear, binding between VWF and other biological entities is suppressed; for high shear rate conditions - as are found near arterial injury sites - VWF elongates, activating its binding with platelets and collagen. Based on parameters derived from single molecule force spectroscopy experiments, we developed a coarse-grain molecular model to simulate bond formation probability as a function of shear rate. By introducing a binding criterion that depends on the conformation of a sub-monomer molecular feature of our model, the model predicts shear-induced binding, even for conditions where binding is highly energetically favorable. We further investigate the influence of various model parameters on the ability to predict shear-induced binding (vWF length, collagen site density and distribution, binding energy landscape, and slip/catch bond length) and demonstrate parameter ranges where the model provides good agreement with existing experimental data. Our results may be important for understanding vWF activity and also for achieving targeted drug therapy via biomimetic synthetic molecules. National Science Foundation (NSF),Division of Mathematical Sciences (DMS).

The Activity of Differentiation Factors Induces Apoptosis in Polyomavirus Large T-Expressing Myoblasts

PubMed Central

Fimia, Gian Maria; Gottifredi, Vanesa; Bellei, Barbara; Ricciardi, Maria Rosaria; Tafuri, Agostino; Amati, Paolo; Maione, Rossella

1998-01-01

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor β or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G00 arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis. PMID:9614186

Robust Distribution Network Reconfiguration

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

Lee, Changhyeok; Liu, Cong; Mehrotra, Sanjay

2015-03-01

We propose a two-stage robust optimization model for the distribution network reconfiguration problem with load uncertainty. The first-stage decision is to configure the radial distribution network and the second-stage decision is to find the optimal a/c power flow of the reconfigured network for given demand realization. We solve the two-stage robust model by using a column-and-constraint generation algorithm, where the master problem and subproblem are formulated as mixed-integer second-order cone programs. Computational results for 16, 33, 70, and 94-bus test cases are reported. We find that the configuration from the robust model does not compromise much the power loss undermore » the nominal load scenario compared to the configuration from the deterministic model, yet it provides the reliability of the distribution system for all scenarios in the uncertainty set.« less

Simulated discharge trends indicate robustness of hydrological models in a changing climate

NASA Astrophysics Data System (ADS)

Addor, Nans; Nikolova, Silviya; Seibert, Jan

2016-04-01

Assessing the robustness of hydrological models under contrasted climatic conditions should be part any hydrological model evaluation. Robust models are particularly important for climate impact studies, as models performing well under current conditions are not necessarily capable of correctly simulating hydrological perturbations caused by climate change. A pressing issue is the usually assumed stationarity of parameter values over time. Modeling experiments using conceptual hydrological models revealed that assuming transposability of parameters values in changing climatic conditions can lead to significant biases in discharge simulations. This raises the question whether parameter values should to be modified over time to reflect changes in hydrological processes induced by climate change. Such a question denotes a focus on the contribution of internal processes (i.e., catchment processes) to discharge generation. Here we adopt a different perspective and explore the contribution of external forcing (i.e., changes in precipitation and temperature) to changes in discharge. We argue that in a robust hydrological model, discharge variability should be induced by changes in the boundary conditions, and not by changes in parameter values. In this study, we explore how well the conceptual hydrological model HBV captures transient changes in hydrological signatures over the period 1970-2009. Our analysis focuses on research catchments in Switzerland undisturbed by human activities. The precipitation and temperature forcing are extracted from recently released 2km gridded data sets. We use a genetic algorithm to calibrate HBV for the whole 40-year period and for the eight successive 5-year periods to assess eventual trends in parameter values. Model calibration is run multiple times to account for parameter uncertainty. We find that in alpine catchments showing a significant increase of winter discharge, this trend can be captured reasonably well with constant

Growth factor involvement in tension-induced skeletal muscle growth

NASA Technical Reports Server (NTRS)

Vandenburgh, H. H.

1987-01-01

Muscle tissue culture techniques were developed to grow skeletal myofibers which differentiate into more adult-like myofibers. Mechanical simulation studies of these muscle cells in a newly developed mechanical cell simulator can now be performed to study growth processes in skeletal muscle. Conditions in the mechanical cell simulator were defined where mechanical activity can either prevent muscle wasting or stimulate muscle growth. The role of endogenous and exogenous growth factors in tension-induced muscle growth is being investigated under the defined conditions of tissue culture.

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition.

PubMed

Ye, Ming; Fang, Zejun; Gu, Hongqian; Song, Rui; Ye, Jiangwei; Li, Hongzhang; Wu, Zhiguang; Zhou, Shenghui; Li, Peng; Cai, Xiang; Ding, Xiaokun; Yu, Songshan

2017-06-01

Hypoxia plays a critical role in the progression and metastasis of hepatocellular carcinoma by activating the key transcription factor, hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of hypoxia-inducible factor-1α in hepatocellular carcinoma. We found that histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular carcinoma, strengthened the migration and invasion of hepatocellular carcinoma cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 5 induced the transcription of hypoxia-inducible factor-1α by silencing homeodomain-interacting protein kinase-2 expression, which was also dependent on hypoxia. And then knockdown of hypoxia-inducible factor-1α decreased the expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin, increased. Phenotype experiments showed that the migration and invasion of hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 5 or hypoxia-inducible factor-1α but rescued when eliminating homeodomain-interacting protein kinase-2 in hepatocellular carcinoma cells, which suggested the critical role of histone deacetylase 5-homeodomain-interacting protein kinase-2-hypoxia-inducible factor-1α pathway in hypoxia-induced metastasis. Finally, clinical analysis confirmed the positive correlation between histone deacetylase 5 and hypoxia-inducible factor-1α in hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of histone deacetylase 5 and hypoxia-inducible factor-1α. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular carcinoma.

Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus.

PubMed

Tanaka, Hiroyuki; Takano, Kazuhiko; Iijima, Hiroaki; Kubo, Hajime; Maruyama, Nobuko; Hashimoto, Toshio; Arakawa, Kenji; Togo, Masanori; Inagaki, Nobuya; Kaku, Kohei

2017-02-01

Sodium glucose co-transporter 2 (SGLT2) inhibitors exhibit diuretic activity, which is a possible mechanism underlying the cardiovascular benefit of these inhibitors. However, the osmotic diuresis-induced increase in urine volume, and the risk of dehydration have been of concern with SGLT2 inhibitor treatment. This study aimed to investigate the mechanism underlying SGLT2 inhibitor canagliflozin-induced diuresis in Japanese type 2 diabetes mellitus (T2DM) patients. Thirteen T2DM patients received a daily oral dose of 100 mg canagliflozin before breakfast for 6 days. Blood and urine samples were collected at predetermined time points. The primary endpoint was evaluation of correlations between changes from baseline in urine volume and factors that are known to affect urine volume and between actual urine volume and these factors. Canagliflozin transiently increased urine volume and urinary sodium excretion on Day 1 with a return to baseline levels thereafter. Canagliflozin administration increased urinary glucose excretion, which was sustained during repeated-dose administration. Plasma atrial natriuretic peptide (ANP) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels decreased, while plasma renin activity increased. On Day 1 of treatment, changes in sodium and potassium excretion were closely correlated with changes in urine output. A post hoc multiple regression analysis showed changes in sodium excretion and water intake as factors that affected urine volume change at Day 1. Furthermore, relative to that at baseline, canagliflozin decreased blood glucose throughout the day and increased plasma total GLP-1 after breakfast. Canagliflozin induced transient sodium excretion and did not induce water intake at Day 1; hence, natriuresis rather than glucose-induced osmotic diuresis may be a major factor involved in the canagliflozin-induced transient increase in urine output. In addition, canagliflozin decreased plasma ANP and NT-proBNP levels and

The Robustness of Acoustic Analogies

NASA Technical Reports Server (NTRS)

Freund, J. B.; Lele, S. K.; Wei, M.

2004-01-01

Acoustic analogies for the prediction of flow noise are exact rearrangements of the flow equations N(right arrow q) = 0 into a nominal sound source S(right arrow q) and sound propagation operator L such that L(right arrow q) = S(right arrow q). In practice, the sound source is typically modeled and the propagation operator inverted to make predictions. Since the rearrangement is exact, any sufficiently accurate model of the source will yield the correct sound, so other factors must determine the merits of any particular formulation. Using data from a two-dimensional mixing layer direct numerical simulation (DNS), we evaluate the robustness of two analogy formulations to different errors intentionally introduced into the source. The motivation is that since S can not be perfectly modeled, analogies that are less sensitive to errors in S are preferable. Our assessment is made within the framework of Goldstein's generalized acoustic analogy, in which different choices of a base flow used in constructing L give different sources S and thus different analogies. A uniform base flow yields a Lighthill-like analogy, which we evaluate against a formulation in which the base flow is the actual mean flow of the DNS. The more complex mean flow formulation is found to be significantly more robust to errors in the energetic turbulent fluctuations, but its advantage is less pronounced when errors are made in the smaller scales.

Singularity-robustness and task-prioritization in configuration control of redundant robots

NASA Technical Reports Server (NTRS)

Seraji, H.; Colbaugh, R.

1990-01-01

The authors present a singularity-robust task-prioritized reformulation of the configuration control for redundant robot manipulators. This reformation suppresses large joint velocities to induce minimal errors in the task performance by modifying the task trajectories. Furthermore, the same framework provides a means for assignment of priorities between the basic task of end-effector motion and the user-defined additional task for utilizing redundancy. This allows automatic relaxation of the additional task constraints in favor of the desired end-effector motion when both cannot be achieved exactly.

[Study on physical deviation factors on laser induced breakdown spectroscopy measurement].

PubMed

Wan, Xiong; Wang, Peng; Wang, Qi; Zhang, Qing; Zhang, Zhi-Min; Zhang, Hua-Ming

2013-10-01

In order to eliminate the deviation between the measured LIBS spectral line and the standard LIBS spectral line, and improve the accuracy of elements measurement, a research of physical deviation factors in laser induced breakdown spectroscopy technology was proposed. Under the same experimental conditions, the relationship of ablated hole effect and spectral wavelength was tested, the Stark broadening data of Mg plasma laser induced breakdown spectroscopy with sampling time-delay from 1.00 to 3.00 micros was also studied, thus the physical deviation influences such as ablated hole effect and Stark broadening could be obtained while collecting the spectrum. The results and the method of the research and analysis can also be applied to other laser induced breakdown spectroscopy experiment system, which is of great significance to improve the accuracy of LIBS elements measuring and is also important to the research on the optimum sampling time-delay of LIBS.

Tumor necrosis factor-inducing activities of Cryptococcus neoformans components.

PubMed Central

Delfino, D; Cianci, L; Migliardo, M; Mancuso, G; Cusumano, V; Corradini, C; Teti, G

1996-01-01

Cryptococcus neoformans-induced tumor necrosis factor alpha (TNF-alpha) production may lead to increased human immunodeficiency virus replication in patients with AIDS. In order to identify cryptococcal components that are predominantly responsible for stimulating TNF production, various concentrations of glucuronoxylomannan (GXM), galactoxylomannan (GalXM), mannoproteins (MP), and alpha(1-3) [corrected] glucan were added to whole-blood cultures. All of the cryptococcal components tested, as well as whole heat-killed cryptococci, were capable of inducing TNF-alpha release in a dose-dependent manner. MP were significantly more potent than any of the other cryptococcal components tested or heat-killed cryptococci in stimulating TNF-alpha production (P < 0.05). GXM, in contrast, was significantly less potent in this activity than either GalXM or MP (P < 0.05). As little as 0.5 microg of MP per ml was sufficient to produce moderate but significant elevations of TNF-alpha release. Maximal MP-induced TNF-alpha levels were similar to those induced by Salmonella enteritidis lipopolysaccharide, our positive control. Further experiments using isolated leukocytes suggested that monocytes were the cell population mainly responsible for TNF-alpha production, although the participation of other cell types could not be excluded. The presence of complement-sufficient plasma was a necessary requirement for TNF-alpha induction by GXM, GalXM, and low doses of MP. High MP concentrations (100 microg/ml) were also capable of stimulating TNF-alpha production in the absence of plasma. These data indicate that soluble products released by C. neoformans are capable of inducing TNF-alpha secretion in human leukocytes. This may be clinically relevant, since high concentrations of such products are frequently found in the body fluids of AIDS patients infected with C. neoformans. PMID:8945566

Using robust Bayesian network to estimate the residuals of fluoroquinolone antibiotic in soil.

PubMed

Li, Xuewen; Xie, Yunfeng; Li, Lianfa; Yang, Xunfeng; Wang, Ning; Wang, Jinfeng

2015-11-01

Prediction of antibiotic pollution and its consequences is difficult, due to the uncertainties and complexities associated with multiple related factors. This article employed domain knowledge and spatial data to construct a Bayesian network (BN) model to assess fluoroquinolone antibiotic (FQs) pollution in the soil of an intensive vegetable cultivation area. The results show: (1) The relationships between FQs pollution and contributory factors: Three factors (cultivation methods, crop rotations, and chicken manure types) were consistently identified as predictors in the topological structures of three FQs, indicating their importance in FQs pollution; deduced with domain knowledge, the cultivation methods are determined by the crop rotations, which require different nutrients (derived from the manure) according to different plant biomass. (2) The performance of BN model: The integrative robust Bayesian network model achieved the highest detection probability (pd) of high-risk and receiver operating characteristic (ROC) area, since it incorporates domain knowledge and model uncertainty. Our encouraging findings have implications for the use of BN as a robust approach to assessment of FQs pollution and for informing decisions on appropriate remedial measures.

Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

PubMed Central

Li, Bo; Wang, Hai; Qiu, Guixing; Su, Xinlin

2016-01-01

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration. PMID:28070506

Vectorology and Factor Delivery in Induced Pluripotent Stem Cell Reprogramming

PubMed Central

2014-01-01

Induced pluripotent stem cell (iPSC) reprogramming requires sustained expression of multiple reprogramming factors for a limited period of time (10–30 days). Conventional iPSC reprogramming was achieved using lentiviral or simple retroviral vectors. Retroviral reprogramming has flaws of insertional mutagenesis, uncontrolled silencing, residual expression and re-activation of transgenes, and immunogenicity. To overcome these issues, various technologies were explored, including adenoviral vectors, protein transduction, RNA transfection, minicircle DNA, excisable PiggyBac (PB) transposon, Cre-lox excision system, negative-sense RNA replicon, positive-sense RNA replicon, Epstein-Barr virus-based episomal plasmids, and repeated transfections of plasmids. This review provides summaries of the main vectorologies and factor delivery systems used in current reprogramming protocols. PMID:24625220

Robust Portfolio Optimization Using Pseudodistances.

PubMed

Toma, Aida; Leoni-Aubin, Samuela

2015-01-01

The presence of outliers in financial asset returns is a frequently occurring phenomenon which may lead to unreliable mean-variance optimized portfolios. This fact is due to the unbounded influence that outliers can have on the mean returns and covariance estimators that are inputs in the optimization procedure. In this paper we present robust estimators of mean and covariance matrix obtained by minimizing an empirical version of a pseudodistance between the assumed model and the true model underlying the data. We prove and discuss theoretical properties of these estimators, such as affine equivariance, B-robustness, asymptotic normality and asymptotic relative efficiency. These estimators can be easily used in place of the classical estimators, thereby providing robust optimized portfolios. A Monte Carlo simulation study and applications to real data show the advantages of the proposed approach. We study both in-sample and out-of-sample performance of the proposed robust portfolios comparing them with some other portfolios known in literature.

Robust Portfolio Optimization Using Pseudodistances

PubMed Central

2015-01-01

The presence of outliers in financial asset returns is a frequently occurring phenomenon which may lead to unreliable mean-variance optimized portfolios. This fact is due to the unbounded influence that outliers can have on the mean returns and covariance estimators that are inputs in the optimization procedure. In this paper we present robust estimators of mean and covariance matrix obtained by minimizing an empirical version of a pseudodistance between the assumed model and the true model underlying the data. We prove and discuss theoretical properties of these estimators, such as affine equivariance, B-robustness, asymptotic normality and asymptotic relative efficiency. These estimators can be easily used in place of the classical estimators, thereby providing robust optimized portfolios. A Monte Carlo simulation study and applications to real data show the advantages of the proposed approach. We study both in-sample and out-of-sample performance of the proposed robust portfolios comparing them with some other portfolios known in literature. PMID:26468948

L-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB), Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2), and Hypoxia-Inducible Factor (HIF)

PubMed Central

Park, Seoung Ju; Lee, Kyung Sun; Lee, Su Jeong; Kim, So Ri; Park, Seung Yong; Jeon, Myoung Shin; Lee, Heung Bum; Lee, Yong Chul

2012-01-01

Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4-carboxylic acid (OTC) or α-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling. PMID:22942681

Tail mean and related robust solution concepts

NASA Astrophysics Data System (ADS)

Ogryczak, Włodzimierz

2014-01-01

Robust optimisation might be viewed as a multicriteria optimisation problem where objectives correspond to the scenarios although their probabilities are unknown or imprecise. The simplest robust solution concept represents a conservative approach focused on the worst-case scenario results optimisation. A softer concept allows one to optimise the tail mean thus combining performances under multiple worst scenarios. We show that while considering robust models allowing the probabilities to vary only within given intervals, the tail mean represents the robust solution for only upper bounded probabilities. For any arbitrary intervals of probabilities the corresponding robust solution may be expressed by the optimisation of appropriately combined mean and tail mean criteria thus remaining easily implementable with auxiliary linear inequalities. Moreover, we use the tail mean concept to develope linear programming implementable robust solution concepts related to risk averse optimisation criteria.

Angiotensin peptides attenuate platelet-activating factor-induced inflammatory activity in rats.

PubMed

Sato, Akira; Yokoyama, Izumi; Ebina, Keiichi

2015-11-01

Angiotensin (Ang)--a peptide that is part of the renin-angiotensin system-induces vasoconstriction and a subsequent increase in blood pressure; Ang peptides, especially AngII, can also act as potent pro-inflammatory mediators. Platelet-activating factor (PAF) is a potent phospholipid mediator that is implicated in many inflammatory diseases. In this study, we investigated the effects of Ang peptides (AngII, AngIII, and AngIV) on PAF-induced inflammatory activity. In experiments using a rat hind-paw oedema model, AngII markedly and dose-dependently attenuated the paw oedema induced by PAF. The inhibitory effects of AngIII and AngIV on PAF-induced paw oedema were lower than that of AngII. Two Ang receptors, the AT1 and AT2 receptors, did not affect the AngII-mediated attenuation of PAF-induced paw oedema. Moreover, intrinsic tyrosine fluorescence studies demonstrated that AngII, AngIII, and AngIV interact with PAF, and that their affinities were closely correlated with their inhibitory effects on PAF-induced rat paw oedema. Also, AngII interacted with metabolite/precursor of PAF (lyso-PAF), and an oxidized phospholipid, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), which bears a marked structural resemblance to PAF. Furthermore, POVPC dose-dependently inhibited AngII-mediated attenuation of PAF-induced paw oedema. These results suggest that Ang peptides can attenuate PAF-induced inflammatory activity through binding to PAF and lyso-PAF in rats. Therefore, Ang peptides may be closely involved in the regulation of many inflammatory diseases caused by PAF. Copyright © 2015 Elsevier Inc. All rights reserved.

Robust detrending, rereferencing, outlier detection, and inpainting for multichannel data.

PubMed

de Cheveigné, Alain; Arzounian, Dorothée

2018-05-15

Electroencephalography (EEG), magnetoencephalography (MEG) and related techniques are prone to glitches, slow drift, steps, etc., that contaminate the data and interfere with the analysis and interpretation. These artifacts are usually addressed in a preprocessing phase that attempts to remove them or minimize their impact. This paper offers a set of useful techniques for this purpose: robust detrending, robust rereferencing, outlier detection, data interpolation (inpainting), step removal, and filter ringing artifact removal. These techniques provide a less wasteful alternative to discarding corrupted trials or channels, and they are relatively immune to artifacts that disrupt alternative approaches such as filtering. Robust detrending allows slow drifts and common mode signals to be factored out while avoiding the deleterious effects of glitches. Robust rereferencing reduces the impact of artifacts on the reference. Inpainting allows corrupt data to be interpolated from intact parts based on the correlation structure estimated over the intact parts. Outlier detection allows the corrupt parts to be identified. Step removal fixes the high-amplitude flux jump artifacts that are common with some MEG systems. Ringing removal allows the ringing response of the antialiasing filter to glitches (steps, pulses) to be suppressed. The performance of the methods is illustrated and evaluated using synthetic data and data from real EEG and MEG systems. These methods, which are mainly automatic and require little tuning, can greatly improve the quality of the data. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

How Robust is Your System Resilience?

NASA Astrophysics Data System (ADS)

Homayounfar, M.; Muneepeerakul, R.

2017-12-01

Robustness and resilience are concepts in system thinking that have grown in importance and popularity. For many complex social-ecological systems, however, robustness and resilience are difficult to quantify and the connections and trade-offs between them difficult to study. Most studies have either focused on qualitative approaches to discuss their connections or considered only one of them under particular classes of disturbances. In this study, we present an analytical framework to address the linkage between robustness and resilience more systematically. Our analysis is based on a stylized dynamical model that operationalizes a widely used concept framework for social-ecological systems. The model enables us to rigorously define robustness and resilience and consequently investigate their connections. The results reveal the tradeoffs among performance, robustness, and resilience. They also show how the nature of the such tradeoffs varies with the choices of certain policies (e.g., taxation and investment in public infrastructure), internal stresses and external disturbances.

Vascular Induction of a Disintegrin and Metalloprotease 17 by Angiotensin II Through Hypoxia Inducible Factor 1α

PubMed Central

Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori; Bourne, Allison M.; Elliott, Katherine J.; Charbonneau, Martine; Dubois, Claire M.

2015-01-01

BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. PMID:24871629

How robust is the Holton-Tan relationship?

NASA Astrophysics Data System (ADS)

Braesicke, Peter; Kerzenmacher, Tobias

2017-04-01

The Holton-Tan relationship explains a possible link between tropical and extratropical variability (foremost in the northern hemisphere). The idea can be rationalised using simple linear wave theory. The quasi-biennial oscillation in the tropical lower stratosphere can be regarded as a kind of switch that influences the propagation of planetary waves. In a westerly phase of the QBO planetary waves in the stratosphere can propagate more equatorward and the polar vortex remains strong and undisturbed. In an easterly phase of the QBO the propagation is more poleward and the polar vortex is weaker and more disturbed. However, the robustness of this relationship depends on the precise definition of the QBO phase and the criteria used to define the polar vortex strength. Here, we will revisit the basic Holton-Tan relationship and will explore how other factors (including the state of the El Nino-Southern Oscillation) modify the relationship. Using reanalysis data and idealised model experiments a possible range for robust manifestations of the Holton-Tan relationship is determined, thus providing an improved framework for a better understanding of teleconnections between tropical and polar latitudes.

Robust optimization of the billet for isothermal local loading transitional region of a Ti-alloy rib-web component based on dual-response surface method

NASA Astrophysics Data System (ADS)

Wei, Ke; Fan, Xiaoguang; Zhan, Mei; Meng, Miao

2018-03-01

Billet optimization can greatly improve the forming quality of the transitional region in the isothermal local loading forming (ILLF) of large-scale Ti-alloy ribweb components. However, the final quality of the transitional region may be deteriorated by uncontrollable factors, such as the manufacturing tolerance of the preforming billet, fluctuation of the stroke length, and friction factor. Thus, a dual-response surface method (RSM)-based robust optimization of the billet was proposed to address the uncontrollable factors in transitional region of the ILLF. Given that the die underfilling and folding defect are two key factors that influence the forming quality of the transitional region, minimizing the mean and standard deviation of the die underfilling rate and avoiding folding defect were defined as the objective function and constraint condition in robust optimization. Then, the cross array design was constructed, a dual-RSM model was established for the mean and standard deviation of the die underfilling rate by considering the size parameters of the billet and uncontrollable factors. Subsequently, an optimum solution was derived to achieve the robust optimization of the billet. A case study on robust optimization was conducted. Good results were attained for improving the die filling and avoiding folding defect, suggesting that the robust optimization of the billet in the transitional region of the ILLF was efficient and reliable.

The developmental genetics of biological robustness

PubMed Central

Mestek Boukhibar, Lamia; Barkoulas, Michalis

2016-01-01

Background Living organisms are continuously confronted with perturbations, such as environmental changes that include fluctuations in temperature and nutrient availability, or genetic changes such as mutations. While some developmental systems are affected by such challenges and display variation in phenotypic traits, others continue consistently to produce invariable phenotypes despite perturbation. This ability of a living system to maintain an invariable phenotype in the face of perturbations is termed developmental robustness. Biological robustness is a phenomenon observed across phyla, and studying its mechanisms is central to deciphering the genotype–phenotype relationship. Recent work in yeast, animals and plants has shown that robustness is genetically controlled and has started to reveal the underlying mechinisms behind it. Scope and Conclusions Studying biological robustness involves focusing on an important property of developmental traits, which is the phenotypic distribution within a population. This is often neglected because the vast majority of developmental biology studies instead focus on population aggregates, such as trait averages. By drawing on findings in animals and yeast, this Viewpoint considers how studies on plant developmental robustness may benefit from strict definitions of what is the developmental system of choice and what is the relevant perturbation, and also from clear distinctions between gene effects on the trait mean and the trait variance. Recent advances in quantitative developmental biology and high-throughput phenotyping now allow the design of targeted genetic screens to identify genes that amplify or restrict developmental trait variance and to study how variation propagates across different phenotypic levels in biological systems. The molecular characterization of more quantitative trait loci affecting trait variance will provide further insights into the evolution of genes modulating developmental robustness. The

Potassium Inhibits Dietary Salt-Induced Transforming Growth Factor-β Production

PubMed Central

Ying, Wei-Zhong; Aaron, Kristal; Wang, Pei-Xuan; Sanders, Paul W.

2009-01-01

Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-β, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-β. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-β demonstrated increased (35.2%) amounts of active TGF-β in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-β but did not affect production of TGF-β by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the α subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-β but did not alter TGF-β production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-β in animals receiving the high-salt diet but did not change urinary active TGF-β in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake. PMID:19738156

Cellular Transcription Factors Induced in Trigeminal Ganglia during Dexamethasone-Induced Reactivation from Latency Stimulate Bovine Herpesvirus 1 Productive Infection and Certain Viral Promoters

PubMed Central

Workman, Aspen; Eudy, James; Smith, Lynette; Frizzo da Silva, Leticia; Sinani, Devis; Bricker, Halie; Cook, Emily; Doster, Alan

2012-01-01

Bovine herpesvirus 1 (BHV-1), an alphaherpesvirinae subfamily member, establishes latency in sensory neurons. Elevated corticosteroid levels, due to stress, reproducibly triggers reactivation from latency in the field. A single intravenous injection of the synthetic corticosteroid dexamethasone (DEX) to latently infected calves consistently induces reactivation from latency. Lytic cycle viral gene expression is detected in sensory neurons within 6 h after DEX treatment of latently infected calves. These observations suggested that DEX stimulated expression of cellular genes leads to lytic cycle viral gene expression and productive infection. In this study, a commercially available assay—Bovine Gene Chip—was used to compare cellular gene expression in the trigeminal ganglia (TG) of calves latently infected with BHV-1 versus DEX-treated animals. Relative to TG prepared from latently infected calves, 11 cellular genes were induced more than 10-fold 3 h after DEX treatment. Pentraxin three, a regulator of innate immunity and neurodegeneration, was stimulated 35- to 63-fold after 3 or 6 h of DEX treatment. Two transcription factors, promyelocytic leukemia zinc finger (PLZF) and Slug were induced more than 15-fold 3 h after DEX treatment. PLZF or Slug stimulated productive infection 20- or 5-fold, respectively, and Slug stimulated the late glycoprotein C promoter more than 10-fold. Additional DEX-induced transcription factors also stimulated productive infection and certain viral promoters. These studies suggest that DEX-inducible cellular transcription factors and/or signaling pathways stimulate lytic cycle viral gene expression, which subsequently leads to successful reactivation from latency in a small subset of latently infected neurons. PMID:22190728

Transforming growth factor-{beta}-inducible phosphorylation of Smad3.

PubMed

Wang, Guannan; Matsuura, Isao; He, Dongming; Liu, Fang

2009-04-10

Smad proteins transduce the transforming growth factor-beta (TGF-beta) signal at the cell surface into gene regulation in the nucleus. Upon TGF-beta treatment, the highly homologous Smad2 and Smad3 are phosphorylated by the TGF-beta receptor at the SSXS motif in the C-terminal tail. Here we show that in addition to the C-tail, three (S/T)-P sites in the Smad3 linker region, Ser(208), Ser(204), and Thr(179) are phosphorylated in response to TGF-beta. The linker phosphorylation peaks at 1 h after TGF-beta treatment, behind the peak of the C-tail phosphorylation. We provide evidence suggesting that the C-tail phosphorylation by the TGF-beta receptor is necessary for the TGF-beta-induced linker phosphorylation. Although the TGF-beta receptor is necessary for the linker phosphorylation, the receptor itself does not phosphorylate these sites. We further show that ERK is not responsible for TGF-beta-dependent phosphorylation of these three sites. We show that GSK3 accounts for TGF-beta-inducible Ser(204) phosphorylation. Flavopiridol, a pan-CDK inhibitor, abolishes TGF-beta-induced phosphorylation of Thr(179) and Ser(208), suggesting that the CDK family is responsible for phosphorylation of Thr(179) and Ser(208) in response to TGF-beta. Mutation of the linker phosphorylation sites to nonphosphorylatable residues increases the ability of Smad3 to activate a TGF-beta/Smad-target gene as well as the growth-inhibitory function of Smad3. Thus, these observations suggest that TGF-beta-induced phosphorylation of Smad3 linker sites inhibits its antiproliferative activity.

Complement factor C5a induces atherosclerotic plaque disruptions

PubMed Central

Wezel, Anouk; de Vries, Margreet R; Lagraauw, H Maxime; Foks, Amanda C; Kuiper, Johan; Quax, Paul HA; Bot, Ilze

2014-01-01

Complement factor C5a and its receptor C5aR are expressed in vulnerable atherosclerotic plaques; however, a causal relation between C5a and plaque rupture has not been established yet. Accelerated atherosclerosis was induced by placing vein grafts in male apoE−/− mice. After 24 days, when advanced plaques had developed, C5a or PBS was applied locally at the lesion site in a pluronic gel. Three days later mice were killed to examine the acute effect of C5a on late stage atherosclerosis. A significant increase in C5aR in the plaque was detectable in mice treated with C5a. Lesion size and plaque morphology did not differ between treatment groups, but interestingly, local treatment with C5a resulted in a striking increase in the amount of plaque disruptions with concomitant intraplaque haemorrhage. To identify the potential underlying mechanisms, smooth muscle cells and endothelial cells were treated in vitro with C5a. Both cell types revealed a marked increase in apoptosis after stimulation with C5a, which may contribute to lesion instability in vivo. Indeed, apoptosis within the plaque was seen to be significantly increased after C5a treatment. We here demonstrate a causal role for C5a in atherosclerotic plaque disruptions, probably by inducing apoptosis. Therefore, intervention in complement factor C5a signalling may be a promising target in the prevention of acute atherosclerotic complications. PMID:25124749

Cell communities and robustness in development.

PubMed

Monk, N A

1997-11-01

The robustness of patterning events in development is a key feature that must be accounted for in proposed models of these events. When considering explicitly cellular systems, robustness can be exhibited at different levels of organization. Consideration of two widespread patterning mechanisms suggests that robustness at the level of cell communities can result from variable development at the level of individual cells; models of these mechanisms show how interactions between participating cells guarantee community-level robustness. Cooperative interactions enhance homogeneity within communities of like cells and the sharpness of boundaries between communities of distinct cells, while competitive interactions amplify small inhomogeneities within communities of initially equivalent cells, resulting in fine-grained patterns of cell specialization.

Robust Control Design for Systems With Probabilistic Uncertainty

NASA Technical Reports Server (NTRS)

Crespo, Luis G.; Kenny, Sean P.

2005-01-01

This paper presents a reliability- and robustness-based formulation for robust control synthesis for systems with probabilistic uncertainty. In a reliability-based formulation, the probability of violating design requirements prescribed by inequality constraints is minimized. In a robustness-based formulation, a metric which measures the tendency of a random variable/process to cluster close to a target scalar/function is minimized. A multi-objective optimization procedure, which combines stability and performance requirements in time and frequency domains, is used to search for robustly optimal compensators. Some of the fundamental differences between the proposed strategy and conventional robust control methods are: (i) unnecessary conservatism is eliminated since there is not need for convex supports, (ii) the most likely plants are favored during synthesis allowing for probabilistic robust optimality, (iii) the tradeoff between robust stability and robust performance can be explored numerically, (iv) the uncertainty set is closely related to parameters with clear physical meaning, and (v) compensators with improved robust characteristics for a given control structure can be synthesized.

The valproic acid-induced rodent model of autism.

PubMed

Nicolini, Chiara; Fahnestock, Margaret

2018-01-01

Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

Sulbutiamine counteracts trophic factor deprivation induced apoptotic cell death in transformed retinal ganglion cells.

PubMed

Kang, Kui Dong; Majid, Aman Shah Abdul; Kim, Kyung-A; Kang, Kyungsu; Ahn, Hong Ryul; Nho, Chu Won; Jung, Sang Hoon

2010-11-01

Sulbutiamine is a highly lipid soluble synthetic analogue of vitamin B(1) and is used clinically for the treatment of asthenia. The aim of our study was to demonstrate whether sulbutiamine is able to attenuate trophic factor deprivation induced cell death to transformed retinal ganglion cells (RGC-5). Cells were subjected to serum deprivation for defined periods and sulbutiamine at different concentrations was added to the cultures. Various procedures (e.g. cell viability assays, apoptosis assay, reactive oxygen species analysis, Western blot analysis, flow cytometric analysis, glutathione (GSH) and glutathione-S-transferase (GST) measurement) were used to demonstrate the effect of sulbutiamine. Sulbutiamine dose-dependently attenuated apoptotic cell death induced by serum deprivation and stimulated GSH and GST activity. Moreover, sulbutiamine decreased the expression of cleaved caspase-3 and AIF. This study demonstrates for the first time that sulbutiamine is able to attenuate trophic factor deprivation induced apoptotic cell death in neuronal cells in culture.

Robustness of airline route networks

NASA Astrophysics Data System (ADS)

Lordan, Oriol; Sallan, Jose M.; Escorihuela, Nuria; Gonzalez-Prieto, David

2016-03-01

Airlines shape their route network by defining their routes through supply and demand considerations, paying little attention to network performance indicators, such as network robustness. However, the collapse of an airline network can produce high financial costs for the airline and all its geographical area of influence. The aim of this study is to analyze the topology and robustness of the network route of airlines following Low Cost Carriers (LCCs) and Full Service Carriers (FSCs) business models. Results show that FSC hubs are more central than LCC bases in their route network. As a result, LCC route networks are more robust than FSC networks.

Attraction Basins as Gauges of Robustness against Boundary Conditions in Biological Complex Systems

PubMed Central

Demongeot, Jacques; Goles, Eric; Morvan, Michel; Noual, Mathilde; Sené, Sylvain

2010-01-01

One fundamental concept in the context of biological systems on which researches have flourished in the past decade is that of the apparent robustness of these systems, i.e., their ability to resist to perturbations or constraints induced by external or boundary elements such as electromagnetic fields acting on neural networks, micro-RNAs acting on genetic networks and even hormone flows acting both on neural and genetic networks. Recent studies have shown the importance of addressing the question of the environmental robustness of biological networks such as neural and genetic networks. In some cases, external regulatory elements can be given a relevant formal representation by assimilating them to or modeling them by boundary conditions. This article presents a generic mathematical approach to understand the influence of boundary elements on the dynamics of regulation networks, considering their attraction basins as gauges of their robustness. The application of this method on a real genetic regulation network will point out a mathematical explanation of a biological phenomenon which has only been observed experimentally until now, namely the necessity of the presence of gibberellin for the flower of the plant Arabidopsis thaliana to develop normally. PMID:20700525

A network property necessary for concentration robustness

NASA Astrophysics Data System (ADS)

Eloundou-Mbebi, Jeanne M. O.; Küken, Anika; Omranian, Nooshin; Kleessen, Sabrina; Neigenfind, Jost; Basler, Georg; Nikoloski, Zoran

2016-10-01

Maintenance of functionality of complex cellular networks and entire organisms exposed to environmental perturbations often depends on concentration robustness of the underlying components. Yet, the reasons and consequences of concentration robustness in large-scale cellular networks remain largely unknown. Here, we derive a necessary condition for concentration robustness based only on the structure of networks endowed with mass action kinetics. The structural condition can be used to design targeted experiments to study concentration robustness. We show that metabolites satisfying the necessary condition are present in metabolic networks from diverse species, suggesting prevalence of this property across kingdoms of life. We also demonstrate that our predictions about concentration robustness of energy-related metabolites are in line with experimental evidence from Escherichia coli. The necessary condition is applicable to mass action biological systems of arbitrary size, and will enable understanding the implications of concentration robustness in genetic engineering strategies and medical applications.

A network property necessary for concentration robustness.

PubMed

Eloundou-Mbebi, Jeanne M O; Küken, Anika; Omranian, Nooshin; Kleessen, Sabrina; Neigenfind, Jost; Basler, Georg; Nikoloski, Zoran

2016-10-19

Maintenance of functionality of complex cellular networks and entire organisms exposed to environmental perturbations often depends on concentration robustness of the underlying components. Yet, the reasons and consequences of concentration robustness in large-scale cellular networks remain largely unknown. Here, we derive a necessary condition for concentration robustness based only on the structure of networks endowed with mass action kinetics. The structural condition can be used to design targeted experiments to study concentration robustness. We show that metabolites satisfying the necessary condition are present in metabolic networks from diverse species, suggesting prevalence of this property across kingdoms of life. We also demonstrate that our predictions about concentration robustness of energy-related metabolites are in line with experimental evidence from Escherichia coli. The necessary condition is applicable to mass action biological systems of arbitrary size, and will enable understanding the implications of concentration robustness in genetic engineering strategies and medical applications.

A robust multi-shot scan strategy for high-resolution diffusion weighted MRI enabled by multiplexed sensitivity-encoding (MUSE)

PubMed Central

Chen, Nan-kuei; Guidon, Arnaud; Chang, Hing-Chiu; Song, Allen W.

2013-01-01

Diffusion weighted magnetic resonance imaging (DWI) data have been mostly acquired with single-shot echo-planar imaging (EPI) to minimize motion induced artifacts. The spatial resolution, however, is inherently limited in single-shot EPI, even when the parallel imaging (usually at an acceleration factor of 2) is incorporated. Multi-shot acquisition strategies could potentially achieve higher spatial resolution and fidelity, but they are generally susceptible to motion-induced phase errors among excitations that are exacerbated by diffusion sensitizing gradients, rendering the reconstructed images unusable. It has been shown that shot-to-shot phase variations may be corrected using navigator echoes, but at the cost of imaging throughput. To address these challenges, a novel and robust multi-shot DWI technique, termed multiplexed sensitivity-encoding (MUSE), is developed here to reliably and inherently correct nonlinear shot-to-shot phase variations without the use of navigator echoes. The performance of the MUSE technique is confirmed experimentally in healthy adult volunteers on 3 Tesla MRI systems. This newly developed technique should prove highly valuable for mapping brain structures and connectivities at high spatial resolution for neuroscience studies. PMID:23370063

Modern CACSD using the Robust-Control Toolbox

NASA Technical Reports Server (NTRS)

Chiang, Richard Y.; Safonov, Michael G.

1989-01-01

The Robust-Control Toolbox is a collection of 40 M-files which extend the capability of PC/PRO-MATLAB to do modern multivariable robust control system design. Included are robust analysis tools like singular values and structured singular values, robust synthesis tools like continuous/discrete H(exp 2)/H infinity synthesis and Linear Quadratic Gaussian Loop Transfer Recovery methods and a variety of robust model reduction tools such as Hankel approximation, balanced truncation and balanced stochastic truncation, etc. The capabilities of the toolbox are described and illustated with examples to show how easily they can be used in practice. Examples include structured singular value analysis, H infinity loop-shaping and large space structure model reduction.

Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity.

PubMed

Qiao, Wen-Bo; Zhao, Yan-Hui; Zhao, Yan-Bin; Wang, Rui-Zhi

2005-05-07

To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during three-dimensional conformal radiotherapy (3D-CRT). We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria. Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus > or =60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, no grade 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P = 0.0001<0.01). Concurrent chemotherapy and the maximal esophageal point dose > or =60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT.

SU-E-T-527: Is CTV-Based Robust Optimized IMPT in Non-Small-Cell Lung Cancer Robust Against Respiratory Motion?

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

Anetai, Y; Mizuno, H; Sumida, I

2015-06-15

Purpose: To determine which proton planning technique on average-CT is more vulnerable to respiratory motion induced density changes and interplay effect among (a) IMPT of CTV-based minimax robust optimization with 5mm set-up error considered, (b, c) IMPT/SFUD of 5mm-expanded PTV optimization. Methods: Three planning techniques were optimized in Raystation with a prescription of 60/25 (Gy/fractions) and almost the same OAR constraints/objectives for each of 10 NSCLC patients. 4D dose without/with interplay effect was recalculated on eight 4D-CT phases and accumulated after deforming the dose of each phase to a reference (exhalation phase). The change of D98% of each CTV causedmore » by density changes and interplay was determined. In addition, evaluation of the DVH information vector (D99%, D98%, D95%, Dave, D50%, D2%, D1%) which compares the whole DVH by η score = (cosine similarity × Pearson correlation coefficient − 0.9) × 1000 quantified the degree of DVH change: score below 100 indicates changed DVH. Results: Three 3D plans of each technique satisfied our clinical goals. D98% shift mean±SD (Gy) due to density changes was largest in (c): −0.78±1.1 while (a): −0.11±0.65 and (b): − 0.59±0.93. Also the shift due to interplay effect most was (c): −.54±0.70 whereas (a): −0.25±0.93 and (b): −0.12±0.13. Moreover lowest η score caused by density change was also (c): 69, while (a) and (b) kept around 90. η score also indicated less effect of interplay than density changes. Note that generally the changed DVH were still acceptable clinically. Paired T-tests showed a significantly smaller density change effect in (a) (p<0.05) than in (b) or (c) and no significant difference in interplay effect. Conclusion: CTV-based robust optimized IMPT was more robust against respiratory motion induced density changes than PTV-based IMPT and SFUD. The interplay effect was smaller than the effect of density changes and similar among the three techniques. The

Macrophage Colony-Stimulating Factor Improves Cardiac Function after Ischemic Injury by Inducing Vascular Endothelial Growth Factor Production and Survival of Cardiomyocytes

PubMed Central

Okazaki, Tatsuma; Ebihara, Satoru; Asada, Masanori; Yamanda, Shinsuke; Saijo, Yoshifumi; Shiraishi, Yasuyuki; Ebihara, Takae; Niu, Kaijun; Mei, He; Arai, Hiroyuki; Yambe, Tomoyuki

2007-01-01

Macrophage colony-stimulating factor (M-CSF), known as a hematopoietic growth factor, induces vascular endothelial growth factor (VEGF) production from skeletal muscles. However, the effects of M-CSF on cardiomyocytes have not been reported. Here, we show M-CSF increases VEGF production from cardiomyocytes, protects cardiomyocytes and myotubes from cell death, and improves cardiac function after ischemic injury. In mice, M-CSF increased VEGF production in hearts and in freshly isolated cardiomyocytes, which showed M-CSF receptor expression. In rat cell line H9c2 cardiomyocytes and myotubes, M-CSF induced VEGF production via the Akt signaling pathway, and M-CSF pretreatment protected these cells from H2O2-induced cell death. M-CSF activated Akt and extracellular signal-regulated kinase signaling pathways and up-regulated downstream anti-apoptotic Bcl-xL expression in these cells. Using goats as a large animal model of myocardial infarction, we found that M-CSF treatment after the onset of myocardial infarction by permanent coronary artery ligation promoted angiogenesis in ischemic hearts but did not reduce the infarct area. M-CSF pretreatment of the goat myocardial infarction model by coronary artery occlusion-reperfusion improved cardiac function, as assessed by hemodynamic parameters and echocardiography. These results suggest M-CSF might be a novel therapeutic agent for ischemic heart disease. PMID:17717142

Mutant botrocetin-2 inhibits von Willebrand factor-induced platelet agglutination.

PubMed

Matsui, T; Hori, A; Hamako, J; Matsushita, F; Ozeki, Y; Sakurai, Y; Hayakawa, M; Matsumoto, M; Fujimura, Y

2017-03-01

Essentials Botrocetin-2 (Bot2) binds to von Willebrand factor (VWF) and induces platelet agglutination. We identified Bot2 residues that are required for binding to VWF and glycoprotein (GP) Ib. We produced a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Mutant Bot2 could be used as a potential anti-thrombotic reagent to block VWF-GPIb interaction. Background Botrocetin-2 (Bot2) is a botrocetin-like protein composed of α and β subunits that have been cloned from the snake Bothrops jararaca. Bot2 binds specifically to von Willebrand factor (VWF), and the complex induces glycoprotein (GP) Ib-dependent platelet agglutination. Objectives To exploit Bot2's VWF-binding capacity in order to attempt to create a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Methods and Results Several point mutations were introduced into Bot2 cDNA, and the recombinant protein (recombinant Bot2 [rBot2]) was purified on an anti-botrocetin column. The mutant rBot2 with either Ala at Asp70 in the β subunit (Aspβ70Ala), or Argβ115Ala and Lysβ117Ala, showed reduced platelet agglutination-inducing activity. rBot2 with Aspβ70Ala showed little binding activity towards immobilized VWF on an ELISA plate, whereas rBot2 with Argβ115Ala/Lysβ117Ala showed reduced binding activity towards GPIb (glycocalicin) after forming a complex with VWF. rBot2 point-mutated to oppositely charged Glu at both Argβ115 and Lysβ117 showed normal binding activity towards VWF but no platelet-agglutinating activity. Furthermore, this doubly mutated protein inhibited ristocetin-induced or high shear stress-induced platelet aggregation, and restrained thrombus formation under flow conditions. Conclusions Asp70 in the β subunit of botrocetin is important for VWF binding, and Arg115 and Lys117 in the β subunit are essential for interaction with GPIb. Doubly mutated rBot2, with Argβ115Glu and Lysβ117Glu, repels GPIb and might have potential as an antithrombotic reagent that

Robustness of Oscillatory Behavior in Correlated Networks

PubMed Central

Sasai, Takeyuki; Morino, Kai; Tanaka, Gouhei; Almendral, Juan A.; Aihara, Kazuyuki

2015-01-01

Understanding network robustness against failures of network units is useful for preventing large-scale breakdowns and damages in real-world networked systems. The tolerance of networked systems whose functions are maintained by collective dynamical behavior of the network units has recently been analyzed in the framework called dynamical robustness of complex networks. The effect of network structure on the dynamical robustness has been examined with various types of network topology, but the role of network assortativity, or degree–degree correlations, is still unclear. Here we study the dynamical robustness of correlated (assortative and disassortative) networks consisting of diffusively coupled oscillators. Numerical analyses for the correlated networks with Poisson and power-law degree distributions show that network assortativity enhances the dynamical robustness of the oscillator networks but the impact of network disassortativity depends on the detailed network connectivity. Furthermore, we theoretically analyze the dynamical robustness of correlated bimodal networks with two-peak degree distributions and show the positive impact of the network assortativity. PMID:25894574

A network property necessary for concentration robustness

PubMed Central

Eloundou-Mbebi, Jeanne M. O.; Küken, Anika; Omranian, Nooshin; Kleessen, Sabrina; Neigenfind, Jost; Basler, Georg; Nikoloski, Zoran

2016-01-01

Maintenance of functionality of complex cellular networks and entire organisms exposed to environmental perturbations often depends on concentration robustness of the underlying components. Yet, the reasons and consequences of concentration robustness in large-scale cellular networks remain largely unknown. Here, we derive a necessary condition for concentration robustness based only on the structure of networks endowed with mass action kinetics. The structural condition can be used to design targeted experiments to study concentration robustness. We show that metabolites satisfying the necessary condition are present in metabolic networks from diverse species, suggesting prevalence of this property across kingdoms of life. We also demonstrate that our predictions about concentration robustness of energy-related metabolites are in line with experimental evidence from Escherichia coli. The necessary condition is applicable to mass action biological systems of arbitrary size, and will enable understanding the implications of concentration robustness in genetic engineering strategies and medical applications. PMID:27759015

Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons

PubMed Central

Borges, Gisela Patrícia; Micó, Juan Antonio; Neto, Fani Lourença

2015-01-01

Background: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus. Methods: Complete Freund’s adjuvant-induced monoarthritis was used as inflammatory chronic pain model. α-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus. Results: Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. α-Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus. Conclusions: Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade. PMID:25716783

Robust peptide bundles designed computationally

NASA Astrophysics Data System (ADS)

Haider, Michael; Zhang, Huixi Violet; Kiick, Kristi; Saven, Jeffery; Pochan, Darrin

Peptides are ideal candidates for the design and controlled assembly of nanoscale materials due to their potential to assemble with atomistic precision as in biological systems. Unlike other work utilizing natural proteins and structural motifs, this effort is completely de novo in order to build arbitrary structures with desired size for the specific placement and separation of functional groups. We have successfully computationally designed soluble, coiled coil, peptide, tetramer bundles which are robust and stable. Using circular dichroism we demonstrated the thermal stability of these bundles as well as confirmed their alpha helical and coiled coil nature. The stability of these bundles arises from the computational design of the coiled coil interior core residues. The coiled coil tetramer was confirmed to be the dominant species by analytical ultra-centrifugation sedimentation studies. We also established how these bundles behave in solution using small angle neutron scattering. The form factor of the bundles is well represented by a cylinder model and their behavior at high concentrations is modeled using a structure factor for aggregates of the cylinders. All of these experiments support our claim that the designed coiled coil bundles were achieved in solution. NSF DMREF 1234161.

Polyanion-Induced Self Association of Complement Factor H1

PubMed Central

Pangburn, Michael K.; Rawal, Nenoo; Cortes, Claudio; Alam, M. Nurul; Ferreira, Viviana P.; Atkinson, Mark A. L.

2008-01-01

Factor H is the primary soluble regulator of activation of the alternative pathway of complement. It prevents activation of complement on host cells and tissues upon association with C3b and surface polyanions such as sialic acids, heparin and other glycosaminoglycans. Here we show that interaction with polyanions causes self-association forming tetramers of the 155,000 Da glycosylated protein. Monomeric human factor H is an extended flexible protein that exhibits an apparent size of 330,000 Da, relative to globular standards, during gel filtration chromatography in the absence of polyanions. In the presence of dextran sulfate (5,000 Da) or heparin an intermediate species of apparent m.w. 700,000 and a limit species of m.w. 1,400,000 were observed by gel filtration. Sedimentation equilibrium analysis by analytical ultracentrifugation indicated a monomer Mr of 163,000 in the absence of polyanions and a Mr of 607,000, corresponding to a tetramer, in the presence of less than a 2-fold molar excess of dextran sulfate. Increasing concentrations of dextran sulfate increased binding of factor H to zymosan-C3b 4.5-fold. This was accompanied by an increase in both the decay accelerating and cofactor activity of factor H on these cells. An expressed fragment encompassing the C-terminal polyanion binding site (complement control protein domains 18–20) also exhibited polyanion-induced self association, suggesting that the C-terminal ends of factor H mediate self-association. The results suggest that recognition of polyanionic markers on host cells and tissues by factor H, and the resulting regulation of complement activation, may involve formation of dimers and tetramers of factor H. PMID:19124749

Effect of the Camelid’s Seminal Plasma Ovulation-Inducing Factor/β-NGF: A Kisspeptin Target Hypothesis

PubMed Central

El Allali, Khalid; El Bousmaki, Najlae; Ainani, Hassan; Simonneaux, Valérie

2017-01-01

Female mammals are classified into spontaneous and induced ovulators based on the mechanism eliciting ovulation. Ovulation in spontaneous species (e.g., human, sheep, cattle, horse, pigs, and most rodents) occurs at regular intervals and depends upon the circulating estradiol. However, in induced ovulators (e.g., rabbits, ferrets, cats, and camelids), ovulation is associated with coitus. In the later, various factors have been proposed to trigger ovulation, including auditory, visual, olfactory, and mechanic stimuli. However, other studies have identified a biochemical component in the semen of induced ovulators responsible for the induction of ovulation and named accordingly ovulation-inducing factor (OIF). In camelids, intramuscular or intrauterine administration of seminal plasma (SP) was shown to induce the preovulatory luteinizing hormone (LH) surge followed by ovulation and subsequent formation of corpus luteum. Recently, this OIF has been identified from SP as a neurotrophin, the β subunit of nerve growth factor (β-NGF). β-NGF is well known as promoting neuron survival and growth, but in this case, it appears to induce ovulation through an endocrine mode of action. Indeed, β-NGF may be absorbed through the endometrium to be conveyed, via the blood stream, to the central structures regulating the LH preovulatory surge. In this review, we provide a summary of the most relevant results obtained in the field, and we propose a working hypothesis for the central action of β-NGF based on our recent demonstration of the presence of neurons expressing kisspeptin, a potent stimulator of GnRH/LH, in the camel hypothalamus. PMID:28713816

Stability characterization and modeling of robust distributed benthic microbial fuel cell (DBMFC) system.

PubMed

Karra, Udayarka; Huang, Guoxian; Umaz, Ridvan; Tenaglier, Christopher; Wang, Lei; Li, Baikun

2013-09-01

A novel and robust distributed benthic microbial fuel cell (DBMFC) was developed to address the energy supply issues for oceanographic sensor network applications, especially under scouring and bioturbation by aquatic life. Multi-anode/cathode configuration was employed in the DBMFC system for enhanced robustness and stability in the harsh ocean environment. The results showed that the DBMFC system achieved peak power and current densities of 190mW/m(2) and 125mA/m(2) respectively. Stability characterization tests indicated the DBMFC with multiple anodes achieved higher power generation over the systems with single anode. A computational model that integrated physical, electrochemical and biological factors of MFCs was developed to validate the overall performance of the DBMFC system. The model simulation well corresponded with the experimental results, and confirmed the hypothesis that using a multi anode/cathode MFC configuration results in reliable and robust power generation. Published by Elsevier Ltd.

Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

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

Kim, Hyung Gyun; Han, Eun Hee; Im, Ji Hye

2015-09-25

Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Takenmore » together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression.« less

Environmental change makes robust ecological networks fragile

USGS Publications Warehouse

Strona, Giovanni; Lafferty, Kevin D.

2016-01-01

Complex ecological networks appear robust to primary extinctions, possibly due to consumers’ tendency to specialize on dependable (available and persistent) resources. However, modifications to the conditions under which the network has evolved might alter resource dependability. Here, we ask whether adaptation to historical conditions can increase community robustness, and whether such robustness can protect communities from collapse when conditions change. Using artificial life simulations, we first evolved digital consumer-resource networks that we subsequently subjected to rapid environmental change. We then investigated how empirical host–parasite networks would respond to historical, random and expected extinction sequences. In both the cases, networks were far more robust to historical conditions than new ones, suggesting that new environmental challenges, as expected under global change, might collapse otherwise robust natural ecosystems.

Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage

PubMed Central

Yang, Bei; Fu, Jingqi; Zheng, Hongzhi; Xue, Peng; Yarborough, Kathy; Woods, Courtney G; Hou, Yongyong; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

2012-01-01

Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of Type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs3+) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic β-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2−/−) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs3+ exposure. As a result, Nrf2-KD MIN6 cells and Nrf2−/− islets were more susceptible to iAs3+ and monomethylarsonous acid (MMA3+)-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs3+-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N-acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs3+. The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic β-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic β-cell dysfunction induced by environmental arsenic exposure. PMID:23000044

Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

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

Zheng, H.; Crowley, J.J.; Chan, J.C.

Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents thatmore » attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.« less

Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells.

PubMed

Lee, S K; Yang, S-H; Kwon, I; Lee, O-H; Heo, J H

2014-09-02

Tumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Robust, flexible, and bioadhesive free-standing films for the co-delivery of antibiotics and growth factors.

PubMed

Chen, Dongdong; Wu, Mingda; Chen, Jie; Zhang, Chunqiu; Pan, Tiezheng; Zhang, Bing; Tian, Huayu; Chen, Xuesi; Sun, Junqi

2014-11-25

Free-standing polymer films that adhere strongly to tissue and can codeliver multiple therapeutic agents in a controlled manner are useful as medical plasters. In this study, a bilayer polymer film comprising a drug reservoir layer and a supporting layer is fabricated by spin-coating poly(lactic-co-glycolic acid) (PLGA) on top of a layer-by-layer assembled film of poly(β-amino esters) (PAE), alginate sodium (ALG), and recombinant human basic fibroblast growth factor (bFGF). Apart from bFGF, the bilayer film can also load antibiotic drug ceftriaxone sodium (CTX) by a postdiffusion process. The PLGA supporting layer facilitates the direct peeling of the bilayer film from substrate to produce a robust and flexible free-standing film with excellent adhesion onto the human skin and porcine liver. The excellent adhesion of the bilayer film originates from the ALG component in the drug reservoir layer. CTX is quickly released by easily breaking its electrostatic interaction with the drug reservoir layer, whereas the sustained release of bFGF is due to the slow degradation of PAE component in the drug reservoir layer. Wounds can be synergetically treated by fast release of CTX to effectively eradicate invasive bacteria and by sustained release of bFGF to accelerate wound healing. Our results serve as a basis for designing multifunctional free-standing films with combination therapy for biomedical applications.

Tumor necrosis factor and interleukin 1 as mediators of endotoxin-induced beneficial effects

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

Urbaschek, R.; Urbaschek, B.

Bacterial lipopolysaccharides or endotoxins are known to induce tumor necrosis; enhanced nonspecific resistance to bacterial, viral, and parasitic infections and to radiation sickness; and tolerance to lethal doses of endotoxin. These beneficial effects are achieved by pretreatment with minute amounts of endotoxin. Recombinant tumor necrosis factor (TNF) and interleukin 1 (IL-1) are among the mediators capable of invoking radioprotection or resistance to the consequences of cecal ligation and puncture. Both cytokines are potent inducers of serum colony-stimulating factor (CSF) in C3H/HeJ mice (low responders to endotoxin). The number of splenic granulocyte-macrophage precursors was found to increase 5 days after injectionmore » of TNF in these mice. Although with IL-1 no increase in the number of granulocyte-macrophage colonies occurred in culture in the presence of serum CSF, a marked stimulation was observed when TNF was added. This stimulation of myelopoiesis observed in vivo and in vitro may be related to the radioprotective effect of TNF. The data presented suggest that TNF and IL-1 released after injection of endotoxin participate in the mediation of endotoxin-induced enhancement of nonspecific resistance and stimulation of hematopoiesis. 76 references.« less

M-estimation for robust sparse unmixing of hyperspectral images

NASA Astrophysics Data System (ADS)

Toomik, Maria; Lu, Shijian; Nelson, James D. B.

2016-10-01

Hyperspectral unmixing methods often use a conventional least squares based lasso which assumes that the data follows the Gaussian distribution. The normality assumption is an approximation which is generally invalid for real imagery data. We consider a robust (non-Gaussian) approach to sparse spectral unmixing of remotely sensed imagery which reduces the sensitivity of the estimator to outliers and relaxes the linearity assumption. The method consists of several appropriate penalties. We propose to use an lp norm with 0 < p < 1 in the sparse regression problem, which induces more sparsity in the results, but makes the problem non-convex. On the other hand, the problem, though non-convex, can be solved quite straightforwardly with an extensible algorithm based on iteratively reweighted least squares. To deal with the huge size of modern spectral libraries we introduce a library reduction step, similar to the multiple signal classification (MUSIC) array processing algorithm, which not only speeds up unmixing but also yields superior results. In the hyperspectral setting we extend the traditional least squares method to the robust heavy-tailed case and propose a generalised M-lasso solution. M-estimation replaces the Gaussian likelihood with a fixed function ρ(e) that restrains outliers. The M-estimate function reduces the effect of errors with large amplitudes or even assigns the outliers zero weights. Our experimental results on real hyperspectral data show that noise with large amplitudes (outliers) often exists in the data. This ability to mitigate the influence of such outliers can therefore offer greater robustness. Qualitative hyperspectral unmixing results on real hyperspectral image data corroborate the efficacy of the proposed method.

Robust, Optimal Subsonic Airfoil Shapes

NASA Technical Reports Server (NTRS)

Rai, Man Mohan

2014-01-01

A method has been developed to create an airfoil robust enough to operate satisfactorily in different environments. This method determines a robust, optimal, subsonic airfoil shape, beginning with an arbitrary initial airfoil shape, and imposes the necessary constraints on the design. Also, this method is flexible and extendible to a larger class of requirements and changes in constraints imposed.

Nuclear Factor YY1 Inhibits Transforming Growth Factor β- and Bone Morphogenetic Protein-Induced Cell Differentiation

PubMed Central

Kurisaki, Keiko; Kurisaki, Akira; Valcourt, Ulrich; Terentiev, Alexei A.; Pardali, Katerina; ten Dijke, Peter; Heldin, Carl-Henrik; Ericsson, Johan; Moustakas, Aristidis

2003-01-01

Smad proteins transduce transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF-β and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1) and the inhibitor of differentiation/inhibitor of DNA binding 1 gene (Id-1). YY1 inhibits binding of Smads to their cognate DNA elements in vitro and blocks Smad recruitment to the Smad-binding element-rich region of the PAI-1 promoter in vivo. YY1 interacts with the conserved N-terminal Mad homology 1 domain of Smad4 and to a lesser extent with Smad1, Smad2, and Smad3. The YY1 zinc finger domain mediates the association with Smads and is necessary for the repressive effect of YY1 on Smad transcriptional activity. Moreover, downregulation of endogenous YY1 by antisense and small interfering RNA strategies results in enhanced transcriptional responses to TGF-β or BMP. Ectopic expression of YY1 inhibits, while knockdown of endogenous YY1 enhances, TGF-β- and BMP-induced cell differentiation. In contrast, overexpression or knockdown of YY1 does not affect growth inhibition induced by TGF-β or BMP. Accordingly, YY1 does not interfere with the regulation of immediate-early genes involved in the TGF-β growth-inhibitory response, the cell cycle inhibitors p15 and p21, and the proto-oncogene c-myc. In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-β superfamily pathways. PMID:12808092

The Bicoid Class Homeodomain Factors ceh-36/OTX and unc-30/PITX Cooperate in C. elegans Embryonic Progenitor Cells to Regulate Robust Development

PubMed Central

Walton, Travis; Preston, Elicia; Nair, Gautham; Zacharias, Amanda L.; Raj, Arjun; Murray, John Isaac

2015-01-01

While many transcriptional regulators of pluripotent and terminally differentiated states have been identified, regulation of intermediate progenitor states is less well understood. Previous high throughput cellular resolution expression studies identified dozens of transcription factors with lineage-specific expression patterns in C. elegans embryos that could regulate progenitor identity. In this study we identified a broad embryonic role for the C. elegans OTX transcription factor ceh-36, which was previously shown to be required for the terminal specification of four neurons. ceh-36 is expressed in progenitors of over 30% of embryonic cells, yet is not required for embryonic viability. Quantitative phenotyping by computational analysis of time-lapse movies of ceh-36 mutant embryos identified cell cycle or cell migration defects in over 100 of these cells, but most defects were low-penetrance, suggesting redundancy. Expression of ceh-36 partially overlaps with that of the PITX transcription factor unc-30. unc-30 single mutants are viable but loss of both ceh-36 and unc-30 causes 100% lethality, and double mutants have significantly higher frequencies of cellular developmental defects in the cells where their expression normally overlaps. These factors are also required for robust expression of the downstream developmental regulator mls-2/HMX. This work provides the first example of genetic redundancy between the related yet evolutionarily distant OTX and PITX families of bicoid class homeodomain factors and demonstrates the power of quantitative developmental phenotyping in C. elegans to identify developmental regulators acting in progenitor cells. PMID:25738873

Measure of robustness for complex networks

NASA Astrophysics Data System (ADS)

Youssef, Mina Nabil

Critical infrastructures are repeatedly attacked by external triggers causing tremendous amount of damages. Any infrastructure can be studied using the powerful theory of complex networks. A complex network is composed of extremely large number of different elements that exchange commodities providing significant services. The main functions of complex networks can be damaged by different types of attacks and failures that degrade the network performance. These attacks and failures are considered as disturbing dynamics, such as the spread of viruses in computer networks, the spread of epidemics in social networks, and the cascading failures in power grids. Depending on the network structure and the attack strength, every network differently suffers damages and performance degradation. Hence, quantifying the robustness of complex networks becomes an essential task. In this dissertation, new metrics are introduced to measure the robustness of technological and social networks with respect to the spread of epidemics, and the robustness of power grids with respect to cascading failures. First, we introduce a new metric called the Viral Conductance (VCSIS ) to assess the robustness of networks with respect to the spread of epidemics that are modeled through the susceptible/infected/susceptible (SIS) epidemic approach. In contrast to assessing the robustness of networks based on a classical metric, the epidemic threshold, the new metric integrates the fraction of infected nodes at steady state for all possible effective infection strengths. Through examples, VCSIS provides more insights about the robustness of networks than the epidemic threshold. In addition, both the paradoxical robustness of Barabasi-Albert preferential attachment networks and the effect of the topology on the steady state infection are studied, to show the importance of quantifying the robustness of networks. Second, a new metric VCSIR is introduced to assess the robustness of networks with respect

Discrimination of corn from monocotyledonous weeds with ultraviolet (UV) induced fluorescence.

PubMed

Panneton, Bernard; Guillaume, Serge; Samson, Guy; Roger, Jean-Michel

2011-01-01

In production agriculture, savings in herbicides can be achieved if weeds can be discriminated from crop, allowing the targeting of weed control to weed-infested areas only. Previous studies demonstrated the potential of ultraviolet (UV) induced fluorescence to discriminate corn from weeds and recently, robust models have been obtained for the discrimination between monocots (including corn) and dicots. Here, we developed a new approach to achieve robust discrimination of monocot weeds from corn. To this end, four corn hybrids (Elite 60T05, Monsanto DKC 26-78, Pioneer 39Y85 (RR), and Syngenta N2555 (Bt, LL)) and four monocot weeds (Digitaria ischaemum (Schreb.) I, Echinochloa crus-galli (L.) Beauv., Panicum capillare (L.), and Setaria glauca (L.) Beauv.) were grown either in a greenhouse or in a growth cabinet and UV (327 nm) induced fluorescence spectra (400 to 755 nm) were measured under controlled or uncontrolled ambient light intensity and temperature. This resulted in three contrasting data sets suitable for testing the robustness of discrimination models. In the blue-green region (400 to 550 nm), the shape of the spectra did not contain any useful information for discrimination. Therefore, the integral of the blue-green region (415 to 455 nm) was used as a normalizing factor for the red fluorescence intensity (670 to 755 nm). The shape of the normalized red fluorescence spectra did not contribute to the discrimination and in the end, only the integral of the normalized red fluorescence intensity was left as a single discriminant variable. Applying a threshold on this variable minimizing the classification error resulted in calibration errors ranging from 14.2% to 15.8%, but this threshold varied largely between data sets. Therefore, to achieve robustness, a model calibration scheme was developed based on the collection of a calibration data set from 75 corn plants. From this set, a new threshold can be estimated as the 85% quantile on the cumulative frequency

Structural integration in hypoxia-inducible factors

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

Wu, Dalei; Potluri, Nalini; Lu, Jingping

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinctmore » pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.« less

Factors influencing the robustness of P-value measurements in CT texture prognosis studies

NASA Astrophysics Data System (ADS)

McQuaid, Sarah; Scuffham, James; Alobaidli, Sheaka; Prakash, Vineet; Ezhil, Veni; Nisbet, Andrew; South, Christopher; Evans, Philip

2017-07-01

Several studies have recently reported on the value of CT texture analysis in predicting survival, although the topic remains controversial, with further validation needed in order to consolidate the evidence base. The aim of this study was to investigate the effect of varying the input parameters in the Kaplan-Meier analysis, to determine whether the resulting P-value can be considered to be a robust indicator of the parameter’s prognostic potential. A retrospective analysis of the CT-based normalised entropy of 51 patients with lung cancer was performed and overall survival data for these patients were collected. A normalised entropy cut-off was chosen to split the patient cohort into two groups and log-rank testing was performed to assess the survival difference of the two groups. This was repeated for varying normalised entropy cut-offs and varying follow-up periods. Our findings were also compared with previously published results to assess robustness of this parameter in a multi-centre patient cohort. The P-value was found to be highly sensitive to the choice of cut-off value, with small changes in cut-off producing substantial changes in P. The P-value was also sensitive to follow-up period, with particularly noisy results at short follow-up periods. Using matched conditions to previously published results, a P-value of 0.162 was obtained. Survival analysis results can be highly sensitive to the choice in texture cut-off value in dichotomising patients, which should be taken into account when performing such studies to avoid reporting false positive results. Short follow-up periods also produce unstable results and should therefore be avoided to ensure the results produced are reproducible. Previously published findings that indicated the prognostic value of normalised entropy were not replicated here, but further studies with larger patient numbers would be required to determine the cause of the different outcomes.

Environmental change makes robust ecological networks fragile

PubMed Central

Strona, Giovanni; Lafferty, Kevin D.

2016-01-01

Complex ecological networks appear robust to primary extinctions, possibly due to consumers' tendency to specialize on dependable (available and persistent) resources. However, modifications to the conditions under which the network has evolved might alter resource dependability. Here, we ask whether adaptation to historical conditions can increase community robustness, and whether such robustness can protect communities from collapse when conditions change. Using artificial life simulations, we first evolved digital consumer-resource networks that we subsequently subjected to rapid environmental change. We then investigated how empirical host–parasite networks would respond to historical, random and expected extinction sequences. In both the cases, networks were far more robust to historical conditions than new ones, suggesting that new environmental challenges, as expected under global change, might collapse otherwise robust natural ecosystems. PMID:27511722

Growth factor deprivation induces cytosolic translocation of SIRT1

NASA Astrophysics Data System (ADS)

Meng, Chengbo; Xing, Da; Wu, Shengnan; Huang, Lei

2010-02-01

Sirtuin type 1 (SIRT1), a NAD+-dependent histone deacetylases, plays a critical role in cellular senescence, aging and longevity. In general, SIRT1 is localized in nucleus and is believed as a nuclear protein. Though overexpression of SIRT1 delays senescence, SIRT1-protein levels decline naturally in thymus and heart during aging. In the present studies, we investigated the subcellular localization of SIRT1 in response to growth factor deprivation in African green monkey SV40-transformed kidney fibroblast cells (COS-7). Using SIRT1-EGFP fluorescence reporter, we found that SIRT1 localized to nucleus in physiological conditions. We devised a model enabling cell senescence via growth factor deprivation, and we found that SIRT1 partially translocated to cytosol under the treatment, suggesting a reduced level of SIRT1's activity. We found PI3K/Akt pathway was involved in the inhibition of SIRT1's cytosolic translocation, because inhibition of these kinases significantly decreased the amount of SIRT1 maintained in nucleus. Taken together, we demonstrated that growth factor deprivation induces cytosolic translocation of SIRT1, which suggesting a possible connection between cytoplasm-localized SIRT1 and the aging process.

Microglia in Glia-Neuron Co-cultures Exhibit Robust Phagocytic Activity Without Concomitant Inflammation or Cytotoxicity.

PubMed

Adams, Alexandra C; Kyle, Michele; Beaman-Hall, Carol M; Monaco, Edward A; Cullen, Matthew; Vallano, Mary Lou

2015-10-01

A simple method to co-culture granule neurons and glia from a single brain region is described, and microglia activation profiles are assessed in response to naturally occurring neuronal apoptosis, excitotoxin-induced neuronal death, and lipopolysaccharide (LPS) addition. Using neonatal rat cerebellar cortex as a tissue source, glial proliferation is regulated by omission or addition of the mitotic inhibitor cytosine arabinoside (AraC). After 7-8 days in vitro, microglia in AraC(-) cultures are abundant and activated based on their amoeboid morphology, expressions of ED1 and Iba1, and ability to phagocytose polystyrene beads and the majority of neurons undergoing spontaneous apoptosis. Microglia and phagocytic activities are sparse in AraC(+) cultures. Following exposure to excitotoxic kainate concentrations, microglia in AraC(-) cultures phagocytose most dead neurons within 24 h without exacerbating neuronal loss or mounting a strong or sustained inflammatory response. LPS addition induces a robust inflammatory response, based on microglial expressions of TNF-α, COX-2 and iNOS proteins, and mRNAs, whereas these markers are essentially undetectable in control cultures. Thus, the functional effector state of microglia is primed for phagocytosis but not inflammation or cytotoxicity even after kainate exposure that triggers death in the majority of neurons. This model should prove useful in studying the progressive activation states of microglia and factors that promote their conversion to inflammatory and cytotoxic phenotypes.

Efficient and robust analysis of complex scattering data under noise in microwave resonators.

PubMed

Probst, S; Song, F B; Bushev, P A; Ustinov, A V; Weides, M

2015-02-01

Superconducting microwave resonators are reliable circuits widely used for detection and as test devices for material research. A reliable determination of their external and internal quality factors is crucial for many modern applications, which either require fast measurements or operate in the single photon regime with small signal to noise ratios. Here, we use the circle fit technique with diameter correction and provide a step by step guide for implementing an algorithm for robust fitting and calibration of complex resonator scattering data in the presence of noise. The speedup and robustness of the analysis are achieved by employing an algebraic rather than an iterative fit technique for the resonance circle.

Inhibition of myeloid differentiation factor-2 attenuates obesity-induced cardiomyopathy and fibrosis.

PubMed

Fang, Qilu; Wang, Jingying; Zhang, Yali; Wang, Lintao; Li, Weixin; Han, Jibo; Huang, Weijian; Liang, Guang; Wang, Yi

2018-01-01

Obesity causes cardiovascular diseases, including cardiac hypertrophy and remodeling, via chronic tissue inflammation. Myeloid differentiation factor-2 (MD2), a binding protein of lipopolysaccharide, is functionally essential for the activation of proinflammatory pathways in endotoxin-induced acute inflammatory diseases. Here we tested the hypothesis that MD2 plays a central role in obesity-induced cardiomyopathy. Wildtype or MD2 knockout mice were fed with a high fat diet (HFD) or normal diet (Control) for total 16weeks, and MD2 inhibitor L6H21 (20mg/kg) or vehicle (1% CMC-Na) were administered from the beginning of the 9th week. HFD induced significant weight gain and cardiac hypertrophy, with increased cardiac fibrosis and inflammation. L6H21 administration or MD2 knockout attenuated HFD-induced obesity, inflammation and cardiac remodeling. In vitro exposure of H9C2 cells to high lipids induced cell hypertrophy with activated JNK/ERK and NF-κB pathways, which was abolished by pretreatment of MD2 inhibitor L6H21. Our results demonstrate that MD2 is essential to obesity-related cardiac hypertrophy through activating JNK/ERK and NF-κB-dependent cardiac inflammatory pathways. Targeting MD2 would be a therapeutic approach to prevent obesity-induced cardiac injury and remodeling. Copyright © 2017. Published by Elsevier B.V.

Adult hippocampus derived soluble factors induce a neuronal-like phenotype in mesenchymal stem cells.

PubMed

Rivera, Francisco J; Sierralta, Walter D; Minguell, Jose J; Aigner, Ludwig

2006-10-02

Bone marrow-derived mesenchymal stem cells (MSCs) are not restricted in their differentiation fate to cells of the mesenchymal lineage. They acquire a neural phenotype in vitro and in vivo after transplantation in the central nervous system. Here we investigated whether soluble factors derived from different brain regions are sufficient to induce a neuronal phenotype in MSCs. We incubated bone marrow-derived MSCs in conditioned medium (CM) derived from adult hippocampus (HCM), cortex (CoCM) or cerebellum (CeCM) and analyzed the cellular morphology and the expression of neuronal and glial markers. In contrast to muscle derived conditioned medium, which served as control, conditioned medium derived from the different brain regions induced a neuronal morphology and the expression of the neuronal markers GAP-43 and neurofilaments in MSCs. Hippocampus derived conditioned medium had the strongest activity. It was independent of NGF or BDNF; and it was restricted to the neuronal differentiation fate, since no induction of the astroglial marker GFAP was observed. The work indicates that soluble factors present in the brain are sufficient to induce a neuronal phenotype in MSCs.

The spontaneous emission factor for lasers with gain induced waveguiding

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

Newstein, M.

1984-11-01

The expression for the spontaneous emission factor for lasers with gain induced waveguiding has a factor K, called by Petermann ''the astigmatism parameter.'' This factor has been invoked to explain spectral and dynamic characteristics of this class of lasers. We contend that the widely accepted form of the K factor is based on a derivation which is not appropriate for the typical laser situation where the spontaneous emission factor is much smaller than unity. An alternative derivation is presented which leads to a different form for the K factor. The new expression predicts much smaller values under conditions where themore » previous theory gave values large compared to unity. Petermann's form for the K factor is shown to be relevant to large gain linear amplifiers where the power is amplified spontaneous emission noise. The expression for the power output has Petermann's value of K as a factor. The difference in the two situations is that in the laser oscillator the typical atom of interest couples a small portion of its incoherent spontaneous emission into the dominant mode, whereas in the amplifier only the atoms at the input end are important as sources and their output is converted to a greater degree into the dominant mode through the propagation process. In this analysis the authors use a classical model of radiating point dipoles in a continuous medium characterized by a complex permittivity. Since uncritical use of this model will lead to infinite radiation resistance they address the problem of its self-consistency.« less

Fatty Acid Synthase as a Factor Required for Exercise-Induced Cognitive Enhancement and Dentate Gyrus Cellular Proliferation

PubMed Central

Chorna, Nataliya E.; Santos-Soto, Iván J.; Carballeira, Nestor M.; Morales, Joan L.; de la Nuez, Janneliz; Cátala-Valentin, Alma; Chornyy, Anatoliy P.; Vázquez-Montes, Adrinel; De Ortiz, Sandra Peña

2013-01-01

Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN), the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis. PMID:24223732

Robustness and fragility in coupled oscillator networks under targeted attacks.

PubMed

Yuan, Tianyu; Aihara, Kazuyuki; Tanaka, Gouhei

2017-01-01

The dynamical tolerance of coupled oscillator networks against local failures is studied. As the fraction of failed oscillator nodes gradually increases, the mean oscillation amplitude in the entire network decreases and then suddenly vanishes at a critical fraction as a phase transition. This critical fraction, widely used as a measure of the network robustness, was analytically derived for random failures but not for targeted attacks so far. Here we derive the general formula for the critical fraction, which can be applied to both random failures and targeted attacks. We consider the effects of targeting oscillator nodes based on their degrees. First we deal with coupled identical oscillators with homogeneous edge weights. Then our theory is applied to networks with heterogeneous edge weights and to those with nonidentical oscillators. The analytical results are validated by numerical experiments. Our results reveal the key factors governing the robustness and fragility of oscillator networks.

Redundancy relations and robust failure detection

NASA Technical Reports Server (NTRS)

Chow, E. Y.; Lou, X. C.; Verghese, G. C.; Willsky, A. S.

1984-01-01

All failure detection methods are based on the use of redundancy, that is on (possible dynamic) relations among the measured variables. Consequently the robustness of the failure detection process depends to a great degree on the reliability of the redundancy relations given the inevitable presence of model uncertainties. The problem of determining redundancy relations which are optimally robust in a sense which includes the major issues of importance in practical failure detection is addressed. A significant amount of intuition concerning the geometry of robust failure detection is provided.

MECHANISMS OF ZN-INDUCED SIGNAL INITIATION THROUGH THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)

EPA Science Inventory

MECHANISMS OF Zn-INDUCED SIGNAL INITIATION THROUGH THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
James M. Samet*, Lee M. Graves? and Weidong Wu?. *Human Studies Division, NHEERL, ORD, Research Triangle Park, NC 27711, and ?Center for Environmental Medicine, University of North C...

Investigation of a measure of robustness in inductively coupled plasma mass spectrometry

NASA Astrophysics Data System (ADS)

Makonnen, Yoseif; Beauchemin, Diane

2015-01-01

In industrial/commercial settings where operators often have minimal expertise in inductively coupled plasma (ICP) mass spectrometry (MS), there is a prevalent need for a response factor indicating robust plasma conditions, which is analogous to the Mg II/Mg I ratio in ICP optical emission spectrometry (OES), whereby a Mg II/Mg I ratio of 10 constitutes robust conditions. While minimizing the oxide ratio usually corresponds to robust conditions, there is no specific target value that is widely accepted as indicating robust conditions. Furthermore, tuning for low oxide ratios does not necessarily guarantee minimal matrix effects, as they really address polyatomic interferences. From experiments, conducted in parallel for both MS and OES, there were some element pairs of similar mass and very different ionization potential that were exploited for such a purpose, the rationale being that, if these elements were ionized to the same extent, then that could be indicative of a robust plasma. The Be II/Li I intensity ratio was directly related to the Mg II/Mg I ratio in OES. Moreover, the 9Be+/7Li+ ratio was inversely related to the CeO+/Ce+ and LaO+/La+ oxide ratios in MS. The effects of different matrices (i.e. 0.01-0.1 M Na) were also investigated and compared to a conventional argon plasma optimized for maximum sensitivity. The suppression effect of these matrices was significantly reduced, if not eliminated in the case of 0.01 M Na, when the 9Be+/7Li+ ratio was around 0.30 on the Varian 820 MS instrument. Moreover, a very similar ratio (0.28) increased robustness to the same extent on a completely different ICP-MS instrument (PerkinElmer NEXION). Much greater robustness was achieved using a mixed-gas plasma with nitrogen in the outer gas and either nitrogen or hydrogen as a sheathing gas, as the 9Be+/7Li+ ratio was then around 1.70. To the best of our knowledge, this is the first report on using a simple analyte intensity ratio, 9Be+/7Li+, to gauge plasma robustness.

The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

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

Munoz, Juan Pablo; Collao, Andres; Chiong, Mario

2009-10-09

Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-inducedmore » MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.« less

Data-Adaptive Bias-Reduced Doubly Robust Estimation.

PubMed

Vermeulen, Karel; Vansteelandt, Stijn

2016-05-01

Doubly robust estimators have now been proposed for a variety of target parameters in the causal inference and missing data literature. These consistently estimate the parameter of interest under a semiparametric model when one of two nuisance working models is correctly specified, regardless of which. The recently proposed bias-reduced doubly robust estimation procedure aims to partially retain this robustness in more realistic settings where both working models are misspecified. These so-called bias-reduced doubly robust estimators make use of special (finite-dimensional) nuisance parameter estimators that are designed to locally minimize the squared asymptotic bias of the doubly robust estimator in certain directions of these finite-dimensional nuisance parameters under misspecification of both parametric working models. In this article, we extend this idea to incorporate the use of data-adaptive estimators (infinite-dimensional nuisance parameters), by exploiting the bias reduction estimation principle in the direction of only one nuisance parameter. We additionally provide an asymptotic linearity theorem which gives the influence function of the proposed doubly robust estimator under correct specification of a parametric nuisance working model for the missingness mechanism/propensity score but a possibly misspecified (finite- or infinite-dimensional) outcome working model. Simulation studies confirm the desirable finite-sample performance of the proposed estimators relative to a variety of other doubly robust estimators.

Tumor Environmental Factors Glucose Deprivation and Lactic Acidosis Induce Mitotic Chromosomal Instability – An Implication in Aneuploid Human Tumors

PubMed Central

Zhu, Chunpeng; Hu, Xun

2013-01-01

Mitotic chromosomal instability (CIN) plays important roles in tumor progression, but what causes CIN is incompletely understood. In general, tumor CIN arises from abnormal mitosis, which is caused by either intrinsic or extrinsic factors. While intrinsic factors such as mitotic checkpoint genes have been intensively studied, the impact of tumor microenvironmental factors on tumor CIN is largely unknown. We investigate if glucose deprivation and lactic acidosis – two tumor microenvironmental factors – could induce cancer cell CIN. We show that glucose deprivation with lactic acidosis significantly increases CIN in 4T1, MCF-7 and HCT116 scored by micronuclei, or aneuploidy, or abnormal mitosis, potentially via damaging DNA, up-regulating mitotic checkpoint genes, and/or amplifying centrosome. Of note, the feature of CIN induced by glucose deprivation with lactic acidosis is similar to that of aneuploid human tumors. We conclude that tumor environmental factors glucose deprivation and lactic acidosis can induce tumor CIN and propose that they are potentially responsible for human tumor aneuploidy. PMID:23675453

Optimization-Based Robust Nonlinear Control

DTIC Science & Technology

2006-08-01

ABSTRACT New control algorithms were developed for robust stabilization of nonlinear dynamical systems . Novel, linear matrix inequality-based synthesis...was to further advance optimization-based robust nonlinear control design, for general nonlinear systems (especially in discrete time ), for linear...Teel, IEEE Transactions on Control Systems Technology, vol. 14, no. 3, p. 398-407, May 2006. 3. "A unified framework for input-to-state stability in

Fast and robust control of two interacting spins

NASA Astrophysics Data System (ADS)

Yu, Xiao-Tong; Zhang, Qi; Ban, Yue; Chen, Xi

2018-06-01

Rapid preparation, manipulation, and correction of spin states with high fidelity are requisite for quantum information processing and quantum computing. In this paper, we propose a fast and robust approach for controlling two spins with Heisenberg and Ising interactions. By using the concept of shortcuts to adiabaticity, we first inverse design the driving magnetic fields for achieving fast spin flip or generating the entangled Bell state, and further optimize them with respect to the error and fluctuation. In particular, the designed shortcut protocols can efficiently suppress the unwanted transition or control error induced by anisotropic antisymmetric Dzyaloshinskii-Moriya exchange. Several examples and comparisons are illustrated, showing the advantages of our methods. Finally, we emphasize that the results can be naturally extended to multiple interacting spins and other quantum systems in an analogous fashion.

3,3'-diindolylmethane potentiates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of gastric cancer cells.

PubMed

Ye, Yang; Miao, Shuhan; Wang, Yan; Zhou, Jianwei; Lu, Rongzhu

2015-05-01

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) specifically kills cancer cells without destroying the majority of healthy cells. However, numerous types of cancer cell, including gastric cancer cells, tend to be resistant to TRAIL. The bioactive product 3,3'-diindolylmethane (DIM), which is derived from cruciferous vegetables, is also currently recognized as a candidate anticancer agent. In the present study, a Cell Counting Kit 8 cell growth assay and an Annexin V-fluorescein isothiocyanate apoptosis assay were performed to investigate the potentiating effect of DIM on TRAIL-induced apoptosis in gastric cancer cells, and the possible mechanisms of this potentiation. The results obtained demonstrated that, compared with TRAIL or DIM treatment alone, co-treatment with TRAIL (25 or 50 ng/ml) and DIM (10 µmol/l) induced cytotoxic and apoptotic effects in BGC-823 and SGC-7901 gastric cancer cells. Furthermore, western blot analysis revealed that the protein expression levels of death receptor 5 (DR5), CCAAT/enhancer binding protein homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) were upregulated in the co-treated gastric cancer cells. To the best of our knowledge, the present study is the first to provide evidence that DIM sensitizes TRAIL-induced inhibition of proliferation and apoptosis in gastric cancer cells, accompanied by the upregulated expression of DR5, CHOP and GRP78 proteins, which may be involved in endoplasmic reticulum stress mechanisms.

Multi-criteria robustness analysis of metro networks

NASA Astrophysics Data System (ADS)

Wang, Xiangrong; Koç, Yakup; Derrible, Sybil; Ahmad, Sk Nasir; Pino, Willem J. A.; Kooij, Robert E.

2017-05-01

Metros (heavy rail transit systems) are integral parts of urban transportation systems. Failures in their operations can have serious impacts on urban mobility, and measuring their robustness is therefore critical. Moreover, as physical networks, metros can be viewed as topological entities, and as such they possess measurable network properties. In this article, by using network science and graph theory, we investigate ten theoretical and four numerical robustness metrics and their performance in quantifying the robustness of 33 metro networks under random failures or targeted attacks. We find that the ten theoretical metrics capture two distinct aspects of robustness of metro networks. First, several metrics place an emphasis on alternative paths. Second, other metrics place an emphasis on the length of the paths. To account for all aspects, we standardize all ten indicators and plot them on radar diagrams to assess the overall robustness for metro networks. Overall, we find that Tokyo and Rome are the most robust networks. Rome benefits from short transferring and Tokyo has a significant number of transfer stations, both in the city center and in the peripheral area of the city, promoting both a higher number of alternative paths and overall relatively short path-lengths.

Stabilization and robustness of non-linear unity-feedback system - Factorization approach

NASA Technical Reports Server (NTRS)

Desoer, C. A.; Kabuli, M. G.

1988-01-01

The paper is a self-contained discussion of a right factorization approach in the stability analysis of the nonlinear continuous-time or discrete-time, time-invariant or time-varying, well-posed unity-feedback system S1(P, C). It is shown that a well-posed stable feedback system S1(P, C) implies that P and C have right factorizations. In the case where C is stable, P has a normalized right-coprime factorization. The factorization approach is used in stabilization and simultaneous stabilization results.

Hypoxia-Inducible Factor Prolyl Hydroxylases are Oxygen Sensors in the Brain

DTIC Science & Technology

2005-03-01

astrocytes. It has been appreciated that increased HIF-1α protein levels are commonly found in several cancer types (Zhong, De Marzo et al. 1999...A 98(17): 9630-5. Zhong, H., A. M. De Marzo , et al. (1999). "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their...rat brain” Discussion 17-23 Bibliography 24 -31 ix INTRODUCTION Vertebrate cells possess adaptive responses to hypoxia

TARCMO: Theory and Algorithms for Robust, Combinatorial, Multicriteria Optimization

DTIC Science & Technology

2016-11-28

objective 9 4.6 On The Recoverable Robust Traveling Salesman Problem . . . . . 11 4.7 A Bicriteria Approach to Robust Optimization...be found. 4.6 On The Recoverable Robust Traveling Salesman Problem The traveling salesman problem (TSP) is a well-known combinatorial optimiza- tion...procedure for the robust traveling salesman problem . While this iterative algorithms results in an optimal solution to the robust TSP, computation

Operator induced multigrid algorithms using semirefinement

NASA Technical Reports Server (NTRS)

Decker, Naomi; Vanrosendale, John

1989-01-01

A variant of multigrid, based on zebra relaxation, and a new family of restriction/prolongation operators is described. Using zebra relaxation in combination with an operator-induced prolongation leads to fast convergence, since the coarse grid can correct all error components. The resulting algorithms are not only fast, but are also robust, in the sense that the convergence rate is insensitive to the mesh aspect ratio. This is true even though line relaxation is performed in only one direction. Multigrid becomes a direct method if an operator-induced prolongation is used, together with the induced coarse grid operators. Unfortunately, this approach leads to stencils which double in size on each coarser grid. The use of an implicit three point restriction can be used to factor these large stencils, in order to retain the usual five or nine point stencils, while still achieving fast convergence. This algorithm achieves a V-cycle convergence rate of 0.03 on Poisson's equation, using 1.5 zebra sweeps per level, while the convergence rate improves to 0.003 if optimal nine point stencils are used. Numerical results for two and three dimensional model problems are presented, together with a two level analysis explaining these results.

PACAP and VIP regulate hypoxia-inducible factors in neuroblastoma cells exposed to hypoxia.

PubMed

Maugeri, Grazia; D'Amico, Agata Grazia; Rasà, Daniela Maria; Saccone, Salvatore; Federico, Concetta; Cavallaro, Sebastiano; D'Agata, Velia

2018-06-01

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two related peptides acting as neurotransmitters/neuromodulators in central and peripheral nervous system. They are also involved in cancer showing a controversial role. Particulary, they are implicated in neuroblastoma differentiation (NB). This pediatric tumor can evolve to a malignant metastatic disease or spontaneously regress towards a benign form, known as ganglioneuroblastoma/ganglioneuroma. A negative hallmark of neoplasia progression is represented by hypoxic microenvironment. Low oxygen tension induces activation of hypoxia-inducible factors (HIFs) promoting cells proliferation and metastasis formation. Moreover, HIFs trigger vascular endothelial growth factor (VEGF) release favouring high-risk NB phenotype development. In the present work, we have investigated for the first time, if PACAP and VIP interfere with NB differentiation through modulation of hypoxic/angiogenic process. To this end, we analyzed their effect in malignant undifferentiated and all-trans retinoic acid (RA) differentiated SH-SY5Y cells, representing the benign form of this tumor. Our results have suggested tha both peptides, but predominantly VIP, induce NB differentiation into benign form by regulating HIFs, VEGF and VEGFRs expression and distribution. All these data give new insight regarding PACAP/VIP regulatory role in NB progression. Copyright © 2018 Elsevier Ltd. All rights reserved.

Factors Influencing the Appearance of Oxaliplatin-Induced Allergy.

PubMed

Nishihara, Masayuki; Nishikura, Kyoko; Morikawa, Norimichi; Yokoyama, Shota

2017-01-01

Several studies reported that the administration of oxaliplatin often induced allergy, but few studies have analyzed the pathogenesis. In this study, we examined the relationship between the incidence of allergy and status of oxaliplatin administration, patient background, laboratory data, or combined drugs. The subjects were 144 patients with colorectal or gastric cancer in whom oxaliplatin administration was started and completed between 2010 and 2016. They were divided into 2 groups: allergy and non-allergy groups. We extracted important factors influencing its appearance using multivariate analysis, and analyzed items of which the influence was suggested, using receiver operating characteristic (ROC) analysis. In 11 patients (7.6%), allergy appeared. The median frequency of appearance was 9 times (range: 5-13), being similar to that previously reported. On multivariate analysis, albumin (Alb) was extracted as an important factor. The cut-off value of Alb for the risk of allergy was 4.1 g/dL. An increase in the number of protein conjugates may have increased the risk of functioning as a hapten. Furthermore, the results suggested that the more frequency of oxaliplatin administration might increase the incidence of allergy, although it was not extracted as an important factor. In addition to young and female patients, as previously indicated, careful follow-up may be necessary for those with an Alb level of ≥4.1 g/dL especially after the 6th course.

Assessment of Risk Factors of Intrauterine Adhesions in Patients With Induced Abortion and the Curative Effect of Hysteroscopic Surgery.

PubMed

Mo, Xiaoliang; Qin, Guirong; Zhou, Zhoulin; Jiang, Xiaoli

2017-10-03

To explore the risk factors for intrauterine adhesions in patients with artificial abortion and clinical efficacy of hysteroscopic dissection. 1500 patients undergoing artificial abortion between January 2014 and June 2015 were enrolled into this study. The patients were divided into two groups with or without intrauterine adhesions. Univariate and Multiple logistic regression were conducted to assess the effects of multiple factors on the development of intrauterine adhesions following induced abortion. The incidence rate for intrauterine adhesions following induced abortion is 17.0%. Univariate showed that preoperative inflammation, multiple pregnancies and suction evacuation time are the influence risk factors of intrauterine adhesions. Multiple logistic regression demonstrates that multiple pregnancies, high intrauterine negative pressure, and long suction evacuation time are independent risk factors for the development of intrauterine adhesions following induced abortion. Additionally, intrauterine adhesions were observed in 105 mild, 80 moderate, and 70 severe cases. The cure rates for these three categories of intrauterine adhesions by hysteroscopic surgery were 100.0%, 93.8%, and 85.7%, respectively. Multiple pregnancies, high negative pressure suction evacuation and long suction evacuation time are independent risk factors for the development of intrauterine adhesions following induced abortions. Hysteroscopic surgery substantially improves the clinical outcomes of intrauterine adhesions.

Annonaceous acetogenin mimic AA005 induces cancer cell death via apoptosis inducing factor through a caspase-3-independent mechanism.

PubMed

Han, Bing; Wang, Tong-Dan; Shen, Shao-Ming; Yu, Yun; Mao, Chan; Yao, Zhu-Jun; Wang, Li-Shun

2015-03-18

Annonaceous acetogenins are a family of natural products with antitumor activities. Annonaceous acetogenin mimic AA005 reportedly inhibits mammalian mitochondrial NADH-ubiquinone reductase (Complex I) and induces gastric cancer cell death. However, the mechanisms underlying its cell-death-inducing activity are unclear. We used SW620 colorectal adenocarcinoma cells to study AA005 cytotoxic activity. Cell deaths were determined by Trypan blue assay and flow cytometry, and related proteins were characterized by western blot. Immunofluorescence and subcellular fractionation were used to evaluate AIF nuclear translocation. Reactive oxygen species were assessed by using redox-sensitive dye DCFDA. AA005 induces a unique type of cell death in colorectal adenocarcinoma cells, characterized by lack of caspase-3 activation or apoptotic body formation, sensitivity to poly (ADP-ribose) polymerase inhibitor Olaparib (AZD2281) but not pan-caspase inhibitor Z-VAD.fmk, and dependence on apoptosis-inducing factor (AIF). AA005 treatment also reduced expression of mitochondrial Complex I components, and leads to accumulation of intracellular reactive oxygen species (ROS) at the early stage. Blocking ROS formation significantly suppresses AA005-induced cell death in SW620 cells. Moreover, blocking activation of RIP-1 by necroptosis inhibitor necrotatin-1 inhibits AIF translocation and partially suppresses AA005-induced cell death in SW620 cells demonstrating that RIP-1 protein may be essential for cell death. AA005 may trigger the cell death via mediated by AIF through caspase-3 independent pathway. Our work provided new mechanisms for AA005-induced cancer cell death and novel clues for cancer treatment via AIF dependent cell death.

Replication and robustness in developmental research.

PubMed

Duncan, Greg J; Engel, Mimi; Claessens, Amy; Dowsett, Chantelle J

2014-11-01

Replications and robustness checks are key elements of the scientific method and a staple in many disciplines. However, leading journals in developmental psychology rarely include explicit replications of prior research conducted by different investigators, and few require authors to establish in their articles or online appendices that their key results are robust across estimation methods, data sets, and demographic subgroups. This article makes the case for prioritizing both explicit replications and, especially, within-study robustness checks in developmental psychology. It provides evidence on variation in effect sizes in developmental studies and documents strikingly different replication and robustness-checking practices in a sample of journals in developmental psychology and a sister behavioral science-applied economics. Our goal is not to show that any one behavioral science has a monopoly on best practices, but rather to show how journals from a related discipline address vital concerns of replication and generalizability shared by all social and behavioral sciences. We provide recommendations for promoting graduate training in replication and robustness-checking methods and for editorial policies that encourage these practices. Although some of our recommendations may shift the form and substance of developmental research articles, we argue that they would generate considerable scientific benefits for the field. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

On the robustness of Herlihy's hierarchy

NASA Technical Reports Server (NTRS)

Jayanti, Prasad

1993-01-01

A wait-free hierarchy maps object types to levels in Z(+) U (infinity) and has the following property: if a type T is at level N, and T' is an arbitrary type, then there is a wait-free implementation of an object of type T', for N processes, using only registers and objects of type T. The infinite hierarchy defined by Herlihy is an example of a wait-free hierarchy. A wait-free hierarchy is robust if it has the following property: if T is at level N, and S is a finite set of types belonging to levels N - 1 or lower, then there is no wait-free implementation of an object of type T, for N processes, using any number and any combination of objects belonging to the types in S. Robustness implies that there are no clever ways of combining weak shared objects to obtain stronger ones. Contrary to what many researchers believe, we prove that Herlihy's hierarchy is not robust. We then define some natural variants of Herlihy's hierarchy, which are also infinite wait-free hierarchies. With the exception of one, which is still open, these are not robust either. We conclude with the open question of whether non-trivial robust wait-free hierarchies exist.

Pigment Epithelium Derived Factor Peptide Protects Murine Hepatocytes from Carbon Tetrachloride-Induced Injury

PubMed Central

Shih, Shou-Chuan; Ho, Tsung-Chuan; Chen, Show-Li; Tsao, Yeou-Ping

2016-01-01

Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl4). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl4, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl4-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl4 caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl4 injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl4 injury. This protective effect may stem from strengthening the counter oxidative stress capacity and

Robust, Adaptive Functional Regression in Functional Mixed Model Framework.

PubMed

Zhu, Hongxiao; Brown, Philip J; Morris, Jeffrey S

2011-09-01

Functional data are increasingly encountered in scientific studies, and their high dimensionality and complexity lead to many analytical challenges. Various methods for functional data analysis have been developed, including functional response regression methods that involve regression of a functional response on univariate/multivariate predictors with nonparametrically represented functional coefficients. In existing methods, however, the functional regression can be sensitive to outlying curves and outlying regions of curves, so is not robust. In this paper, we introduce a new Bayesian method, robust functional mixed models (R-FMM), for performing robust functional regression within the general functional mixed model framework, which includes multiple continuous or categorical predictors and random effect functions accommodating potential between-function correlation induced by the experimental design. The underlying model involves a hierarchical scale mixture model for the fixed effects, random effect and residual error functions. These modeling assumptions across curves result in robust nonparametric estimators of the fixed and random effect functions which down-weight outlying curves and regions of curves, and produce statistics that can be used to flag global and local outliers. These assumptions also lead to distributions across wavelet coefficients that have outstanding sparsity and adaptive shrinkage properties, with great flexibility for the data to determine the sparsity and the heaviness of the tails. Together with the down-weighting of outliers, these within-curve properties lead to fixed and random effect function estimates that appear in our simulations to be remarkably adaptive in their ability to remove spurious features yet retain true features of the functions. We have developed general code to implement this fully Bayesian method that is automatic, requiring the user to only provide the functional data and design matrices. It is efficient

Robust, Adaptive Functional Regression in Functional Mixed Model Framework

PubMed Central

Zhu, Hongxiao; Brown, Philip J.; Morris, Jeffrey S.

2012-01-01

Functional data are increasingly encountered in scientific studies, and their high dimensionality and complexity lead to many analytical challenges. Various methods for functional data analysis have been developed, including functional response regression methods that involve regression of a functional response on univariate/multivariate predictors with nonparametrically represented functional coefficients. In existing methods, however, the functional regression can be sensitive to outlying curves and outlying regions of curves, so is not robust. In this paper, we introduce a new Bayesian method, robust functional mixed models (R-FMM), for performing robust functional regression within the general functional mixed model framework, which includes multiple continuous or categorical predictors and random effect functions accommodating potential between-function correlation induced by the experimental design. The underlying model involves a hierarchical scale mixture model for the fixed effects, random effect and residual error functions. These modeling assumptions across curves result in robust nonparametric estimators of the fixed and random effect functions which down-weight outlying curves and regions of curves, and produce statistics that can be used to flag global and local outliers. These assumptions also lead to distributions across wavelet coefficients that have outstanding sparsity and adaptive shrinkage properties, with great flexibility for the data to determine the sparsity and the heaviness of the tails. Together with the down-weighting of outliers, these within-curve properties lead to fixed and random effect function estimates that appear in our simulations to be remarkably adaptive in their ability to remove spurious features yet retain true features of the functions. We have developed general code to implement this fully Bayesian method that is automatic, requiring the user to only provide the functional data and design matrices. It is efficient