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Sample records for mice revealed robust

  1. Robust Central Nervous System Pathology in Transgenic Mice following Peripheral Injection of α-Synuclein Fibrils.

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    Ayers, Jacob I; Brooks, Mieu M; Rutherford, Nicola J; Howard, Jasie K; Sorrentino, Zachary A; Riffe, Cara J; Giasson, Benoit I

    2017-01-15

    Misfolded α-synuclein (αS) is hypothesized to spread throughout the central nervous system (CNS) by neuronal connectivity leading to widespread pathology. Increasing evidence indicates that it also has the potential to invade the CNS via peripheral nerves in a prion-like manner. On the basis of the effectiveness following peripheral routes of prion administration, we extend our previous studies of CNS neuroinvasion in M83 αS transgenic mice following hind limb muscle (intramuscular [i.m.]) injection of αS fibrils by comparing various peripheral sites of inoculations with different αS protein preparations. Following intravenous injection in the tail veins of homozygous M83 transgenic (M83 +/+ ) mice, robust αS pathology was observed in the CNS without the development of motor impairments within the time frame examined. Intraperitoneal (i.p.) injections of αS fibrils in hemizygous M83 transgenic (M83 +/- ) mice resulted in CNS αS pathology associated with paralysis. Interestingly, injection with soluble, nonaggregated αS resulted in paralysis and pathology in only a subset of mice, whereas soluble Δ71-82 αS, human βS, and keyhole limpet hemocyanin (KLH) control proteins induced no symptoms or pathology. Intraperitoneal injection of αS fibrils also induced CNS αS pathology in another αS transgenic mouse line (M20), albeit less robustly in these mice. In comparison, i.m. injection of αS fibrils was more efficient in inducing CNS αS pathology in M83 mice than i.p. or tail vein injections. Furthermore, i.m. injection of soluble, nonaggregated αS in M83 +/- mice also induced paralysis and CNS αS pathology, although less efficiently. These results further demonstrate the prion-like characteristics of αS and reveal its efficiency to invade the CNS via multiple routes of peripheral administration. The misfolding and accumulation of α-synuclein (αS) inclusions are found in a number of neurodegenerative disorders and is a hallmark feature of Parkinson

  2. Robust

    DEFF Research Database (Denmark)

    2017-01-01

    Robust – Reflections on Resilient Architecture’, is a scientific publication following the conference of the same name in November of 2017. Researches and PhD-Fellows, associated with the Masters programme: Cultural Heritage, Transformation and Restoration (Transformation), at The Royal Danish...

  3. Head direction cell activity in mice: robust directional signal depends on intact otolith organs

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    Yoder, Ryan M.; Taube, Jeffrey S.

    2009-01-01

    The head direction (HD) cell signal is a representation of an animal's perceived directional heading with respect to its environment. This signal appears to originate in the vestibular system, which includes the semicircular canals and otolith organs. Preliminary studies indicate the semicircular canals provide a necessary component of the HD signal, but involvement of otolithic information in the HD signal has not been tested. The present study was designed to determine the otolithic contribution to the HD signal, as well as to compare HD cell activity of mice to that of rats. HD cell activity in the anterodorsal thalamus was assessed in wild-type C57BL/6J and otoconia-deficient tilted mice during locomotion within a cylinder containing a prominent visual landmark. HD cell firing properties in C57BL/6J mice were generally similar to those in rats. However, in C57BL/6J mice, landmark rotation failed to demonstrate dominant control of the HD signal in 36% of the sessions. In darkness, directional firing became unstable during 42% of the sessions, but landmark control was not associated with HD signal stability in darkness. HD cells were identified in tilted mice, but directional firing properties were not as robust as those of C57BL/6J mice. Most HD cells in tilted mice were controlled by landmark rotation, but showed substantial signal degradation across trials. These results support current models that suggest otolithic information is involved in the perception of directional heading. Furthermore, compared to rats, the HD signal in mice appears to be less reliably anchored to prominent environmental cues. PMID:19176815

  4. Immunization of neonatal mice with LAMP/p55 HIV gag DNA elicits robust immune responses that last to adulthood

    International Nuclear Information System (INIS)

    Ordonhez Rigato, Paula; Maciel, Milton; Goldoni, Adriana Leticia; Piubelli, Orlando; Alves de Brito, Cyro; Fusaro, Ana Elisa; Eurico de Alencar, Liciana Xavier; August, Thomas; Torres Azevedo Marques, Ernesto; Silva Duarte, Alberto Jose da; Sato, Maria Notomi

    2010-01-01

    Successful T cell priming in early postnatal life that can generate effective long-lasting responses until adulthood is critical in HIV vaccination strategies because it prevents early sexual initiation and breastfeeding transmission of HIV. A chimeric DNA vaccine encoding p55 HIV gag associated with lysosome-associated membrane protein 1 (LAMP-1; which drives the antigen to the MIIC compartment), has been used to enhance cellular and humoral antigen-specific responses in adult mice and macaques. Herein, we investigated LAMP-1/gag vaccine immunogenicity in the neonatal period in mice and its ability to generate long-lasting effects. Neonatal vaccination with chimeric LAMP/gag generated stronger Gag-specific immune responses, as measured by the breadth of the Gag peptide-specific IFN-γ, proliferative responsiveness, cytokine production and antibody production, all of which revealed activation of CD4+ T cells as well as the generation of a more robust CTL response compared to gag vaccine alone. To induce long-lived T and B cell memory responses, it was necessary to immunize neonates with the chimeric LAMP/gag DNA vaccine. The LAMP/gag DNA vaccine strategy could be particularly useful for generating an anti-HIV immune response in the early postnatal period capable of inducing long-term immunological memory.

  5. Instantaneous, Simple, and Reversible Revealing of Invisible Patterns Encrypted in Robust Hollow Sphere Colloidal Photonic Crystals.

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    Zhong, Kuo; Li, Jiaqi; Liu, Liwang; Van Cleuvenbergen, Stijn; Song, Kai; Clays, Koen

    2018-05-04

    The colors of photonic crystals are based on their periodic crystalline structure. They show clear advantages over conventional chromophores for many applications, mainly due to their anti-photobleaching and responsiveness to stimuli. More specifically, combining colloidal photonic crystals and invisible patterns is important in steganography and watermarking for anticounterfeiting applications. Here a convenient way to imprint robust invisible patterns in colloidal crystals of hollow silica spheres is presented. While these patterns remain invisible under static environmental humidity, even up to near 100% relative humidity, they are unveiled immediately (≈100 ms) and fully reversibly by dynamic humid flow, e.g., human breath. They reveal themselves due to the extreme wettability of the patterned (etched) regions, as confirmed by contact angle measurements. The liquid surface tension threshold to induce wetting (revealing the imprinted invisible images) is evaluated by thermodynamic predictions and subsequently verified by exposure to various vapors with different surface tension. The color of the patterned regions is furthermore independently tuned by vapors with different refractive indices. Such a system can play a key role in applications such as anticounterfeiting, identification, and vapor sensing. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. mRNA-Seq Reveals Novel Molecular Mechanisms and a Robust Fingerprint in Graves' Disease

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    Sachidanandam, Ravi; Morshed, Syed; Latif, Rauf; Shi, Ruijin; Davies, Terry F.

    2014-01-01

    Context: The immune response in autoimmune thyroid disease has been shown to occur primarily within the thyroid gland in which the most abundant antigens can be found. A variety of capture molecules are known to be expressed by thyroid epithelial cells and serve to attract and help retain an intrathyroidal immune infiltrate. Objective: To explore the entire repertoire of expressed genes in human thyroid tissue, we have deep sequenced the transcriptome (referred to as mRNA-Seq). Design and Patients: We applied mRNA-Seq to thyroid tissue from nine patients with Graves' disease subjected to total thyroidectomy and compared the data with 12 samples of normal thyroid tissue obtained from patients having a thyroid nodule removed. The expression for each gene was calculated from the sequencing data by taking the median of the coverage across the length of the gene. The expression levels were quantile normalized and a gene signature was derived from these. Results: On comparison of expression levels in tissues derived from Graves' patients and controls, there was clear evidence for overexpression of the antigen presentation pathway consisting of HLA and associated genes. We also found a robust disease signature and discovered active innate and adaptive immune signaling networks. Conclusions: These data reveal an active immune defense system in Graves' disease, which involves novel molecular mechanisms in its pathogenesis and development. PMID:24971664

  7. Bmp indicator mice reveal dynamic regulation of transcriptional response.

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    Anna L Javier

    Full Text Available Cellular responses to Bmp ligands are regulated at multiple levels, both extracellularly and intracellularly. Therefore, the presence of these growth factors is not an accurate indicator of Bmp signaling activity. While a common approach to detect Bmp signaling activity is to determine the presence of phosphorylated forms of Smad1, 5 and 8 by immunostaining, this approach is time consuming and not quantitative. In order to provide a simpler readout system to examine the presence of Bmp signaling in developing animals, we developed BRE-gal mouse embryonic stem cells and a transgenic mouse line that specifically respond to Bmp ligand stimulation. Our reporter identifies specific transcriptional responses that are mediated by Smad1 and Smad4 with the Schnurri transcription factor complex binding to a conserved Bmp-Responsive Element (BRE, originally identified among Drosophila, Xenopus and human Bmp targets. Our BRE-gal mES cells specifically respond to Bmp ligands at concentrations as low as 5 ng/ml; and BRE-gal reporter mice, derived from the BRE-gal mES cells, show dynamic activity in many cellular sites, including extraembryonic structures and mammary glands, thereby making this a useful scientific tool.

  8. Design process robustness: A bi-partite network analysis reveals the central importance of people

    DEFF Research Database (Denmark)

    Piccolo, Sebastiano; Jørgensen, Sune Lehmann; Maier, Anja

    2018-01-01

    , reducing the risk of rework and delays. Although there has been much progress in modelling and understanding design processes, little is known about the interplay between people and the activities they perform and its influence on design process robustness. To analyse this interplay, we model a large...

  9. Essential gene disruptions reveal complex relationships between phenotypic robustness, pleiotropy, and fitness

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    Bauer, Christopher R; Li, Shuang; Siegal, Mark L

    2015-01-01

    The concept of robustness in biology has gained much attention recently, but a mechanistic understanding of how genetic networks regulate phenotypic variation has remained elusive. One approach to understand the genetic architecture of variability has been to analyze dispensable gene deletions in model organisms; however, the most important genes cannot be deleted. Here, we have utilized two systems in yeast whereby essential genes have been altered to reduce expression. Using high-throughput microscopy and image analysis, we have characterized a large number of morphological phenotypes, and their associated variation, for the majority of essential genes in yeast. Our results indicate that phenotypic robustness is more highly dependent upon the expression of essential genes than on the presence of dispensable genes. Morphological robustness appears to be a general property of a genotype that is closely related to pleiotropy. While the fitness profile across a range of expression levels is idiosyncratic to each gene, the global pattern indicates that there is a window in which phenotypic variation can be released before fitness effects are observable. PMID:25609648

  10. Human glial chimeric mice reveal astrocytic dependence of JC virus infection

    DEFF Research Database (Denmark)

    Kondo, Yoichi; Windrem, Martha S; Zou, Lisa

    2014-01-01

    with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than...... that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection...

  11. Multiplex social ecological network analysis reveals how social changes affect community robustness more than resource depletion.

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    Baggio, Jacopo A; BurnSilver, Shauna B; Arenas, Alex; Magdanz, James S; Kofinas, Gary P; De Domenico, Manlio

    2016-11-29

    Network analysis provides a powerful tool to analyze complex influences of social and ecological structures on community and household dynamics. Most network studies of social-ecological systems use simple, undirected, unweighted networks. We analyze multiplex, directed, and weighted networks of subsistence food flows collected in three small indigenous communities in Arctic Alaska potentially facing substantial economic and ecological changes. Our analysis of plausible future scenarios suggests that changes to social relations and key households have greater effects on community robustness than changes to specific wild food resources.

  12. An adenoviral vector expressing lipoprotein A, a major antigen of Mycoplasma mycoides subspecies mycoides, elicits robust immune responses in mice.

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    Carozza, Marlène; Rodrigues, Valérie; Unterfinger, Yves; Galea, Sandra; Coulpier, Muriel; Klonjkowski, Bernard; Thiaucourt, François; Totté, Philippe; Richardson, Jennifer

    2015-01-01

    Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides small colony type (MmmSC), is a devastating respiratory disease of cattle. In sub-Saharan Africa, where CBPP is enzootic, live attenuated vaccines are deployed but afford only short-lived protection. In cattle, recovery from experimental MmmSC infection has been associated with the presence of CD4(+) T lymphocytes that secrete interferon gamma in response to MmmSC, and in particular to the lipoprotein A (LppA) antigen. In an effort to develop a better vaccine against CBPP, a viral vector (Ad5-LppA) that expressed LppA was generated from human adenovirus type 5. The LppA-specific immune responses elicited by the Ad5-LppA vector were evaluated in mice, and compared to those elicited by recombinant LppA formulated with a potent adjuvant. Notably, a single administration of Ad5-LppA, but not recombinant protein, sufficed to elicit a robust LppA-specific humoral response. After a booster administration, both vector and recombinant protein elicited strong LppA-specific humoral and cell-mediated responses. Ex vivo stimulation of splenocytes induced extensive proliferation of CD4(+) T cells for mice immunized with vector or protein, and secretion of T helper 1-associated and proinflammatory cytokines for mice immunized with Ad5-LppA. Our study - by demonstrating the potential of a viral-vectored prototypic vaccine to elicit prompt and robust immune responses against a major antigen of MmmSC - represents a first step in developing a recombinant vaccine against CBPP. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Metabolic Flux Analysis of Shewanella spp. Reveals Evolutionary Robustness in Central Carbon Metabolism

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    Tang, Yinjie J.; Martin, Hector Garcia; Dehal, Paramvir S.; Deutschbauer, Adam; Llora, Xavier; Meadows, Adam; Arkin, Adam; Keasling, Jay D.

    2009-08-19

    Shewanella spp. are a group of facultative anaerobic bacteria widely distributed in marine and fresh-water environments. In this study, we profiled the central metabolic fluxes of eight recently sequenced Shewanella species grown under the same condition in minimal med-ium with [3-13C] lactate. Although the tested Shewanella species had slightly different growth rates (0.23-0.29 h31) and produced different amounts of acetate and pyruvate during early exponential growth (pseudo-steady state), the relative intracellular metabolic flux distributions were remarkably similar. This result indicates that Shewanella species share similar regulation in regard to central carbon metabolic fluxes under steady growth conditions: the maintenance of metabolic robustness is not only evident in a single species under genetic perturbations (Fischer and Sauer, 2005; Nat Genet 37(6):636-640), but also observed through evolutionary related microbial species. This remarkable conservation of relative flux profiles through phylogenetic differences prompts us to introduce the concept of metabotype as an alternative scheme to classify microbial fluxomics. On the other hand, Shewanella spp. display flexibility in the relative flux profiles when switching their metabolism from consuming lactate to consuming pyruvate and acetate.

  14. Mcph1-deficient mice reveal a role for MCPH1 in otitis media.

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    Jing Chen

    Full Text Available Otitis media is a common reason for hearing loss, especially in children. Otitis media is a multifactorial disease and environmental factors, anatomic dysmorphology and genetic predisposition can all contribute to its pathogenesis. However, the reasons for the variable susceptibility to otitis media are elusive. MCPH1 mutations cause primary microcephaly in humans. So far, no hearing impairment has been reported either in the MCPH1 patients or mouse models with Mcph1 deficiency. In this study, Mcph1-deficient (Mcph1(tm1a (/tm1a mice were produced using embryonic stem cells with a targeted mutation by the Sanger Institute's Mouse Genetics Project. Auditory brainstem response measurements revealed that Mcph1(tm1a (/tm1a mice had mild to moderate hearing impairment with around 70% penetrance. We found otitis media with effusion in the hearing-impaired Mcph1(tm1a (/tm1a mice by anatomic and histological examinations. Expression of Mcph1 in the epithelial cells of middle ear cavities supported its involvement in the development of otitis media. Other defects of Mcph1(tm1a (/tm1a mice included small skull sizes, increased micronuclei in red blood cells, increased B cells and ocular abnormalities. These findings not only recapitulated the defects found in other Mcph1-deficient mice or MCPH1 patients, but also revealed an unexpected phenotype, otitis media with hearing impairment, which suggests Mcph1 is a new gene underlying genetic predisposition to otitis media.

  15. The behavioral economics of social anxiety disorder reveal a robust effect for interpersonal traits.

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    Rodebaugh, Thomas L; Tonge, Natasha A; Weisman, Jaclyn S; Lim, Michelle H; Fernandez, Katya C; Bogdan, Ryan

    2017-08-01

    Recent evidence suggests that reduced generosity among individuals with social anxiety disorder (SAD) in behavioral economic tasks may result from constraint in changing behavior according to interpersonal contingencies. That is, people with SAD may be slower to be more generous when the situation warrants. Conversely, more global effects on generosity may be related to interpersonal vindictiveness, a dimension only somewhat related to SAD. A total of 133 participants, 73 with the generalized form of SAD, completed self-report instruments and a behavioral economic task with simulated interpersonal (friend, romantic partner, stranger) interactions. In a separate visit, friends (n = 88) also came to the lab and rated participants on vindictiveness. Interpersonal vindictiveness was associated with reduced initial and overall giving to simulated friends. SAD predicted a lack of increased giving to a simulated friend, and attenuated an increase in giving to simulated known versus unknown players compared to participants without SAD. Friend-reported vindictiveness predicted in the same direction as diagnosis. However, the findings for SAD were less robust than those for vindictiveness. SAD is perhaps weakly related to behavioral constraint in economic tasks that simulate interpersonal interactions, whereas vindictiveness is strongly related to lower overall generosity as well as (via friend report) behavioral constraint. Further study is needed to better characterize the construct of vindictiveness. Our findings dovetail with the suggestion that SAD is related to impairment in the proposed affiliation and attachment system, but further suggest that direct study of that system may be more fruitful than focusing on disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice

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    Swelm, Rachel P.L. van [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Laarakkers, Coby M.M. [Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Pertijs, Jeanne C.L.M.; Verweij, Vivienne; Masereeuw, Rosalinde [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands); Russel, Frans G.M., E-mail: F.Russel@pharmtox.umcn.nl [Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen (Netherlands)

    2013-06-01

    Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75 mg/kg bw DF by oral gavage and 24 h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p < 0.01). Kidney injury was confirmed by histology and increased Kim1 and Il-6 mRNA expression levels (p < 0.001 and p < 0.01). Liver histology and plasma ALT levels in DF-treated mice were not different from control, but mRNA expression of Stat3 (p < 0.001) and protein expression of PCNA (p < 0.05) were increased, indicating liver regeneration. In conclusion, urinary proteome analysis revealed that DF treatment in mice induced kidney and liver injury. Within 24 h, however, the liver was able to recover by activating tissue regeneration processes. Hence, the proteins found in urine of DF-treated mice represent kidney damage rather than hepatic injury. - Highlights: • The urinary proteome shows biological processes involved in adverse drug reactions. • Urine proteins of DF-treated mice relate to kidney injury rather than liver injury. • Liver regeneration, not liver injury, is apparent 24h after oral DF administration. • Pretreatment with LPS does not enhance DF-induced liver injury in mice.

  17. GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

    DEFF Research Database (Denmark)

    Bartoi, Tudor; Rigbolt, Kristoffer T G; Du, Dan

    2010-01-01

    lines that allow a straightforward biochemical isolation of GABA(B) receptors. The transgenic mice express GABA(B1) isoforms that contain sequences for a two-step affinity purification, in addition to their endogenous subunit repertoire. Comparative analyses of purified samples from the transgenic mice...... and wild-type control animals revealed two novel components of the GABA(B1) complex. One of the identified proteins, potassium channel tetramerization domain-containing protein 12, associates with heterodimeric GABA(B) receptors via the GABA(B2) subunit. In transfected hippocampal neurons, potassium...

  18. Toxicogenomic analysis reveals profibrogenic effects of trichloroethylene in autoimmune-mediated cholangitis in mice.

    Science.gov (United States)

    Kopec, Anna K; Sullivan, Bradley P; Kassel, Karen M; Joshi, Nikita; Luyendyk, James P

    2014-10-01

    Epidemiological studies suggest that exposure to environmental chemicals increases the risk of developing autoimmune liver disease. However, the identity of specific chemical perpetrators and the mechanisms whereby environmental chemicals modify liver disease is unclear. Previous studies link exposure to trichloroethylene (TCE) with the development of autoimmune liver disease and exacerbation of autoimmunity in lupus-prone MRL mice. In this study, we utilized NOD.c3c4 mice, which spontaneously develop autoimmune cholangitis bearing resemblance to some features of primary biliary cirrhosis. Nine-week-old female NOD.c3c4 mice were given TCE (0.5 mg/ml) or its vehicle (1% Cremophor-EL) in drinking water for 4 weeks. TCE had little effect on clinical chemistry, biliary cyst formation, or hepatic CD3+ T-cell accumulation. Hepatic microarray profiling revealed a dramatic suppression of early growth response 1 (EGR1) mRNA in livers of TCE-treated mice, which was verified by qPCR and immunohistochemical staining. Consistent with a reported link between reduced EGR1 expression and liver fibrosis, TCE increased hepatic type I collagen (COL1A1) mRNA and protein levels in livers of NOD.c3c4 mice. In contrast, TCE did not increase COL1A1 expression in NOD.ShiLtJ mice, which do not develop autoimmune cholangitis. These results suggest that in the context of concurrent autoimmune liver disease with a genetic basis, modification of hepatic gene expression by TCE may increase profibrogenic signaling in the liver. Moreover, these studies suggest that NOD.c3c4 mice may be a novel model to study gene-environment interactions critical for the development of autoimmune liver disease. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. [18F]DPA 714 PET Imaging Reveals Global Neuroinflammation in Zika Virus Infected Mice

    Science.gov (United States)

    2017-09-12

    with neurotropic viruses and the evaluation of therapeutics being developed for treatment of infectious diseases. Keywords: Zika virus , Animal...18F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus - Infected Mice Kyle Kuszpit1†, Bradley S. Hollidge2†, Xiankun Zeng3, Robert...Running Head: PET Imaging of Zika Virus -Induced Neuroinflammation Manuscript Category: Article Affiliations: 1Molecular and Translational

  20. Robust Regression Analysis of GCMS Data Reveals Differential Rewiring of Metabolic Networks in Hepatitis B and C Patients

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    Cedric Simillion

    2017-10-01

    Full Text Available About one in 15 of the world’s population is chronically infected with either hepatitis virus B (HBV or C (HCV, with enormous public health consequences. The metabolic alterations caused by these infections have never been directly compared and contrasted. We investigated groups of HBV-positive, HCV-positive, and uninfected healthy controls using gas chromatography-mass spectrometry analyses of their plasma and urine. A robust regression analysis of the metabolite data was conducted to reveal correlations between metabolite pairs. Ten metabolite correlations appeared for HBV plasma and urine, with 18 for HCV plasma and urine, none of which were present in the controls. Metabolic perturbation networks were constructed, which permitted a differential view of the HBV- and HCV-infected liver. HBV hepatitis was consistent with enhanced glucose uptake, glycolysis, and pentose phosphate pathway metabolism, the latter using xylitol and producing threonic acid, which may also be imported by glucose transporters. HCV hepatitis was consistent with impaired glucose uptake, glycolysis, and pentose phosphate pathway metabolism, with the tricarboxylic acid pathway fueled by branched-chain amino acids feeding gluconeogenesis and the hepatocellular loss of glucose, which most probably contributed to hyperglycemia. It is concluded that robust regression analyses can uncover metabolic rewiring in disease states.

  1. Voronoi-based spatial analysis reveals selective interneuron changes in the cortex of FALS mice.

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    Minciacchi, Diego; Kassa, Roman M; Del Tongo, Claudia; Mariotti, Raffaella; Bentivoglio, Marina

    2009-01-01

    The neurodegenerative disease amyotrophic lateral sclerosis affects lower motoneurons and corticospinal cells. Mice expressing human mutant superoxide dismutase (SOD)1 provide widely investigated models of the familial form of disease, but information on cortical changes in these mice is still limited. We here analyzed the spatial organization of interneurons characterized by parvalbumin immunoreactivity in the motor, somatosensory, and visual cortical areas of SOD1(G93A) mice. Cell number and sociological spatial behavior were assessed by digital charts of cell location in cortical samples, cell counts, and generation of two-dimensional Voronoi diagrams. In end-stage SOD1-mutant mice, an increase of parvalbumin-containing cortical interneurons was found in the motor and somatosensory areas (about 35% and 20%, respectively) with respect to wild-type littermates. Changes in cell spatial distribution, as documented by Voronoi-derived coefficients of variation, indicated increased tendency of parvalbumin cells to aggregate into clusters in the same areas of the SOD1-mutant cortex. Counts and coefficients of variation of parvalbumin cells in the visual cortex gave instead similar results in SOD1-mutant and wild-type mice. Analyses of motor and somatosensory areas in presymptomatic SOD1-mutant mice provided findings very similar to those obtained at end-stage, indicating early changes of interneurons in these cortical areas during the pathology. Altogether the data reveal in the SOD1-mutant mouse cortex an altered architectonic pattern of interneurons, which selectively affects areas involved in motor control. The findings, which can be interpreted as pathogenic factors or early disease-related adaptations, point to changes in the cortical regulation and modulation of the motor circuit during motoneuron disease.

  2. Speed-Dependent Modulation of the Locomotor Behavior in Adult Mice Reveals Attractor and Transitional Gaits.

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    Lemieux, Maxime; Josset, Nicolas; Roussel, Marie; Couraud, Sébastien; Bretzner, Frédéric

    2016-01-01

    Locomotion results from an interplay between biomechanical constraints of the muscles attached to the skeleton and the neuronal circuits controlling and coordinating muscle activities. Quadrupeds exhibit a wide range of locomotor gaits. Given our advances in the genetic identification of spinal and supraspinal circuits important to locomotion in the mouse, it is now important to get a better understanding of the full repertoire of gaits in the freely walking mouse. To assess this range, young adult C57BL/6J mice were trained to walk and run on a treadmill at different locomotor speeds. Instead of using the classical paradigm defining gaits according to their footfall pattern, we combined the inter-limb coupling and the duty cycle of the stance phase, thus identifying several types of gaits: lateral walk, trot, out-of-phase walk, rotary gallop, transverse gallop, hop, half-bound, and full-bound. Out-of-phase walk, trot, and full-bound were robust and appeared to function as attractor gaits (i.e., a state to which the network flows and stabilizes) at low, intermediate, and high speeds respectively. In contrast, lateral walk, hop, transverse gallop, rotary gallop, and half-bound were more transient and therefore considered transitional gaits (i.e., a labile state of the network from which it flows to the attractor state). Surprisingly, lateral walk was less frequently observed. Using graph analysis, we demonstrated that transitions between gaits were predictable, not random. In summary, the wild-type mouse exhibits a wider repertoire of locomotor gaits than expected. Future locomotor studies should benefit from this paradigm in assessing transgenic mice or wild-type mice with neurotraumatic injury or neurodegenerative disease affecting gait.

  3. Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice.

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    Nathalie Le Clef

    Full Text Available Acute kidney injury (AKI is an underestimated, yet important risk factor for development of chronic kidney disease (CKD. Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD. Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data.

  4. Phenotype selection reveals coevolution of muscle glycogen and protein and PTEN as a gate keeper for the accretion of muscle mass in adult female mice.

    Directory of Open Access Journals (Sweden)

    Mandy Sawitzky

    Full Text Available We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK, were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice.

  5. Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing.

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    Helen J Renaud

    Full Text Available The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n = 3/age. The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5-Day 5 (perinatal-enriched, Day 10-Day 20 (pre-weaning-enriched, and Day 25-Day 60 (adolescence/adulthood-enriched. Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid β-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal β-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty

  6. Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

    Science.gov (United States)

    Raife, Thomas J; Dwyre, Denis M; Stevens, Jeff W; Erger, Rochelle A; Leo, Lorie; Wilson, Katina M; Fernández, Jose A; Wilder, Jennifer; Kim, Hyung-Suk; Griffin, John H; Maeda, Nobuyo; Lentz, Steven R

    2011-11-01

    We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo. Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (Pknock-in mice compared with wild-type mice (Pknock-in mice (12±3 minutes) than in wild-type mice (31±6 minutes; Pknock-in and wild-type mice after injection of endotoxin. When crossed with apolipoprotein E-deficient mice and fed a Western diet, knock-in mice had a further decrease in protein C activation but did not exhibit increased atherosclerosis. Expression of human thrombomodulin in place of murine thrombomodulin produces viable mice with a prothrombotic phenotype but unaltered responses to systemic inflammatory or atherogenic stimuli. This humanized animal model will be useful for investigating the function of human thrombomodulin under pathophysiological conditions in vivo.

  7. Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

    Directory of Open Access Journals (Sweden)

    Grau Georges E

    2007-12-01

    Full Text Available Abstract Background Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R and CM-susceptible (CM-S mice, upon infection by Plasmodium berghei ANKA (PbA. We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c, and in CM-S (CBA/J and C57BL/6 mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

  8. Radioresistance of intermediate TCR cells and their localization in the body of mice revealed by irradiation

    International Nuclear Information System (INIS)

    Kimura, Motohiko; Watanabe, Hisami; Ohtsuka, Kazuo; Iiai, Tsuneo; Tsuchida, Masanori; Sato, Shotaro; Abo, Toru

    1993-01-01

    Extrathymic generation of T cells in the liver and in the intestine was recently demonstrated. We investigated herein whether such T cells, especially those in the liver, are present in other organs of mice. This investigation is possible employing our recently introduced method with which even a minor proportion of extrathymic, intermediate T-cell receptor (TCR) cells in organs other than the liver can be identified. Intermediate TCR cells expressed higher levels of IL-2Rβ and lymphocyte function-associated antigen-1 (LFA-1) than bright TCR cells (i.e., T cells of thymic origin) as revealed by two-color staining. Although intermediate TCR cells were present at a small proportion in the spleen and thymus, they predominated in these organs after irradiation (9 Gy) and bone marrow reconstitution, or after low dose irradiation (6 Gy). This was due to that intermediate TCR cells were relatively radioresistant, whereas bright TCR cells were radiosensitive. Microscopic observation and immunochemical staining showed that intermediate TCR cells in the spleen localized in the red pulp and those in the thymus localized in the medulla. These intermediate TCR cells displayed a large light scatter, similar to such cells in the liver. The present results suggest that intermediate TCR cells may proliferate at multiple sites in the body. (author)

  9. A novel motion analysis approach reveals late recovery in C57BL/6 mice and deficits in NCAM-deficient mice after sciatic nerve crush.

    Science.gov (United States)

    Fey, Andreas; Schachner, Melitta; Irintchev, Andrey

    2010-05-01

    Assessment of motor abilities after sciatic nerve injury in rodents, in particular mice, relies exclusively on walking track (footprint) analysis despite known limitations of this method. Using principles employed recently for video-based motion analyses after femoral nerve and spinal cord injuries, we have designed and report here a novel approach for functional assessments after sciatic nerve lesions in mice. Functional deficits are estimated by angle and distance measurements on single video frames recorded during beam-walking and inclined ladder climbing. Analyses of adult C57BL/6J mice after crush of the sciatic, tibial, or peroneal nerve allowed the identification of six numerical parameters, detecting impairments of the plantar flexion of the foot and the toe spread. Some of these parameters, as well as footprint functional indices, revealed severe impairment after crush injury of the sciatic or tibial, but not the peroneal nerve, and complete recovery within 3 weeks after lesion. Other novel estimates, however, showed that complete recovery is reached as late as 2-3 months after sciatic nerve crush. These measures detected both tibial and peroneal dysfunction. In contrast to the complete restoration of function in wild-type mice (100%), our new parameters, in contrast to the sciatic functional index, showed incomplete recovery (85%) 90 days after sciatic nerve crush in mice deficient in the neural cell adhesion molecule (NCAM). We conclude that the novel video-based approach is more precise, sensitive, and versatile than established tests, allowing objective numerical assessment of different motor functions in a sciatic nerve injury paradigm in mice.

  10. Transcriptome profiling in engrailed-2 mutant mice reveals common molecular pathways associated with autism spectrum disorders.

    Science.gov (United States)

    Sgadò, Paola; Provenzano, Giovanni; Dassi, Erik; Adami, Valentina; Zunino, Giulia; Genovesi, Sacha; Casarosa, Simona; Bozzi, Yuri

    2013-12-19

    Transcriptome analysis has been used in autism spectrum disorder (ASD) to unravel common pathogenic pathways based on the assumption that distinct rare genetic variants or epigenetic modifications affect common biological pathways. To unravel recurrent ASD-related neuropathological mechanisms, we took advantage of the En2-/- mouse model and performed transcriptome profiling on cerebellar and hippocampal adult tissues. Cerebellar and hippocampal tissue samples from three En2-/- and wild type (WT) littermate mice were assessed for differential gene expression using microarray hybridization followed by RankProd analysis. To identify functional categories overrepresented in the differentially expressed genes, we used integrated gene-network analysis, gene ontology enrichment and mouse phenotype ontology analysis. Furthermore, we performed direct enrichment analysis of ASD-associated genes from the SFARI repository in our differentially expressed genes. Given the limited number of animals used in the study, we used permissive criteria and identified 842 differentially expressed genes in En2-/- cerebellum and 862 in the En2-/- hippocampus. Our functional analysis revealed that the molecular signature of En2-/- cerebellum and hippocampus shares convergent pathological pathways with ASD, including abnormal synaptic transmission, altered developmental processes and increased immune response. Furthermore, when directly compared to the repository of the SFARI database, our differentially expressed genes in the hippocampus showed enrichment of ASD-associated genes significantly higher than previously reported. qPCR was performed for representative genes to confirm relative transcript levels compared to those detected in microarrays. Despite the limited number of animals used in the study, our bioinformatic analysis indicates the En2-/- mouse is a valuable tool for investigating molecular alterations related to ASD.

  11. Pam heterozygous mice reveal essential role for Cu in amygdalar behavioral and synaptic function.

    Science.gov (United States)

    Gaier, Eric D; Eipper, Betty A; Mains, Richard E

    2014-05-01

    Copper (Cu) is an essential element with many biological roles, but its roles in the mammalian nervous system are poorly understood. Mice deficient in the cuproenzyme peptidylglycine α-amidating monooxygenase (Pam(+/-) mice) were initially generated to study neuropeptide amidation. Pam(+/-) mice exhibit profound deficits in a few behavioral tasks, including enhancements in innate fear along with deficits in acquired fear. Interestingly, several Pam(+/-) phenotypes were recapitulated in Cu-restricted wild-type mice and rescued in Cu-supplemented Pam(+/-) mice. These behaviors correspond to enhanced excitability and deficient synaptic plasticity in the amygdala of Pam(+/-) mice, which are also rescued by Cu supplementation. Cu and ATP7A are present at synapses, in key positions to respond to and influence synaptic activity. Further study demonstrated that extracellular Cu is necessary for wild-type synaptic plasticity and sufficient to induce long-term potentiation. These experiments support roles for PAM in Cu homeostasis and for synaptic Cu in amygdalar function. © 2014 New York Academy of Sciences.

  12. Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice.

    Science.gov (United States)

    Nam, Kyong Nyon; Wolfe, Cody M; Fitz, Nicholas F; Letronne, Florent; Castranio, Emilie L; Mounier, Anais; Schug, Jonathan; Lefterov, Iliya; Koldamova, Radosveta

    2018-01-01

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice. To identify differentially expressed genes and gene-networks correlated to diet, APOE isoform and sex, we performed RNA sequencing and applied Weighted Gene Co-expression Network Analysis. We determined that the immune response network with major hubs Tyrobp/DAP12, Csf1r, Tlr2, C1qc and Laptm5 correlated significantly and positively to the phenotype of female APP/E4-HFD mice. Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage around plaques, particularly of larger size, was significantly reduced. This suggests altered containment of the plaque growth and sex-dependent vulnerability in response to diet. The results of our study show concurrent impact of diet, APOE isoform and sex on the brain transcriptome and AD-like phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Energy landscape reveals that the budding yeast cell cycle is a robust and adaptive multi-stage process.

    Directory of Open Access Journals (Sweden)

    Cheng Lv

    2015-03-01

    Full Text Available Quantitatively understanding the robustness, adaptivity and efficiency of cell cycle dynamics under the influence of noise is a fundamental but difficult question to answer for most eukaryotic organisms. Using a simplified budding yeast cell cycle model perturbed by intrinsic noise, we systematically explore these issues from an energy landscape point of view by constructing an energy landscape for the considered system based on large deviation theory. Analysis shows that the cell cycle trajectory is sharply confined by the ambient energy barrier, and the landscape along this trajectory exhibits a generally flat shape. We explain the evolution of the system on this flat path by incorporating its non-gradient nature. Furthermore, we illustrate how this global landscape changes in response to external signals, observing a nice transformation of the landscapes as the excitable system approaches a limit cycle system when nutrients are sufficient, as well as the formation of additional energy wells when the DNA replication checkpoint is activated. By taking into account the finite volume effect, we find additional pits along the flat cycle path in the landscape associated with the checkpoint mechanism of the cell cycle. The difference between the landscapes induced by intrinsic and extrinsic noise is also discussed. In our opinion, this meticulous structure of the energy landscape for our simplified model is of general interest to other cell cycle dynamics, and the proposed methods can be applied to study similar biological systems.

  14. Pan-Antarctic analysis aggregating spatial estimates of Adélie penguin abundance reveals robust dynamics despite stochastic noise.

    Science.gov (United States)

    Che-Castaldo, Christian; Jenouvrier, Stephanie; Youngflesh, Casey; Shoemaker, Kevin T; Humphries, Grant; McDowall, Philip; Landrum, Laura; Holland, Marika M; Li, Yun; Ji, Rubao; Lynch, Heather J

    2017-10-10

    Colonially-breeding seabirds have long served as indicator species for the health of the oceans on which they depend. Abundance and breeding data are repeatedly collected at fixed study sites in the hopes that changes in abundance and productivity may be useful for adaptive management of marine resources, but their suitability for this purpose is often unknown. To address this, we fit a Bayesian population dynamics model that includes process and observation error to all known Adélie penguin abundance data (1982-2015) in the Antarctic, covering >95% of their population globally. We find that process error exceeds observation error in this system, and that continent-wide "year effects" strongly influence population growth rates. Our findings have important implications for the use of Adélie penguins in Southern Ocean feedback management, and suggest that aggregating abundance across space provides the fastest reliable signal of true population change for species whose dynamics are driven by stochastic processes.Adélie penguins are a key Antarctic indicator species, but data patchiness has challenged efforts to link population dynamics to key drivers. Che-Castaldo et al. resolve this issue using a pan-Antarctic Bayesian model to infer missing data, and show that spatial aggregation leads to more robust inference regarding dynamics.

  15. A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice.

    Directory of Open Access Journals (Sweden)

    Michela Riba

    Full Text Available Control of systemic iron homeostasis is interconnected with the inflammatory response through the key iron regulator, the antimicrobial peptide hepcidin. We have previously shown that mice with iron deficiency anemia (IDA-low hepcidin show a pro-inflammatory response that is blunted in iron deficient-high hepcidin Tmprss6 KO mice. The transcriptional response associated with chronic hepcidin overexpression due to genetic inactivation of Tmprss6 is unknown. By using whole genome transcription profiling of the liver and analysis of spleen immune-related genes we identified several functional pathways differentially expressed in Tmprss6 KO mice, compared to IDA animals and thus irrespective of the iron status. In the effort of defining genes potentially targets of Tmprss6 we analyzed liver gene expression changes according to the genotype and independently of treatment. Tmprss6 inactivation causes down-regulation of liver pathways connected to immune and inflammatory response as well as spleen genes related to macrophage activation and inflammatory cytokines production. The anti-inflammatory status of Tmprss6 KO animals was confirmed by the down-regulation of pathways related to immunity, stress response and intracellular signaling in both liver and spleen after LPS treatment. Opposite to Tmprss6 KO mice, Hfe(-/- mice are characterized by iron overload with inappropriately low hepcidin levels. Liver expression profiling of Hfe(-/- deficient versus iron loaded mice show the opposite expression of some of the genes modulated by the loss of Tmprss6. Altogether our results confirm the anti-inflammatory status of Tmprss6 KO mice and identify new potential target pathways/genes of Tmprss6.

  16. Burn injury reveals altered phenotype in mannan-binding lectin-deficient mice

    DEFF Research Database (Denmark)

    Møller-Kristensen, Mette; Hamblin, Michael R; Thiel, Steffen

    2007-01-01

    Burn injury destroys skin, the second largest innate immune organ in the body, and triggers chaotic immune and inflammatory responses. The pattern recognition molecule, mannan-binding lectin (MBL), plays an important role in the first-line host defense against infectious agents. MBL initiates...... the lectin complement pathway and acts as an opsonin. Recent studies suggest that MBL also modulates inflammatory responses. We report that local responses after burn in MBL null mice differ from those found in wild-type (WT) mice in the following important biological markers: spontaneous eschar separation......, thinned epidermis and dermis, upregulation of soluble factors including cytokines, chemokines, cell adhesion molecules, a growth factor-binding protein, and matrix metalloproteinases. Mice lacking C1q, C4, or C3 did not show the lack of eschar separation seen in MBL null-burn phenotype. These findings...

  17. Knockout mice reveal a role for protein tyrosine phosphatase H1 in cognition

    Directory of Open Access Journals (Sweden)

    Ardizzone Michele

    2008-08-01

    Full Text Available Abstract Background The present study has investigated the protein tyrosine phosphatase H1 (PTPH1 expression pattern in mouse brain and its impact on CNS functions. Methods We have previously described a PTPH1-KO mouse, generated by replacing the PTP catalytic and the PDZ domain with a LacZ neomycin cassette. PTPH1 expression pattern was evaluated by LacZ staining in the brain and PTPH1-KO and WT mice (n = 10 per gender per genotype were also behaviorally tested for CNS functions. Results In CNS, PTPH1 is expressed during development and in adulthood and mainly localized in hippocampus, thalamus, cortex and cerebellum neurons. The behavioral tests performed on the PTPH1-KO mice showed an impact on working memory in male mice and an impaired learning performance at rotarod in females. Conclusion These results demonstrate for the first time a neuronal expression of PTPH1 and its functionality at the level of cognition.

  18. Sequence analysis of chromosome 1 revealed different selection patterns between Chinese wild mice and laboratory strains.

    Science.gov (United States)

    Xu, Fuyi; Hu, Shixian; Chao, Tianzhu; Wang, Maochun; Li, Kai; Zhou, Yuxun; Xu, Hongyan; Xiao, Junhua

    2017-10-01

    Both natural and artificial selection play a critical role in animals' adaptation to the environment. Detection of the signature of selection in genomic regions can provide insights for understanding the function of specific phenotypes. It is generally assumed that laboratory mice may experience intense artificial selection while wild mice more natural selection. However, the differences of selection signature in the mouse genome and underlying genes between wild and laboratory mice remain unclear. In this study, we used two mouse populations: chromosome 1 (Chr 1) substitution lines (C1SLs) derived from Chinese wild mice and mouse genome project (MGP) sequenced inbred strains and two selection detection statistics: Fst and Tajima's D to identify the signature of selection footprint on Chr 1. For the differentiation between the C1SLs and MGP, 110 candidate selection regions containing 47 protein coding genes were detected. A total of 149 selection regions which encompass 7.215 Mb were identified in the C1SLs by Tajima's D approach. While for the MGP, we identified nearly twice selection regions (243) compared with the C1SLs which accounted for 13.27 Mb Chr 1 sequence. Through functional annotation, we identified several biological processes with significant enrichment including seven genes in the olfactory transduction pathway. In addition, we searched the phenotypes associated with the 47 candidate selection genes identified by Fst. These genes were involved in behavior, growth or body weight, mortality or aging, and immune systems which align well with the phenotypic differences between wild and laboratory mice. Therefore, the findings would be helpful for our understanding of the phenotypic differences between wild and laboratory mice and applications for using this new mouse resource (C1SLs) for further genetics studies.

  19. Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk

    Directory of Open Access Journals (Sweden)

    Villeneuve Daniel L

    2010-06-01

    elucidation but microarray evidence shows that homeostatic regulation of the steroidogenic network is likely maintained by a mildly sensitive interaction. We hypothesize that effective network elucidation must consider both the sensitivity of the target as well as the target's robustness to biological noise (in this case, to cross-talk when identifying possible points of regulation.

  20. Brain transcriptional responses to high-fat diet in Acads-deficient mice reveal energy sensing pathways.

    Directory of Open Access Journals (Sweden)

    Claudia Kruger

    Full Text Available How signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of Acads (acyl-coenzyme A dehydrogenase, short-chain, the enzyme responsible for mitochondrial beta-oxidation of C4-C6 short-chain fatty acids (SCFAs, shift consumption away from fat and toward carbohydrate when offered a choice between diets. In the current study, we sought to indentify candidate genes and pathways underlying the effects of SCFA oxidation deficiency on food intake in Acads-/- mice.We performed a transcriptional analysis of gene expression in brain tissue of Acads-/- and Acads+/+ mice fed either a high-fat (HF or low-fat (LF diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF Acads-/- vs. HF Acads+/+ (3917 and Acads+/+ HF vs. LF Acads+/+ (3879 revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that HF-fed Acads-deficient mice display transcriptional responses that strongly resemble those of Acads+/+ mice fed LF diet. Intriguingly, genes involved in both AMP-kinase regulation and the neural control of food intake followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of genes in these pathways. Western blotting showed an increase in hypothalamic AMP-kinase in Acads-/- mice and HF diet increased, a key protein in an energy-sensing cascade that responds to depletion of ATP.Our results suggest that the decreased beta-oxidation of short-chain fatty acids in Acads-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase may be the cellular energy

  1. Transcriptional profiling reveals progeroid Ercc1(-/Δ) mice as a model system for glomerular aging.

    Science.gov (United States)

    Schermer, Bernhard; Bartels, Valerie; Frommolt, Peter; Habermann, Bianca; Braun, Fabian; Schultze, Joachim L; Roodbergen, Marianne; Hoeijmakers, Jan Hj; Schumacher, Björn; Nürnberg, Peter; Dollé, Martijn Et; Benzing, Thomas; Müller, Roman-Ulrich; Kurschat, Christine E

    2013-08-16

    Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1(-/Δ) progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1(-/Δ) mice showed cluster formation between young WT and Ercc1(-/Δ) as well as old WT and Ercc1(-/Δ) samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1(-/Δ) mice (p aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1(-/Δ) mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies.

  2. Transcriptional profiling reveals progeroid Ercc1-/Δ mice as a model system for glomerular aging

    Science.gov (United States)

    2013-01-01

    Background Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1-/Δ progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. Results In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1-/Δ mice showed cluster formation between young WT and Ercc1-/Δ as well as old WT and Ercc1-/Δ samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1-/Δ mice (p aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1-/Δ mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies. PMID:23947592

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

    Science.gov (United States)

    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.

  4. In Situ Microscopy Analysis Reveals Local Innate Immune Response Developed around Brucella Infected Cells in Resistant and Susceptible Mice

    Science.gov (United States)

    Copin, Richard; Vitry, Marie-Alice; Hanot Mambres, Delphine; Machelart, Arnaud; De Trez, Carl; Vanderwinden, Jean-Marie; Magez, Stefan; Akira, Shizuo; Ryffel, Bernhard; Carlier, Yves; Letesson, Jean-Jacques; Muraille, Eric

    2012-01-01

    Brucella are facultative intracellular bacteria that chronically infect humans and animals causing brucellosis. Brucella are able to invade and replicate in a broad range of cell lines in vitro, however the cells supporting bacterial growth in vivo are largely unknown. In order to identify these, we used a Brucella melitensis strain stably expressing mCherry fluorescent protein to determine the phenotype of infected cells in spleen and liver, two major sites of B. melitensis growth in mice. In both tissues, the majority of primary infected cells expressed the F4/80 myeloid marker. The peak of infection correlated with granuloma development. These structures were mainly composed of CD11b+ F4/80+ MHC-II+ cells expressing iNOS/NOS2 enzyme. A fraction of these cells also expressed CD11c marker and appeared similar to inflammatory dendritic cells (DCs). Analysis of genetically deficient mice revealed that differentiation of iNOS+ inflammatory DC, granuloma formation and control of bacterial growth were deeply affected by the absence of MyD88, IL-12p35 and IFN-γ molecules. During chronic phase of infection in susceptible mice, we identified a particular subset of DC expressing both CD11c and CD205, serving as a reservoir for the bacteria. Taken together, our results describe the cellular nature of immune effectors involved during Brucella infection and reveal a previously unappreciated role for DC subsets, both as effectors and reservoir cells, in the pathogenesis of brucellosis. PMID:22479178

  5. Phenotypic characterization of speed-associated gait changes in mice reveals modular organization of locomotor networks

    DEFF Research Database (Denmark)

    Bellardita, Carmelo; Kiehn, Ole

    2015-01-01

    behavioral outcomes expressed at different speeds of locomotion. Here, we use detailed kinematic analyses to search for signatures of a modular organization of locomotor circuits in intact and genetically modified mice moving at different speeds of locomotion. We show that wild-type mice display three...... distinct gaits: two alternating, walk and trot, and one synchronous, bound. Each gait is expressed in distinct ranges of speed with phenotypic inter-limb and intra-limb coordination. A fourth gait, gallop, closely resembled bound in most of the locomotor parameters but expressed diverse inter......-limb coordination. Genetic ablation of commissural V0V neurons completely removed the expression of one alternating gait, trot, but left intact walk, gallop, and bound. Ablation of commissural V0V and V0D neurons led to a loss of walk, trot, and gallop, leaving bound as the default gait. Our study provides...

  6. Hepatic Proteomic Analysis Revealed Altered Metabolic Pathways in Insulin Resistant Akt1+/-/Akt2-/-Mice

    Science.gov (United States)

    Pedersen, Brian A; Wang, Weiwen; Taylor, Jared F; Khattab, Omar S; Chen, Yu-Han; Edwards, Robert A; Yazdi, Puya G; Wang, Ping H

    2015-01-01

    Objective The aim of this study was to identify liver proteome changes in a mouse model of severe insulin resistance and markedly decreased leptin levels. Methods Two-dimensional differential gel electrophoresis was utilized to identify liver proteome changes in AKT1+/-/AKT2-/- mice. Proteins with altered levels were identified with tandem mass spectrometry. Ingenuity Pathway analysis was performed for the interpretation of the biological significance of the observed proteomic changes. Results 11 proteins were identified from 2 biological replicates to be differentially expressed by a ratio of at least 1.3 between age-matched insulin resistant (Akt1+/-/Akt2-/-) and wild type mice. Albumin and mitochondrial ornithine aminotransferase were detected from multiple spots, which suggest post-translational modifications. Enzymes of the urea cycle were common members of top regulated pathways. Conclusion Our results help to unveil the regulation of the liver proteome underlying altered metabolism in an animal model of severe insulin resistance. PMID:26455965

  7. Illumination of murine gammaherpesvirus-68 cycle reveals a sexual transmission route from females to males in laboratory mice.

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    Sylvie François

    Full Text Available Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. As the known human gammaherpesviruses, Epstein-Barr virus and Kaposi's Sarcoma-associated Herpesvirus are host-specific and lack a convenient in vivo infection model; related animal gammaherpesviruses, such as murine gammaherpesvirus-68 (MHV-68, are commonly used as general models of gammaherpesvirus infections in vivo. To date, it has however never been possible to monitor viral excretion or virus transmission of MHV-68 in laboratory mice population. In this study, we have used MHV-68 associated with global luciferase imaging to investigate potential excretion sites of this virus in laboratory mice. This allowed us to identify a genital excretion site of MHV-68 following intranasal infection and latency establishment in female mice. This excretion occurred at the external border of the vagina and was dependent on the presence of estrogens. However, MHV-68 vaginal excretion was not associated with vertical transmission to the litter or with horizontal transmission to female mice. In contrast, we observed efficient virus transmission to naïve males after sexual contact. In vivo imaging allowed us to show that MHV-68 firstly replicated in penis epithelium and corpus cavernosum before spreading to draining lymph nodes and spleen. All together, those results revealed the first experimental transmission model for MHV-68 in laboratory mice. In the future, this model could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent

  8. Suppressing an anti-inflammatory cytokine reveals a strong age-dependent survival cost in mice.

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    Virginia Belloni

    Full Text Available BACKGROUND: The central paradigm of ecological immunology postulates that selection acts on immunity as to minimize its cost/benefit ratio. Costs of immunity may arise because the energetic requirements of the immune response divert resources that are no longer available for other vital functions. In addition to these resource-based costs, mis-directed or over-reacting immune responses can be particularly harmful for the host. In spite of the potential importance of immunopathology, most studies dealing with the evolution of the immune response have neglected such non resource-based costs. To keep the immune response under control, hosts have evolved regulatory pathways that should be considered when studying the target of the selection pressures acting on immunity. Indeed, variation in regulation may strongly modulate the negative outcome of immune activation, with potentially important fitness consequences. METHODOLOGY/PRINCIPAL FINDINGS: Here, we experimentally assessed the survival costs of reduced immune regulation by inhibiting an anti-inflammatory cytokine (IL-10 with anti-IL-10 receptor antibodies (anti-IL-10R in mice that were either exposed to a mild inflammation or kept as control. The experiment was performed on young (3 months and old (15 months individuals, as to further assess the age-dependent cost of suppressing immune regulation. IL-10 inhibition induced high mortality in old mice exposed to the mild inflammatory insult, whereas no mortality was observed in young mice. However, young mice experienced a transitory lost in body mass when injected with the anti-IL-10R antibodies, showing that the treatment was to a lesser extent also costly for young individuals. CONCLUSIONS: These results suggest a major role of immune regulation that deserves attention when investigating the evolution of immunity, and indicate that the capacity to down-regulate the inflammatory response is crucial for late survival and longevity.

  9. Pyrosequencing the Bemisia tabaci transcriptome reveals a highly diverse bacterial community and a robust system for insecticide resistance.

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    Wen Xie

    Full Text Available BACKGROUND: Bemisia tabaci (Gennadius is a phloem-feeding insect poised to become one of the major insect pests in open field and greenhouse production systems throughout the world. The high level of resistance to insecticides is a main factor that hinders continued use of insecticides for suppression of B. tabaci. Despite its prevalence, little is known about B. tabaci at the genome level. To fill this gap, an invasive B. tabaci B biotype was subjected to pyrosequencing-based transcriptome analysis to identify genes and gene networks putatively involved in various physiological and toxicological processes. METHODOLOGY AND PRINCIPAL FINDINGS: Using Roche 454 pyrosequencing, 857,205 reads containing approximately 340 megabases were obtained from the B. tabaci transcriptome. De novo assembly generated 178,669 unigenes including 30,980 from insects, 17,881 from bacteria, and 129,808 from the nohit. A total of 50,835 (28.45% unigenes showed similarity to the non-redundant database in GenBank with a cut-off E-value of 10-5. Among them, 40,611 unigenes were assigned to one or more GO terms and 6,917 unigenes were assigned to 288 known pathways. De novo metatranscriptome analysis revealed highly diverse bacterial symbionts in B. tabaci, and demonstrated the host-symbiont cooperation in amino acid production. In-depth transcriptome analysis indentified putative molecular markers, and genes potentially involved in insecticide resistance and nutrient digestion. The utility of this transcriptome was validated by a thiamethoxam resistance study, in which annotated cytochrome P450 genes were significantly overexpressed in the resistant B. tabaci in comparison to its susceptible counterparts. CONCLUSIONS: This transcriptome/metatranscriptome analysis sheds light on the molecular understanding of symbiosis and insecticide resistance in an agriculturally important phloem-feeding insect pest, and lays the foundation for future functional genomics research of the

  10. Integromics network meta-analysis on cardiac aging offers robust multi-layer modular signatures and reveals micronome synergism.

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    Dimitrakopoulou, Konstantina; Vrahatis, Aristidis G; Bezerianos, Anastasios

    2015-03-04

    The avalanche of integromics and panomics approaches shifted the deciphering of aging mechanisms from single molecular entities to communities of them. In this orientation, we explore the cardiac aging mechanisms - risk factor for multiple cardiovascular diseases - by capturing the micronome synergism and detecting longevity signatures in the form of communities (modules). For this, we developed a meta-analysis scheme that integrates transcriptome expression data from multiple cardiac-specific independent studies in mouse and human along with proteome and micronome interaction data in the form of multiple independent weighted networks. Modularization of each weighted network produced modules, which in turn were further analyzed so as to define consensus modules across datasets that change substantially during lifespan. Also, we established a metric that determines - from the modular perspective - the synergism of microRNA-microRNA interactions as defined by significantly functionally associated targets. The meta-analysis provided 40 consensus integromics modules across mouse datasets and revealed microRNA relations with substantial collective action during aging. Three modules were reproducible, based on homology, when mapped against human-derived modules. The respective homologs mainly represent NADH dehydrogenases, ATP synthases, cytochrome oxidases, Ras GTPases and ribosomal proteins. Among various observations, we corroborate to the involvement of miR-34a (included in consensus modules) as proposed recently; yet we report that has no synergistic effect. Moving forward, we determined its age-related neighborhood in which HCN3, a known heart pacemaker channel, was included. Also, miR-125a-5p/-351, miR-200c/-429, miR-106b/-17, miR-363/-92b, miR-181b/-181d, miR-19a/-19b, let-7d/-7f, miR-18a/-18b, miR-128/-27b and miR-106a/-291a-3p pairs exhibited significant synergy and their association to aging and/or cardiovascular diseases is supported in many cases by a

  11. Targeted Metabolomics Reveals Early Dominant Optic Atrophy Signature in Optic Nerves of Opa1delTTAG/+ Mice.

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    Chao de la Barca, Juan Manuel; Simard, Gilles; Sarzi, Emmanuelle; Chaumette, Tanguy; Rousseau, Guillaume; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Ferré, Marc; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Gueguen, Naïg; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Amati-Bonneau, Patrizia; Procaccio, Vincent; Hamel, Christian; Lenaers, Guy; Reynier, Pascal; Prunier-Mirebeau, Delphine

    2017-02-01

    Dominant optic atrophy (MIM No. 165500) is a blinding condition related to mutations in OPA1, a gene encoding a large GTPase involved in mitochondrial inner membrane dynamics. Although several mouse models mimicking the disease have been developed, the pathophysiological mechanisms responsible for retinal ganglion cell degeneration remain poorly understood. Using a targeted metabolomic approach, we measured the concentrations of 188 metabolites in nine tissues, that is, brain, three types of skeletal muscle, heart, liver, retina, optic nerve, and plasma in symptomatic 11-month-old Opa1delTTAG/+ mice. Significant metabolic signatures were found only in the optic nerve and plasma of female mice. The optic nerve signature was characterized by altered concentrations of phospholipids, amino acids, acylcarnitines, and carnosine, whereas the plasma signature showed decreased concentrations of amino acids and sarcosine associated with increased concentrations of several phospholipids. In contrast, the investigation of 3-month-old presymptomatic Opa1delTTAG/+ mice showed no specific plasma signature but revealed a significant optic nerve signature in both sexes, although with a sex effect. The Opa1delTTAG/+ versus wild-type optic nerve signature was characterized by the decreased concentrations of 10 sphingomyelins and 10 lysophosphatidylcholines, suggestive of myelin sheath alteration, and by alteration in the concentrations of metabolites involved in neuroprotection, such as dimethylarginine, carnitine, spermine, spermidine, carnosine, and glutamate, suggesting a concomitant axonal metabolic dysfunction. Our comprehensive metabolomic investigations revealed in symptomatic as well as in presymptomatic Opa1delTTAG/+ mice, a specific sensitiveness of the optic nerve to Opa1 insufficiency, opening new routes for protective therapeutic strategies.

  12. A novel system for tracking social preference dynamics in mice reveals sex- and strain-specific characteristics.

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    Netser, Shai; Haskal, Shani; Magalnik, Hen; Wagner, Shlomo

    2017-01-01

    Deciphering the biological mechanisms underlying social behavior in animal models requires standard behavioral paradigms that can be unbiasedly employed in an observer- and laboratory-independent manner. During the past decade, the three-chamber test has become such a standard paradigm used to evaluate social preference (sociability) and social novelty preference in mice. This test suffers from several caveats, including its reliance on spatial navigation skills and negligence of behavioral dynamics. Here, we present a novel experimental apparatus and an automated analysis system which offer an alternative to the three-chamber test while solving the aforementioned caveats. The custom-made apparatus is simple for production, and the analysis system is publically available as an open-source software, enabling its free use. We used this system to compare the dynamics of social behavior during the social preference and social novelty preference tests between male and female C57BL/6J mice. We found that in both tests, male mice keep their preference towards one of the stimuli for longer periods than females. We then employed our system to define several new parameters of social behavioral dynamics in mice and revealed that social preference behavior is segregated in time into two distinct phases. An early exploration phase, characterized by high rate of transitions between stimuli and short bouts of stimulus investigation, is followed by an interaction phase with low transition rate and prolonged interactions, mainly with the preferred stimulus. Finally, we compared the dynamics of social behavior between C57BL/6J and BTBR male mice, the latter of which are considered as asocial strain serving as a model for autism spectrum disorder. We found that BTBR mice ( n  = 8) showed a specific deficit in transition from the exploration phase to the interaction phase in the social preference test, suggesting a reduced tendency towards social interaction. We successfully

  13. Analysis of the robustness of network-based disease-gene prioritization methods reveals redundancy in the human interactome and functional diversity of disease-genes.

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    Emre Guney

    Full Text Available Complex biological systems usually pose a trade-off between robustness and fragility where a small number of perturbations can substantially disrupt the system. Although biological systems are robust against changes in many external and internal conditions, even a single mutation can perturb the system substantially, giving rise to a pathophenotype. Recent advances in identifying and analyzing the sequential variations beneath human disorders help to comprehend a systemic view of the mechanisms underlying various disease phenotypes. Network-based disease-gene prioritization methods rank the relevance of genes in a disease under the hypothesis that genes whose proteins interact with each other tend to exhibit similar phenotypes. In this study, we have tested the robustness of several network-based disease-gene prioritization methods with respect to the perturbations of the system using various disease phenotypes from the Online Mendelian Inheritance in Man database. These perturbations have been introduced either in the protein-protein interaction network or in the set of known disease-gene associations. As the network-based disease-gene prioritization methods are based on the connectivity between known disease-gene associations, we have further used these methods to categorize the pathophenotypes with respect to the recoverability of hidden disease-genes. Our results have suggested that, in general, disease-genes are connected through multiple paths in the human interactome. Moreover, even when these paths are disturbed, network-based prioritization can reveal hidden disease-gene associations in some pathophenotypes such as breast cancer, cardiomyopathy, diabetes, leukemia, parkinson disease and obesity to a greater extend compared to the rest of the pathophenotypes tested in this study. Gene Ontology (GO analysis highlighted the role of functional diversity for such diseases.

  14. ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.

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    Gaynor Miller

    2010-02-01

    Full Text Available Fibrillins 1 (FBN1 and 2 (FBN2 are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes.As part of a large-scale N-ethyl-N-nitrosourea (ENU mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp, identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice.These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further.

  15. Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

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    Askmyr, M; Ågerstam, H; Lilljebjörn, H; Hansen, N; Karlsson, C; Palffy, S von; Landberg, N; Högberg, C; Lassen, C; Rissler, M; Richter, J; Ehinger, M; Järås, M; Fioretos, T

    2014-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34 + cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML

  16. Immunogenomics reveal molecular circuits of diclofenac induced liver injury in mice

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    Lee, Eun-Hee; Oh, Jung-Hwa; Selvaraj, Saravanakumar; Park, Se-Myo; Choi, Mi-Sun; Spanel, Reinhard

    2016-01-01

    Diclofenac is a non-steroidal anti-inflammatory drug and its use can be associated with severe adverse reactions, notably myocardial infarction, stroke and drug-induced liver injury (DILI). In pursue of immune-mediated DILI mechanisms an immunogenomic study was carried out. Diclofenac treatment of mice at 30 mg/kg for 3 days caused significant serum ALT and AST elevations, hepatomegaly and degenerative changes including hepatic glycogen depletion, hydropic swelling, cholesterolosis and eosinophilic hepatocytes with one animal presenting subsegmental infarction due to portal vein thrombosis. Furthermore, portal/periportal induction of the rate limiting enzyme in ammonia detoxification, i.e. carbamoyl phosphate synthetase 1 was observed. The performed microarray studies informed on > 600 differential expressed genes of which 35, 37 and 50 coded for inflammation, 51, 44 and 61 for immune and 116, 129 and 169 for stress response, respectively after single and repeated dosing for 3 and 14 days. Bioinformatic analysis defined molecular circuits of hepatic inflammation with the growth hormone (Ghr)− and leptin receptor, the protein-tyrosine-phosphatase, selectin and the suppressor-of-cytokine-signaling (Socs) to function as key nodes in gene regulatory networks. Western blotting confirmed induction of fibronectin and M-CSF to hallmark tissue repair and differentiation of monocytes and macrophages. Transcript expression of the macrophage receptor with collagenous structure increased > 7-fold and immunohistochemistry of CD68 evidenced activation of tissue-resident macrophages. Importantly, diclofenac treatment prompted strong expression of phosphorylated Stat3 amongst individual animals and the associated 8- and 4-fold Soc3 and Il-6 induction reinforced Ghr degradation as evidenced by immunoblotting. Moreover, immunohistochemistry confirmed regulation of master regulatory proteins of diclofenac treated mice to suggest complex pro-and anti-inflammatory reactions in immune

  17. Sodium Iodide Symporter PET and BLI Noninvasively Reveal Mesoangioblast Survival in Dystrophic Mice

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    Bryan Holvoet

    2015-12-01

    Full Text Available Muscular dystrophies are a heterogeneous group of myopathies, characterized by muscle weakness and degeneration, without curative treatment. Mesoangioblasts (MABs have been proposed as a potential regenerative therapy. To improve our understanding of the in vivo behavior of MABs and the effect of different immunosuppressive therapies, like cyclosporine A or co-stimulation-adhesion blockade therapy, on cell survival noninvasive cell monitoring is required. Therefore, cells were transduced with a lentiviral vector encoding firefly luciferase (Fluc and the human sodium iodide transporter (hNIS to allow cell monitoring via bioluminescence imaging (BLI and small-animal positron emission tomography (PET. Non-H2 matched mMABs were injected in the femoral artery of dystrophic mice and were clearly visible via small-animal PET and BLI. Based on noninvasive imaging data, we were able to show that co-stim was clearly superior to CsA in reducing cell rejection and this was mediated via a reduction in cytotoxic T cells and upregulation of regulatory T cells.

  18. Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment.

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    Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin; Nijem, Nadine; Walker, Angela K; Chen, Fei; Zhang, Shuyuan; Chung, Andrew S; Nguyen, Liem H; Nassour, Ibrahim; Budhipramono, Albert; Sun, Xuxu; Bok, Levinus A; McEntagart, Meriel; Gevers, Evelien F; Birnbaum, Shari G; Eisch, Amelia J; Powell, Craig M; Ge, Woo-Ping; Santen, Gijs We; Chahrour, Maria; Zhu, Hao

    2017-07-11

    Sequencing studies have implicated haploinsufficiency of ARID1B , a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.

  19. Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice.

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    Matsuo, Tomohiko; Hattori, Tatsuya; Asaba, Akari; Inoue, Naokazu; Kanomata, Nobuhiro; Kikusui, Takefumi; Kobayakawa, Reiko; Kobayakawa, Ko

    2015-01-20

    Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.

  20. Conditional RARα Knockout Mice Reveal Acute Requirement for Retinoic Acid and RARα in Homeostatic Plasticity

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    Federica eSarti

    2012-02-01

    Full Text Available All-trans retinoic acid (RA plays important roles in brain development through regulating gene transcription. Recently, a novel postdevelopmental role of RA in mature brain was proposed. Specifically, RA rapidly enhanced excitatory synaptic transmission independent of transcriptional regulation. RA synthesis was induced when excitatory synaptic transmission was chronically blocked, and RA then activated dendritic protein synthesis and synaptic insertion of homomeric GluA1 AMPA receptors, thereby compensating for the loss of neuronal activity in a homeostatic fashion. This action of RA was suggested to be mediated by its canonical receptor RARα but no genetic evidence was available. Thus, we here tested the fundamental requirement of RARα in homeostatic plasticity using conditional RARα knockout mice, and additionally performed a structure-function analysis of RARα. We show that acutely deleting RARα in neurons eliminated RA’s effect on excitatory synaptic transmission, and inhibited activity blockade-induced homeostatic synaptic plasticity. By expressing various RARα rescue constructs in RARα knockout neurons, we found that the DNA-binding domain of RARα was dispensable for its role in regulating synaptic strength, further supporting the notion that RA and RARα act in a non-transcriptional manner in this context. By contrast, the ligand-binding domain (LBD and the mRNA-binding domain (F-domain are both necessary and sufficient for the function of RARα in homeostatic plasticity. Furthermore, we found that homeostatic regulation performed by the LBD/F domains leads to insertion of calcium-permeable AMPA receptors. Our results confirm with unequivocal genetic approaches that RA and RARα perform essential non-transcriptional functions in regulating synaptic strength, and establish a functional link between the various domains of RARα and their involvement in regulating protein synthesis and excitatory synaptic transmission during

  1. FDG PET imaging of Ela1-myc mice reveals major biological differences between pancreatic acinar and ductal tumours

    International Nuclear Information System (INIS)

    Abasolo, Ibane; Pujal, Judit; Navarro, Pilar; Rabanal, Rosa M.; Serafin, Anna; Millan, Olga; Real, Francisco X.

    2009-01-01

    The aim was to evaluate FDG PET imaging in Ela1-myc mice, a pancreatic cancer model resulting in the development of tumours with either acinar or mixed acinar-ductal phenotype. Transversal and longitudinal FDG PET studies were conducted; selected tissue samples were subjected to autoradiography and ex vivo organ counting. Glucose transporter and hexokinase mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR); Glut2 expression was analysed by immunohistochemistry. Transversal studies showed that mixed acinar-ductal tumours could be identified by FDG PET several weeks before they could be detected by hand palpation. Longitudinal studies revealed that ductal - but not acinar - tumours could be detected by FDG PET. Autoradiographic analysis confirmed that tumour areas with ductal differentiation incorporated more FDG than areas displaying acinar differentiation. Ex vivo radioactivity measurements showed that tumours of solely acinar phenotype incorporated more FDG than pancreata of non-transgenic littermates despite the fact that they did not yield positive PET images. To gain insight into the biological basis of the differential FDG uptake, glucose transporter and hexokinase transcript expression was studied in microdissected tumour areas enriched for acinar or ductal cells and validated using cell-specific markers. Glut2 and hexokinase I and II mRNA levels were up to 20-fold higher in ductal than in acinar tumours. Besides, Glut2 protein overexpression was found in ductal neoplastic cells but not in the surrounding stroma. In Ela1-myc mice, ductal tumours incorporate significantly more FDG than acinar tumours. This difference likely results from differential expression of Glut2 and hexokinases. These findings reveal previously unreported biological differences between acinar and ductal pancreatic tumours. (orig.)

  2. FDG PET imaging of Ela1-myc mice reveals major biological differences between pancreatic acinar and ductal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Abasolo, Ibane [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, Departament de Ciencies Experimentals i de la Salut, Barcelona (Spain); Institut d' Alta Tecnologia - CRC, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Pujal, Judit; Navarro, Pilar [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Rabanal, Rosa M.; Serafin, Anna [Universitat Autonoma de Barcelona, Departament de Medicina i Cirurgia Animals, Barcelona (Spain); Millan, Olga [Institut d' Alta Tecnologia - CRC, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Real, Francisco X. [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, Departament de Ciencies Experimentals i de la Salut, Barcelona (Spain); Programa de Patologia Molecular, Centro Nacional de Investigaciones Oncologicas, Madrid (Spain)

    2009-07-15

    The aim was to evaluate FDG PET imaging in Ela1-myc mice, a pancreatic cancer model resulting in the development of tumours with either acinar or mixed acinar-ductal phenotype. Transversal and longitudinal FDG PET studies were conducted; selected tissue samples were subjected to autoradiography and ex vivo organ counting. Glucose transporter and hexokinase mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR); Glut2 expression was analysed by immunohistochemistry. Transversal studies showed that mixed acinar-ductal tumours could be identified by FDG PET several weeks before they could be detected by hand palpation. Longitudinal studies revealed that ductal - but not acinar - tumours could be detected by FDG PET. Autoradiographic analysis confirmed that tumour areas with ductal differentiation incorporated more FDG than areas displaying acinar differentiation. Ex vivo radioactivity measurements showed that tumours of solely acinar phenotype incorporated more FDG than pancreata of non-transgenic littermates despite the fact that they did not yield positive PET images. To gain insight into the biological basis of the differential FDG uptake, glucose transporter and hexokinase transcript expression was studied in microdissected tumour areas enriched for acinar or ductal cells and validated using cell-specific markers. Glut2 and hexokinase I and II mRNA levels were up to 20-fold higher in ductal than in acinar tumours. Besides, Glut2 protein overexpression was found in ductal neoplastic cells but not in the surrounding stroma. In Ela1-myc mice, ductal tumours incorporate significantly more FDG than acinar tumours. This difference likely results from differential expression of Glut2 and hexokinases. These findings reveal previously unreported biological differences between acinar and ductal pancreatic tumours. (orig.)

  3. IL-15 deficient tax mice reveal a role for IL-1α in tumor immunity.

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    Daniel A Rauch

    Full Text Available IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia/lymphoma (ATL and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15(-/- TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma.

  4. Profiling trait anxiety: transcriptome analysis reveals cathepsin B (Ctsb as a novel candidate gene for emotionality in mice.

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    Ludwig Czibere

    Full Text Available Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait "anxiety". We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB or low (LAB anxiety-related behavior, and also show signs of comorbid depression-like behavior. We identified and confirmed sex-independent differences in the basal expression of 13 candidate genes, using tissue from the entire brain, including coronin 7 (Coro7, cathepsin B (Ctsb, muscleblind-like 1 (Mbnl1, metallothionein 1 (Mt1, solute carrier family 25 member 17 (Slc25a17, tribbles homolog 2 (Trib2, zinc finger protein 672 (Zfp672, syntaxin 3 (Stx3, ATP-binding cassette, sub-family A member 2 (Abca2, ectonucleotide pyrophosphatase/phosphodiesterase 5 (Enpp5, high mobility group nucleosomal binding domain 3 (Hmgn3 and pyruvate dehydrogenase beta (Pdhb. Additionally, we confirmed brain region-specific differences in the expression of synaptotagmin 4 (Syt4.Our identification of about 90 polymorphisms in Ctsb suggested that this gene might play a critical role in shaping our mouse model's behavioral endophenotypes. Indeed, the assessment of anxiety-related and depression-like behaviors of Ctsb knock-out mice revealed an increase in depression-like behavior in females. Altogether, our results suggest that Ctsb has significant effects on emotionality, irrespective of the tested mouse strain, making it a promising target for future pharmacotherapy.

  5. Aspartame and the hippocampus: Revealing a bi-directional, dose/time-dependent behavioural and morphological shift in mice.

    Science.gov (United States)

    Onaolapo, Adejoke Y; Onaolapo, Olakunle J; Nwoha, Polycarp U

    2017-03-01

    Changes, in behaviour, oxidative markers of stress and hippocampal morphology were evaluated following aspartame administration. Mice, (20-22g each) were given vehicle (10ml/kg) or aspartame (20, 40, 80 and 160mg/kg) daily for 28days. They were tested in the Y-maze, radial-arm maze and elevated plus-maze (EPM) after the first and last dose of vehicle or aspartame; and then sacrificed. Hippocampal slices were analysed for aspartic acid, nitric oxide (NO) and superoxide dismutase (SOD); and processed for general histology and neuritic plaques. Glial fibrillary-acid protein (GFAP) expression and neuron-specific enolase (NSE) activities were determined. Radial-arm maze scores increased significantly after acute administration at 80 and 160mg/kg. Repeated administration at 20 and 40mg/kg (Y-maze) and at 40mg/kg (radial-arm maze) was also associated with increased scores, however, performance decreased at higher doses. EPM tests revealed anxiogenic responses following both acute and repeated administration. Significant increase in SOD and NO activities were observed at 40, 80 and 160mg/kg. Neuron counts reduced at higher doses of aspartame. At 40, 80 and 160mg/kg, fewer GFAP-reactive astrocytes were observed in the cornus ammonis, but increased GFAP-reactivity was observed in the dentate gyrus subgranular zone. NSE-positive neurons were readily identifiable within the dentate gyrus at the lower doses of aspartame; but at 160mg/kg, there was marked neuron loss and reduction in NSE-positive neurons. Oral aspartame significantly altered behaviour, anti-oxidant status and morphology of the hippocampus in mice; also, it may probably trigger hippocampal adult neurogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Sepsis reveals compartment-specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re-enter the cell cycle.

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    Lyons, John D; Klingensmith, Nathan J; Otani, Shunsuke; Mittal, Rohit; Liang, Zhe; Ford, Mandy L; Coopersmith, Craig M

    2017-12-01

    Cell production and death are tightly regulated in the rapidly renewing gut epithelium, with proliferation confined to crypts and apoptosis occurring in villi and crypts. This study sought to determine how stress alters these compartmentalized processes. Wild-type mice made septic via cecal ligation and puncture had decreased crypt proliferation and increased crypt and villus apoptosis. Fabpi -TAg mice expressing large T-antigen solely in villi had ectopic enterocyte proliferation with increased villus apoptosis in unmanipulated animals. Septic fabpi -TAg mice had an unexpected increase in villus proliferation compared with unmanipulated littermates, whereas crypt proliferation was decreased. Cell cycle regulators cyclin D1 and cyclin D2 were decreased in jejunal tissue in septic transgenic mice. In contrast, villus and crypt apoptosis were increased in septic fabpi -TAg mice. To examine the relationship between apoptosis and proliferation in a compartment-specific manner, fabpi -TAg mice were crossed with fabpl -Bcl-2 mice, resulting in expression of both genes in the villus but Bcl-2 alone in the crypt. Septic bi-transgenic animals had decreased crypt apoptosis but had a paradoxical increase in villus apoptosis compared with septic fabpi -TAg mice, associated with decreased proliferation in both compartments. Thus, sepsis unmasks compartment-specific proliferative and apoptotic regulation that is not present under homeostatic conditions.-Lyons, J. D., Klingensmith, N. J., Otani, S., Mittal, R., Liang, Z., Ford, M. L., Coopersmith, C. M. Sepsis reveals compartment-specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re-enter the cell cycle. © FASEB.

  7. Expression and assembly of largest foreign protein in chloroplasts: oral delivery of human FVIII made in lettuce chloroplasts robustly suppresses inhibitor formation in haemophilia A mice.

    Science.gov (United States)

    Kwon, Kwang-Chul; Sherman, Alexandra; Chang, Wan-Jung; Kamesh, Aditya; Biswas, Moanaro; Herzog, Roland W; Daniell, Henry

    2017-11-06

    Inhibitor formation is a serious complication of factor VIII (FVIII) replacement therapy for the X-linked bleeding disorder haemophilia A and occurs in 20%-30% of patients. No prophylactic tolerance protocol currently exists. Although we reported oral tolerance induction using FVIII domains expressed in tobacco chloroplasts, significant challenges in clinical advancement include expression of the full-length CTB-FVIII sequence to cover the entire patient population, regardless of individual CD4 + T-cell epitope responses. Codon optimization of FVIII heavy chain (HC) and light chain (LC) increased expression 15- to 42-fold higher than the native human genes. Homoplasmic lettuce lines expressed CTB fusion proteins of FVIII-HC (99.3 kDa), LC (91.8 kDa), C2 (31 kDa) or single chain (SC, 178.2 kDa) up to 3622, 263, 3321 and 852 μg/g in lyophilized plant cells, when grown in a cGMP hydroponic facility (Fraunhofer). CTB-FVIII-SC is the largest foreign protein expressed in chloroplasts; despite a large pentamer size (891 kDa), assembly, folding and disulphide bonds were maintained upon lyophilization and long-term storage as revealed by GM1-ganglioside receptor binding assays. Repeated oral gavages (twice/week for 2 months) of CTB-FVIII-HC/CTB-FVIII-LC reduced inhibitor titres ~10-fold (average 44 BU/mL to 4.7 BU/mL) in haemophilia A mice. Most importantly, increase in the frequency of circulating LAP-expressing CD4 + CD25 + FoxP3 + Treg in tolerized mice could be used as an important cellular biomarker in human clinical trials for plant-based oral tolerance induction. In conclusion, this study reports the first clinical candidate for oral tolerance induction that is urgently needed to protect haemophilia A patients receiving FVIII injections. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  8. Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography

    Science.gov (United States)

    Kerckhofs, G.; Durand, M.; Vangoitsenhoven, R.; Marin, C.; van der Schueren, B.; Carmeliet, G.; Luyten, F. P.; Geris, L.; Vandamme, K.

    2016-10-01

    High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 μm scale, no change was observed in the intracortical structure. At 1 μm scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging.

  9. Multiplex Brain Proteomic Analysis Revealed the Molecular Therapeutic Effects of Buyang Huanwu Decoction on Cerebral Ischemic Stroke Mice.

    Directory of Open Access Journals (Sweden)

    Hong-Jhang Chen

    Full Text Available Stroke is the second-leading cause of death worldwide, and tissue plasminogen activator (TPA is the only drug used for a limited group of stroke patients in the acute phase. Buyang Huanwu Decoction (BHD, a traditional Chinese medicine prescription, has long been used for improving neurological functional recovery in stroke. In this study, we characterized the therapeutic effect of TPA and BHD in a cerebral ischemia/reperfusion (CIR injury mouse model using multiplex proteomics approach. After the iTRAQ-based proteomics analysis, 1310 proteins were identified from the mouse brain with <1% false discovery rate. Among them, 877 quantitative proteins, 10.26% (90/877, 1.71% (15/877, and 2.62% (23/877 of the proteins was significantly changed in the CIR, BHD treatment, and TPA treatment, respectively. Functional categorization analysis showed that BHD treatment preserved the integrity of the blood-brain barrier (BBB (Alb, Fga, and Trf, suppressed excitotoxicity (Grm5, Gnai, and Gdi, and enhanced energy metabolism (Bdh, thereby revealing its multiple effects on ischemic stroke mice. Moreover, the neurogenesis marker doublecortin was upregulated, and the activity of glycogen synthase kinase 3 (GSK-3 and Tau was inhibited, which represented the neuroprotective effects. However, TPA treatment deteriorated BBB breakdown. This study highlights the potential of BHD in clinical applications for ischemic stroke.

  10. Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography

    Science.gov (United States)

    Kerckhofs, G.; Durand, M.; Vangoitsenhoven, R.; Marin, C.; Van der Schueren, B.; Carmeliet, G.; Luyten, F. P.; Geris, L.; Vandamme, K.

    2016-01-01

    High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 μm scale, no change was observed in the intracortical structure. At 1 μm scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging. PMID:27759061

  11. Paleogenetic analyses reveal unsuspected phylogenetic affinities between mice and the extinct Malpaisomys insularis, an endemic rodent of the Canaries.

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    Marie Pagès

    Full Text Available BACKGROUND: The lava mouse, Malpaisomys insularis, was endemic to the Eastern Canary islands and became extinct at the beginning of the 14(th century when the Europeans reached the archipelago. Studies to determine Malpaisomys' phylogenetic affinities, based on morphological characters, remained inconclusive because morphological changes experienced by this insular rodent make phylogenetic investigations a real challenge. Over 20 years since its first description, Malpaisomys' phylogenetic position remains enigmatic. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we resolved this issue using molecular characters. Mitochondrial and nuclear markers were successfully amplified from subfossils of three lava mouse samples. Molecular phylogenetic reconstructions revealed, without any ambiguity, unsuspected relationships between Malpaisomys and extant mice (genus Mus, Murinae. Moreover, through molecular dating we estimated the origin of the Malpaisomys/mouse clade at 6.9 Ma, corresponding to the maximal age at which the archipelago was colonised by the Malpaisomys ancestor via natural rafting. CONCLUSION/SIGNIFICANCE: This study reconsiders the derived morphological characters of Malpaisomys in light of this unexpected molecular finding. To reconcile molecular and morphological data, we propose to consider Malpaisomys insularis as an insular lineage of mouse.

  12. Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior

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    Toru eNakamura

    2014-07-01

    Full Text Available Both D1R and D2R knock out (KO mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT mice. First, we examined spontaneous motor activity in the home cage environment for consecutive five days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT

  13. Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and In Vitro Cytomegalovirus Infection Reveal Plastic and Robust Immune Pathway Biology Responses

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    Widad Dantoft

    2017-09-01

    Full Text Available Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1 and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1 roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity

  14. Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and In Vitro Cytomegalovirus Infection Reveal Plastic and Robust Immune Pathway Biology Responses.

    Science.gov (United States)

    Dantoft, Widad; Martínez-Vicente, Pablo; Jafali, James; Pérez-Martínez, Lara; Martin, Kim; Kotzamanis, Konstantinos; Craigon, Marie; Auer, Manfred; Young, Neil T; Walsh, Paul; Marchant, Arnaud; Angulo, Ana; Forster, Thorsten; Ghazal, Peter

    2017-01-01

    Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These

  15. MicroRNA profiling in Muc2 knockout mice of colitis-associated cancer model reveals epigenetic alterations during chronic colitis malignant transformation.

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    Yonghua Bao

    Full Text Available Our previous studies have demonstrated that genetic deletion of the Muc2 gene causes colorectal cancers in mice. The current study further showed that at the early stage (3 months the mice exhibited colorectal cancer, including a unique phenotype of rectal prolapsed (rectal severe inflammation and adenocarcinoma. Thus, the age of 3 months might be the key point of the transition from chronic inflammation to cancer. To determine the mechanisms of the malignant transformation, we conducted miRNA array on the colonic epithelial cells from the 3-month Muc2-/- and +/+ mice. MicroRNA profiling showed differential expression of miRNAs (i.e. lower or higher expression enrichments in Muc2-/- mice. 15 of them were validated by quantitative PCR. Based on relevance to cytokine and cancer, 4 miRNAs (miR-138, miR-145, miR-146a, and miR-150 were validate and were found significantly downregulated in human colitis and colorectal cancer tissues. The network of the targets of these miRNAs was characterized, and interestedly, miRNA-associated cytokines were significantly increased in Muc2-/-mice. This is the first to reveal the importance of aberrant expression of miRNAs in dynamically transformation from chronic colitis to colitis-associated cancer. These findings shed light on revealing the mechanisms of chronic colitis malignant transformation.

  16. Deletion of the Androgen Receptor in Adipose Tissue in Male Mice Elevates Retinol Binding Protein 4 and Reveals Independent Effects on Visceral Fat Mass and on Glucose Homeostasis

    Science.gov (United States)

    McInnes, Kerry J.; Smith, Lee B.; Hunger, Nicole I.; Saunders, Philippa T.K.; Andrew, Ruth; Walker, Brian R.

    2012-01-01

    Testosterone deficiency is epidemic in obese ageing males with type 2 diabetes, but the direction of causality remains unclear. Testosterone-deficient males and global androgen receptor (AR) knockout mice are insulin resistant with increased fat, but it is unclear whether AR signaling in adipose tissue mediates body fat redistribution and alters glucose homoeostasis. To investigate this, mice with selective knockdown of AR in adipocytes (fARKO) were generated. Male fARKO mice on normal diet had reduced perigonadal fat but were hyperinsulinemic and by age 12 months, were insulin deficient in the absence of obesity. On high-fat diet, fARKO mice had impaired compensatory insulin secretion and hyperglycemia, with increased susceptibility to visceral obesity. Adipokine screening in fARKO mice revealed a selective increase in plasma and intra-adipose retinol binding protein 4 (RBP4) that preceded obesity. AR activation in murine 3T3 adipocytes downregulated RBP4 mRNA. We conclude that AR signaling in adipocytes not only protects against high-fat diet–induced visceral obesity but also regulates insulin action and glucose homeostasis, independently of adiposity. Androgen deficiency in adipocytes in mice resembles human type 2 diabetes, with early insulin resistance and evolving insulin deficiency. PMID:22415878

  17. Phenotypic characterization of miR-92a-/- mice reveals an important function of miR-92a in skeletal development.

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    Daniela Penzkofer

    Full Text Available MicroRNAs (miRNAs, miRs emerged as key regulators of gene expression. Germline hemizygous deletion of the gene that encodes the miR-17∼92 miRNA cluster was associated with microcephaly, short stature and digital abnormalities in humans. Mice deficient for the miR-17∼92 cluster phenocopy several features such as growth and skeletal development defects and exhibit impaired B cell development. However, the individual contribution of miR-17∼92 cluster members to this phenotype is unknown. Here we show that germline deletion of miR-92a in mice is not affecting heart development and does not reduce circulating or bone marrow-derived hematopoietic cells, but induces skeletal defects. MiR-92a-/- mice are born at a reduced Mendelian ratio, but surviving mice are viable and fertile. However, body weight of miR-92a-/- mice was reduced during embryonic and postnatal development and adulthood. A significantly reduced body and skull length was observed in miR-92a-/- mice compared to wild type littermates. µCT analysis revealed that the length of the 5th mesophalanx to 5th metacarpal bone of the forelimbs was significantly reduced, but bones of the hindlimbs were not altered. Bone density was not affected. These findings demonstrate that deletion of miR-92a is sufficient to induce a developmental skeletal defect.

  18. Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen.

    Science.gov (United States)

    Inglis, Julia J; Criado, Gabriel; Medghalchi, Mino; Andrews, Melanie; Sandison, Ann; Feldmann, Marc; Williams, Richard O

    2007-01-01

    Many genetically modified mouse strains are now available on a C57BL/6 (H-2b) background, a strain that is relatively resistant to collagen-induced arthritis. To facilitate the molecular understanding of autoimmune arthritis, we characterised the induction of arthritis in C57BL/6 mice and then validated the disease as a relevant pre-clinical model for rheumatoid arthritis. C57BL/6 mice were immunised with type II collagen using different protocols, and arthritis incidence, severity, and response to commonly used anti-arthritic drugs were assessed and compared with DBA/1 mice. We confirmed that C57BL/6 mice are susceptible to arthritis induced by immunisation with chicken type II collagen and develop strong and sustained T-cell responses to type II collagen. Arthritis was milder in C57BL/6 mice than DBA/1 mice and more closely resembled rheumatoid arthritis in its response to therapeutic intervention. Our findings show that C57BL/6 mice are susceptible to collagen-induced arthritis, providing a valuable model for assessing the role of specific genes involved in the induction and/or maintenance of arthritis and for evaluating the efficacy of novel drugs, particularly those targeted at T cells.

  19. Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology.

    Science.gov (United States)

    Capuani, Barbara; Della-Morte, David; Donadel, Giulia; Caratelli, Sara; Bova, Luca; Pastore, Donatella; De Canio, Michele; D'Aguanno, Simona; Coppola, Andrea; Pacifici, Francesca; Arriga, Roberto; Bellia, Alfonso; Ferrelli, Francesca; Tesauro, Manfredi; Federici, Massimo; Neri, Anna; Bernardini, Sergio; Sbraccia, Paolo; Di Daniele, Nicola; Sconocchia, Giuseppe; Orlandi, Augusto; Urbani, Andrea; Lauro, Davide

    2015-05-01

    Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications. Copyright © 2015 the American Physiological Society.

  20. Activity-Based Protein Profiling Reveals Mitochondrial Oxidative Enzyme Impairment and Restoration in Diet-Induced Obese Mice

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    Sadler, Natalie C.; Angel, Thomas E.; Lewis, Michael P.; Pederson, Leeanna M.; Chauvigne-Hines, Lacie M.; Wiedner, Susan D.; Zink, Erika M.; Smith, Richard D.; Wright, Aaron T.

    2012-10-24

    High-fat diet (HFD) induced obesity and concomitant development of insulin resistance (IR) and type 2 diabetes mellitus have been linked to mitochondrial dysfunction. However, it is not clear whether mitochondrial dysfunction is a direct effect of a HFD or if the mitochondrial function is reduced with increased HFD duration. We hypothesized that the function of mitochondrial oxidative and lipid metabolism functions in skeletal muscle mitochondria for HFD mice are similar or elevated relative to standard diet (SD) mice, thereby IR is neither cause nor consequence of mitochondrial dysfunction. We applied a chemical probe approach to identify functionally reactive ATPases and nucleotide-binding proteins in mitochondria isolated from skeletal muscle of C57Bl/6J mice fed HFD or SD chow for 2-, 8-, or 16-weeks; feeding time points known to induce IR. A total of 293 probe-labeled proteins were identified by mass spectrometry-based proteomics, of which 54 differed in abundance between HFD and SD mice. We found proteins associated with the TCA cycle, oxidative phosphorylation (OXPHOS), and lipid metabolism were altered in function when comparing SD to HFD fed mice at 2-weeks, however by 16-weeks HFD mice had TCA cycle, β-oxidation, and respiratory chain function at levels similar to or higher than SD mice.

  1. Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice*

    Science.gov (United States)

    Kasaikina, Marina V.; Fomenko, Dmitri E.; Labunskyy, Vyacheslav M.; Lachke, Salil A.; Qiu, Wenya; Moncaster, Juliet A.; Zhang, Jie; Wojnarowicz, Mark W.; Natarajan, Sathish Kumar; Malinouski, Mikalai; Schweizer, Ulrich; Tsuji, Petra A.; Carlson, Bradley A.; Maas, Richard L.; Lou, Marjorie F.; Goldstein, Lee E.; Hatfield, Dolph L.; Gladyshev, Vadim N.

    2011-01-01

    The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency. PMID:21768092

  2. Mouse lysozyme-M knockout mice reveal how the self-determinant hierarchy shapes the T cell repertoire against this circulating self antigen in wild-type mice

    NARCIS (Netherlands)

    Sinha, Pratima; Chi, Howard H.; Kim, Hong R.; Clausen, Björn E.; Pederson, Brian; Sercarz, Eli E.; Forster, Irmgard; Moudgil, Kamal D.

    2004-01-01

    We have studied T cell tolerance to defined determinants within ML-M using wild-type (WT; ML-M+/+) and LysMcre (ML-M-/-) C3H (H-2(k)) mice to determine the relative contribution of ML-M-derived epitopes vs those from other self Ags in selection of the ML-M-specific T cell repertoire. ML-M was

  3. Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen

    OpenAIRE

    Inglis, Julia J; Criado, Gabriel; Medghalchi, Mino; Andrews, Melanie; Sandison, Ann; Feldmann, Marc; Williams, Richard O

    2007-01-01

    Many genetically modified mouse strains are now available on a C57BL/6 (H-2b) background, a strain that is relatively resistant to collagen-induced arthritis. To facilitate the molecular understanding of autoimmune arthritis, we characterised the induction of arthritis in C57BL/6 mice and then validated the disease as a relevant pre-clinical model for rheumatoid arthritis. C57BL/6 mice were immunised with type II collagen using different protocols, and arthritis incidence, severity, and respo...

  4. Noninvasive Assessment of Antenatal Hydronephrosis in Mice Reveals a Critical Role for Robo2 in Maintaining Anti-Reflux Mechanism

    Science.gov (United States)

    Wang, Hang; Li, Qinggang; Liu, Juan; Mendelsohn, Cathy; Salant, David J.; Lu, Weining

    2011-01-01

    Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR. PMID:21949750

  5. Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes

    DEFF Research Database (Denmark)

    Albrechtsen, Nicolai Jacob Wewer; Kuhre, Rune Ehrenreich; Windeløv, Johanne Agerlin

    2016-01-01

    Glucagon is a metabolically important hormone, but many aspects of its physiology remain obscure, because glucagon secretion is difficult to measure in mice and rats due to methodological inadequacies. Here, we introduce and validate a low-volume, enzyme-linked immunosorbent glucagon assay...... according to current analytical guidelines, including tests of sensitivity, specificity, and accuracy, and compare it, using the Bland-Altman algorithm and size-exclusion chromatography, with three other widely cited assays. After demonstrating adequate performance of the assay, we measured glucagon...... and returning to basal levels at 6 min (mice) and 12 min (rats). d-Mannitol (osmotic control) was without effect. Ketamine/xylazine anesthesia in mice strongly attenuated (P assay. In conclusion, dynamic analysis...

  6. Quantitative proteomics and network analysis of SSA1 and SSB1 deletion mutants reveals robustness of chaperone HSP70 network in Saccharomyces cerevisiae.

    Science.gov (United States)

    Jarnuczak, Andrew F; Eyers, Claire E; Schwartz, Jean-Marc; Grant, Christopher M; Hubbard, Simon J

    2015-09-01

    Molecular chaperones play an important role in protein homeostasis and the cellular response to stress. In particular, the HSP70 chaperones in yeast mediate a large volume of protein folding through transient associations with their substrates. This chaperone interaction network can be disturbed by various perturbations, such as environmental stress or a gene deletion. Here, we consider deletions of two major chaperone proteins, SSA1 and SSB1, from the chaperone network in Sacchromyces cerevisiae. We employ a SILAC-based approach to examine changes in global and local protein abundance and rationalise our results via network analysis and graph theoretical approaches. Although the deletions result in an overall increase in intracellular protein content, correlated with an increase in cell size, this is not matched by substantial changes in individual protein concentrations. Despite the phenotypic robustness to deletion of these major hub proteins, it cannot be simply explained by the presence of paralogues. Instead, network analysis and a theoretical consideration of folding workload suggest that the robustness to perturbation is a product of the overall network structure. This highlights how quantitative proteomics and systems modelling can be used to rationalise emergent network properties, and how the HSP70 system can accommodate the loss of major hubs. © 2015 The Authors. PROTEOMICS published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development.

    Science.gov (United States)

    Bruining, Hilgo; Matsui, Asuka; Oguro-Ando, Asami; Kahn, René S; Van't Spijker, Heleen M; Akkermans, Guus; Stiedl, Oliver; van Engeland, Herman; Koopmans, Bastijn; van Lith, Hein A; Oppelaar, Hugo; Tieland, Liselotte; Nonkes, Lourens J; Yagi, Takeshi; Kaneko, Ryosuke; Burbach, J Peter H; Yamamoto, Nobuhiko; Kas, Martien J

    2015-10-01

    Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development. Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology. Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed. This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published

  8. GC/TOFMS analysis of metabolites in serum and urine reveals metabolic perturbation of TCA cycle in db/db mice involved in diabetic nephropathy.

    Science.gov (United States)

    Li, Mengjie; Wang, Xufang; Aa, Jiye; Qin, Weisong; Zha, Weibin; Ge, Yongchun; Liu, Linsheng; Zheng, Tian; Cao, Bei; Shi, Jian; Zhao, Chunyan; Wang, Xinwen; Yu, Xiaoyi; Wang, Guangji; Liu, Zhihong

    2013-06-01

    Early diagnosis of diabetic nephropathy (DN) is difficult although it is of crucial importance to prevent its development. To probe potential markers and the underlying mechanism of DN, an animal model of DN, the db/db mice, was used and serum and urine metabolites were profiled using gas chromatography/time-of-flight mass spectrometry. Metabolic patterns were evaluated based on serum and urine data. Principal component analysis of the data revealed an obvious metabonomic difference between db/db mice and controls, and db/db mice showed distinctly different metabolic patterns during the progression from diabetes to early, medium, and later DN. The identified metabolites discriminating between db/db mice and controls suggested that db/db mice have perturbations in the tricarboxylic acid cycle (TCA, citrate, malate, succinate, and aconitate), lipid metabolism, glycolysis, and amino acid turnover. The db/db mice were characterized by acidic urine, high TCA intermediates in serum at week 6 and a sharp decline thereafter, and gradual elevation of free fatty acids in the serum. The sharp drop of serum TCA intermediates from week 6 to 8 indicated the downregulated glycolysis and insulin resistance. However, urinary TCA intermediates did not decrease in parallel with those in the serum from week 6 to 10, and an increased portion of TCA intermediates in the serum was excreted into the urine at 8, 10, and 12 wk than at 6 wk, indicating kidney dysfunction occurred. The relative abundances of TCA intermediates in urine relative to those in serum were suggested as an index of renal damage.

  9. Species-related exposure of phase II metabolite gemfibrozil 1-O-β-glucuronide between human and mice: A net induction of mouse P450 activity was revealed.

    Science.gov (United States)

    Luo, Min; Dai, Manyun; Lin, Hante; Xie, Minzhu; Lin, Jiao; Liu, Aiming; Yang, Julin

    2017-12-01

    Gemfibrozil is a fibrate drug used widely for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil 1-O-β-glucuronide (gem-glu) are involved in drug-drug interaction (DDI). But the DDI risk caused by gem-glu between human and mice has not been compared. In this study, six volunteers were recruited and took a therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem-glu level in human. Male mice were fed a gemfibrozil diet (0.75%) for 7 days, following which a cocktail-based inhibitory DDI experiment was performed. Plasma samples and liver tissues from mice were collected for determination of gemfibrozil, gem-glu concentration and cytochrome p450 enzyme (P450) induction analysis. In human, the molar ratio of gem-glu/gemfibrozil was 15% and 10% at the trough concentration and the concentration at 1.5 h after the 6th dose. In contrast, this molar ratio at steady state in mice was 91%, demonstrating a 6- to 9-fold difference compared with that in human. Interestingly, a net induction of P450 activity and in vivo inductive DDI potential in mice was revealed. The P450 activity was not inhibited although the gem-glu concentration was high. These data suggested species difference of relative gem-glu exposure between human and mice, as well as a net inductive DDI potential of gemfibrozil in mouse model. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis

    NARCIS (Netherlands)

    Frank, Deborah U.; Carter, Kandis L.; Thomas, Kirk R.; Burr, R. Michael; Bakker, Martijn L.; Coetzee, William A.; Tristani-Firouzi, Martin; Bamshad, Michael J.; Christoffels, Vincent M.; Moon, Anne M.

    2012-01-01

    TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development,

  11. Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.

    Directory of Open Access Journals (Sweden)

    Adeline M Hajjar

    Full Text Available Although lipopolysaccharide (LPS stimulation through the Toll-like receptor (TLR-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for "humanized" TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with "humanized" TLR4/MD-2 transgenic mice.

  12. Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.

    Science.gov (United States)

    Hajjar, Adeline M; Ernst, Robert K; Fortuno, Edgardo S; Brasfield, Alicia S; Yam, Cathy S; Newlon, Lindsay A; Kollmann, Tobias R; Miller, Samuel I; Wilson, Christopher B

    2012-01-01

    Although lipopolysaccharide (LPS) stimulation through the Toll-like receptor (TLR)-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for "humanized" TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with "humanized" TLR4/MD-2 transgenic mice.

  13. Quantitative lipidomics reveals age-dependent perturbations of whole-body lipid metabolism in ACBP deficient mice

    DEFF Research Database (Denmark)

    Gallego, Sandra F; Sprenger, Richard R; Neess, Ditte

    2017-01-01

    The acyl-CoA binding protein (ACBP) plays a key role in chaperoning long-chain acyl-CoAs into lipid metabolic processes and acts as an important regulatory hub in mammalian physiology. This is highlighted by the recent finding that mice devoid of ACBP suffer from a compromised epidermal barrier a...

  14. Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells.

    Directory of Open Access Journals (Sweden)

    João A Paredes

    Full Text Available Loss of thymidine kinase 2 (TK2 causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA depletion syndrome (MDS in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.

  15. Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells.

    Science.gov (United States)

    Paredes, João A; Zhou, Xiaoshan; Höglund, Stefan; Karlsson, Anna

    2013-01-01

    Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.

  16. A chimera embryo assay reveals a decrease in embryonic cellular proliferation induced by sperm from X-irradiated male mice

    International Nuclear Information System (INIS)

    Obasaju, M.F.; Wiley, L.M.; Oudiz, D.J.; Raabe, O.; Overstreet, J.W.

    1989-01-01

    Male mice were divided into three experimental groups and a control group. Mice in the experimental groups received one of three doses of acute X irradiation (1.73, 0.29, and 0.05 Gy) and together with the control unirradiated mice were then mated weekly to unirradiated female mice for a 9-week experimental period. Embryos were recovered from the weekly matings at the four-cell stage and examined by the chimera assay for proliferative disadvantage. Aggregation chimeras were constructed of embryos from female mice mated to irradiated males (experimental embryos) and embryos from females mated to unexposed males (control embryos) and contained either one experimental embryo and one control embryo (heterologous chimera) or two control embryos (control chimera). The control embryo in heterologous chimeras and either embryo in control chimeras were prelabeled with the vital dye fluorescein isothiocyanate (FITC), and the chimeras were cultured for 40 h and viewed under phase-contrast and epifluorescence microscopy to obtain total embryo cell number and the cellular contribution from the FITC-labeled embryo. Experimental and control embryos that were cultured singly were also examined for embryo cell number at the end of the 40-h culture period. In control chimeras, the mean ratio of the unlabeled cells:total chimera cell number (henceforth referred to as ''mean ratio'') was 0.50 with little or no weekly variation over the 9-week experimental period. During Weeks 4-7, the mean ratios of heterologous chimeras differed significantly from the mean ratio of control chimeras with the greatest differences occurring during Week 7 (0.41 for chimeras of 0.05 Gy dose group, 0.40 for chimeras of the 0.29 Gy dose group, and 0.17 for chimeras of the 1.73 Gy dose group)

  17. Postnatal mandible growth in wild and laboratory mice: Differences revealed from bone remodeling patterns and geometric morphometrics.

    Science.gov (United States)

    Martínez-Vargas, Jessica; Muñoz-Muñoz, Francesc; Martinez-Maza, Cayetana; Molinero, Amalia; Ventura, Jacint

    2017-08-01

    Comparative information on the variation in the temporospatial patterning of mandible growth in wild and laboratory mice during early postnatal ontogeny is scarce but important to understand variation among wild rodent populations. Here, we compare mandible growth between two ontogenetic series from the second to the eighth week of postnatal life, corresponding to two different groups of mice reared under the same conditions: the classical inbred strain C57BL/6J, and Mus musculus domesticus. We characterize the ontogenetic patterns of bone remodeling of the mandibles belonging to these laboratory and wild mice by analyzing bone surface, as well as examine their ontogenetic form changes and bimodular organization using geometric morphometrics. Through ontogeny, the two mouse groups display similar directions of mandible growth, according to the temporospatial distribution of bone remodeling fields. The allometric shape variation of the mandibles of these mice entails the relative enlargement of the ascending ramus. The organization of the mandible into two modules is confirmed in both groups during the last postnatal weeks. However, especially after weaning, the mandibles of wild and laboratory mice differ in the timing and localization of several remodeling fields, in addition to exhibiting different patterns of shape variation and differences in size. The stimulation of dentary bone growth derived from the harder post-weaning diet might account for some features of postnatal mandible growth common to both groups. Nonetheless, a large component of the postnatal growth of the mouse mandible appears to be driven by the inherent genetic programs, which might explain between-group differences. © 2017 Wiley Periodicals, Inc.

  18. Robust Scientists

    DEFF Research Database (Denmark)

    Gorm Hansen, Birgitte

    their core i nterests, 2) developing a selfsupply of industry interests by becoming entrepreneurs and thus creating their own compliant industry partner and 3) balancing resources within a larger collective of researchers, thus countering changes in the influx of funding caused by shifts in political...... knowledge", Danish research policy seems to have helped develop politically and economically "robust scientists". Scientific robustness is acquired by way of three strategies: 1) tasting and discriminating between resources so as to avoid funding that erodes academic profiles and push scientists away from...

  19. Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Katrina L Paumier

    Full Text Available Parkinson's disease (PD pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn. Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age. Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1-2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD. Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic

  20. Behavioral Characterization of A53T Mice Reveals Early and Late Stage Deficits Related to Parkinson’s Disease

    Science.gov (United States)

    Paumier, Katrina L.; Sukoff Rizzo, Stacey J.; Berger, Zdenek; Chen, Yi; Gonzales, Cathleen; Kaftan, Edward; Li, Li; Lotarski, Susan; Monaghan, Michael; Shen, Wei; Stolyar, Polina; Vasilyev, Dmytro; Zaleska, Margaret; D. Hirst, Warren; Dunlop, John

    2013-01-01

    Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1–2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments

  1. Motor coordination and balance measurements reveal differential pathogenicity of currently spreading enterovirus 71 strains in human SCARB2 transgenic mice.

    Science.gov (United States)

    Chen, Mei-Feng; Shih, Shin-Ru

    2016-12-01

    Enterovirus 71 (EV71) has caused large-scale epidemics with neurological complications in the Asia-Pacific region. The C4a and B5 strains are the two major genotypes circulating in many countries recently. This study used a new protocol, a motor coordination task, to assess the differential pathogenicity of C4a and B5 strains in human SCARB2 transgenic mice. We found that the pathogenicity of C4a viruses was more severe than that of B5 viruses. Moreover, we discovered that an increased level of monocyte chemoattractant protein-1 was positively correlated with severely deficient motor function. This study provides a new method for evaluating EV71 infection in mice and distinguishing the severity of the symptoms caused by different clinical strains, which would contribute to studies of pathogenesis and development of vaccines and antivirals in EV71 infections.

  2. Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice.

    Science.gov (United States)

    Pardo, Marta; Cheng, Yuyan; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Martinez, Ana; Faghihi, Mohammad A; Jope, Richard S; Beurel, Eleonore

    2017-03-23

    Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA- or HDAC4 siRNA-induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1 -/- mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets.

  3. Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing.

    Science.gov (United States)

    Gallistel, C R; Tucci, Valter; Nolan, Patrick M; Schachner, Melitta; Jakovcevski, Igor; Kheifets, Aaron; Barboza, Luendro

    2014-03-05

    We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.

  4. BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

    Directory of Open Access Journals (Sweden)

    Kelsey Moore

    2016-11-01

    Full Text Available Blood oxygen level dependent (BOLD imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ opioid receptor knock-outs (MuKO in response to oxycodone (OXY. Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus, and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex. Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas. This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects. OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122 and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum, and in some case intensified (hippocampus. Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects. Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY

  5. Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight.

    Directory of Open Access Journals (Sweden)

    Paul A Baldock

    Full Text Available Changes in whole body energy levels are closely linked to alterations in body weight and bone mass. Here, we show that hypothalamic signals contribute to the regulation of bone mass in a manner consistent with the central perception of energy status. Mice lacking neuropeptide Y (NPY, a well-known orexigenic factor whose hypothalamic expression is increased in fasting, have significantly increased bone mass in association with enhanced osteoblast activity and elevated expression of bone osteogenic transcription factors, Runx2 and Osterix. In contrast, wild type and NPY knockout (NPY (-/- mice in which NPY is specifically over expressed in the hypothalamus (AAV-NPY+ show a significant reduction in bone mass despite developing an obese phenotype. The AAV-NPY+ induced loss of bone mass is consistent with models known to mimic the central effects of fasting, which also show increased hypothalamic NPY levels. Thus these data indicate that, in addition to well characterized responses to body mass, skeletal tissue also responds to the perception of nutritional status by the hypothalamus independently of body weight. In addition, the reduction in bone mass by AAV NPY+ administration does not completely correct the high bone mass phenotype of NPY (-/- mice, indicating the possibility that peripheral NPY may also be an important regulator of bone mass. Indeed, we demonstrate the expression of NPY specifically in osteoblasts. In conclusion, these data identifies NPY as a critical integrator of bone homeostatic signals; increasing bone mass during times of obesity when hypothalamic NPY expression levels are low and reducing bone formation to conserve energy under 'starving' conditions, when hypothalamic NPY expression levels are high.

  6. Neonatal maternal deprivation response and developmental changes in gene expression revealed by hypothalamic gene expression profiling in mice.

    Directory of Open Access Journals (Sweden)

    Feng Ding

    Full Text Available Neonatal feeding problems are observed in several genetic diseases including Prader-Willi syndrome (PWS. Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesized that failure to thrive in infancy and later-onset hyperphagia are related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to maternal deprivation in neonatal wild-type and Snord116del mice, a mouse model for PWS in which a cluster of imprinted C/D box snoRNAs is deleted. The neonatal starvation response in both strains was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation showed no expression change in the hypothalamus of 5 day-old pups after 6 hours of maternal deprivation. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndp, Brms1l, Mett10d, and Snx1 were decreased after neonatal deprivation. In addition, we compared hypothalamic gene expression profiles at postnatal days 5 and 13 and observed significant developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at all time points and conditions, arguing against a role of Snord116 in feeding regulation in the neonatal period.

  7. Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination

    Science.gov (United States)

    Ehrenstein, Michael R.; Rada, Cristina; Jones, Anne-Marie; Milstein, César; Neuberger, Michael S.

    2001-01-01

    Isotype switching involves a region-specific, nonhomologous recombinational deletion that has been suggested to occur by nonhomologous joining of broken DNA ends. Here, we find increased donor/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can occur by microhomology-mediated end-joining. Interestingly, although isotype switching and somatic hypermutation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nucleotide substitutions generated during somatic hypermutation. This finding is in contrast to MSH2 deficiency. With MSH2, the altered pattern of switch recombination and hypermutation suggests parallels in the mechanics of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may reflect differences in the pathways of break resolution. PMID:11717399

  8. Comparative analysis of kisspeptin-immunoreactivity reveals genuine differences in the hypothalamic Kiss1 systems between rats and mice

    DEFF Research Database (Denmark)

    Overgaard, Agnete; Tena-Sempere, Manuel; Franceschini, Isabelle

    2013-01-01

    cells, only after axonal transport inhibition. Interestingly, the density of kisspeptin innervation in the anterior periventricular area was higher in female compared to male in both species. Species differences in the ARC were evident, with the mouse ARC containing dense fibers, while the rat ARC......-immunoreactivity in the mouse compared to the rat, independently of brain region and gender. In the female mouse AVPV high numbers of kisspeptin-immunoreactive neurons were present, while in the rat, the female AVPV displays a similar number of kisspeptin-immunoreactive neurons compared to the level of Kiss1 mRNA expressing...... contains clearly discernable cells. In addition, we show a marked sex difference in the ARC, with higher kisspeptin levels in females. These findings show that the translation of Kiss1 mRNA and/or the degradation/transportation/release of kisspeptins are different in mice and rats....

  9. Touchscreen-paradigm for mice reveals cross-species evidence for an antagonistic relationship of cognitive flexibility and stability

    Directory of Open Access Journals (Sweden)

    S Helene Richter

    2014-05-01

    Full Text Available The abilities to either flexibly adjust behavior according to changing demands (cognitive flexibility or to maintain it in the face of potential distractors (cognitive stability are critical for adaptive behavior in many situations. Recently, a novel human paradigm has found individual differences of cognitive flexibility and stability to be related to common prefrontal networks. The aims of the present study were, first, to translate this paradigm from humans to mice and, second, to test conceptual predictions of a computational model of prefrontal working memory mechanisms, the Dual State Theory, which assumes an antagonistic relation between cognitive flexibility and stability.Mice were trained in a touchscreen-paradigm to discriminate visual cues. The task involved ‘ongoing’ and cued ‘switch’ trials. In addition distractor cues were interspersed to test the ability to resist distraction, and an ambiguous condition assessed the spontaneous switching between two possible responses without explicit cues. While response times did not differ substantially between conditions, error rates increased from the ‘ongoing’ baseline condition to the most complex condition, where subjects were required to switch between two responses in the presence of a distracting cue. Importantly, subjects switching more often spontaneously were found to be more distractible by task irrelevant cues, but also more flexible in situations, where switching was required. These results support a dichotomy of cognitive flexibility and stability as predicted by the Dual State Theory. Furthermore, they replicate critical aspects of the human paradigm, which indicates the translational potential of the testing procedure and supports the use of touchscreen procedures in preclinical animal research.

  10. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

    DEFF Research Database (Denmark)

    Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C

    2015-01-01

    Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been ...

  11. Analysis of morphine responses in mice reveals a QTL on Chromosome 7 [version 1; referees: 2 approved

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    Wim E. Crusio

    2016-09-01

    Full Text Available In this study we identified a quantitative trait locus (QTL on mouse Chromosome 7 associated with locomotor activity and rearing post morphine treatment. This QTL was revealed after correcting for the effects of another QTL peak on Chromosome 10 using composite interval mapping. The positional candidate genes are Syt9 and Ppfibp2. Several other genes within the interval are linked to neural processes, locomotor activity, and the defensive response to harmful stimuli.

  12. Analysis of morphine responses in mice reveals a QTL on Chromosome 7 [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Wim E. Crusio

    2016-10-01

    Full Text Available In this study we identified a quantitative trait locus (QTL on mouse Chromosome 7 associated with locomotor activity and rearing post morphine treatment. This QTL was revealed after correcting for the effects of another QTL peak on Chromosome 10 using composite interval mapping. The positional candidate genes are Syt9 and Ppfibp2. Several other genes within the interval are linked to neural processes, locomotor activity, and the defensive response to harmful stimuli.

  13. Two-photon imaging during prolonged middle cerebral artery occlusion in mice reveals recovery of dendritic structure after reperfusion.

    Science.gov (United States)

    Li, Ping; Murphy, Timothy H

    2008-11-12

    Filament occlusion of the middle cerebral artery (MCA) is a well accepted animal model of focal ischemia. Advantages of the model are relatively long occlusion times and a large penumbra region that simulates aspects of human stroke. Here, we use two-photon and confocal microscopy in combination with regional measurement of blood flow using laser speckle to assess the spatial relationship between the borders of the MCA ischemic territory and loss of dendrite structure, as well as the effect of reperfusion on dendritic damage in adult YFP (yellow fluorescent protein) and GFP (green fluorescent protein) C57BL/6 transgenic mice with fluorescent (predominantly layer 5) neurons. By examining the spatial extent of dendritic damage, we determined that 60 min of MCA occlusion produced a core with severe structural damage that did not recover after reperfusion (begins approximately 3.8 mm lateral to midline), a reversibly damaged area up to 0.6 mm medial to the core that recovered after reperfusion (penumbra), and a relatively structurally intact area ( approximately 1 mm wide; medial penumbra) with hypoperfusion. Loss of structure was preceded by a single ischemic depolarization 122.1 +/- 10.2 s after occlusion onset. Reperfusion of animals after 60 min of ischemia was not associated with exacerbation of damage (reperfusion injury) and resulted in a significant restoration of blebbed dendritic structure, but only within approximately 0.6 mm lateral of the dendritic damage structural border. In summary, we find that recovery of dendritic structure can occur after reperfusion after even 60 min of ischemia, but is likely restricted to a relatively small penumbra region with partial blood flow or oxygenation.

  14. Phenotypic characterization of Grm1crv4 mice reveals a functional role for the type 1 metabotropic glutamate receptor in bone mineralization.

    Science.gov (United States)

    Musante, Ilaria; Mattinzoli, Deborah; Otescu, Lavinia Alexandra; Bossi, Simone; Ikehata, Masami; Gentili, Chiara; Cangemi, Giuliana; Gatti, Cinzia; Emionite, Laura; Messa, Piergiorgio; Ravazzolo, Roberto; Rastaldi, Maria Pia; Riccardi, Daniela; Puliti, Aldamaria

    2017-01-01

    Recent increasing evidence supports a role for neuronal type signaling in bone. Specifically glutamate receptors have been found in cells responsible for bone remodeling, namely the osteoblasts and the osteoclasts. While most studies have focused on ionotropic glutamate receptors, the relevance of the metabotropic glutamate signaling in bone is poorly understood. Specifically type 1 metabotropic glutamate (mGlu1) receptors are expressed in bone, but the effect of its ablation on skeletal development has never been investigated. Here we report that Grm1 crv4/crv4 mice, homozygous for an inactivating mutation of the mGlu1 receptor, and mainly characterized by ataxia and renal dysfunction, exhibit decreased body weight, bone length and bone mineral density compared to wild type (WT) animals. Blood analyses of the affected mice demonstrate the absence of changes in circulating factors, such as vitamin D and PTH, suggesting renal damage is not the main culprit of the skeletal phenotype. Cultures of osteoblasts lacking functional mGlu1 receptors exhibit less homogeneous collagen deposition than WT cells, and present increased expression of osteocalcin, a marker of osteoblast maturation. These data suggest that the skeletal damage is directly linked to the absence of the receptor, which in turn leads to osteoblasts dysfunction and earlier maturation. Accordingly, skeletal histomorphology suggests that Grm1 crv4/crv4 mice exhibit enhanced bone maturation, resulting in premature fusion of the growth plate and shortened long bones, and further slowdown of bone apposition rate compared to the WT animals. In summary, this work reveals novel functions of mGlu1 receptors in the bone and indicates that in osteoblasts mGlu1 receptors are necessary for production of normal bone matrix, longitudinal bone growth, and normal skeletal development. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Proteomic analysis of tissue from α1,3-galactosyltransferase knockout mice reveals that a wide variety of proteins and protein fragments change expression level.

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    Louise Thorlacius-Ussing

    Full Text Available A barrier in a pig-to-man xenotransplantation is that the Galα1-3Galβ1-4GlcNAc-R carbohydrate (α-Gal epitope expressed on pig endothelial cells reacts with naturally occurring antibodies in the recipient's blood leading to rejection. Deletion of the α1,3-galactosyltransferase gene prevents the synthesis of the α-Gal epitope. Therefore, knockout models of the α1,3-galactosyltransferase gene are widely used to study xenotransplantation. We have performed proteomic studies on liver and pancreas tissues from wild type and α1,3-galactosyltransferase gene knockout mice. The tissues were analyzed by two-dimensional polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry. The analyses revealed that a wide variety of proteins and protein fragments are differentially expressed suggesting that knockout of the α1,3-galactosyltransferase gene affects the expression of several other genes.

  16. Unbiased cell quantification reveals a continued increase in the number of neocortical neurones during early post-natal development in mice

    DEFF Research Database (Denmark)

    Lyck, Lise; Krøigård, Thomas; Finsen, Bente

    2007-01-01

    The post-natal growth spurt of the mammalian neocortex has been attributed to maturation of dendritic arborizations, growth and myelination of axons, and addition of glia. It is unclear whether this growth may also involve recruitment of additional neurones. Using stereological methods, we analysed...... the number of neurones and glia in the neocortex during post-natal development in two separate strains of mice. Cell counting by the optical fractionator revealed that the number of neurones increased 80-100% from the time of birth to post-natal day (P)16, followed by a reduction by approximately 25...... was delayed until P16. The number of glia reached its maximum at P16, whereas the number of oligodendroglia, identified using a transgenic marker, increased until P55, the latest time of observation. Neurones continued to accumulate in the developing neocortex during the first 2 weeks of post...

  17. Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice

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    Ran Huimin

    2008-08-01

    Full Text Available Abstract Background Prosaposin encodes, in tandem, four small acidic activator proteins (saposins with specificities for glycosphingolipid (GSL hydrolases in lysosomes. Extensive GSL storage occurs in various central nervous system regions in mammalian prosaposin deficiencies. Results Our hypomorphic prosaposin deficient mouse, PS-NA, exhibited 45% WT levels of brain saposins and showed neuropathology that included neuronal GSL storage and Purkinje cell loss. Impairment of neuronal function was observed as early as 6 wks as demonstrated by the narrow bridges tests. Temporal transcriptome microarray analyses of brain tissues were conducted with mRNA from three prosaposin deficient mouse models: PS-NA, prosaposin null (PS-/- and a V394L/V394L glucocerebrosidase mutation combined with PS-NA (4L/PS-NA. Gene expression alterations in cerebrum and cerebellum were detectable at birth preceding the neuronal deficits. Differentially expressed genes encompassed a broad spectrum of cellular functions. The number of down-regulated genes was constant, but up-regulated gene numbers increased with age. CCAAT/enhancer-binding protein delta (CEBPD was the only up-regulated transcription factor in these two brain regions of all three models. Network analyses revealed that CEBPD has functional relationships with genes in transcription, pro-inflammation, cell death, binding, myelin and transport. Conclusion These results show that: 1 Regionally specific gene expression abnormalities precede the brain histological and neuronal function changes, 2 Temporal gene expression profiles provide insights into the molecular mechanism during the GSL storage disease course, and 3 CEBPD is a candidate regulator of brain disease in prosaposin deficiency to participate in modulating disease acceleration or progression.

  18. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    International Nuclear Information System (INIS)

    Zgoda-Pols, Joanna R.; Chowdhury, Swapan; Wirth, Mark; Milburn, Michael V.; Alexander, Danny C.; Alton, Kevin B.

    2011-01-01

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research highlights: → Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. → MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. → 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than

  19. Studies of UCP2 transgenic and knockout mice reveal that liver UCP2 is not essential for the antiobesity effects of fish oil.

    Science.gov (United States)

    Tsuboyama-Kasaoka, Nobuyo; Sano, Kayo; Shozawa, Chikako; Osaka, Toshimasa; Ezaki, Osamu

    2008-03-01

    Uncoupling protein 2 (UCP2) is a possible target molecule for energy dissipation. Many dietary fats, including safflower oil and lard, induce obesity in C57BL/6 mice, whereas fish oil does not. Fish oil increases UCP2 expression in hepatocytes and may enhance UCP2 activity by activating the UCP2 molecule or altering the lipid bilayer environment. To examine the role of liver UCP2 in obesity, we created transgenic mice that overexpressed human UCP2 in hepatocytes and examined whether UCP2 transgenic mice showed less obesity when fed a high-fat diet (safflower oil or lard). In addition, we examined whether fish oil had antiobesity effects in UCP2 knockout mice. UCP2 transgenic and wild-type mice fed a high-fat diet (safflower oil or lard) developed obesity to a similar degree. UCP2 knockout and wild-type mice fed fish oil had lower rates of obesity than mice fed safflower oil. Remarkably, safflower oil did not induce obesity in female UCP2 knockout mice, an unexpected phenotype for which we presently have no explanation. However, this unexpected effect was not observed in male UCP2 knockout mice or in UCP2 knockout mice fed a high-lard diet. These data indicate that liver UCP2 is not essential for fish oil-induced decreases in body fat.

  20. miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity.

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    Judit Remenyi

    Full Text Available miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity.

  1. Microarray Analysis Reveals Higher Gestational Folic Acid Alters Expression of Genes in the Cerebellum of Mice Offspring—A Pilot Study

    Directory of Open Access Journals (Sweden)

    Subit Barua

    2015-01-01

    Full Text Available Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development.

  2. Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.

    Science.gov (United States)

    Okuda, Kosuke; Takao, Keizo; Watanabe, Aya; Miyakawa, Tsuyoshi; Mizuguchi, Masashi; Tanaka, Teruyuki

    2018-01-01

    Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the

  3. Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.

    Directory of Open Access Journals (Sweden)

    Kosuke Okuda

    Full Text Available Mutations in the Cyclin-dependent kinase-like 5 (CDKL5 gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be

  4. Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory

    Science.gov (United States)

    Okuda, Kosuke; Takao, Keizo; Watanabe, Aya; Miyakawa, Tsuyoshi; Mizuguchi, Masashi

    2018-01-01

    Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the

  5. Rosa26-GFP direct repeat (RaDR-GFP mice reveal tissue- and age-dependence of homologous recombination in mammals in vivo.

    Directory of Open Access Journals (Sweden)

    Michelle R Sukup-Jackson

    2014-06-01

    Full Text Available Homologous recombination (HR is critical for the repair of double strand breaks and broken replication forks. Although HR is mostly error free, inherent or environmental conditions that either suppress or induce HR cause genomic instability. Despite its importance in carcinogenesis, due to limitations in our ability to detect HR in vivo, little is known about HR in mammalian tissues. Here, we describe a mouse model in which a direct repeat HR substrate is targeted to the ubiquitously expressed Rosa26 locus. In the Rosa26 Direct Repeat-GFP (RaDR-GFP mice, HR between two truncated EGFP expression cassettes can yield a fluorescent signal. In-house image analysis software provides a rapid method for quantifying recombination events within intact tissues, and the frequency of recombinant cells can be evaluated by flow cytometry. A comparison among 11 tissues shows that the frequency of recombinant cells varies by more than two orders of magnitude among tissues, wherein HR in the brain is the lowest. Additionally, de novo recombination events accumulate with age in the colon, showing that this mouse model can be used to study the impact of chronic exposures on genomic stability. Exposure to N-methyl-N-nitrosourea, an alkylating agent similar to the cancer chemotherapeutic temozolomide, shows that the colon, liver and pancreas are susceptible to DNA damage-induced HR. Finally, histological analysis of the underlying cell types reveals that pancreatic acinar cells and liver hepatocytes undergo HR and also that HR can be specifically detected in colonic somatic stem cells. Taken together, the RaDR-GFP mouse model provides new understanding of how tissue and age impact susceptibility to HR, and enables future studies of genetic, environmental and physiological factors that modulate HR in mammals.

  6. Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development

    Directory of Open Access Journals (Sweden)

    Kyle J. Beauchemin

    2016-08-01

    Full Text Available To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ. Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS. Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO archive (GSE74243. Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org.

  7. Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development.

    Science.gov (United States)

    Beauchemin, Kyle J; Wells, Julie M; Kho, Alvin T; Philip, Vivek M; Kamir, Daniela; Kohane, Isaac S; Graber, Joel H; Bult, Carol J

    2016-01-01

    To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ). Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS). Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular) defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO) archive (GSE74243). Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org).

  8. Metabolite profiles reveal energy failure and impaired beta-oxidation in liver of mice with complex III deficiency due to a BCS1L mutation.

    Directory of Open Access Journals (Sweden)

    Heike Kotarsky

    Full Text Available BACKGROUND & AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2O(2 production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions.

  9. Overcoming antigen masking of anti-amyloidbeta antibodies reveals breaking of B cell tolerance by virus-like particles in amyloidbeta immunized amyloid precursor protein transgenic mice

    Directory of Open Access Journals (Sweden)

    Ugen Kenneth E

    2004-06-01

    Full Text Available Abstract Background In prior work we detected reduced anti-Aβ antibody titers in Aβ-vaccinated transgenic mice expressing the human amyloid precursor protein (APP compared to nontransgenic littermates. We investigated this observation further by vaccinating APP and nontransgenic mice with either the wild-type human Aβ peptide, an Aβ peptide containing the "Dutch Mutation", E22Q, or a wild-type Aβ peptide conjugated to papillomavirus virus-like particles (VLPs. Results Anti-Aβ antibody titers were lower in vaccinated APP than nontransgenic mice even when vaccinated with the highly immunogenic Aβ E22Q. One concern was that human Aβ derived from the APP transgene might mask anti-Aβ antibodies in APP mice. To test this possibility, we dissociated antigen-antibody complexes by incubation at low pH. The low pH incubation increased the anti-Aβ antibody titers 20–40 fold in APP mice but had no effect in sera from nontransgenic mice. However, even after dissociation, the anti-Aβ titers were still lower in transgenic mice vaccinated with wild-type Aβ or E22Q Aβ relative to non-transgenic mice. Importantly, the dissociated anti-Aβ titers were equivalent in nontransgenic and APP mice after VLP-based vaccination. Control experiments demonstrated that after acid-dissociation, the increased antibody titer did not cross react with bovine serum albumin nor alpha-synuclein, and addition of Aβ back to the dissociated serum blocked the increase in antibody titers. Conclusions Circulating human Aβ can interfere with ELISA assay measurements of anti-Aβ titers. The E22Q Aβ peptide vaccine is more immunogenic than the wild-type peptide. Unlike peptide vaccines, VLP-based vaccines against Aβ abrogate the effects of Aβ self-tolerance.

  10. Methods for robustness programming

    NARCIS (Netherlands)

    Olieman, N.J.

    2008-01-01

    Robustness of an object is defined as the probability that an object will have properties as required. Robustness Programming (RP) is a mathematical approach for Robustness estimation and Robustness optimisation. An example in the context of designing a food product, is finding the best composition

  11. Robustness in laying hens

    NARCIS (Netherlands)

    Star, L.

    2008-01-01

    The aim of the project ‘The genetics of robustness in laying hens’ was to investigate nature and regulation of robustness in laying hens under sub-optimal conditions and the possibility to increase robustness by using animal breeding without loss of production. At the start of the project, a robust

  12. Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

    Science.gov (United States)

    Tanila, H; Mustonen, K; Sallinen, J; Scheinin, M; Riekkinen, P

    1999-02-01

    The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

  13. Flow cytometry analysis reveals different activation profiles of thrombin- or TRAP-stimulated platelets in db/db mice. The regulatory role of PAR-3.

    Science.gov (United States)

    Kassassir, Hassan; Siewiera, Karolina; Talar, Marcin; Przygodzki, Tomasz; Watala, Cezary

    2017-06-01

    Recent studies have shown that it may be the concentration of thrombin, which is discriminative in determining of the mechanism of platelet activation via protease activated receptors (PARs). Whether the observed phenomenon of differentiated responses of mouse platelets to various thrombin concentrations in non-diabetic db/+ and diabetic db/db mice depends upon the concerted action of various PARs, remains to be established. We found elevated reactivity of platelets, as well as the enhanced PAR-3 expression in response to both the used concentrations of AYPGKF in db/db mice, as compared to db/+ heterozygotes. At low concentration of thrombin platelets from diabetic mice demonstrated hyperreactivity, reflected by higher expression of PAR-3. For higher thrombin concentration, blood platelets from db/db mice appeared hyporeactive, compared to db/+ animals, while no significant differences in PAR-3 expression were observed between diabetic and non-diabetic mice. The novel and previously unreported finding resulting from our study is that the increased expression of PAR-3 in response to either TRAP for PAR-4 or low thrombin (when PAR-4 is not the efficient thrombin receptor) may be one of the key events contributing to higher reactivity of platelets in db/db mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes-prone but not in diabetes-resistant mice.

    Science.gov (United States)

    Presa, Maximiliano; Ortiz, Angela Zarama; Garabatos, Nahir; Izquierdo, Cristina; Rivas, Elisa I; Teyton, Luc; Mora, Conchi; Serreze, David; Stratmann, Thomas

    2013-11-01

    The cholera toxin B subunit (CTB) has been used as adjuvant to improve oral vaccine delivery in type 1 diabetes. The effect of CTB/peptide formulations on Ag-specific CD4(+) T cells has remained largely unexplored. Here, using tetramer analysis, we investigated how oral delivery of CTB fused to two CD4(+) T-cell epitopes, the BDC-2.5 T-cell 2.5 mi mimotope and glutamic acid decarboxylase (GAD) 286-300, affected diabetogenic CD4(+) T cells in nonobese diabetic (NOD) mice. When administered i.p., CTB-2.5 mi activated 2.5 mi(+) T cells and following intragastric delivery generated Ag-specific Foxp3(+) Treg and Th2 cells. While 2.5 mi(+) and GAD-specific T cells were tolerized in diabetes-resistant NODxB6.Foxp3(EGFP) F1 and nonobese resistant (NOR) mice, this did not occur in NOD mice. This indicated that NOD mice had a recessive genetic resistance to induce oral tolerance to both CTB-fused epitopes. In contrast to NODxB6.Foxp3(EGFP) F1 mice, oral treatment in NOD mice lead to strong 2.5 mi(+) T-cell activation and the sequestration of these cells to the effector-memory pool. Oral treatment of NOD mice with CTB-2.5 mi failed to prevent diabetes. These findings underline the importance of investigating the effect of oral vaccine formulations on diabetogenic T cells as in selected cases they may have counterproductive consequences in human patients. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Host transcriptomic responses to pneumonic plague reveal that Yersinia pestis inhibits both the initial adaptive and innate immune responses in mice.

    Science.gov (United States)

    Yang, Huiying; Wang, Tong; Tian, Guang; Zhang, Qingwen; Wu, Xiaohong; Xin, Youqian; Yan, Yanfeng; Tan, Yafang; Cao, Shiyang; Liu, Wanbing; Cui, Yujun; Yang, Ruifu; Du, Zongmin

    2017-01-01

    Pneumonic plague is the most deadly form of infection caused by Yersinia pestis and can progress extremely fast. However, our understanding on the host transcriptomic response to pneumonic plague is insufficient. Here, we used RNA-sequencing technology to analyze transcriptomic responses in mice infected with fully virulent strain 201 or EV76, a live attenuated vaccine strain lacking the pigmentation locus. Approximately 600 differentially expressed genes (DEGs) were detected in lungs from both 201- and EV76-infected mice at 12h post-infection (hpi). DEGs in lungs of 201-infected mice exceeded 2000 at 48hpi, accompanied by sustained large numbers of DEGs in the liver and spleen; however, limited numbers of DEGs were detected in those organs of EV-infected mice. Remarkably, DEGs in lungs were significantly enriched in critical immune responses pathways in EV76-infected but not 201-infected mice, including antigen processing and presentation, T cell receptor signaling among others. Pathological and bacterial load analyses confirmed the rapid systemic dissemination of 201-infection and the confined EV76-infection in lungs. Our results suggest that fully virulent Y. pestis inhibits both the innate and adaptive immune responses that are substantially stimulated in a self-limited infection, which update our holistic views on the transcriptomic response to pneumonic plague. Copyright © 2016 Elsevier GmbH. All rights reserved.

  16. Depletion of cytotoxic T-cells does not protect NUP98-HOXD13 mice from myelodysplastic syndrome but reveals a modest tumor immunosurveillance effect.

    Directory of Open Access Journals (Sweden)

    Sheryl M Gough

    Full Text Available Myelodysplastic syndrome (MDS and aplastic anemia (AA patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13 transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML. We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO to determine if the absence of lymphocytes might 1 delay the onset and/or diminish the severity of the MDS, or 2 effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal.

  17. Perceptual Robust Design

    DEFF Research Database (Denmark)

    Pedersen, Søren Nygaard

    The research presented in this PhD thesis has focused on a perceptual approach to robust design. The results of the research and the original contribution to knowledge is a preliminary framework for understanding, positioning, and applying perceptual robust design. Product quality is a topic...... been presented. Therefore, this study set out to contribute to the understanding and application of perceptual robust design. To achieve this, a state-of-the-art and current practice review was performed. From the review two main research problems were identified. Firstly, a lack of tools...... for perceptual robustness was found to overlap with the optimum for functional robustness and at most approximately 2.2% out of the 14.74% could be ascribed solely to the perceptual robustness optimisation. In conclusion, the thesis have offered a new perspective on robust design by merging robust design...

  18. Genetic manipulation of the ghrelin signaling system in male mice reveals bone compartment specificity of acylated and unacylated ghrelin in the regulation of bone remodeling

    Science.gov (United States)

    Ghrelin receptor-deficient (Ghsr-/-) mice that lack acylated ghrelin (AG) signaling retain a metabolic response to unacylated ghrelin (UAG). Recently, we showed that Ghsr-deficiency affects bone metabolism. The aim of this study was to further establish the impact of AG and UAG on bone metabolism. W...

  19. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Hansotia, Tanya; Baggio, Laurie L; Delmeire, Dominique

    2004-01-01

    with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin...

  20. Mice lacking the UbCKmit isoform of creatine kinase reveal slower spatial learning acquisition, diminished exploration and habituation, and reduced acoustic startle reflex responses.

    NARCIS (Netherlands)

    Streijger, F.; Jost, C.R.; Oerlemans, F.T.J.J.; Ellenbroek, B.A.; Cools, A.R.; Wieringa, B.; Zee, C.E.E.M. van der

    2004-01-01

    Brain-type creatine kinases B-CK (cytosolic) and UbCKmit (mitochondrial) are considered important for the maintenance and distribution of cellular energy in the central nervous system. Previously, we have demonstrated an abnormal behavioral phenotype in mice lacking the B-CK creatine kinase isoform,

  1. Robustness of Structural Systems

    DEFF Research Database (Denmark)

    Canisius, T.D.G.; Sørensen, John Dalsgaard; Baker, J.W.

    2007-01-01

    The importance of robustness as a property of structural systems has been recognised following several structural failures, such as that at Ronan Point in 1968,where the consequenceswere deemed unacceptable relative to the initiating damage. A variety of research efforts in the past decades have...... attempted to quantify aspects of robustness such as redundancy and identify design principles that can improve robustness. This paper outlines the progress of recent work by the Joint Committee on Structural Safety (JCSS) to develop comprehensive guidance on assessing and providing robustness in structural...... systems. Guidance is provided regarding the assessment of robustness in a framework that considers potential hazards to the system, vulnerability of system components, and failure consequences. Several proposed methods for quantifying robustness are reviewed, and guidelines for robust design...

  2. Robust multivariate analysis

    CERN Document Server

    J Olive, David

    2017-01-01

    This text presents methods that are robust to the assumption of a multivariate normal distribution or methods that are robust to certain types of outliers. Instead of using exact theory based on the multivariate normal distribution, the simpler and more applicable large sample theory is given.  The text develops among the first practical robust regression and robust multivariate location and dispersion estimators backed by theory.   The robust techniques  are illustrated for methods such as principal component analysis, canonical correlation analysis, and factor analysis.  A simple way to bootstrap confidence regions is also provided. Much of the research on robust multivariate analysis in this book is being published for the first time. The text is suitable for a first course in Multivariate Statistical Analysis or a first course in Robust Statistics. This graduate text is also useful for people who are familiar with the traditional multivariate topics, but want to know more about handling data sets with...

  3. Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling

    Directory of Open Access Journals (Sweden)

    Yeunkum Lee

    2017-06-01

    Full Text Available Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3-overexpressing transgenic (TG mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1 signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1, TSC2 and Ras homolog enriched in striatum (Rhes, via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1 proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD. Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream

  4. Antibody repertoires in humanized NOD-scid-IL2Rγ(null mice and human B cells reveals human-like diversification and tolerance checkpoints in the mouse.

    Directory of Open Access Journals (Sweden)

    Gregory C Ippolito

    Full Text Available Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2Rγ(null engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH and light (IGK and IGL genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2Rγ(null mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3 repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential D(H-J(H pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by

  5. Somatostatin receptor 2 knockout/lacZ knockin mice show impaired motor coordination and reveal sites of somatostatin action within the striatum.

    Science.gov (United States)

    Allen, Jeremy P; Hathway, Gareth J; Clarke, Neil J; Jowett, Mike I; Topps, Stephanie; Kendrick, Keith M; Humphrey, Patrick P A; Wilkinson, Lawrence S; Emson, Piers C

    2003-05-01

    The peptide somatostatin can modulate the functional output of the basal ganglia. The exact sites and mechanisms of this action, however, are poorly understood, and the physiological context in which somatostatin acts is unknown. Somatostatin acts as a neuromodulator via a family of five 7-transmembrane G protein-coupled receptors, SSTR1-5, one of which, SSTR2, is known to be functional in the striatum. We have investigated the role of SSTR2 in basal ganglia function using mice in which Sstr2 has been inactivated and replaced by the lacZ reporter gene. Analysis of Sstr2lacZ expression in the brain by beta-galactosidase histochemistry demonstrated a widespread pattern of expression. By comparison to previously published in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown to accurately recapitulate that of Sstr2 and thus provided a highly sensitive model to investigate cell-type-specific expression of Sstr2. In the striatum, Sstr2 expression was identified in medium spiny projection neurons restricted to the matrix compartment and in cholinergic interneurons. Sstr2 expression was not detected in any other nuclei of the basal ganglia except for a sparse number of nondopaminergic neurons in the substantia nigra. Microdialysis in the striatum showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine and glutamate release. In behavioural tests, Sstr2-null mice showed normal levels of locomotor activity and normal coordination in undemanding tasks. However, in beam-walking, a test of fine motor control, Sstr2-null mice were severely impaired. Together these data implicate an important neuromodulatory role for SSTR2 in the striatum.

  6. Combined untargeted and targeted fingerprinting by comprehensive two-dimensional gas chromatography: revealing fructose-induced changes in mice urinary metabolic signatures.

    Science.gov (United States)

    Bressanello, Davide; Liberto, Erica; Collino, Massimo; Chiazza, Fausto; Mastrocola, Raffaella; Reichenbach, Stephen E; Bicchi, Carlo; Cordero, Chiara

    2018-04-01

    This study exploits the information potential of comprehensive two-dimensional gas chromatography configured with a parallel dual secondary column-dual detection by mass spectrometry and flame ionization (GC×2GC-MS/FID) to study changes in urinary metabolic signatures of mice subjected to high-fructose diets. Samples are taken from mice fed with normal or fructose-enriched diets provided either in aqueous solution or in solid form and analyzed at three stages of the dietary intervention (1, 6, and 12 weeks). Automated Untargeted and Targeted fingerprinting for 2D data elaboration is adopted for the most inclusive data mining of GC×GC patterns. The UT fingerprinting strategy performs a fully automated peak-region features fingerprinting and combines results from pre-targeted compounds and unknowns across the sample-set. The most informative metabolites, with statistically relevant differences between sample groups, are obtained by unsupervised multivariate analysis (MVA) and cross-validated by multi-factor analysis (MFA) with external standard quantitation by GC-MS. Results indicate coherent clustering of mice urine signatures according to dietary manipulation. Notably, the metabolite fingerprints of mice fed with liquid fructose exhibited greater derangement in fructose, glucose, citric, pyruvic, malic, malonic, gluconic, cis-aconitic, succinic and 2-keto glutaric acids, glycine acyl derivatives (N-carboxy glycine, N-butyrylglycine, N-isovaleroylglycine, N-phenylacetylglycine), and hippuric acid. Untargeted fingerprinting indicates some analytes which were not a priori pre-targeted which provide additional insights: N-acetyl glucosamine, N-acetyl glutamine, malonyl glycine, methyl malonyl glycine, and glutaric acid. Visual features fingerprinting is used to track individual variations during experiments, thereby extending the panorama of possible data elaboration tools. Graphical abstract ᅟ.

  7. Analysis of meiosis in SUN1 deficient mice reveals a distinct role of SUN2 in mammalian meiotic LINC complex formation and function.

    Directory of Open Access Journals (Sweden)

    Jana Link

    2014-02-01

    Full Text Available LINC complexes are evolutionarily conserved nuclear envelope bridges, composed of SUN (Sad-1/UNC-84 and KASH (Klarsicht/ANC-1/Syne/homology domain proteins. They are crucial for nuclear positioning and nuclear shape determination, and also mediate nuclear envelope (NE attachment of meiotic telomeres, essential for driving homolog synapsis and recombination. In mice, SUN1 and SUN2 are the only SUN domain proteins expressed during meiosis, sharing their localization with meiosis-specific KASH5. Recent studies have shown that loss of SUN1 severely interferes with meiotic processes. Absence of SUN1 provokes defective telomere attachment and causes infertility. Here, we report that meiotic telomere attachment is not entirely lost in mice deficient for SUN1, but numerous telomeres are still attached to the NE through SUN2/KASH5-LINC complexes. In Sun1(-/- meiocytes attached telomeres retained the capacity to form bouquet-like clusters. Furthermore, we could detect significant numbers of late meiotic recombination events in Sun1(-/- mice. Together, this indicates that even in the absence of SUN1 telomere attachment and their movement within the nuclear envelope per se can be functional.

  8. Differential Proteomic Analysis of the Pancreas of Diabetic db/db Mice Reveals the Proteins Involved in the Development of Complications of Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Victoriano Pérez-Vázquez

    2014-05-01

    Full Text Available Type 2 diabetes mellitus is characterized by hyperglycemia and insulin-resistance. Diabetes results from pancreatic inability to secrete the insulin needed to overcome this resistance. We analyzed the protein profile from the pancreas of ten-week old diabetic db/db and wild type mice through proteomics. Pancreatic proteins were separated in two-dimensional polyacrylamide gel electrophoresis (2D-PAGE and significant changes in db/db mice respect to wild type mice were observed in 27 proteins. Twenty five proteins were identified by matrix-assisted laser desorption/ionization (MALDI time-of-flight (TOF and their interactions were analyzed using search tool for the retrieval of interacting genes/proteins (STRING and database for annotation, visualization and integrated discovery (DAVID. Some of these proteins were Pancreatic α-amylase, Cytochrome b5, Lithostathine-1, Lithostathine-2, Chymotrypsinogen B, Peroxiredoxin-4, Aspartyl aminopeptidase, Endoplasmin, and others, which are involved in the metabolism of carbohydrates and proteins, as well as in oxidative stress, and inflammation. Remarkably, these are mostly endoplasmic reticulum proteins related to peptidase activity, i.e., they are involved in proteolysis, glucose catabolism and in the tumor necrosis factor-mediated signaling pathway. These results suggest mechanisms for insulin resistance, and the chronic inflammatory state observed in diabetes.

  9. Novel human mutation and CRISPR/Cas genome-edited mice reveal the importance of C-terminal domain of MSX1 in tooth and palate development.

    Science.gov (United States)

    Mitsui, Silvia Naomi; Yasue, Akihiro; Masuda, Kiyoshi; Naruto, Takuya; Minegishi, Yoshiyuki; Oyadomari, Seiichi; Noji, Sumihare; Imoto, Issei; Tanaka, Eiji

    2016-12-05

    Several mutations, located mainly in the MSX1 homeodomain, have been identified in non-syndromic tooth agenesis predominantly affecting premolars and third molars. We identified a novel frameshift mutation of the highly conserved C-terminal domain of MSX1, known as Msx homology domain 6 (MH6), in a Japanese family with non-syndromic tooth agenesis. To investigate the importance of MH6 in tooth development, Msx1 was targeted in mice with CRISPR/Cas system. Although heterozygous MH6 disruption did not alter craniofacial development, homozygous mice exhibited agenesis of lower incisors with or without cleft palate at E16.5. In addition, agenesis of the upper third molars and the lower second and third molars were observed in 4-week-old mutant mice. Although the upper second molars were present, they were abnormally small. These results suggest that the C-terminal domain of MSX1 is important for tooth and palate development, and demonstrate that that CRISPR/Cas system can be used as a tool to assess causality of human disorders in vivo and to study the importance of conserved domains in genes.

  10. IMMUNOHISTOCHEMICAL APPROACH REVEALS LOCALIZATION OF CYSTATHIONINE-?-LYASE AND CYSTATHIONINE-ß-SYNTHETASE IN ETHANOL-INDUCED GASTRIC MUCOSA DAMAGE IN MICE

    Directory of Open Access Journals (Sweden)

    Jand-Venes Rolim MEDEIROS

    2013-04-01

    Full Text Available Context Hydrogen sulphide (H2S has been proved to be a neuromodulator and contributes to the maintenance of gastric mucosal integrity in damage caused by anti-inflammatory nonsteroidal drugs. Previously, we demonstrated that H2S synthesis is essential to gastric protection against ethanol. Objective To better understanding the role of H2S and the detailed localization of its production in both normal and injured stomach due to ethanol injection, we studied the expression of cystathionine-γ-lyase (CSE and cystathionine-β-synthetase (CBS isoforms in gastric mucosa of mice treated with saline or 50% ethanol. Methods Mice were treated by gavage with saline or 50% ethanol (0.5 mL/25 g. After 1 hour, mice were sacrificed, and gastric tissue was evaluated by histological and immunohistochemical analysis specific for CSE and CBS. Results We have demonstrated a non-specific expression of CBS in the normal gastric mucosa and expression of CSE occurring mainly in the parietal cells of the animals treated with ethanol. Conclusion Thus, we demonstrated that the expression of CBS appears to be constitutive and diffuse across the gastric epithelium, while the expression of CSE appears to be induced in parietal cells by damage agents such as ethanol.

  11. Robustness of Structures

    DEFF Research Database (Denmark)

    Faber, Michael Havbro; Vrouwenvelder, A.C.W.M.; Sørensen, John Dalsgaard

    2011-01-01

    In 2005, the Joint Committee on Structural Safety (JCSS) together with Working Commission (WC) 1 of the International Association of Bridge and Structural Engineering (IABSE) organized a workshop on robustness of structures. Two important decisions resulted from this workshop, namely...... ‘COST TU0601: Robustness of Structures’ was initiated in February 2007, aiming to provide a platform for exchanging and promoting research in the area of structural robustness and to provide a basic framework, together with methods, strategies and guidelines enhancing robustness of structures...... the development of a joint European project on structural robustness under the COST (European Cooperation in Science and Technology) programme and the decision to develop a more elaborate document on structural robustness in collaboration between experts from the JCSS and the IABSE. Accordingly, a project titled...

  12. Robust Growth Determinants

    OpenAIRE

    Doppelhofer, Gernot; Weeks, Melvyn

    2011-01-01

    This paper investigates the robustness of determinants of economic growth in the presence of model uncertainty, parameter heterogeneity and outliers. The robust model averaging approach introduced in the paper uses a flexible and parsi- monious mixture modeling that allows for fat-tailed errors compared to the normal benchmark case. Applying robust model averaging to growth determinants, the paper finds that eight out of eighteen variables found to be significantly related to economic growth ...

  13. Robust Programming by Example

    OpenAIRE

    Bishop , Matt; Elliott , Chip

    2011-01-01

    Part 2: WISE 7; International audience; Robust programming lies at the heart of the type of coding called “secure programming”. Yet it is rarely taught in academia. More commonly, the focus is on how to avoid creating well-known vulnerabilities. While important, that misses the point: a well-structured, robust program should anticipate where problems might arise and compensate for them. This paper discusses one view of robust programming and gives an example of how it may be taught.

  14. Bone Abnormalities in Mice with Protein Kinase A (PKA) Defects Reveal a Role of Cyclic AMP Signaling in Bone Stromal Cell-Dependent Tumor Development.

    Science.gov (United States)

    Liu, S; Shapiro, J M; Saloustros, E; Stratakis, C A

    2016-11-01

    Protein kinase A (PKA) is an important enzyme for all eukaryotic cells. PKA phosphorylates other proteins, thus, it is essential for the regulation of many diverse cellular functions, including cytoplasmic trafficking and signaling, organelle structure and mitochondrial oxidation, nuclear gene expression, the cell cycle, and cellular division. The PKA holoenzyme is composed of 2 regulatory and 2 catalytic subunits. Four regulatory (R1α, R1β, R2α, and R2β) and 4 catalytic subunits (Cα, Cβ, Cγ, and Prkx) have been identified, giving rise to mainly PKA-I (when the 2 regulatory subunits are either R1α or R1β), or PKA-II (when the 2 regulatory subunits are either R2α or R2β). Mutations in the PKA subunits can lead to altered total PKA activity or abnormal PKA-I to PKA-II ratio, leading to various abnormalities in both humans and mice. These effects can be tissue-specific. We studied the effect of PKA subunit defects on PKA activity and bone morphology of mice that were single or double heterozygous for null alleles of the various PKA subunit genes. Bone lesions including fibrous dysplasia, myxomas, osteo-sarcomas, -chondromas and -chondrosarcomas were found in these mice. Observational and molecular studies showed that these lesions were derived from bone stromal cells (BSCs). We conclude that haploinsufficiency for different PKA subunit genes affected bone lesion formation, new bone generation, organization, and mineralization in variable ways. This work identified a PKA subunit- and activity-dependent pathway of bone lesion formation from BSCs with important implications for understanding how cyclic AMP affects the skeleton and its tumorigenesis. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Analyses of Selenotranscriptomes and Selenium Concentrations in Response to Dietary Selenium Deficiency and Age Reveal Common and Distinct Patterns by Tissue and Sex in Telomere-Dysfunctional Mice.

    Science.gov (United States)

    Cao, Lei; Zhang, Li; Zeng, Huawei; Wu, Ryan Ty; Wu, Tung-Lung; Cheng, Wen-Hsing

    2017-10-01

    Background: The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity. Objective: We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice. Methods: Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo. Plasma, hearts, kidneys, livers, and testes were collected to assay for selenotranscriptomes, selected selenoproteins, and tissue selenium concentrations. Data were analyzed with the use of 2-factor ANOVA (diet × age) in both sexes. Results: Dietary selenium deficiency decreased ( P ≤ 0.05) selenium concentrations (65-72%) and glutathione peroxidase (GPX) 3 (82-94%) and selenoprotein P (SELENOP) (17-41%) levels in the plasma of both sexes of mice and mRNA levels (9-68%) of 4, 4, and 12 selenoproteins in the heart, kidney, and liver of males, respectively, and 5, 16, and 14 selenoproteins, respectively, in females. Age increased selenium concentrations and SELENOP levels (27% and 30%, respectively; P ≤ 0.05) in the plasma of males only but decreased (12-46%; P selenium deficiency and age in ≥1 tissue or sex, or both. Dietary selenium deficiency upregulated (40-160%; P ≤ 0.05) iodothyronine deiodinase 2 ( Dio2 ) and selenoprotein N ( Selenon ) in the kidneys of males. Age upregulated (11-44%; P selenium status and selenotranscriptomes because of dietary selenium deficiency and age. © 2017 American Society for Nutrition.

  16. Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveal Patterned Activity That Is Modulated by Gonadal Steroids in Male Mice.

    Science.gov (United States)

    Vanacker, Charlotte; Moya, Manuel Ricu; DeFazio, R Anthony; Johnson, Michael L; Moenter, Suzanne M

    2017-10-01

    Pulsatile release of gonadotropin-releasing hormone (GnRH) is key to fertility. Pulse frequency is modulated by gonadal steroids and likely arises subsequent to coordination of GnRH neuron firing activity. The source of rhythm generation and the site of steroid feedback remain critical unanswered questions. Arcuate neurons that synthesize kisspeptin, neurokinin B, and dynorphin (KNDy) may be involved in both of these processes. We tested the hypotheses that action potential firing in KNDy neurons is episodic and that gonadal steroids regulate this pattern. Targeted extracellular recordings were made of green fluorescent protein-identified KNDy neurons in brain slices from adult male mice that were intact, castrated, or castrated and treated with estradiol or dihydrotestosterone (DHT). KNDy neurons exhibited marked peaks and nadirs in action potential firing activity during recordings lasting 1 to 3.5 hours. Peaks, identified by Cluster analysis, occurred more frequently in castrated than intact mice, and either estradiol or DHT in vivo or blocking neurokinin type 3 receptor in vitro restored peak frequency to intact levels. The frequency of peaks in firing rate and estradiol regulation of this frequency is similar to that observed for GnRH neurons, whereas DHT suppressed firing in KNDy but not GnRH neurons. We further examined the patterning of action potentials to identify bursts that may be associated with increased neuromodulator release. Burst frequency and duration are increased in castrated compared with intact and steroid-treated mice. The observation that KNDy neurons fire in an episodic manner that is regulated by steroid feedback is consistent with a role for these neurons in GnRH pulse generation and regulation. Copyright © 2017 Endocrine Society.

  17. Bone marrow chimeric mice reveal a role for CX₃CR1 in maintenance of the monocyte-derived cell population in the olfactory neuroepithelium.

    Science.gov (United States)

    Vukovic, Jana; Blomster, Linda V; Chinnery, Holly R; Weninger, Wolfgang; Jung, Steffen; McMenamin, Paul G; Ruitenberg, Marc J

    2010-10-01

    Macrophages in the olfactory neuroepithelium are thought to play major roles in tissue homeostasis and repair. However, little information is available at present about possible heterogeneity of these monocyte-derived cells, their turnover rates, and the role of chemokine receptors in this process. To start addressing these issues, this study used Cx₃cr1(gfp) mice, in which the gene sequence for eGFP was knocked into the CX₃CR1 gene locus in the mutant allele. Using neuroepithelial whole-mounts from Cx₃cr1(gfp/+) mice, we show that eGFP(+) cells of monocytic origin are distributed in a loose network throughout this tissue and can be subdivided further into two immunophenotypically distinct subsets based on MHC-II glycoprotein expression. BM chimeric mice were created using Cx₃cr1(gfp/+) donors to investigate turnover of macrophages (and other monocyte-derived cells) in the olfactory neuroepithelium. Our data indicate that the monocyte-derived cell population in the olfactory neuroepithelium is actively replenished by circulating monocytes and under the experimental conditions, completely turned over within 6 months. Transplantation of Cx₃cr1(gfp/gfp) (i.e., CX₃CR1-deficient) BM partially impaired the replenishment process and resulted in an overall decline of the total monocyte-derived cell number in the olfactory epithelium. Interestingly, replenishment of the CD68(low)MHC-II(+) subset appeared minimally affected by CX₃CR1 deficiency. Taken together, the established baseline data about heterogeneity of monocyte-derived cells, their replenishment rates, and the role of CX₃CR1 provide a solid basis to further examine the importance of different monocyte subsets for neuroregeneration at this unique frontier with the external environment.

  18. Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice*

    OpenAIRE

    Kasaikina, Marina V.; Fomenko, Dmitri E.; Labunskyy, Vyacheslav M.; Lachke, Salil A.; Qiu, Wenya; Moncaster, Juliet A.; Zhang, Jie; Wojnarowicz, Mark W.; Natarajan, Sathish Kumar; Malinouski, Mikalai; Schweizer, Ulrich; Tsuji, Petra A.; Carlson, Bradley A.; Maas, Richard L.; Lou, Marjorie F.

    2011-01-01

    The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-gl...

  19. Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes

    DEFF Research Database (Denmark)

    Kool, Jaap; Uren, Anthony G; Martins, Carla P

    2010-01-01

    -throughput murine leukemia virus insertional mutagenesis screens in mice that are deficient for one or two CDK inhibitors. We retrieved 9,117 retroviral insertions from 476 lymphomas to define hundreds of loci that are mutated more frequently than expected by chance. Many of these loci are skewed toward a specific...... revealed a significant overlap between the datasets. Together, our findings highlight the importance of genetic context within large-scale mutation detection studies, and they show a novel use for insertional mutagenesis data in prioritizing disease-associated genes that emerge from genome-wide association...

  20. Skeletal muscle microRNA and messenger RNA profiling in cofilin-2 deficient mice reveals cell cycle dysregulation hindering muscle regeneration.

    Directory of Open Access Journals (Sweden)

    Sarah U Morton

    Full Text Available Congenital myopathies are rare skeletal muscle diseases presenting in early age with hypotonia and weakness often linked to a genetic defect. Mutations in the gene for cofilin-2 (CFL2 have been identified in several families as a cause of congenital myopathy with nemaline bodies and cores. Here we explore the global messenger and microRNA expression patterns in quadriceps muscle samples from cofillin-2-null mice and compare them with sibling-matched wild-type mice to determine the molecular pathways and mechanisms involved. Cell cycle processes are markedly dysregulated, with altered expression of genes involved in mitotic spindle formation, and evidence of loss of cell cycle checkpoint regulation. Importantly, alterations in cell cycle, apoptosis and proliferation pathways are present in both mRNA and miRNA expression patterns. Specifically, p21 transcript levels were increased, and the expression of p21 targets, such as cyclin D and cyclin E, was decreased. We therefore hypothesize that deficiency of cofilin-2 is associated with interruption of the cell cycle at several checkpoints, hindering muscle regeneration. Identification of these pathways is an important step towards developing appropriate therapies against various congenital myopathies.

  1. Analysis of the liver lipidome reveals insights into the protective effect of exercise on high fat diet induced hepatosteatosis in mice

    DEFF Research Database (Denmark)

    Jordy, Andreas Børsting; Kraakman, Michael J; Gardner, Tim

    2015-01-01

    The accumulation of lipid at ectopic sites including the skeletal muscle and liver is a common consequence of obesity and is associated with tissue-specific and whole-body insulin resistance. Exercise is well known to improve insulin resistance by mechanisms not completely understood. We performe...... in fatty acid entry into hepatocytes. Given the important role of the liver in the regulation of whole body glucose homeostasis, hepatic lipid regression may be a key component by which exercise can improve metabolism.......The accumulation of lipid at ectopic sites including the skeletal muscle and liver is a common consequence of obesity and is associated with tissue-specific and whole-body insulin resistance. Exercise is well known to improve insulin resistance by mechanisms not completely understood. We performed...... lipidomic profiling via mass spectrometry in liver and skeletal muscle samples from exercise trained mice, to decipher the lipid changes associated with exercise-induced improvements in whole body glucose metabolism. Obesity and insulin resistance was induced in C57BL/6J mice by high fat feeding for four...

  2. MER5101, a novel Aβ1-15:DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuates Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice.

    Science.gov (United States)

    Liu, Bin; Frost, Jeffrey L; Sun, Jing; Fu, Hongjun; Grimes, Stephen; Blackburn, Peter; Lemere, Cynthia A

    2013-04-17

    Active amyloid-β (Aβ) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in ∼6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-Aβ antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of Aβ1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1ΔE9 transgenic (Tg) and wild-type (Wt) mice. High anti-Aβ antibody levels were observed in both vaccinated APPswe/PS1ΔE9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aβ1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aβ1-15 or Aβ1-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aβ-specific T-cell response. Moreover, significant reductions in cerebral Aβ plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1ΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1ΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aβ conjugate vaccine, MER5101, shows promise for improving Aβ vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.

  3. Robust procedures in chemometrics

    DEFF Research Database (Denmark)

    Kotwa, Ewelina

    properties of the analysed data. The broad theoretical background of robust procedures was given as a very useful supplement to the classical methods, and a new tool, based on robust PCA, aiming at identifying Rayleigh and Raman scatters in excitation-mission (EEM) data was developed. The results show...

  4. Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice.

    Science.gov (United States)

    Chandler, Joshua D; Hu, Xin; Ko, Eun-Ju; Park, Soojin; Lee, Young-Tae; Orr, Michael; Fernandes, Jolyn; Uppal, Karan; Kang, Sang-Moo; Jones, Dean P; Go, Young-Mi

    2016-11-01

    Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation. Copyright © 2016 the American Physiological Society.

  5. How Robust is Your System Resilience?

    Science.gov (United States)

    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.

  6. Robustness Beamforming Algorithms

    Directory of Open Access Journals (Sweden)

    Sajad Dehghani

    2014-04-01

    Full Text Available Adaptive beamforming methods are known to degrade in the presence of steering vector and covariance matrix uncertinity. In this paper, a new approach is presented to robust adaptive minimum variance distortionless response beamforming make robust against both uncertainties in steering vector and covariance matrix. This method minimize a optimization problem that contains a quadratic objective function and a quadratic constraint. The optimization problem is nonconvex but is converted to a convex optimization problem in this paper. It is solved by the interior-point method and optimum weight vector to robust beamforming is achieved.

  7. Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague.

    Science.gov (United States)

    Tiner, Bethany L; Sha, Jian; Ponnusamy, Duraisamy; Baze, Wallace B; Fitts, Eric C; Popov, Vsevolod L; van Lier, Christina J; Erova, Tatiana E; Chopra, Ashok K

    2015-12-01

    Earlier, we showed that the Δlpp ΔmsbB Δail triple mutant of Yersinia pestis CO92 with deleted genes encoding Braun lipoprotein (Lpp), an acyltransferase (MsbB), and the attachment invasion locus (Ail), respectively, was avirulent in a mouse model of pneumonic plague. In this study, we further evaluated the immunogenic potential of the Δlpp ΔmsbB Δail triple mutant and its derivative by different routes of vaccination. Mice were immunized via the subcutaneous (s.c.) or the intramuscular (i.m.) route with two doses (2 × 10(6) CFU/dose) of the above-mentioned triple mutant with 100% survivability of the animals. Upon subsequent pneumonic challenge with 70 to 92 50% lethal doses (LD(50)) of wild-type (WT) strain CO92, all of the mice survived when immunization occurred by the i.m. route. Since Ail has virulence and immunogenic potential, a mutated version of Ail devoid of its virulence properties was created, and the genetically modified ail replaced the native ail gene on the chromosome of the Δlpp ΔmsbB double mutant, creating a Δlpp ΔmsbB::ailL2 vaccine strain. This newly generated mutant was attenuated similarly to the Δlpp ΔmsbB Δail triple mutant when administered by the i.m. route and provided 100% protection to animals against subsequent pneumonic challenge. Not only were the two above-mentioned mutants cleared rapidly from the initial i.m. site of injection in animals with no histopathological lesions, the immunized mice did not exhibit any disease symptoms during immunization or after subsequent exposure to WT CO92. These two mutants triggered balanced Th1- and Th2-based antibody responses and cell-mediated immunity. A substantial increase in interleukin-17 (IL-17) from the T cells of vaccinated mice, a cytokine of the Th17 cells, further augmented their vaccine potential. Thus, the Δlpp ΔmsbB Δail and Δlpp ΔmsbB::ailL2 mutants represent excellent vaccine candidates for plague, with the latter mutant still retaining Ail immunogenicity but

  8. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response

    Directory of Open Access Journals (Sweden)

    Ryan James C

    2010-08-01

    Full Text Available Abstract Background Ciguatoxins (CTXs are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO and molecular pathway enrichment of the gene expression data. Results A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p Conclusions Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against

  9. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response.

    Science.gov (United States)

    Ryan, James C; Morey, Jeanine S; Bottein, Marie-Yasmine Dechraoui; Ramsdell, John S; Van Dolah, Frances M

    2010-08-26

    Ciguatoxins (CTXs) are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO) and molecular pathway enrichment of the gene expression data. A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p < 0.0001) with microarray results. Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against neuroinflammation. Pathologic

  10. Robustness Metrics: Consolidating the multiple approaches to quantify Robustness

    DEFF Research Database (Denmark)

    Göhler, Simon Moritz; Eifler, Tobias; Howard, Thomas J.

    2016-01-01

    robustness metrics; 3) Functional expectancy and dispersion robustness metrics; and 4) Probability of conformance robustness metrics. The goal was to give a comprehensive overview of robustness metrics and guidance to scholars and practitioners to understand the different types of robustness metrics...

  11. Robustness of Structures

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard

    2008-01-01

    This paper describes the background of the robustness requirements implemented in the Danish Code of Practice for Safety of Structures and in the Danish National Annex to the Eurocode 0, see (DS-INF 146, 2003), (DS 409, 2006), (EN 1990 DK NA, 2007) and (Sørensen and Christensen, 2006). More...... frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure combined with increased requirements to efficiency in design and execution followed by increased risk of human errors has made the need of requirements to robustness of new structures essential....... According to Danish design rules robustness shall be documented for all structures in high consequence class. The design procedure to document sufficient robustness consists of: 1) Review of loads and possible failure modes / scenarios and determination of acceptable collapse extent; 2) Review...

  12. Robustness of structures

    DEFF Research Database (Denmark)

    Vrouwenvelder, T.; Sørensen, John Dalsgaard

    2009-01-01

    After the collapse of the World Trade Centre towers in 2001 and a number of collapses of structural systems in the beginning of the century, robustness of structural systems has gained renewed interest. Despite many significant theoretical, methodical and technological advances, structural...... of robustness for structural design such requirements are not substantiated in more detail, nor have the engineering profession been able to agree on an interpretation of robustness which facilitates for its uantification. A European COST action TU 601 on ‘Robustness of structures' has started in 2007...... by a group of members of the CSS. This paper describes the ongoing work in this action, with emphasis on the development of a theoretical and risk based quantification and optimization procedure on the one side and a practical pre-normative guideline on the other....

  13. Robust Approaches to Forecasting

    OpenAIRE

    Jennifer Castle; David Hendry; Michael P. Clements

    2014-01-01

    We investigate alternative robust approaches to forecasting, using a new class of robust devices, contrasted with equilibrium correction models. Their forecasting properties are derived facing a range of likely empirical problems at the forecast origin, including measurement errors, implulses, omitted variables, unanticipated location shifts and incorrectly included variables that experience a shift. We derive the resulting forecast biases and error variances, and indicate when the methods ar...

  14. Robustness - theoretical framework

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard; Rizzuto, Enrico; Faber, Michael H.

    2010-01-01

    More frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure combined with increased requirements to efficiency in design and execution followed by increased risk of human errors has made the need of requirements to robustness of new struct...... of this fact sheet is to describe a theoretical and risk based framework to form the basis for quantification of robustness and for pre-normative guidelines....

  15. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide

    Directory of Open Access Journals (Sweden)

    Rodrigo Juliano Oliveira

    2014-01-01

    Full Text Available β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63-116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20-52.54% and -0.95-62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide.

  16. Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice.

    Science.gov (United States)

    Lim, Joohyun; Burclaff, Joseph; He, Guangxu; Mills, Jason C; Long, Fanxin

    2017-01-01

    Cre/loxP technology has been widely used to study cell type-specific functions of genes. Proper interpretation of such data critically depends on a clear understanding of the tissue specificity of Cre expression. The Dmp1-Cre mouse, expressing Cre from a 14-kb DNA fragment of the mouse Dmp1 gene, has become a common tool for studying gene function in osteocytes, but the presumed cell specificity is yet to be fully established. By using the Ai9 reporter line that expresses a red fluorescent protein upon Cre recombination, we find that in 2-month-old mice, Dmp1-Cre targets not only osteocytes within the bone matrix but also osteoblasts on the bone surface and preosteoblasts at the metaphyseal chondro-osseous junction. In the bone marrow, Cre activity is evident in certain stromal cells adjacent to the blood vessels, but not in adipocytes. Outside the skeleton, Dmp1-Cre marks not only the skeletal muscle fibers, certain cells in the cerebellum and the hindbrain but also gastric and intestinal mesenchymal cells that express Pdgfra . Confirming the utility of Dmp1-Cre in the gastrointestinal mesenchyme, deletion of Bmpr1a with Dmp1-Cre causes numerous large polyps along the gastrointestinal tract, consistent with prior work involving inhibition of BMP signaling. Thus, caution needs to be exercised when using Dmp1-Cre because it targets not only the osteoblast lineage at an earlier stage than previously appreciated, but also a number of non-skeletal cell types.

  17. Social interaction and cocaine conditioning in mice increase spontaneous spike frequency in the nucleus accumbens or septal nuclei as revealed by multielectrode array recordings.

    Science.gov (United States)

    Kummer, Kai K; El Rawas, Rana; Kress, Michaela; Saria, Alois; Zernig, Gerald

    2015-01-01

    Both cocaine and social interaction place preference conditioning lead to increased neuronal expression of the immediate early gene EGR1 in the nucleus accumbens, a central region of the reward pathway, suggesting that both drug and natural rewards may be processed in similar brain regions. In order to gain novel insights into the intrinsic in vitro electrical activity of the nucleus accumbens and adjacent brain regions and to explore the effects of reward conditioning on network activity, we performed multielectrode array recordings of spontaneous firing in acute brain slices of mice conditioned to either cocaine or social interaction place preference. Cocaine conditioning increased the spike frequency of neurons in the septal nuclei, whereas social interaction conditioning increased the spike frequency in the nucleus accumbens compared to saline control animals. In addition, social interaction conditioning decreased the amount of active neuron clusters in the nucleus accumbens. Our findings suggest that place preference conditioning for both drug and natural rewards may induce persistent changes in neuronal network activity in the nucleus accumbens and the septum that are still preserved in acute slice preparations. © 2015 S. Karger AG, Basel.

  18. RNA sequencing reveals differential expression of mitochondrial and oxidation reduction genes in the long-lived naked mole-rat when compared to mice.

    Science.gov (United States)

    Yu, Chuanfei; Li, Yang; Holmes, Andrew; Szafranski, Karol; Faulkes, Chris G; Coen, Clive W; Buffenstein, Rochelle; Platzer, Matthias; de Magalhães, João Pedro; Church, George M

    2011-01-01

    The naked mole-rat (Heterocephalus glaber) is a long-lived, cancer resistant rodent and there is a great interest in identifying the adaptations responsible for these and other of its unique traits. We employed RNA sequencing to compare liver gene expression profiles between naked mole-rats and wild-derived mice. Our results indicate that genes associated with oxidoreduction and mitochondria were expressed at higher relative levels in naked mole-rats. The largest effect is nearly 300-fold higher expression of epithelial cell adhesion molecule (Epcam), a tumour-associated protein. Also of interest are the protease inhibitor, alpha2-macroglobulin (A2m), and the mitochondrial complex II subunit Sdhc, both ageing-related genes found strongly over-expressed in the naked mole-rat. These results hint at possible candidates for specifying species differences in ageing and cancer, and in particular suggest complex alterations in mitochondrial and oxidation reduction pathways in the naked mole-rat. Our differential gene expression analysis obviated the need for a reference naked mole-rat genome by employing a combination of Illumina/Solexa and 454 platforms for transcriptome sequencing and assembling transcriptome contigs of the non-sequenced species. Overall, our work provides new research foci and methods for studying the naked mole-rat's fascinating characteristics.

  19. RNA sequencing reveals differential expression of mitochondrial and oxidation reduction genes in the long-lived naked mole-rat when compared to mice.

    Directory of Open Access Journals (Sweden)

    Chuanfei Yu

    Full Text Available The naked mole-rat (Heterocephalus glaber is a long-lived, cancer resistant rodent and there is a great interest in identifying the adaptations responsible for these and other of its unique traits. We employed RNA sequencing to compare liver gene expression profiles between naked mole-rats and wild-derived mice. Our results indicate that genes associated with oxidoreduction and mitochondria were expressed at higher relative levels in naked mole-rats. The largest effect is nearly 300-fold higher expression of epithelial cell adhesion molecule (Epcam, a tumour-associated protein. Also of interest are the protease inhibitor, alpha2-macroglobulin (A2m, and the mitochondrial complex II subunit Sdhc, both ageing-related genes found strongly over-expressed in the naked mole-rat. These results hint at possible candidates for specifying species differences in ageing and cancer, and in particular suggest complex alterations in mitochondrial and oxidation reduction pathways in the naked mole-rat. Our differential gene expression analysis obviated the need for a reference naked mole-rat genome by employing a combination of Illumina/Solexa and 454 platforms for transcriptome sequencing and assembling transcriptome contigs of the non-sequenced species. Overall, our work provides new research foci and methods for studying the naked mole-rat's fascinating characteristics.

  20. Qualitative Robustness in Estimation

    Directory of Open Access Journals (Sweden)

    Mohammed Nasser

    2012-07-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Times New Roman","serif";} Qualitative robustness, influence function, and breakdown point are three main concepts to judge an estimator from the viewpoint of robust estimation. It is important as well as interesting to study relation among them. This article attempts to present the concept of qualitative robustness as forwarded by first proponents and its later development. It illustrates intricacies of qualitative robustness and its relation with consistency, and also tries to remove commonly believed misunderstandings about relation between influence function and qualitative robustness citing some examples from literature and providing a new counter-example. At the end it places a useful finite and a simulated version of   qualitative robustness index (QRI. In order to assess the performance of the proposed measures, we have compared fifteen estimators of correlation coefficient using simulated as well as real data sets.

  1. Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR knockout mice: implications on anti-glucagon therapies for diabetes

    Directory of Open Access Journals (Sweden)

    Molloy Mark P

    2011-06-01

    Full Text Available Abstract Background Glucagon is an important hormone in the regulation of glucose homeostasis, particularly in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM, glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Efforts to discover and evaluate glucagon receptor antagonists for the treatment of T2DM have been ongoing for approximately two decades, with the challenge being to identify an agent with appropriate pharmaceutical properties and efficacy relative to potential side effects. We sought to determine the hepatic & systemic consequence of full glucagon receptor antagonism through the study of the glucagon receptor knock-out mouse (Gcgr-/- compared to wild-type littermates. Results Liver transcriptomics was performed using Affymetric expression array profiling, and liver proteomics was performed by iTRAQ global protein analysis. To complement the transcriptomic and proteomic analyses, we also conducted metabolite profiling (~200 analytes using mass spectrometry in plasma. Overall, there was excellent concordance (R = 0.88 for changes associated with receptor knock-out between the transcript and protein analysis. Pathway analysis tools were used to map the metabolic processes in liver altered by glucagon receptor ablation, the most notable being significant down-regulation of gluconeogenesis, amino acid catabolism, and fatty acid oxidation processes, with significant up-regulation of glycolysis, fatty acid synthesis, and cholesterol biosynthetic processes. These changes at the level of the liver were manifested through an altered plasma metabolite profile in the receptor knock-out mice, e.g. decreased glucose and glucose-derived metabolites, and increased amino acids, cholesterol, and bile acid levels. Conclusions In sum, the results of this study suggest that the complete ablation

  2. 5′ Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice

    Directory of Open Access Journals (Sweden)

    Eric Waltari

    2018-03-01

    Full Text Available Using 5′ rapid amplification of cDNA ends, Illumina MiSeq, and basic flow cytometry, we systematically analyzed the expressed B cell receptor (BCR repertoire in 14 healthy adult PBMCs, 5 HIV-1+ adult PBMCs, 5 cord blood samples, and 3 HIS-CD4/B mice, examining the full-length variable region of μ, γ, α, κ, and λ chains for V-gene usage, somatic hypermutation (SHM, and CDR3 length. Adding to the known repertoire of healthy adults, Illumina MiSeq consistently detected small fractions of reads with high mutation frequencies including hypermutated μ reads, and reads with long CDR3s. Additionally, the less studied IgA repertoire displayed similar characteristics to that of IgG. Compared to healthy adults, the five HIV-1 chronically infected adults displayed elevated mutation frequencies for all μ, γ, α, κ, and λ chains examined and slightly longer CDR3 lengths for γ, α, and λ. To evaluate the reconstituted human BCR sequences in a humanized mouse model, we analyzed cord blood and HIS-CD4/B mice, which all lacked the typical SHM seen in the adult reference. Furthermore, MiSeq revealed identical unmutated IgM sequences derived from separate cell aliquots, thus for the first time demonstrating rare clonal members of unmutated IgM B cells by sequencing.

  3. 5' Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice.

    Science.gov (United States)

    Waltari, Eric; Jia, Manxue; Jiang, Caroline S; Lu, Hong; Huang, Jing; Fernandez, Cristina; Finzi, Andrés; Kaufmann, Daniel E; Markowitz, Martin; Tsuji, Moriya; Wu, Xueling

    2018-01-01

    Using 5' rapid amplification of cDNA ends, Illumina MiSeq, and basic flow cytometry, we systematically analyzed the expressed B cell receptor (BCR) repertoire in 14 healthy adult PBMCs, 5 HIV-1+ adult PBMCs, 5 cord blood samples, and 3 HIS-CD4/B mice, examining the full-length variable region of μ, γ, α, κ, and λ chains for V-gene usage, somatic hypermutation (SHM), and CDR3 length. Adding to the known repertoire of healthy adults, Illumina MiSeq consistently detected small fractions of reads with high mutation frequencies including hypermutated μ reads, and reads with long CDR3s. Additionally, the less studied IgA repertoire displayed similar characteristics to that of IgG. Compared to healthy adults, the five HIV-1 chronically infected adults displayed elevated mutation frequencies for all μ, γ, α, κ, and λ chains examined and slightly longer CDR3 lengths for γ, α, and λ. To evaluate the reconstituted human BCR sequences in a humanized mouse model, we analyzed cord blood and HIS-CD4/B mice, which all lacked the typical SHM seen in the adult reference. Furthermore, MiSeq revealed identical unmutated IgM sequences derived from separate cell aliquots, thus for the first time demonstrating rare clonal members of unmutated IgM B cells by sequencing.

  4. Robustness in econometrics

    CERN Document Server

    Sriboonchitta, Songsak; Huynh, Van-Nam

    2017-01-01

    This book presents recent research on robustness in econometrics. Robust data processing techniques – i.e., techniques that yield results minimally affected by outliers – and their applications to real-life economic and financial situations are the main focus of this book. The book also discusses applications of more traditional statistical techniques to econometric problems. Econometrics is a branch of economics that uses mathematical (especially statistical) methods to analyze economic systems, to forecast economic and financial dynamics, and to develop strategies for achieving desirable economic performance. In day-by-day data, we often encounter outliers that do not reflect the long-term economic trends, e.g., unexpected and abrupt fluctuations. As such, it is important to develop robust data processing techniques that can accommodate these fluctuations.

  5. Robust Manufacturing Control

    CERN Document Server

    2013-01-01

    This contributed volume collects research papers, presented at the CIRP Sponsored Conference Robust Manufacturing Control: Innovative and Interdisciplinary Approaches for Global Networks (RoMaC 2012, Jacobs University, Bremen, Germany, June 18th-20th 2012). These research papers present the latest developments and new ideas focusing on robust manufacturing control for global networks. Today, Global Production Networks (i.e. the nexus of interconnected material and information flows through which products and services are manufactured, assembled and distributed) are confronted with and expected to adapt to: sudden and unpredictable large-scale changes of important parameters which are occurring more and more frequently, event propagation in networks with high degree of interconnectivity which leads to unforeseen fluctuations, and non-equilibrium states which increasingly characterize daily business. These multi-scale changes deeply influence logistic target achievement and call for robust planning and control ...

  6. Robust plasmonic substrates

    DEFF Research Database (Denmark)

    Kostiučenko, Oksana; Fiutowski, Jacek; Tamulevicius, Tomas

    2014-01-01

    Robustness is a key issue for the applications of plasmonic substrates such as tip-enhanced Raman spectroscopy, surface-enhanced spectroscopies, enhanced optical biosensing, optical and optoelectronic plasmonic nanosensors and others. A novel approach for the fabrication of robust plasmonic...... substrates is presented, which relies on the coverage of gold nanostructures with diamond-like carbon (DLC) thin films of thicknesses 25, 55 and 105 nm. DLC thin films were grown by direct hydrocarbon ion beam deposition. In order to find the optimum balance between optical and mechanical properties...

  7. Robust Self Tuning Controllers

    DEFF Research Database (Denmark)

    Poulsen, Niels Kjølstad

    1985-01-01

    The present thesis concerns robustness properties of adaptive controllers. It is addressed to methods for robustifying self tuning controllers with respect to abrupt changes in the plant parameters. In the thesis an algorithm for estimating abruptly changing parameters is presented. The estimator...... has several operation modes and a detector for controlling the mode. A special self tuning controller has been developed to regulate plant with changing time delay.......The present thesis concerns robustness properties of adaptive controllers. It is addressed to methods for robustifying self tuning controllers with respect to abrupt changes in the plant parameters. In the thesis an algorithm for estimating abruptly changing parameters is presented. The estimator...

  8. Robust surgery loading

    NARCIS (Netherlands)

    Hans, Elias W.; Wullink, Gerhard; van Houdenhoven, Mark; Kazemier, Geert

    2008-01-01

    We consider the robust surgery loading problem for a hospital’s operating theatre department, which concerns assigning surgeries and sufficient planned slack to operating room days. The objective is to maximize capacity utilization and minimize the risk of overtime, and thus cancelled patients. This

  9. Robustness Envelopes of Networks

    NARCIS (Netherlands)

    Trajanovski, S.; Martín-Hernández, J.; Winterbach, W.; Van Mieghem, P.

    2013-01-01

    We study the robustness of networks under node removal, considering random node failure, as well as targeted node attacks based on network centrality measures. Whilst both of these have been studied in the literature, existing approaches tend to study random failure in terms of average-case

  10. A robust classic.

    Science.gov (United States)

    Kutzner, Florian; Vogel, Tobias; Freytag, Peter; Fiedler, Klaus

    2011-01-01

    In the present research, we argue for the robustness of illusory correlations (ICs, Hamilton & Gifford, 1976) regarding two boundary conditions suggested in previous research. First, we argue that ICs are maintained under extended experience. Using simulations, we derive conflicting predictions. Whereas noise-based accounts predict ICs to be maintained (Fielder, 2000; Smith, 1991), a prominent account based on discrepancy-reducing feedback learning predicts ICs to disappear (Van Rooy et al., 2003). An experiment involving 320 observations with majority and minority members supports the claim that ICs are maintained. Second, we show that actively using the stereotype to make predictions that are met with reward and punishment does not eliminate the bias. In addition, participants' operant reactions afford a novel online measure of ICs. In sum, our findings highlight the robustness of ICs that can be explained as a result of unbiased but noisy learning.

  11. Robust Airline Schedules

    OpenAIRE

    Eggenberg, Niklaus; Salani, Matteo; Bierlaire, Michel

    2010-01-01

    Due to economic pressure industries, when planning, tend to focus on optimizing the expected profit or the yield. The consequence of highly optimized solutions is an increased sensitivity to uncertainty. This generates additional "operational" costs, incurred by possible modifications of the original plan to be performed when reality does not reflect what was expected in the planning phase. The modern research trend focuses on "robustness" of solutions instead of yield or profit. Although ro...

  12. The Crane Robust Control

    Directory of Open Access Journals (Sweden)

    Marek Hicar

    2004-01-01

    Full Text Available The article is about a control design for complete structure of the crane: crab, bridge and crane uplift.The most important unknown parameters for simulations are burden weight and length of hanging rope. We will use robustcontrol for crab and bridge control to ensure adaptivity for burden weight and rope length. Robust control will be designed for current control of the crab and bridge, necessary is to know the range of unknown parameters. Whole robust will be splitto subintervals and after correct identification of unknown parameters the most suitable robust controllers will be chosen.The most important condition at the crab and bridge motion is avoiding from burden swinging in the final position. Crab and bridge drive is designed by asynchronous motor fed from frequency converter. We will use crane uplift with burden weightobserver in combination for uplift, crab and bridge drive with cooperation of their parameters: burden weight, rope length and crab and bridge position. Controllers are designed by state control method. We will use preferably a disturbance observerwhich will identify burden weight as a disturbance. The system will be working in both modes at empty hook as well asat maximum load: burden uplifting and dropping down.

  13. Phylogenomics reveal a robust fungal tree of life

    NARCIS (Netherlands)

    Kuramae, Eiko E.; Robert, Vincent; Snel, Berend; Weiß, Michael; Boekhout, Teun

    2006-01-01

    Our understanding of the tree of life (TOL) is still fragmentary. Until recently, molecular phylogeneticists have built trees based on ribosomal RNA sequences and selected protein sequences, which, however, usually suffered from lack of support for the deeper branches and inconsistencies probably

  14. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

    Directory of Open Access Journals (Sweden)

    Morgan Kristen

    2011-01-01

    characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge.

  15. Robust efficient video fingerprinting

    Science.gov (United States)

    Puri, Manika; Lubin, Jeffrey

    2009-02-01

    We have developed a video fingerprinting system with robustness and efficiency as the primary and secondary design criteria. In extensive testing, the system has shown robustness to cropping, letter-boxing, sub-titling, blur, drastic compression, frame rate changes, size changes and color changes, as well as to the geometric distortions often associated with camcorder capture in cinema settings. Efficiency is afforded by a novel two-stage detection process in which a fast matching process first computes a number of likely candidates, which are then passed to a second slower process that computes the overall best match with minimal false alarm probability. One key component of the algorithm is a maximally stable volume computation - a three-dimensional generalization of maximally stable extremal regions - that provides a content-centric coordinate system for subsequent hash function computation, independent of any affine transformation or extensive cropping. Other key features include an efficient bin-based polling strategy for initial candidate selection, and a final SIFT feature-based computation for final verification. We describe the algorithm and its performance, and then discuss additional modifications that can provide further improvement to efficiency and accuracy.

  16. Incentive-Compatible Robust Line Planning

    Science.gov (United States)

    Bessas, Apostolos; Kontogiannis, Spyros; Zaroliagis, Christos

    The problem of robust line planning requests for a set of origin-destination paths (lines) along with their frequencies in an underlying railway network infrastructure, which are robust to fluctuations of real-time parameters of the solution. In this work, we investigate a variant of robust line planning stemming from recent regulations in the railway sector that introduce competition and free railway markets, and set up a new application scenario: there is a (potentially large) number of line operators that have their lines fixed and operate as competing entities issuing frequency requests, while the management of the infrastructure itself remains the responsibility of a single entity, the network operator. The line operators are typically unwilling to reveal their true incentives, while the network operator strives to ensure a fair (or socially optimal) usage of the infrastructure, e.g., by maximizing the (unknown to him) aggregate incentives of the line operators.

  17. Robust automated knowledge capture.

    Energy Technology Data Exchange (ETDEWEB)

    Stevens-Adams, Susan Marie; Abbott, Robert G.; Forsythe, James Chris; Trumbo, Michael Christopher Stefan; Haass, Michael Joseph; Hendrickson, Stacey M. Langfitt

    2011-10-01

    This report summarizes research conducted through the Sandia National Laboratories Robust Automated Knowledge Capture Laboratory Directed Research and Development project. The objective of this project was to advance scientific understanding of the influence of individual cognitive attributes on decision making. The project has developed a quantitative model known as RumRunner that has proven effective in predicting the propensity of an individual to shift strategies on the basis of task and experience related parameters. Three separate studies are described which have validated the basic RumRunner model. This work provides a basis for better understanding human decision making in high consequent national security applications, and in particular, the individual characteristics that underlie adaptive thinking.

  18. Passion, Robustness and Perseverance

    DEFF Research Database (Denmark)

    Lim, Miguel Antonio; Lund, Rebecca

    2016-01-01

    Evaluation and merit in the measured university are increasingly based on taken-for-granted assumptions about the “ideal academic”. We suggest that the scholar now needs to show that she is passionate about her work and that she gains pleasure from pursuing her craft. We suggest that passion...... and pleasure achieve an exalted status as something compulsory. The scholar ought to feel passionate about her work and signal that she takes pleasure also in the difficult moments. Passion has become a signal of robustness and perseverance in a job market characterised by funding shortages, increased pressure...... way to demonstrate their potential and, crucially, their passion for their work. Drawing on the literature on technologies of governance, we reflect on what is captured and what is left out by these two evaluation instruments. We suggest that bibliometric analysis at the individual level is deeply...

  19. Robust Optical Flow Estimation

    Directory of Open Access Journals (Sweden)

    Javier Sánchez Pérez

    2013-10-01

    Full Text Available n this work, we describe an implementation of the variational method proposed by Brox etal. in 2004, which yields accurate optical flows with low running times. It has several benefitswith respect to the method of Horn and Schunck: it is more robust to the presence of outliers,produces piecewise-smooth flow fields and can cope with constant brightness changes. Thismethod relies on the brightness and gradient constancy assumptions, using the information ofthe image intensities and the image gradients to find correspondences. It also generalizes theuse of continuous L1 functionals, which help mitigate the effect of outliers and create a TotalVariation (TV regularization. Additionally, it introduces a simple temporal regularizationscheme that enforces a continuous temporal coherence of the flow fields.

  20. Robust Multimodal Dictionary Learning

    Science.gov (United States)

    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

  1. Robust snapshot interferometric spectropolarimetry.

    Science.gov (United States)

    Kim, Daesuk; Seo, Yoonho; Yoon, Yonghee; Dembele, Vamara; Yoon, Jae Woong; Lee, Kyu Jin; Magnusson, Robert

    2016-05-15

    This Letter describes a Stokes vector measurement method based on a snapshot interferometric common-path spectropolarimeter. The proposed scheme, which employs an interferometric polarization-modulation module, can extract the spectral polarimetric parameters Ψ(k) and Δ(k) of a transmissive anisotropic object by which an accurate Stokes vector can be calculated in the spectral domain. It is inherently strongly robust to the object 3D pose variation, since it is designed distinctly so that the measured object can be placed outside of the interferometric module. Experiments are conducted to verify the feasibility of the proposed system. The proposed snapshot scheme enables us to extract the spectral Stokes vector of a transmissive anisotropic object within tens of msec with high accuracy.

  2. International Conference on Robust Statistics

    CERN Document Server

    Filzmoser, Peter; Gather, Ursula; Rousseeuw, Peter

    2003-01-01

    Aspects of Robust Statistics are important in many areas. Based on the International Conference on Robust Statistics 2001 (ICORS 2001) in Vorau, Austria, this volume discusses future directions of the discipline, bringing together leading scientists, experienced researchers and practitioners, as well as younger researchers. The papers cover a multitude of different aspects of Robust Statistics. For instance, the fundamental problem of data summary (weights of evidence) is considered and its robustness properties are studied. Further theoretical subjects include e.g.: robust methods for skewness, time series, longitudinal data, multivariate methods, and tests. Some papers deal with computational aspects and algorithms. Finally, the aspects of application and programming tools complete the volume.

  3. Robustness Analyses of Timber Structures

    DEFF Research Database (Denmark)

    Kirkegaard, Poul Henning; Sørensen, John Dalsgaard; Hald, Frederik

    2013-01-01

    The robustness of structural systems has obtained a renewed interest arising from a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure. In order to minimise the likelihood of such disproportionate structural failures, many mo...... with respect to robustness of timber structures and will discuss the consequences of such robustness issues related to the future development of timber structures.......The robustness of structural systems has obtained a renewed interest arising from a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure. In order to minimise the likelihood of such disproportionate structural failures, many...... modern building codes consider the need for the robustness of structures and provide strategies and methods to obtain robustness. Therefore, a structural engineer may take necessary steps to design robust structures that are insensitive to accidental circumstances. The present paper summaries issues...

  4. Mice, men and MHC supertypes

    DEFF Research Database (Denmark)

    Lundegaard, Claus

    2010-01-01

    vaccine formulations. Toxoplasma gondii, an intracellular parasite, causes severe neurologic and ocular disease in congenitally infected and immunocompromised individuals. No protective vaccine exists against human toxoplasmosis. However, studies with mice have revealed immunodominant cytotoxic T...

  5. Dynamics robustness of cascading systems.

    Directory of Open Access Journals (Sweden)

    Jonathan T Young

    2017-03-01

    Full Text Available A most important property of biochemical systems is robustness. Static robustness, e.g., homeostasis, is the insensitivity of a state against perturbations, whereas dynamics robustness, e.g., homeorhesis, is the insensitivity of a dynamic process. In contrast to the extensively studied static robustness, dynamics robustness, i.e., how a system creates an invariant temporal profile against perturbations, is little explored despite transient dynamics being crucial for cellular fates and are reported to be robust experimentally. For example, the duration of a stimulus elicits different phenotypic responses, and signaling networks process and encode temporal information. Hence, robustness in time courses will be necessary for functional biochemical networks. Based on dynamical systems theory, we uncovered a general mechanism to achieve dynamics robustness. Using a three-stage linear signaling cascade as an example, we found that the temporal profiles and response duration post-stimulus is robust to perturbations against certain parameters. Then analyzing the linearized model, we elucidated the criteria of when signaling cascades will display dynamics robustness. We found that changes in the upstream modules are masked in the cascade, and that the response duration is mainly controlled by the rate-limiting module and organization of the cascade's kinetics. Specifically, we found two necessary conditions for dynamics robustness in signaling cascades: 1 Constraint on the rate-limiting process: The phosphatase activity in the perturbed module is not the slowest. 2 Constraints on the initial conditions: The kinase activity needs to be fast enough such that each module is saturated even with fast phosphatase activity and upstream changes are attenuated. We discussed the relevance of such robustness to several biological examples and the validity of the above conditions therein. Given the applicability of dynamics robustness to a variety of systems, it

  6. mPeriod2 Brdm1 and other single Period mutant mice have normal food anticipatory activity.

    Science.gov (United States)

    Pendergast, Julie S; Wendroth, Robert H; Stenner, Rio C; Keil, Charles D; Yamazaki, Shin

    2017-11-14

    Animals anticipate the timing of food availability via the food-entrainable oscillator (FEO). The anatomical location and timekeeping mechanism of the FEO are unknown. Several studies showed the circadian gene, Period 2, is critical for FEO timekeeping. However, other studies concluded that canonical circadian genes are not essential for FEO timekeeping. In this study, we re-examined the effects of the Per2 Brdm1 mutation on food entrainment using methods that have revealed robust food anticipatory activity in other mutant lines. We examined food anticipatory activity, which is the output of the FEO, in single Period mutant mice. Single Per1, Per2, and Per3 mutant mice had robust food anticipatory activity during restricted feeding. In addition, we found that two different lines of Per2 mutant mice (ldc and Brdm1) anticipated restricted food availability. To determine if FEO timekeeping persisted in the absence of the food cue, we assessed activity during fasting. Food anticipatory (wheel-running) activity in all Period mutant mice was also robust during food deprivation. Together, our studies demonstrate that the Period genes are not necessary for the expression of food anticipatory activity.

  7. Robust continuous clustering.

    Science.gov (United States)

    Shah, Sohil Atul; Koltun, Vladlen

    2017-09-12

    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.

  8. Robust Trust in Expert Testimony

    Directory of Open Access Journals (Sweden)

    Christian Dahlman

    2015-05-01

    Full Text Available The standard of proof in criminal trials should require that the evidence presented by the prosecution is robust. This requirement of robustness says that it must be unlikely that additional information would change the probability that the defendant is guilty. Robustness is difficult for a judge to estimate, as it requires the judge to assess the possible effect of information that the he or she does not have. This article is concerned with expert witnesses and proposes a method for reviewing the robustness of expert testimony. According to the proposed method, the robustness of expert testimony is estimated with regard to competence, motivation, external strength, internal strength and relevance. The danger of trusting non-robust expert testimony is illustrated with an analysis of the Thomas Quick Case, a Swedish legal scandal where a patient at a mental institution was wrongfully convicted for eight murders.

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

    Directory of Open Access Journals (Sweden)

    Charo Israel F

    2004-09-01

    Full Text Available Abstract 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.

  10. Robust and distributed hypothesis testing

    CERN Document Server

    Gül, Gökhan

    2017-01-01

    This book generalizes and extends the available theory in robust and decentralized hypothesis testing. In particular, it presents a robust test for modeling errors which is independent from the assumptions that a sufficiently large number of samples is available, and that the distance is the KL-divergence. Here, the distance can be chosen from a much general model, which includes the KL-divergence as a very special case. This is then extended by various means. A minimax robust test that is robust against both outliers as well as modeling errors is presented. Minimax robustness properties of the given tests are also explicitly proven for fixed sample size and sequential probability ratio tests. The theory of robust detection is extended to robust estimation and the theory of robust distributed detection is extended to classes of distributions, which are not necessarily stochastically bounded. It is shown that the quantization functions for the decision rules can also be chosen as non-monotone. Finally, the boo...

  11. Robustness of IPTV business models

    NARCIS (Netherlands)

    Bouwman, H.; Zhengjia, M.; Duin, P. van der; Limonard, S.

    2008-01-01

    The final stage in the STOF method is an evaluation of the robustness of the design, for which the method provides some guidelines. For many innovative services, the future holds numerous uncertainties, which makes evaluating the robustness of a business model a difficult task. In this chapter, we

  12. Robustness Evaluation of Timber Structures

    DEFF Research Database (Denmark)

    Kirkegaard, Poul Henning; Sørensen, John Dalsgaard

    2009-01-01

    Robustness of structural systems has obtained a renewed interest due to a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure.......Robustness of structural systems has obtained a renewed interest due to a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure....

  13. An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

    Science.gov (United States)

    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.

  14. Robust statistical methods with R

    CERN Document Server

    Jureckova, Jana

    2005-01-01

    Robust statistical methods were developed to supplement the classical procedures when the data violate classical assumptions. They are ideally suited to applied research across a broad spectrum of study, yet most books on the subject are narrowly focused, overly theoretical, or simply outdated. Robust Statistical Methods with R provides a systematic treatment of robust procedures with an emphasis on practical application.The authors work from underlying mathematical tools to implementation, paying special attention to the computational aspects. They cover the whole range of robust methods, including differentiable statistical functions, distance of measures, influence functions, and asymptotic distributions, in a rigorous yet approachable manner. Highlighting hands-on problem solving, many examples and computational algorithms using the R software supplement the discussion. The book examines the characteristics of robustness, estimators of real parameter, large sample properties, and goodness-of-fit tests. It...

  15. Robust loss functions for boosting.

    Science.gov (United States)

    Kanamori, Takafumi; Takenouchi, Takashi; Eguchi, Shinto; Murata, Noboru

    2007-08-01

    Boosting is known as a gradient descent algorithm over loss functions. It is often pointed out that the typical boosting algorithm, Adaboost, is highly affected by outliers. In this letter, loss functions for robust boosting are studied. Based on the concept of robust statistics, we propose a transformation of loss functions that makes boosting algorithms robust against extreme outliers. Next, the truncation of loss functions is applied to contamination models that describe the occurrence of mislabels near decision boundaries. Numerical experiments illustrate that the proposed loss functions derived from the contamination models are useful for handling highly noisy data in comparison with other loss functions.

  16. Theoretical Framework for Robustness Evaluation

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard

    2011-01-01

    This paper presents a theoretical framework for evaluation of robustness of structural systems, incl. bridges and buildings. Typically modern structural design codes require that ‘the consequence of damages to structures should not be disproportional to the causes of the damages’. However, although...... the importance of robustness for structural design is widely recognized the code requirements are not specified in detail, which makes the practical use difficult. This paper describes a theoretical and risk based framework to form the basis for quantification of robustness and for pre-normative guidelines...

  17. Robustness of airline route networks

    Science.gov (United States)

    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.

  18. Robust Portfolio Optimization Using Pseudodistances.

    Science.gov (United States)

    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.

  19. CAST/EiJ and C57BL/6J Mice Differ in Their Oral and Postoral Attraction to Glucose and Fructose.

    Science.gov (United States)

    Sclafani, Anthony; Vural, Austin S; Ackroff, Karen

    2017-03-01

    A recent study indicated that CAST/EiJ and C57BL/6J mice differ in their taste preferences for maltodextrin but display similar sucrose preferences. The present study revealed strain differences in preferences for the constituent sugars of sucrose. Whereas B6 mice preferred 8% glucose to 8% fructose in 2-day tests, the CAST mice preferred fructose to glucose. These preferences emerged with repeated testing which suggested post-oral influences. In a second experiment, 2-day choice tests were conducted with the sugars versus a sucralose + saccharin (SS) mixture which is highly preferred in brief access tests. B6 mice strongly preferred glucose but not fructose to the non-nutritive SS whereas CAST mice preferred SS to both glucose and fructose even when food restricted. This implied that CAST mice are insensitive to the postoral appetite stimulating actions of the 2 sugars. A third experiment revealed, however, that intragastric glucose and fructose infusions conditioned significant but mild flavor preferences in CAST mice, whereas in B6 mice glucose conditioned a robust preference but fructose was ineffective. Thus, unlike other mouse strains and rats, glucose is not more reinforcing than fructose in CAST mice. Their oral preference for fructose over glucose may be related to a subsensitive maltodextrin receptor or glucose-specific receptor which is stimulated by glucose but not fructose. The failure of CAST mice to prefer glucose to a non-nutritive sweetener distinguishes this strain from other mouse strains and rats. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Robust methods for data reduction

    CERN Document Server

    Farcomeni, Alessio

    2015-01-01

    Robust Methods for Data Reduction gives a non-technical overview of robust data reduction techniques, encouraging the use of these important and useful methods in practical applications. The main areas covered include principal components analysis, sparse principal component analysis, canonical correlation analysis, factor analysis, clustering, double clustering, and discriminant analysis.The first part of the book illustrates how dimension reduction techniques synthesize available information by reducing the dimensionality of the data. The second part focuses on cluster and discriminant analy

  1. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome.

    Science.gov (United States)

    Moore, Aleisha M; Prescott, Mel; Marshall, Christopher J; Yip, Siew Hoong; Campbell, Rebecca E

    2015-01-13

    Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor-expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral-mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome.

  2. In vivo mutational analysis of the N-terminal region of HIV-1 Nef reveals critical motifs for the development of an AIDS-like disease in CD4C/HIV transgenic mice

    International Nuclear Information System (INIS)

    Hanna, Zaher; Priceputu, Elena; Kay, Denis G.; Poudrier, Johanne; Chrobak, Pavel; Jolicoeur, Paul

    2004-01-01

    HIV-1 Nef is a critical determinant of pathogenicity in humans and transgenic (Tg) mice. To gain a better understanding of the molecular mechanisms by which Nef induces an AIDS-like disease in Tg mice, a mutational analysis of the N-terminal domain, involved in anchoring Nef to the plasma membrane, was carried out. The pathogenic effects of these Nef mutant alleles were evaluated in Tg mice by FACS analysis and by histopathological assessment. Mutation of the myristoylation site (G2A) completely abrogated the development of the AIDS-like organ disease in Tg mice, although partial downregulation of the CD4 cell surface protein and depletion of peripheral CD4 + T-cells, but not of CD4 + CD8 + thymocytes, still occurred. Despite that, the peripheral CD4 + T cells expressing Nef G2A show normal spontaneous proliferation in vivo or after stimulation in vitro, including in an allogenic mixed leukocyte reaction (MLR). Three other internal deletion mutants of Nef, spanning amino acids 8-17 (Nef Δ8-17 ), 25-35 (Nef Δ25-35 ), and 57-66 (Nef Δ57-66 ), were also studied. Nef Δ8-17 retained full pathogenic potential, although Nef Δ25-35 and Nef Δ57-66 Tg mice were free of organ disease. However, Nef Δ25-35 Tg mice exhibited disorganization of thymic architecture and a partial depletion of peripheral CD4 + T cells. These data indicate that myristoylation and other regions at the N-terminus of Nef (aa 25-35 and 57-66) are involved in mediating severe T-cell phenotypes and organ disease, although residues 8-17 are dispensable for these Nef functions. In addition, these results indicate that at least some of the CD4 + T-cell phenotypes can develop independently of the other AIDS-like organ phenotypes. This apparent segregation of different Nef-mediated phenotypes suggests distinct mechanisms of Nef action in different populations of target cells, and may be relevant to human AIDS

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

    Science.gov (United States)

    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.

  4. Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice.

    Science.gov (United States)

    Lu, Yong Ping; Tsuprykov, Oleg; Vignon-Zellweger, Nicolas; Heiden, Susi; Hocher, Berthold

    2016-01-01

    ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference: -2.57 mmHg, 95% CI: -4.98∼ -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95% CI: -10.76∼ -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure. © 2016 The Author(s) Published by S. Karger AG, Basel.

  5. Advances in robust fractional control

    CERN Document Server

    Padula, Fabrizio

    2015-01-01

    This monograph presents design methodologies for (robust) fractional control systems. It shows the reader how to take advantage of the superior flexibility of fractional control systems compared with integer-order systems in achieving more challenging control requirements. There is a high degree of current interest in fractional systems and fractional control arising from both academia and industry and readers from both milieux are catered to in the text. Different design approaches having in common a trade-off between robustness and performance of the control system are considered explicitly. The text generalizes methodologies, techniques and theoretical results that have been successfully applied in classical (integer) control to the fractional case. The first part of Advances in Robust Fractional Control is the more industrially-oriented. It focuses on the design of fractional controllers for integer processes. In particular, it considers fractional-order proportional-integral-derivative controllers, becau...

  6. Robustness of digital artist authentication

    DEFF Research Database (Denmark)

    Jacobsen, Robert; Nielsen, Morten

    In many cases it is possible to determine the authenticity of a painting from digital reproductions of the paintings; this has been demonstrated for a variety of artists and with different approaches. Common to all these methods in digital artist authentication is that the potential of the method...... is in focus, while the robustness has not been considered, i.e. the degree to which the data collection process influences the decision of the method. However, in order for an authentication method to be successful in practice, it needs to be robust to plausible error sources from the data collection....... In this paper we investigate the robustness of the newly proposed authenticity method introduced by the authors based on second generation multiresolution analysis. This is done by modelling a number of realistic factors that can occur in the data collection....

  7. Attractive ellipsoids in robust control

    CERN Document Server

    Poznyak, Alexander; Azhmyakov, Vadim

    2014-01-01

    This monograph introduces a newly developed robust-control design technique for a wide class of continuous-time dynamical systems called the “attractive ellipsoid method.” Along with a coherent introduction to the proposed control design and related topics, the monograph studies nonlinear affine control systems in the presence of uncertainty and presents a constructive and easily implementable control strategy that guarantees certain stability properties. The authors discuss linear-style feedback control synthesis in the context of the above-mentioned systems. The development and physical implementation of high-performance robust-feedback controllers that work in the absence of complete information is addressed, with numerous examples to illustrate how to apply the attractive ellipsoid method to mechanical and electromechanical systems. While theorems are proved systematically, the emphasis is on understanding and applying the theory to real-world situations. Attractive Ellipsoids in Robust Control will a...

  8. Robustness of holonomic quantum gates

    International Nuclear Information System (INIS)

    Solinas, P.; Zanardi, P.; Zanghi, N.

    2005-01-01

    Full text: If the driving field fluctuates during the quantum evolution this produces errors in the applied operator. The holonomic (and geometrical) quantum gates are believed to be robust against some kind of noise. Because of the geometrical dependence of the holonomic operators can be robust against this kind of noise; in fact if the fluctuations are fast enough they cancel out leaving the final operator unchanged. I present the numerical studies of holonomic quantum gates subject to this parametric noise, the fidelity of the noise and ideal evolution is calculated for different noise correlation times. The holonomic quantum gates seem robust not only for fast fluctuating fields but also for slow fluctuating fields. These results can be explained as due to the geometrical feature of the holonomic operator: for fast fluctuating fields the fluctuations are canceled out, for slow fluctuating fields the fluctuations do not perturb the loop in the parameter space. (author)

  9. Robust estimation and hypothesis testing

    CERN Document Server

    Tiku, Moti L

    2004-01-01

    In statistical theory and practice, a certain distribution is usually assumed and then optimal solutions sought. Since deviations from an assumed distribution are very common, one cannot feel comfortable with assuming a particular distribution and believing it to be exactly correct. That brings the robustness issue in focus. In this book, we have given statistical procedures which are robust to plausible deviations from an assumed mode. The method of modified maximum likelihood estimation is used in formulating these procedures. The modified maximum likelihood estimators are explicit functions of sample observations and are easy to compute. They are asymptotically fully efficient and are as efficient as the maximum likelihood estimators for small sample sizes. The maximum likelihood estimators have computational problems and are, therefore, elusive. A broad range of topics are covered in this book. Solutions are given which are easy to implement and are efficient. The solutions are also robust to data anomali...

  10. Robustness in Railway Operations (RobustRailS)

    DEFF Research Database (Denmark)

    Jensen, Jens Parbo; Nielsen, Otto Anker

    This study considers the problem of enhancing railway timetable robustness without adding slack time, hence increasing the travel time. The approach integrates a transit assignment model to assess how passengers adapt their behaviour whenever operations are changed. First, the approach considers...

  11. A Robust Design Applicability Model

    DEFF Research Database (Denmark)

    Ebro, Martin; Lars, Krogstie; Howard, Thomas J.

    2015-01-01

    to be applicable in organisations assigning a high importance to one or more factors that are known to be impacted by RD, while also experiencing a high level of occurrence of this factor. The RDAM supplements existing maturity models and metrics to provide a comprehensive set of data to support management......This paper introduces a model for assessing the applicability of Robust Design (RD) in a project or organisation. The intention of the Robust Design Applicability Model (RDAM) is to provide support for decisions by engineering management considering the relevant level of RD activities...

  12. Ins-Robust Primitive Words

    OpenAIRE

    Srivastava, Amit Kumar; Kapoor, Kalpesh

    2017-01-01

    Let Q be the set of primitive words over a finite alphabet with at least two symbols. We characterize a class of primitive words, Q_I, referred to as ins-robust primitive words, which remain primitive on insertion of any letter from the alphabet and present some properties that characterizes words in the set Q_I. It is shown that the language Q_I is dense. We prove that the language of primitive words that are not ins-robust is not context-free. We also present a linear time algorithm to reco...

  13. Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M

    Directory of Open Access Journals (Sweden)

    Daniel E. Rothschild

    2017-02-01

    Full Text Available Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m−/− mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m−/− animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m−/− mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT, increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m−/− mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.

  14. Essays on robust asset pricing

    NARCIS (Netherlands)

    Horváth, Ferenc

    2017-01-01

    The central concept of this doctoral dissertation is robustness. I analyze how model and parameter uncertainty affect financial decisions of investors and fund managers, and what their equilibrium consequences are. Chapter 1 gives an overview of the most important concepts and methodologies used in

  15. Robust visual hashing via ICA

    International Nuclear Information System (INIS)

    Fournel, Thierry; Coltuc, Daniela

    2010-01-01

    Designed to maximize information transmission in the presence of noise, independent component analysis (ICA) could appear in certain circumstances as a statistics-based tool for robust visual hashing. Several ICA-based scenarios can attempt to reach this goal. A first one is here considered.

  16. Robustness of raw quantum tomography

    Science.gov (United States)

    Asorey, M.; Facchi, P.; Florio, G.; Man'ko, V. I.; Marmo, G.; Pascazio, S.; Sudarshan, E. C. G.

    2011-01-01

    We scrutinize the effects of non-ideal data acquisition on the tomograms of quantum states. The presence of a weight function, schematizing the effects of a finite window or equivalently noise, only affects the state reconstruction procedure by a normalization constant. The results are extended to a discrete mesh and show that quantum tomography is robust under incomplete and approximate knowledge of tomograms.

  17. Robustness of raw quantum tomography

    Energy Technology Data Exchange (ETDEWEB)

    Asorey, M. [Departamento de Fisica Teorica, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza (Spain); Facchi, P. [Dipartimento di Matematica, Universita di Bari, I-70125 Bari (Italy); INFN, Sezione di Bari, I-70126 Bari (Italy); MECENAS, Universita Federico II di Napoli and Universita di Bari (Italy); Florio, G. [Dipartimento di Fisica, Universita di Bari, I-70126 Bari (Italy); INFN, Sezione di Bari, I-70126 Bari (Italy); MECENAS, Universita Federico II di Napoli and Universita di Bari (Italy); Man' ko, V.I., E-mail: manko@lebedev.r [P.N. Lebedev Physical Institute, Leninskii Prospect 53, Moscow 119991 (Russian Federation); Marmo, G. [Dipartimento di Scienze Fisiche, Universita di Napoli ' Federico II' , I-80126 Napoli (Italy); INFN, Sezione di Napoli, I-80126 Napoli (Italy); MECENAS, Universita Federico II di Napoli and Universita di Bari (Italy); Pascazio, S. [Dipartimento di Fisica, Universita di Bari, I-70126 Bari (Italy); INFN, Sezione di Bari, I-70126 Bari (Italy); MECENAS, Universita Federico II di Napoli and Universita di Bari (Italy); Sudarshan, E.C.G. [Department of Physics, University of Texas, Austin, TX 78712 (United States)

    2011-01-31

    We scrutinize the effects of non-ideal data acquisition on the tomograms of quantum states. The presence of a weight function, schematizing the effects of a finite window or equivalently noise, only affects the state reconstruction procedure by a normalization constant. The results are extended to a discrete mesh and show that quantum tomography is robust under incomplete and approximate knowledge of tomograms.

  18. Aspects of robust linear regression

    NARCIS (Netherlands)

    Davies, P.L.

    1993-01-01

    Section 1 of the paper contains a general discussion of robustness. In Section 2 the influence function of the Hampel-Rousseeuw least median of squares estimator is derived. Linearly invariant weak metrics are constructed in Section 3. It is shown in Section 4 that $S$-estimators satisfy an exact

  19. Manipulation Robustness of Collaborative Filtering

    OpenAIRE

    Benjamin Van Roy; Xiang Yan

    2010-01-01

    A collaborative filtering system recommends to users products that similar users like. Collaborative filtering systems influence purchase decisions and hence have become targets of manipulation by unscrupulous vendors. We demonstrate that nearest neighbors algorithms, which are widely used in commercial systems, are highly susceptible to manipulation and introduce new collaborative filtering algorithms that are relatively robust.

  20. Robustness Regions for Dichotomous Decisions.

    Science.gov (United States)

    Vijn, Pieter; Molenaar, Ivo W.

    1981-01-01

    In the case of dichotomous decisions, the total set of all assumptions/specifications for which the decision would have been the same is the robustness region. Inspection of this (data-dependent) region is a form of sensitivity analysis which may lead to improved decision making. (Author/BW)

  1. Theoretical Framework for Robustness Evaluation

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard

    2011-01-01

    This paper presents a theoretical framework for evaluation of robustness of structural systems, incl. bridges and buildings. Typically modern structural design codes require that ‘the consequence of damages to structures should not be disproportional to the causes of the damages’. However, althou...

  2. Robust control design with MATLAB

    CERN Document Server

    Gu, Da-Wei; Konstantinov, Mihail M

    2013-01-01

    Robust Control Design with MATLAB® (second edition) helps the student to learn how to use well-developed advanced robust control design methods in practical cases. To this end, several realistic control design examples from teaching-laboratory experiments, such as a two-wheeled, self-balancing robot, to complex systems like a flexible-link manipulator are given detailed presentation. All of these exercises are conducted using MATLAB® Robust Control Toolbox 3, Control System Toolbox and Simulink®. By sharing their experiences in industrial cases with minimum recourse to complicated theories and formulae, the authors convey essential ideas and useful insights into robust industrial control systems design using major H-infinity optimization and related methods allowing readers quickly to move on with their own challenges. The hands-on tutorial style of this text rests on an abundance of examples and features for the second edition: ·        rewritten and simplified presentation of theoretical and meth...

  3. Robust Portfolio Optimization Using Pseudodistances

    Science.gov (United States)

    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

  4. Facial Symmetry in Robust Anthropometrics

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2012-01-01

    Roč. 57, č. 3 (2012), s. 691-698 ISSN 0022-1198 R&D Projects: GA MŠk(CZ) 1M06014 Institutional research plan: CEZ:AV0Z10300504 Keywords : forensic science * anthropology * robust image analysis * correlation analysis * multivariate data * classification Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 1.244, year: 2012

  5. Sparse and Robust Factor Modelling

    NARCIS (Netherlands)

    C. Croux (Christophe); P. Exterkate (Peter)

    2011-01-01

    textabstractFactor construction methods are widely used to summarize a large panel of variables by means of a relatively small number of representative factors. We propose a novel factor construction procedure that enjoys the properties of robustness to outliers and of sparsity; that is, having

  6. Robust distributed cognitive relay beamforming

    KAUST Repository

    Pandarakkottilil, Ubaidulla; Aissa, Sonia

    2012-01-01

    design takes into account a parameter of the error in the channel state information (CSI) to render the performance of the beamformer robust in the presence of imperfect CSI. Though the original problem is non-convex, we show that the proposed design can

  7. Approximability of Robust Network Design

    NARCIS (Netherlands)

    Olver, N.K.; Shepherd, F.B.

    2014-01-01

    We consider robust (undirected) network design (RND) problems where the set of feasible demands may be given by an arbitrary convex body. This model, introduced by Ben-Ameur and Kerivin [Ben-Ameur W, Kerivin H (2003) New economical virtual private networks. Comm. ACM 46(6):69-73], generalizes the

  8. Aldosterone Inhibits the Fetal Program and Increases Hypertrophy in the Heart of Hypertensive Mice

    Science.gov (United States)

    Azibani, Feriel; Devaux, Yvan; Coutance, Guillaume; Schlossarek, Saskia; Polidano, Evelyne; Fazal, Loubina; Merval, Regine; Carrier, Lucie; Solal, Alain Cohen; Chatziantoniou, Christos; Launay, Jean-Marie; Samuel, Jane-Lise; Delcayre, Claude

    2012-01-01

    Background Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of “fetal” gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. Methodology/Principal Findings RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (−75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. Conclusions/Significance Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of

  9. Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice.

    Directory of Open Access Journals (Sweden)

    Feriel Azibani

    Full Text Available BACKGROUND: Arterial hypertension (AH induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren with cardiac hyperaldosteronism (AS mice and systemic hypertension (Ren. AS-Ren mice had increased (x2 angiotensin II in plasma and increased (x2 aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70% versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41% in AS-Ren mice (P<0.05 vs Ren. The increase of ANP (x 2.5; P<0.01 mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001 in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05, an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. CONCLUSIONS/SIGNIFICANCE: Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction

  10. Mathematics revealed

    CERN Document Server

    Berman, Elizabeth

    1979-01-01

    Mathematics Revealed focuses on the principles, processes, operations, and exercises in mathematics.The book first offers information on whole numbers, fractions, and decimals and percents. Discussions focus on measuring length, percent, decimals, numbers as products, addition and subtraction of fractions, mixed numbers and ratios, division of fractions, addition, subtraction, multiplication, and division. The text then examines positive and negative numbers and powers and computation. Topics include division and averages, multiplication, ratios, and measurements, scientific notation and estim

  11. Robust Reliability or reliable robustness? - Integrated consideration of robustness and reliability aspects

    DEFF Research Database (Denmark)

    Kemmler, S.; Eifler, Tobias; Bertsche, B.

    2015-01-01

    products are and vice versa. For a comprehensive understanding and to use existing synergies between both domains, this paper discusses the basic principles of Reliability- and Robust Design theory. The development of a comprehensive model will enable an integrated consideration of both domains...

  12. Robust Watermarking of Video Streams

    Directory of Open Access Journals (Sweden)

    T. Polyák

    2006-01-01

    Full Text Available In the past few years there has been an explosion in the use of digital video data. Many people have personal computers at home, and with the help of the Internet users can easily share video files on their computer. This makes possible the unauthorized use of digital media, and without adequate protection systems the authors and distributors have no means to prevent it.Digital watermarking techniques can help these systems to be more effective by embedding secret data right into the video stream. This makes minor changes in the frames of the video, but these changes are almost imperceptible to the human visual system. The embedded information can involve copyright data, access control etc. A robust watermark is resistant to various distortions of the video, so it cannot be removed without affecting the quality of the host medium. In this paper I propose a video watermarking scheme that fulfills the requirements of a robust watermark. 

  13. Robust Decentralized Formation Flight Control

    Directory of Open Access Journals (Sweden)

    Zhao Weihua

    2011-01-01

    Full Text Available Motivated by the idea of multiplexed model predictive control (MMPC, this paper introduces a new framework for unmanned aerial vehicles (UAVs formation flight and coordination. Formulated using MMPC approach, the whole centralized formation flight system is considered as a linear periodic system with control inputs of each UAV subsystem as its periodic inputs. Divided into decentralized subsystems, the whole formation flight system is guaranteed stable if proper terminal cost and terminal constraints are added to each decentralized MPC formulation of the UAV subsystem. The decentralized robust MPC formulation for each UAV subsystem with bounded input disturbances and model uncertainties is also presented. Furthermore, an obstacle avoidance control scheme for any shape and size of obstacles, including the nonapriorily known ones, is integrated under the unified MPC framework. The results from simulations demonstrate that the proposed framework can successfully achieve robust collision-free formation flights.

  14. Robust tumor morphometry in multispectral fluorescence microscopy

    Science.gov (United States)

    Tabesh, Ali; Vengrenyuk, Yevgen; Teverovskiy, Mikhail; Khan, Faisal M.; Sapir, Marina; Powell, Douglas; Mesa-Tejada, Ricardo; Donovan, Michael J.; Fernandez, Gerardo

    2009-02-01

    Morphological and architectural characteristics of primary tissue compartments, such as epithelial nuclei (EN) and cytoplasm, provide important cues for cancer diagnosis, prognosis, and therapeutic response prediction. We propose two feature sets for the robust quantification of these characteristics in multiplex immunofluorescence (IF) microscopy images of prostate biopsy specimens. To enable feature extraction, EN and cytoplasm regions were first segmented from the IF images. Then, feature sets consisting of the characteristics of the minimum spanning tree (MST) connecting the EN and the fractal dimension (FD) of gland boundaries were obtained from the segmented compartments. We demonstrated the utility of the proposed features in prostate cancer recurrence prediction on a multi-institution cohort of 1027 patients. Univariate analysis revealed that both FD and one of the MST features were highly effective for predicting cancer recurrence (p <= 0.0001). In multivariate analysis, an MST feature was selected for a model incorporating clinical and image features. The model achieved a concordance index (CI) of 0.73 on the validation set, which was significantly higher than the CI of 0.69 for the standard multivariate model based solely on clinical features currently used in clinical practice (p < 0.0001). The contributions of this work are twofold. First, it is the first demonstration of the utility of the proposed features in morphometric analysis of IF images. Second, this is the largest scale study of the efficacy and robustness of the proposed features in prostate cancer prognosis.

  15. Inefficient but robust public leadership.

    OpenAIRE

    Matsumura, Toshihiro; Ogawa, Akira

    2014-01-01

    We investigate endogenous timing in a mixed duopoly in a differentiated product market. We find that private leadership is better than public leadership from a social welfare perspective if the private firm is domestic, regardless of the degree of product differentiation. Nevertheless, the public leadership equilibrium is risk-dominant, and it is thus robust if the degree of product differentiation is high. We also find that regardless of the degree of product differentiation, the public lead...

  16. Testing Heteroscedasticity in Robust Regression

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2011-01-01

    Roč. 1, č. 4 (2011), s. 25-28 ISSN 2045-3345 Grant - others:GA ČR(CZ) GA402/09/0557 Institutional research plan: CEZ:AV0Z10300504 Keywords : robust regression * heteroscedasticity * regression quantiles * diagnostics Subject RIV: BB - Applied Statistics , Operational Research http://www.researchjournals.co.uk/documents/Vol4/06%20Kalina.pdf

  17. Robust power system frequency control

    CERN Document Server

    Bevrani, Hassan

    2014-01-01

    This updated edition of the industry standard reference on power system frequency control provides practical, systematic and flexible algorithms for regulating load frequency, offering new solutions to the technical challenges introduced by the escalating role of distributed generation and renewable energy sources in smart electric grids. The author emphasizes the physical constraints and practical engineering issues related to frequency in a deregulated environment, while fostering a conceptual understanding of frequency regulation and robust control techniques. The resulting control strategi

  18. Multiparametric analysis of host response to murine cytomegalovirus in MHC class I-disparate mice reveals primacy of Dk-licensed Ly49G2+ NK cells in viral control.

    Science.gov (United States)

    Prince, Jessica; Lundgren, Alyssa; Stadnisky, Michael D; Nash, William T; Beeber, Amira; Turner, Stephen D; Brown, Michael G

    2013-11-01

    MHC class I D(k) and Ly49G2 (G2) inhibitory receptor-expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D(k), G2(+) NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G2, D(k) licenses G2(+) NK cells for effector activity. These data suggested that D(k)-licensed G2(+) NK cells might recognize and control MCMV infection. However, a role for licensed NK cells in viral immunity is uncertain. We combined classical genetics with flow cytometry to visualize the host response to MCMV. Immune cells collected from individuals of a diverse cohort of MA/My × C57L offspring segregating D(k) were examined before infection and postinfection, including Ly49(+) NK subsets, receptor expression features, and other phenotypic traits. To identify critical NK cell features, automated analysis of 110 traits was performed in R using the Pearson correlation, followed with a Bonferroni correction for multiple tests. Hierarchical clustering of trait associations and principal component analyses were used to discern shared immune response and genetic relationships. The results demonstrate that G2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G2(+) NK cell expansion following viral exposure occurred selectively in D(k) offspring; this response was more highly correlated with MCMV control than all other immune cell features. We infer that D(k)-licensed G2(+) NK cells efficiently detected missing-self MHC cues on viral targets, which elicited cellular expansion and target cell killing. Therefore, MHC polymorphism regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control.

  19. Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice.

    Science.gov (United States)

    Zhao, Yue; Liu, Min; Chan, Xue Ying; Tan, Sue Yee; Subramaniam, Sharrada; Fan, Yong; Loh, Eva; Chang, Kenneth Tou En; Tan, Thiam Chye; Chen, Qingfeng

    2017-11-02

    Many immune parameters show circadian rhythms during the 24-hour day in mammals. The most striking circadian oscillation is the number of circulating immune cells that display an opposite rhythm between humans and mice. The physiological roles and mechanisms of circadian variations in mouse leukocytes are well studied, whereas for humans they remain unclear because of the lack of a proper model. In this study, we found that consistent with their natural host species, mouse and human circulating leukocytes exhibited opposite circadian oscillations in humanized mice. This cyclic pattern of trafficking correlated well with the diurnal expression levels of C-X-C chemokine receptor 4, which were controlled by the intracellular hypoxia-inducible factor 1α/aryl hydrocarbon receptor nuclear translocator-like heterodimer. Furthermore, we also discovered that p38 mitogen-activated protein kinases/mitogen-activated 2 had opposite effects between mice and humans in generating intracellular reactive oxygen species, which subsequently regulated HIF-1α expression. In conclusion, we propose humanized mice as a robust model for human circadian studies and reveal insights on a novel molecular clock network in the human circadian rhythm. © 2017 by The American Society of Hematology.

  20. GH and IGF1: Roles in Energy Metabolism of Long-Living GH Mutant Mice

    OpenAIRE

    Brown-Borg, Holly M.; Bartke, Andrzej

    2012-01-01

    Of the multiple theories to explain exceptional longevity, the most robust of these has centered on the reduction of three anabolic protein hormones, growth hormone (GH), insulin-like growth factor, and insulin. GH mutant mice live 50% longer and exhibit significant differences in several aspects of energy metabolism as compared with wild-type mice. Mitochondrial metabolism is upregulated in the absence of GH, whereas in GH transgenic mice and dwarf mice treated with GH, multiple aspects of t...

  1. Robustness Analysis of Timber Truss Structure

    DEFF Research Database (Denmark)

    Rajčić, Vlatka; Čizmar, Dean; Kirkegaard, Poul Henning

    2010-01-01

    The present paper discusses robustness of structures in general and the robustness requirements given in the codes. Robustness of timber structures is also an issues as this is closely related to Working group 3 (Robustness of systems) of the COST E55 project. Finally, an example of a robustness...... evaluation of a widespan timber truss structure is presented. This structure was built few years ago near Zagreb and has a span of 45m. Reliability analysis of the main members and the system is conducted and based on this a robustness analysis is preformed....

  2. Soliton robustness in optical fibers

    International Nuclear Information System (INIS)

    Menyuk, C.R.

    1993-01-01

    Simulations and experiments indicate that solitons in optical fibers are robust in the presence of Hamiltonian deformations such as higher-order dispersion and birefringence but are destroyed in the presence of non-Hamiltonian deformations such as attenuation and the Raman effect. Two hypotheses are introduced that generalize these observations and give a recipe for when deformations will be Hamiltonian. Concepts from nonlinear dynamics are used to make these two hypotheses plausible. Soliton stabilization with frequency filtering is also briefly discussed from this point of view

  3. Robust and Sparse Factor Modelling

    DEFF Research Database (Denmark)

    Croux, Christophe; Exterkate, Peter

    Factor construction methods are widely used to summarize a large panel of variables by means of a relatively small number of representative factors. We propose a novel factor construction procedure that enjoys the properties of robustness to outliers and of sparsity; that is, having relatively few...... nonzero factor loadings. Compared to the traditional factor construction method, we find that this procedure leads to a favorable forecasting performance in the presence of outliers and to better interpretable factors. We investigate the performance of the method in a Monte Carlo experiment...

  4. Robustness Evaluation of Timber Structures

    DEFF Research Database (Denmark)

    Kirkegaard, Poul Henning; Sørensen, John Dalsgaard; čizmar, D.

    2010-01-01

    The present paper outlines results from working group 3 (WG3) in the EU COST Action E55 – ‘Modelling of the performance of timber structures’. The objectives of the project are related to the three main research activities: the identification and modelling of relevant load and environmental...... exposure scenarios, the improvement of knowledge concerning the behaviour of timber structural elements and the development of a generic framework for the assessment of the life-cycle vulnerability and robustness of timber structures....

  5. Sustainable Resilient, Robust & Resplendent Enterprises

    DEFF Research Database (Denmark)

    Edgeman, Rick

    to their impact. Resplendent enterprises are introduced with resplendence referring not to some sort of public or private façade, but instead refers to organizations marked by dual brilliance and nobility of strategy, governance and comportment that yields superior and sustainable triple bottom line performance....... Herein resilience, robustness, and resplendence (R3) are integrated with sustainable enterprise excellence (Edgeman and Eskildsen, 2013) or SEE and social-ecological innovation (Eskildsen and Edgeman, 2012) to aid progress of a firm toward producing continuously relevant performance that proceed from...

  6. Revealing Rembrandt

    Directory of Open Access Journals (Sweden)

    Andrew J Parker

    2014-04-01

    Full Text Available The power and significance of artwork in shaping human cognition is self-evident. The starting point for our empirical investigations is the view that the task of neuroscience is to integrate itself with other forms of knowledge, rather than to seek to supplant them. In our recent work, we examined a particular aspect of the appreciation of artwork using present-day functional magnetic resonance imaging (fMRI. Our results emphasised the continuity between viewing artwork and other human cognitive activities. We also showed that appreciation of a particular aspect of artwork, namely authenticity, depends upon the co-ordinated activity between the brain regions involved in multiple decision making and those responsible for processing visual information. The findings about brain function probably have no specific consequences for understanding how people respond to the art of Rembrandt in comparison with their response to other artworks. However, the use of images of Rembrandt’s portraits, his most intimate and personal works, clearly had a significant impact upon our viewers, even though they have been spatially confined to the interior of an MRI scanner at the time of viewing. Neuroscientific studies of humans viewing artwork have the capacity to reveal the diversity of human cognitive responses that may be induced by external advice or context as people view artwork in a variety of frameworks and settings.

  7. Cloning Mice.

    Science.gov (United States)

    Ogura, Atsuo

    2017-08-01

    Viable and fertile mice can be generated by somatic nuclear transfer into enucleated oocytes, presumably because the transplanted somatic cell genome becomes reprogrammed by factors in the oocyte. The first somatic cloned offspring of mice were obtained by directly injecting donor nuclei into recipient enucleated oocytes. When this method is used (the so-called Honolulu method of somatic cell nuclear transfer [SCNT]), the donor nuclei readily and completely condense within the enucleated metaphase II-arrested oocytes, which contain high levels of M-phase-promoting factor (MPF). It is believed that the condensation of the donor chromosomes promotes complete reprogramming of the donor genome within the mouse oocytes. Another key to the success of mouse cloning is the use of blunt micropipettes attached to a piezo impact-driving micromanipulation device. This system saves a significant amount of time during the micromanipulation of oocytes and thus minimizes the loss of oocyte viability in vitro. For example, a group of 20 oocytes can be enucleated within 10 min by an experienced operator. This protocol is composed of seven parts: (1) preparing micropipettes, (2) setting up the enucleation and injection micropipettes, (3) collecting and enucleating oocytes, (4) preparing nucleus donor cells, (5) injecting donor nuclei, (6) activating embryos and culturing, and (7) transferring cloned embryos. © 2017 Cold Spring Harbor Laboratory Press.

  8. Robust Instrumentation[Water treatment for power plant]; Robust Instrumentering

    Energy Technology Data Exchange (ETDEWEB)

    Wik, Anders [Vattenfall Utveckling AB, Stockholm (Sweden)

    2003-08-01

    Cementa Slite Power Station is a heat recovery steam generator (HRSG) with moderate steam data; 3.0 MPa and 420 deg C. The heat is recovered from Cementa, a cement industry, without any usage of auxiliary fuel. The Power station commenced operation in 2001. The layout of the plant is unusual, there are no similar in Sweden and very few world-wide, so the operational experiences are limited. In connection with the commissioning of the power plant a R and D project was identified with the objective to minimise the manpower needed for chemistry management of the plant. The lean chemistry management is based on robust instrumentation and chemical-free water treatment plant. The concept with robust instrumentation consists of the following components; choice of on-line instrumentation with a minimum of O and M and a chemical-free water treatment. The parameters are specific conductivity, cation conductivity, oxygen and pH. In addition to that, two fairly new on-line instruments were included; corrosion monitors and differential pH calculated from specific and cation conductivity. The chemical-free water treatment plant consists of softening, reverse osmosis and electro-deionisation. The operational experience shows that the cycle chemistry is not within the guidelines due to major problems with the operation of the power plant. These problems have made it impossible to reach steady state and thereby not viable to fully verify and validate the concept with robust instrumentation. From readings on the panel of the online analysers some conclusions may be drawn, e.g. the differential pH measurements have fulfilled the expectations. The other on-line analysers have been working satisfactorily apart from contamination with turbine oil, which has been noticed at least twice. The corrosion monitors seem to be working but the lack of trend curves from the mainframe computer system makes it hard to draw any clear conclusions. The chemical-free water treatment has met all

  9. Masking responses to light in period mutant mice.

    Science.gov (United States)

    Pendergast, Julie S; Yamazaki, Shin

    2011-10-01

    Masking is an acute effect of an external signal on an overt rhythm and is distinct from the process of entrainment. In the current study, we investigated the phase dependence and molecular mechanisms regulating masking effects of light pulses on spontaneous locomotor activity in mice. The circadian genes, Period1 (Per1) and Per2, are necessary components of the timekeeping machinery and entrainment by light appears to involve the induction of the expression of Per1 and Per2 mRNAs in the suprachiasmatic nuclei (SCN). We assessed the roles of the Per genes in regulating masking by assessing the effects of light pulses on nocturnal locomotor activity in C57BL/6J Per mutant mice. We found that Per1(-/-) and Per2(-/-) mice had robust negative masking responses to light. In addition, the locomotor activity of Per1(-/-)/Per2(-/-) mice appeared to be rhythmic in the light-dark (LD) cycle, and the phase of activity onset was advanced (but varied among individual mice) relative to lights off. This rhythm persisted for 1 to 2 days in constant darkness in some Per1(-/-)/Per2(-/-) mice. Furthermore, Per1(-/-)/Per2(-/-) mice exhibited robust negative masking responses to light. Negative masking was phase dependent in wild-type mice such that maximal suppression was induced by light pulses at zeitgeber time 14 (ZT14) and gradually weaker suppression occurred during light pulses at ZT16 and ZT18. By measuring the phase shifts induced by the masking protocol (light pulses were administered to mice maintained in the LD cycle), we found that the phase responsiveness of Per mutant mice was altered compared to wild-types. Together, our data suggest that negative masking responses to light are robust in Per mutant mice and that the Per1(-/-)/Per2(-/-) SCN may be a light-driven, weak/damping oscillator.

  10. Prefrontal single-unit firing associated with deficient extinction in mice

    Science.gov (United States)

    Fitzgerald, Paul J; Whittle, Nigel; Flynn, Shaun M; Graybeal, Carolyn; Pinard, Courtney; Gunduz-Cinar, Ozge; Kravitz, Alexxai; Singewald, Nicolas; Holmes, Andrew

    2014-01-01

    The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing B6 mice, consistent with the hypothesized pro-fear contribution of PL. Analysis of local field potentials also revealed significantly higher gamma power in the PL of Sthan B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in S1 mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABAA receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and

  11. Perspective: Evolution and detection of genetic robustness

    NARCIS (Netherlands)

    Visser, de J.A.G.M.; Hermisson, J.; Wagner, G.P.; Ancel Meyers, L.; Bagheri-Chaichian, H.; Blanchard, J.L.; Chao, L.; Cheverud, J.M.; Elena, S.F.; Fontana, W.; Gibson, G.; Hansen, T.F.; Krakauer, D.; Lewontin, R.C.; Ofria, C.; Rice, S.H.; Dassow, von G.; Wagner, A.; Whitlock, M.C.

    2003-01-01

    Robustness is the invariance of phenotypes in the face of perturbation. The robustness of phenotypes appears at various levels of biological organization, including gene expression, protein folding, metabolic flux, physiological homeostasis, development, and even organismal fitness. The mechanisms

  12. Robust lyapunov controller for uncertain systems

    KAUST Repository

    Laleg-Kirati, Taous-Meriem; Elmetennani, Shahrazed

    2017-01-01

    Various examples of systems and methods are provided for Lyapunov control for uncertain systems. In one example, a system includes a process plant and a robust Lyapunov controller configured to control an input of the process plant. The robust

  13. Robust distributed cognitive relay beamforming

    KAUST Repository

    Pandarakkottilil, Ubaidulla

    2012-05-01

    In this paper, we present a distributed relay beamformer design for a cognitive radio network in which a cognitive (or secondary) transmit node communicates with a secondary receive node assisted by a set of cognitive non-regenerative relays. The secondary nodes share the spectrum with a licensed primary user (PU) node, and each node is assumed to be equipped with a single transmit/receive antenna. The interference to the PU resulting from the transmission from the cognitive nodes is kept below a specified limit. The proposed robust cognitive relay beamformer design seeks to minimize the total relay transmit power while ensuring that the transceiver signal-to-interference- plus-noise ratio and PU interference constraints are satisfied. The proposed design takes into account a parameter of the error in the channel state information (CSI) to render the performance of the beamformer robust in the presence of imperfect CSI. Though the original problem is non-convex, we show that the proposed design can be reformulated as a tractable convex optimization problem that can be solved efficiently. Numerical results are provided and illustrate the performance of the proposed designs for different network operating conditions and parameters. © 2012 IEEE.

  14. Adaptive integral robust control and application to electromechanical servo systems.

    Science.gov (United States)

    Deng, Wenxiang; Yao, Jianyong

    2017-03-01

    This paper proposes a continuous adaptive integral robust control with robust integral of the sign of the error (RISE) feedback for a class of uncertain nonlinear systems, in which the RISE feedback gain is adapted online to ensure the robustness against disturbances without the prior bound knowledge of the additive disturbances. In addition, an adaptive compensation integrated with the proposed adaptive RISE feedback term is also constructed to further reduce design conservatism when the system also exists parametric uncertainties. Lyapunov analysis reveals the proposed controllers could guarantee the tracking errors are asymptotically converging to zero with continuous control efforts. To illustrate the high performance nature of the developed controllers, numerical simulations are provided. At the end, an application case of an actual electromechanical servo system driven by motor is also studied, with some specific design consideration, and comparative experimental results are obtained to verify the effectiveness of the proposed controllers. Copyright © 2017 ISA. Published by Elsevier Ltd. All rights reserved.

  15. Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

    Directory of Open Access Journals (Sweden)

    Ullrich Stephen E

    2011-01-01

    Full Text Available Abstract Background The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. Methods UVB-irradiated p53+/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. Results UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19+, CD5+, B220+, IgM+ and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19 translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. Conclusion UV-irradiated p53+/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal

  16. Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

    International Nuclear Information System (INIS)

    Puebla-Osorio, Nahum; Miyahara, Yasuko; Coimbatore, Sreevidya; Limón-Flores, Alberto Y; Kazimi, Nasser; Ullrich, Stephen E; Zhu, Chengming

    2011-01-01

    The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation. UVB-irradiated p53 +/- mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling. UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19 + , CD5 + , B220 + , IgM + and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression. UV-irradiated p53 +/- mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The

  17. Robust canonical correlations: A comparative study

    OpenAIRE

    Branco, JA; Croux, Christophe; Filzmoser, P; Oliveira, MR

    2005-01-01

    Several approaches for robust canonical correlation analysis will be presented and discussed. A first method is based on the definition of canonical correlation analysis as looking for linear combinations of two sets of variables having maximal (robust) correlation. A second method is based on alternating robust regressions. These methods axe discussed in detail and compared with the more traditional approach to robust canonical correlation via covariance matrix estimates. A simulation study ...

  18. Functional PAK-2 knockout and replacement with a caspase cleavage-deficient mutant in mice reveals differential requirements of full-length PAK-2 and caspase-activated PAK-2p34.

    Science.gov (United States)

    Marlin, Jerry W; Chang, Yu-Wen E; Ober, Margaret; Handy, Amy; Xu, Wenhao; Jakobi, Rolf

    2011-06-01

    p21-Activated protein kinase 2 (PAK-2) has both anti- and pro-apoptotic functions depending on its mechanism of activation. Activation of full-length PAK-2 by the monomeric GTPases Cdc42 or Rac stimulates cell survival, whereas caspase activation of PAK-2 to the PAK-2p34 fragment is involved in the apoptotic response. In this study we use functional knockout of PAK-2 and gene replacement with the caspase cleavage-deficient PAK-2D212N mutant to differentiate the biological functions of full-length PAK-2 and caspase-activated PAK-2p34. Knockout of PAK-2 results in embryonic lethality at early stages before organ development, whereas replacement with the caspase cleavage-deficient PAK-2D212N results in viable and healthy mice, indicating that early embryonic lethality is caused by deficiency of full-length PAK-2 rather than lack of caspase activation to the PAK-2p34 fragment. However, deficiency of caspase activation of PAK-2 decreased spontaneous cell death of primary mouse embryonic fibroblasts and increased cell growth at high cell density. In contrast, stress-induced cell death by treatment with the anti-cancer drug cisplatin was not reduced by deficiency of caspase activation of PAK-2, but switched from an apoptotic to a nonapoptotic, caspase-independent mechanism. Homozygous PAK-2D212N primary mouse embryonic fibroblasts that lack the ability to generate the proapoptotic PAK-2p34 show less activation of the effector caspase 3, 6, and 7, indicating that caspase activation of PAK-2 amplifies the apoptotic response through a positive feedback loop resulting in more activation of effector caspases.

  19. Robust adaptive synchronization of general dynamical networks ...

    Indian Academy of Sciences (India)

    Home; Journals; Pramana – Journal of Physics; Volume 86; Issue 6. Robust ... A robust adaptive synchronization scheme for these general complex networks with multiple delays and uncertainties is established and raised by employing the robust adaptive control principle and the Lyapunov stability theory. We choose ...

  20. Robust portfolio selection under norm uncertainty

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2016-06-01

    Full Text Available Abstract In this paper, we consider the robust portfolio selection problem which has a data uncertainty described by the ( p , w $(p,w$ -norm in the objective function. We show that the robust formulation of this problem is equivalent to a linear optimization problem. Moreover, we present some numerical results concerning our robust portfolio selection problem.

  1. A robust standard deviation control chart

    NARCIS (Netherlands)

    Schoonhoven, M.; Does, R.J.M.M.

    2012-01-01

    This article studies the robustness of Phase I estimators for the standard deviation control chart. A Phase I estimator should be efficient in the absence of contaminations and resistant to disturbances. Most of the robust estimators proposed in the literature are robust against either diffuse

  2. Methodology in robust and nonparametric statistics

    CERN Document Server

    Jurecková, Jana; Picek, Jan

    2012-01-01

    Introduction and SynopsisIntroductionSynopsisPreliminariesIntroductionInference in Linear ModelsRobustness ConceptsRobust and Minimax Estimation of LocationClippings from Probability and Asymptotic TheoryProblemsRobust Estimation of Location and RegressionIntroductionM-EstimatorsL-EstimatorsR-EstimatorsMinimum Distance and Pitman EstimatorsDifferentiable Statistical FunctionsProblemsAsymptotic Representations for L-Estimators

  3. Elastic hydrogel substrate supports robust expansion of murine myoblasts and enhances their engraftment

    International Nuclear Information System (INIS)

    Ding, Ke; Yang, Zhong; Xu, Jian-zhong; Liu, Wen-ying; Zeng, Qiang; Hou, Fang; Lin, Sen

    2015-01-01

    The application of satellite cell-derived myoblasts in regenerative medicine has been restricted by the rapid loss of stemness during in vitro cell expansion using traditional culture systems. However, studies published in the past decade have highlighted the influence of substrate elasticity on stem cell fate and revealed that culture on a soft hydrogel substrate can promote self-renewal and prolong the regenerative potential of muscle stem cells. Whether hydrogel substrates have similar effects after long-term robust expansion remains to be determined. Herein we prepared an elastic chitosan/beta-glycerophosphate/collagen hydrogel mimicking the soft microenvironment of muscle tissues for use as the substrate for satellite cell culture and investigated its influence on long-term cell expansion. After 20 passages in culture, satellite cell-derived myoblasts cultured on our hydrogel substrate exhibited significant improvements in proliferation capability, cell viability, colony forming frequency, and potential for myogenic differentiation compared to those cultured on a routine rigid culture surface. Immunochemical staining and western blot analysis both confirmed that myoblasts cultured on the hydrogel substrate expressed higher levels of several differentiation-related markers, including Pax7, Pax3, and SSEA-1, and a lower level of MyoD compared to myoblasts cultured on rigid culture plates (all p<0.05). After transplantation into the tibialis anterior of nude mice, myoblasts that had been cultured on the hydrogel substrate demonstrated a significantly greater engraftment efficacy than those cultured on the traditional surface. Collectively, these results indicate that the elastic hydrogel substrate supported robust expansion of murine myoblasts and enhanced their engraftment in vivo. - Highlights: • An elastic hydrogel was designed to mimic the pliable muscle tissue microenvironment. • Myoblasts retained their stemness in long-term culture on the elastic

  4. Elastic hydrogel substrate supports robust expansion of murine myoblasts and enhances their engraftment

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Ke, E-mail: dk1118@yeah.net [Department of Pediatric Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu 610072 (China); Yang, Zhong [Department of Clinical Hematology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Xu, Jian-zhong, E-mail: xjzspine@163.com [Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Liu, Wen-ying; Zeng, Qiang; Hou, Fang [Department of Pediatric Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu 610072 (China); Lin, Sen [Department of Anatomy and Histology & Embryology, Chengdu Medical College, Chengdu 610500 (China)

    2015-09-10

    The application of satellite cell-derived myoblasts in regenerative medicine has been restricted by the rapid loss of stemness during in vitro cell expansion using traditional culture systems. However, studies published in the past decade have highlighted the influence of substrate elasticity on stem cell fate and revealed that culture on a soft hydrogel substrate can promote self-renewal and prolong the regenerative potential of muscle stem cells. Whether hydrogel substrates have similar effects after long-term robust expansion remains to be determined. Herein we prepared an elastic chitosan/beta-glycerophosphate/collagen hydrogel mimicking the soft microenvironment of muscle tissues for use as the substrate for satellite cell culture and investigated its influence on long-term cell expansion. After 20 passages in culture, satellite cell-derived myoblasts cultured on our hydrogel substrate exhibited significant improvements in proliferation capability, cell viability, colony forming frequency, and potential for myogenic differentiation compared to those cultured on a routine rigid culture surface. Immunochemical staining and western blot analysis both confirmed that myoblasts cultured on the hydrogel substrate expressed higher levels of several differentiation-related markers, including Pax7, Pax3, and SSEA-1, and a lower level of MyoD compared to myoblasts cultured on rigid culture plates (all p<0.05). After transplantation into the tibialis anterior of nude mice, myoblasts that had been cultured on the hydrogel substrate demonstrated a significantly greater engraftment efficacy than those cultured on the traditional surface. Collectively, these results indicate that the elastic hydrogel substrate supported robust expansion of murine myoblasts and enhanced their engraftment in vivo. - Highlights: • An elastic hydrogel was designed to mimic the pliable muscle tissue microenvironment. • Myoblasts retained their stemness in long-term culture on the elastic

  5. Robust network topologies for generating switch-like cellular responses.

    Directory of Open Access Journals (Sweden)

    Najaf A Shah

    2011-06-01

    Full Text Available Signaling networks that convert graded stimuli into binary, all-or-none cellular responses are critical in processes ranging from cell-cycle control to lineage commitment. To exhaustively enumerate topologies that exhibit this switch-like behavior, we simulated all possible two- and three-component networks on random parameter sets, and assessed the resulting response profiles for both steepness (ultrasensitivity and extent of memory (bistability. Simulations were used to study purely enzymatic networks, purely transcriptional networks, and hybrid enzymatic/transcriptional networks, and the topologies in each class were rank ordered by parametric robustness (i.e., the percentage of applied parameter sets exhibiting ultrasensitivity or bistability. Results reveal that the distribution of network robustness is highly skewed, with the most robust topologies clustering into a small number of motifs. Hybrid networks are the most robust in generating ultrasensitivity (up to 28% and bistability (up to 18%; strikingly, a purely transcriptional framework is the most fragile in generating either ultrasensitive (up to 3% or bistable (up to 1% responses. The disparity in robustness among the network classes is due in part to zero-order ultrasensitivity, an enzyme-specific phenomenon, which repeatedly emerges as a particularly robust mechanism for generating nonlinearity and can act as a building block for switch-like responses. We also highlight experimentally studied examples of topologies enabling switching behavior, in both native and synthetic systems, that rank highly in our simulations. This unbiased approach for identifying topologies capable of a given response may be useful in discovering new natural motifs and in designing robust synthetic gene networks.

  6. Robustness of muscle synergies during visuomotor adaptation

    Directory of Open Access Journals (Sweden)

    Reinhard eGentner

    2013-09-01

    Full Text Available During visuomotor adaptation a novel mapping between visual targets and motor commands is gradually acquired. How muscle activation patterns are affected by this process is an open question. We tested whether the structure of muscle synergies is preserved during adaptation to a visuomotor rotation. Eight subjects applied targeted isometric forces on a handle instrumented with a force transducer while electromyographic (EMG activity was recorded from 13 shoulder and elbow muscles. The recorded forces were mapped into horizontal displacements of a virtual sphere with simulated mass, elasticity, and damping. The task consisted of moving the sphere to a target at one of eight equally spaced directions. Subjects performed three baseline blocks of 32 trials, followed by six blocks with a 45° CW rotation applied to the planar force, and finally three wash-out blocks without the perturbation. The sphere position at 100 ms after movement onset revealed significant directional error at the beginning of the rotation, a gradual learning in subsequent blocks, and aftereffects at the beginning of the wash-out. The change in initial force direction was closely related to the change in directional tuning of the initial EMG activity of most muscles. Throughout the experiment muscle synergies extracted using a non-negative matrix factorization algorithm from the muscle patterns recorded during the baseline blocks could reconstruct the muscle patterns of all other blocks with an accuracy significantly higher than chance indicating structural robustness. In addition, the synergies extracted from individual blocks remained similar to the baseline synergies throughout the experiment. Thus synergy structure is robust during visuomotor adaptation suggesting that changes in muscle patterns are obtained by rotating the directional tuning of the synergy recruitment.

  7. Container Materials, Fabrication And Robustness

    International Nuclear Information System (INIS)

    Dunn, K.; Louthan, M.; Rawls, G.; Sindelar, R.; Zapp, P.; Mcclard, J.

    2009-01-01

    The multi-barrier 3013 container used to package plutonium-bearing materials is robust and thereby highly resistant to identified degradation modes that might cause failure. The only viable degradation mechanisms identified by a panel of technical experts were pressurization within and corrosion of the containers. Evaluations of the container materials and the fabrication processes and resulting residual stresses suggest that the multi-layered containers will mitigate the potential for degradation of the outer container and prevent the release of the container contents to the environment. Additionally, the ongoing surveillance programs and laboratory studies should detect any incipient degradation of containers in the 3013 storage inventory before an outer container is compromised.

  8. Robust matching for voice recognition

    Science.gov (United States)

    Higgins, Alan; Bahler, L.; Porter, J.; Blais, P.

    1994-10-01

    This paper describes an automated method of comparing a voice sample of an unknown individual with samples from known speakers in order to establish or verify the individual's identity. The method is based on a statistical pattern matching approach that employs a simple training procedure, requires no human intervention (transcription, work or phonetic marketing, etc.), and makes no assumptions regarding the expected form of the statistical distributions of the observations. The content of the speech material (vocabulary, grammar, etc.) is not assumed to be constrained in any way. An algorithm is described which incorporates frame pruning and channel equalization processes designed to achieve robust performance with reasonable computational resources. An experimental implementation demonstrating the feasibility of the concept is described.

  9. A robust, efficient and flexible method for staining myelinated axons in blocks of brain tissue.

    Science.gov (United States)

    Wahlsten, Douglas; Colbourne, Frederick; Pleus, Richard

    2003-03-15

    Previous studies have demonstrated the utility of the gold chloride method for en bloc staining of a bisected brain in mice and rats. The present study explores several variations in the method, assesses its reliability, and extends the limits of its application. We conclude that the method is very efficient, highly robust, sufficiently accurate for most purposes, and adaptable to many morphometric measures. We obtained acceptable staining of commissures in every brain, despite a wide variety of fixation methods. One-half could be stained 24 h after the brain was extracted and the other half could be stained months later. When staining failed because of an exhausted solution, the brain could be stained successfully in fresh solution. Relatively small changes were found in the sizes of commissures several weeks after initial fixation or staining. A half brain stained to reveal the mid-sagittal section could then be sectioned coronally and stained again in either gold chloride for myelin or cresyl violet for Nissl substance. Uncertainty, arising from pixelation of digitized images was far less than errors arising from human judgments about the histological limits of major commissures. Useful data for morphometric analysis were obtained by scanning the surface of a gold chloride stained block of brain with an inexpensive flatbed scanner.

  10. Robustness Assessment of Spatial Timber Structures

    DEFF Research Database (Denmark)

    Kirkegaard, Poul Henning

    2012-01-01

    Robustness of structural systems has obtained a renewed interest due to a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure. In order to minimise the likelihood of such disproportionate structural failures many modern buildi...... to robustness of spatial timber structures and will discuss the consequences of such robustness issues related to the future development of timber structures.......Robustness of structural systems has obtained a renewed interest due to a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure. In order to minimise the likelihood of such disproportionate structural failures many modern building...... codes consider the need for robustness of structures and provide strategies and methods to obtain robustness. Therefore a structural engineer may take necessary steps to design robust structures that are insensitive to accidental circumstances. The present paper summaries issues with respect...

  11. Zinc metabolism in genetically obese mice

    International Nuclear Information System (INIS)

    Kennedy, M.L.; Failla, M.L.

    1986-01-01

    Recent reports indicate that the concentrations and total amounts of several essential trace metals in various tissues of genetically obese rodents differ markedly from lean controls. In the present studies the absorption, retention and tissue distribution of zinc was compared in obese (ob/ob) and lean (+/?) C57BL/6J mice. When administered 0.1 and 1 umole 65 Zn by stomach tube and killed after 4 h, fasted 10 week old obese mice had 2.7 and 2.2 times more radioactivity in their carcasses, respectively, than age-matched lean mice. Higher levels of 65 Zn were also present in the intestinal mucosa of obese mice. To eliminate possible differences in the effects of fasting and gastric emptying rates between the phenotypes, zinc absorption and retention were determined according to the method of Heth and Hoekstra. Analysis of data revealed that obese and lean mice absorbed 43 and 18% of the oral dose, respectively. Also, the rate of 65 Zn excretion between 2 and 6 days post-treatment was similar for obese and lean mice. After 6 days obese mice had significantly lower levels of radioisotope in skin, muscle plus bone, spleen and testes and higher levels of 65 Zn in liver, small intestine and adipose tissue compared to tissues from lean mice. These results demonstrate increased absorption, altered tissue distribution and similar excretion of zinc in ob/ob mice

  12. A robust multivariate long run analysis of European electricity prices

    OpenAIRE

    Bruno Bosco; Lucia Parisio; Matteo Pelagatti; Fabio Baldi

    2007-01-01

    This paper analyses the interdependencies existing in wholesale electricity prices in six major European countries. The results of our robust multivariate long run dynamic analysis reveal the presence of four highly integrated central European markets (France, Germany, the Netherlands and Austria). The trend shared by these four electricity markets appears to be common also to gas prices, but not to oil prices. The existence of long term dynamics among electricity prices and between electrici...

  13. Robust Multimodal Cognitive Load Measurement

    Science.gov (United States)

    2014-03-26

    75th percentiles. Results and Discussion: As an example, Figure 2 shows the median of the extracted HRE from the frontal channels in scale 5, for...the extracted HRE are able to distinguish the seven task loads better with q closer to 1, as it consistently reveals a decreasing median with

  14. Robust holographic storage system design.

    Science.gov (United States)

    Watanabe, Takahiro; Watanabe, Minoru

    2011-11-21

    Demand is increasing daily for large data storage systems that are useful for applications in spacecraft, space satellites, and space robots, which are all exposed to radiation-rich space environment. As candidates for use in space embedded systems, holographic storage systems are promising because they can easily provided the demanded large-storage capability. Particularly, holographic storage systems, which have no rotation mechanism, are demanded because they are virtually maintenance-free. Although a holographic memory itself is an extremely robust device even in a space radiation environment, its associated lasers and drive circuit devices are vulnerable. Such vulnerabilities sometimes engendered severe problems that prevent reading of all contents of the holographic memory, which is a turn-off failure mode of a laser array. This paper therefore presents a proposal for a recovery method for the turn-off failure mode of a laser array on a holographic storage system, and describes results of an experimental demonstration. © 2011 Optical Society of America

  15. Efficient robust conditional random fields.

    Science.gov (United States)

    Song, Dongjin; Liu, Wei; Zhou, Tianyi; Tao, Dacheng; Meyer, David A

    2015-10-01

    Conditional random fields (CRFs) are a flexible yet powerful probabilistic approach and have shown advantages for popular applications in various areas, including text analysis, bioinformatics, and computer vision. Traditional CRF models, however, are incapable of selecting relevant features as well as suppressing noise from noisy original features. Moreover, conventional optimization methods often converge slowly in solving the training procedure of CRFs, and will degrade significantly for tasks with a large number of samples and features. In this paper, we propose robust CRFs (RCRFs) to simultaneously select relevant features. An optimal gradient method (OGM) is further designed to train RCRFs efficiently. Specifically, the proposed RCRFs employ the l1 norm of the model parameters to regularize the objective used by traditional CRFs, therefore enabling discovery of the relevant unary features and pairwise features of CRFs. In each iteration of OGM, the gradient direction is determined jointly by the current gradient together with the historical gradients, and the Lipschitz constant is leveraged to specify the proper step size. We show that an OGM can tackle the RCRF model training very efficiently, achieving the optimal convergence rate [Formula: see text] (where k is the number of iterations). This convergence rate is theoretically superior to the convergence rate O(1/k) of previous first-order optimization methods. Extensive experiments performed on three practical image segmentation tasks demonstrate the efficacy of OGM in training our proposed RCRFs.

  16. Robust boosting via convex optimization

    Science.gov (United States)

    Rätsch, Gunnar

    2001-12-01

    In this work we consider statistical learning problems. A learning machine aims to extract information from a set of training examples such that it is able to predict the associated label on unseen examples. We consider the case where the resulting classification or regression rule is a combination of simple rules - also called base hypotheses. The so-called boosting algorithms iteratively find a weighted linear combination of base hypotheses that predict well on unseen data. We address the following issues: o The statistical learning theory framework for analyzing boosting methods. We study learning theoretic guarantees on the prediction performance on unseen examples. Recently, large margin classification techniques emerged as a practical result of the theory of generalization, in particular Boosting and Support Vector Machines. A large margin implies a good generalization performance. Hence, we analyze how large the margins in boosting are and find an improved algorithm that is able to generate the maximum margin solution. o How can boosting methods be related to mathematical optimization techniques? To analyze the properties of the resulting classification or regression rule, it is of high importance to understand whether and under which conditions boosting converges. We show that boosting can be used to solve large scale constrained optimization problems, whose solutions are well characterizable. To show this, we relate boosting methods to methods known from mathematical optimization, and derive convergence guarantees for a quite general family of boosting algorithms. o How to make Boosting noise robust? One of the problems of current boosting techniques is that they are sensitive to noise in the training sample. In order to make boosting robust, we transfer the soft margin idea from support vector learning to boosting. We develop theoretically motivated regularized algorithms that exhibit a high noise robustness. o How to adapt boosting to regression problems

  17. Robust AIC with High Breakdown Scale Estimate

    Directory of Open Access Journals (Sweden)

    Shokrya Saleh

    2014-01-01

    Full Text Available Akaike Information Criterion (AIC based on least squares (LS regression minimizes the sum of the squared residuals; LS is sensitive to outlier observations. Alternative criterion, which is less sensitive to outlying observation, has been proposed; examples are robust AIC (RAIC, robust Mallows Cp (RCp, and robust Bayesian information criterion (RBIC. In this paper, we propose a robust AIC by replacing the scale estimate with a high breakdown point estimate of scale. The robustness of the proposed methods is studied through its influence function. We show that, the proposed robust AIC is effective in selecting accurate models in the presence of outliers and high leverage points, through simulated and real data examples.

  18. Towards Robust Face Recognition from Video

    International Nuclear Information System (INIS)

    Price, JR

    2001-01-01

    A novel, template-based method for face recognition is presented. The goals of the proposed method are to integrate multiple observations for improved robustness and to provide auxiliary confidence data for subsequent use in an automated video surveillance system. The proposed framework consists of a parallel system of classifiers, referred to as observers, where each observer is trained on one face region. The observer outputs are combined to yield the final recognition result. Three of the four confounding factors-expression, illumination, and decoration-are specifically addressed in this paper. The extension of the proposed approach to address the fourth confounding factor-pose-is straightforward and well supported in previous work. A further contribution of the proposed approach is the computation of a revealing confidence measure. This confidence measure will aid the subsequent application of the proposed method to video surveillance scenarios. Results are reported for a database comprising 676 images of 160 subjects under a variety of challenging circumstances. These results indicate significant performance improvements over previous methods and demonstrate the usefulness of the confidence data

  19. Multimodel Robust Control for Hydraulic Turbine

    OpenAIRE

    Osuský, Jakub; Števo, Stanislav

    2014-01-01

    The paper deals with the multimodel and robust control system design and their combination based on M-Δ structure. Controller design will be done in the frequency domain with nominal performance specified by phase margin. Hydraulic turbine model is analyzed as system with unstructured uncertainty, and robust stability condition is included in controller design. Multimodel and robust control approaches are presented in detail on hydraulic turbine model. Control design approaches are compared a...

  20. Forecasting exchange rates: a robust regression approach

    OpenAIRE

    Preminger, Arie; Franck, Raphael

    2005-01-01

    The least squares estimation method as well as other ordinary estimation method for regression models can be severely affected by a small number of outliers, thus providing poor out-of-sample forecasts. This paper suggests a robust regression approach, based on the S-estimation method, to construct forecasting models that are less sensitive to data contamination by outliers. A robust linear autoregressive (RAR) and a robust neural network (RNN) models are estimated to study the predictabil...

  1. Robustness: confronting lessons from physics and biology.

    Science.gov (United States)

    Lesne, Annick

    2008-11-01

    The term robustness is encountered in very different scientific fields, from engineering and control theory to dynamical systems to biology. The main question addressed herein is whether the notion of robustness and its correlates (stability, resilience, self-organisation) developed in physics are relevant to biology, or whether specific extensions and novel frameworks are required to account for the robustness properties of living systems. To clarify this issue, the different meanings covered by this unique term are discussed; it is argued that they crucially depend on the kind of perturbations that a robust system should by definition withstand. Possible mechanisms underlying robust behaviours are examined, either encountered in all natural systems (symmetries, conservation laws, dynamic stability) or specific to biological systems (feedbacks and regulatory networks). Special attention is devoted to the (sometimes counterintuitive) interrelations between robustness and noise. A distinction between dynamic selection and natural selection in the establishment of a robust behaviour is underlined. It is finally argued that nested notions of robustness, relevant to different time scales and different levels of organisation, allow one to reconcile the seemingly contradictory requirements for robustness and adaptability in living systems.

  2. Robustness of Long Span Reciprocal Timber Structures

    DEFF Research Database (Denmark)

    Balfroid, Nathalie; Kirkegaard, Poul Henning

    2011-01-01

    engineer may take necessary steps to design robust structures that are insensitive to accidental circumstances. The present paper makes a discussion of such robustness issues related to the future development of reciprocal timber structures. The paper concludes that these kind of structures can have...... a potential as long span timber structures in real projects if they are carefully designed with respect to the overall robustness strategies.......Robustness of structural systems has obtained a renewed interest due to a much more frequent use of advanced types of structures with limited redundancy and serious consequences in case of failure. The interest has also been facilitated due to recently severe structural failures...

  3. Histomorphometry and cortical robusticity of the adult human femur.

    Science.gov (United States)

    Miszkiewicz, Justyna Jolanta; Mahoney, Patrick

    2018-01-13

    Recent quantitative analyses of human bone microanatomy, as well as theoretical models that propose bone microstructure and gross anatomical associations, have started to reveal insights into biological links that may facilitate remodeling processes. However, relationships between bone size and the underlying cortical bone histology remain largely unexplored. The goal of this study is to determine the extent to which static indicators of bone remodeling and vascularity, measured using histomorphometric techniques, relate to femoral midshaft cortical width and robusticity. Using previously published and new quantitative data from 450 adult human male (n = 233) and female (n = 217) femora, we determine if these aspects of femoral size relate to bone microanatomy. Scaling relationships are explored and interpreted within the context of tissue form and function. Analyses revealed that the area and diameter of Haversian canals and secondary osteons, and densities of secondary osteons and osteocyte lacunae from the sub-periosteal region of the posterior midshaft femur cortex were significantly, but not consistently, associated with femoral size. Cortical width and bone robusticity were correlated with osteocyte lacunae density and scaled with positive allometry. Diameter and area of osteons and Haversian canals decreased as the width of cortex and bone robusticity increased, revealing a negative allometric relationship. These results indicate that microscopic products of cortical bone remodeling and vascularity are linked to femur size. Allometric relationships between more robust human femora with thicker cortical bone and histological products of bone remodeling correspond with principles of bone functional adaptation. Future studies may benefit from exploring scaling relationships between bone histomorphometric data and measurements of bone macrostructure.

  4. Robust and efficient walking with spring-like legs

    Energy Technology Data Exchange (ETDEWEB)

    Rummel, J; Blum, Y; Seyfarth, A, E-mail: juergen.rummel@uni-jena.d, E-mail: andre.seyfarth@uni-jena.d [Lauflabor Locomotion Laboratory, University of Jena, Dornburger Strasse 23, 07743 Jena (Germany)

    2010-12-15

    The development of bipedal walking robots is inspired by human walking. A way of implementing walking could be performed by mimicking human leg dynamics. A fundamental model, representing human leg dynamics during walking and running, is the bipedal spring-mass model which is the basis for this paper. The aim of this study is the identification of leg parameters leading to a compromise between robustness and energy efficiency in walking. It is found that, compared to asymmetric walking, symmetric walking with flatter angles of attack reveals such a compromise. With increasing leg stiffness, energy efficiency increases continuously. However, robustness is the maximum at moderate leg stiffness and decreases slightly with increasing stiffness. Hence, an adjustable leg compliance would be preferred, which is adaptable to the environment. If the ground is even, a high leg stiffness leads to energy efficient walking. However, if external perturbations are expected, e.g. when the robot walks on uneven terrain, the leg should be softer and the angle of attack flatter. In the case of underactuated robots with constant physical springs, the leg stiffness should be larger than k-tilde = 14 in order to use the most robust gait. Soft legs, however, lack in both robustness and efficiency.

  5. Robust and efficient walking with spring-like legs

    International Nuclear Information System (INIS)

    Rummel, J; Blum, Y; Seyfarth, A

    2010-01-01

    The development of bipedal walking robots is inspired by human walking. A way of implementing walking could be performed by mimicking human leg dynamics. A fundamental model, representing human leg dynamics during walking and running, is the bipedal spring-mass model which is the basis for this paper. The aim of this study is the identification of leg parameters leading to a compromise between robustness and energy efficiency in walking. It is found that, compared to asymmetric walking, symmetric walking with flatter angles of attack reveals such a compromise. With increasing leg stiffness, energy efficiency increases continuously. However, robustness is the maximum at moderate leg stiffness and decreases slightly with increasing stiffness. Hence, an adjustable leg compliance would be preferred, which is adaptable to the environment. If the ground is even, a high leg stiffness leads to energy efficient walking. However, if external perturbations are expected, e.g. when the robot walks on uneven terrain, the leg should be softer and the angle of attack flatter. In the case of underactuated robots with constant physical springs, the leg stiffness should be larger than k-tilde = 14 in order to use the most robust gait. Soft legs, however, lack in both robustness and efficiency.

  6. Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension.

    Science.gov (United States)

    Kashyap, Sonu; Warner, Gina; Hu, Zeng; Gao, Feng; Osman, Mazen; Al Saiegh, Yousif; Lien, Karen R; Nath, Karl; Grande, Joseph P

    2017-01-01

    Renovascular hypertension (RVH) has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kidney 1-clip (2K1C) model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO) protects the stenotic kidney (STK) from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS) was established in Wild-type (WT) and Smad3 KO mice (129 genetic background) by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10-14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.

  7. Implicitly Weighted Methods in Robust Image Analysis

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2012-01-01

    Roč. 44, č. 3 (2012), s. 449-462 ISSN 0924-9907 R&D Projects: GA MŠk(CZ) 1M06014 Institutional research plan: CEZ:AV0Z10300504 Keywords : robustness * high breakdown point * outlier detection * robust correlation analysis * template matching * face recognition Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 1.767, year: 2012

  8. What is it to be sturdy (robust)?

    DEFF Research Database (Denmark)

    Nielsen, Niss Skov; Zwisler, Lars Pagter; Bojsen, Ann Kristina Mikkelsen

    Purpose: This paper intends to give a first insight into the concept of being "sturdy/robust"; To develop and test a Danish model of how to measure sturdi-ness/robustness; To test the scale's ability to identify people in emergency situa-tions who have high risk of developing psychological illness....

  9. Structural Robustness Evaluation of Offshore Wind Turbines

    DEFF Research Database (Denmark)

    Giuliani, Luisa; Bontempi, Franco

    2010-01-01

    in the framework of a safe design: it depends on different factors, like exposure, vulnerability and robustness. Particularly, the requirement of structural vulnerability and robustness are discussed in this paper and a numerical application is presented, in order to evaluate the effects of a ship collision...

  10. In Silico Design of Robust Bolalipid Membranes

    NARCIS (Netherlands)

    Bulacu, Monica; Periole, Xavier; Marrink, Siewert J.; Périole, Xavier

    The robustness of microorganisms used in industrial fermentations is essential for the efficiency and yield of the production process. A viable tool to increase the robustness is through engineering of the cell membrane and especially by incorporating lipids from species that survive under harsh

  11. Assessment of Process Robustness for Mass Customization

    DEFF Research Database (Denmark)

    Nielsen, Kjeld; Brunø, Thomas Ditlev

    2013-01-01

    robustness and their capability to develop it. Through literature study and analysis of robust process design characteristics a number of metrics are described which can be used for assessment. The metrics are evaluated and analyzed to be applied as KPI’s to help MC companies prioritize efforts in business...

  12. Applying Robust Design in an Industrial Context

    DEFF Research Database (Denmark)

    Christensen, Martin Ebro

    mechanical architectures. Furthermore a set of 15 robust design principles for reducing the variation in functional performance is compiled in a format directly supporting the work of the design engineer. With these foundational methods in place, the existing tools, methods and KPIs of Robust Design...

  13. The importance of robust design methodology

    DEFF Research Database (Denmark)

    Eifler, Tobias; Howard, Thomas J.

    2018-01-01

    infamous recalls in automotive history, that of the GM ignition switch, from the perspective of Robust Design. It is investigated if available Robust Design methods such as sensitivity analysis, tolerance stack-ups, design clarity, etc. would have been suitable to account for the performance variation...

  14. Robust Control Charts for Time Series Data

    NARCIS (Netherlands)

    Croux, C.; Gelper, S.; Mahieu, K.

    2010-01-01

    This article presents a control chart for time series data, based on the one-step- ahead forecast errors of the Holt-Winters forecasting method. We use robust techniques to prevent that outliers affect the estimation of the control limits of the chart. Moreover, robustness is important to maintain

  15. Efficient reanalysis techniques for robust topology optimization

    DEFF Research Database (Denmark)

    Amir, Oded; Sigmund, Ole; Lazarov, Boyan Stefanov

    2012-01-01

    efficient robust topology optimization procedures based on reanalysis techniques. The approach is demonstrated on two compliant mechanism design problems where robust design is achieved by employing either a worst case formulation or a stochastic formulation. It is shown that the time spent on finite...

  16. Extending the Scope of Robust Quadratic Optimization

    NARCIS (Netherlands)

    Marandi, Ahmadreza; Ben-Tal, A.; den Hertog, Dick; Melenberg, Bertrand

    In this paper, we derive tractable reformulations of the robust counterparts of convex quadratic and conic quadratic constraints with concave uncertainties for a broad range of uncertainty sets. For quadratic constraints with convex uncertainty, it is well-known that the robust counterpart is, in

  17. Security and robustness for collaborative monitors

    NARCIS (Netherlands)

    Testerink, Bas; Bulling, Nils; Dastani, Mehdi

    2016-01-01

    Decentralized monitors can be subject to robustness and security risks. Robustness risks include attacks on the monitor’s infrastructure in order to disable parts of its functionality. Security risks include attacks that try to extract information from the monitor and thereby possibly leak sensitive

  18. Spatial delayed nonmatching-to-sample performances in long-living Ames dwarf mice.

    Science.gov (United States)

    Derenne, Adam; Brown-Borg, Holly M; Martner, Sarah; Wolff, Wendy; Frerking, Morgan

    2014-01-17

    Ames dwarf mice have an extended lifespan by comparison with normal mice. Behavioral testing has revealed that sometimes Ames dwarf mice also evince superior performances relative to normal mice, but in other cases they do not. In this experiment, Ames dwarf and normal mice were compared on a T-maze test and on a delayed nonmatching-to-sample variant of a T-maze test. On the simple T-maze, Ames dwarf and normal mice committed comparable numbers of errors. On the nonmatching-to-sample task, normal mice mastered the discrimination by the end of the experiment while Ames dwarf mice did not. The apparatus, distances traveled and session duration were equivalent between the two tasks. The poorer performances of Ames dwarf mice on the nonmatching-to-sample task suggests that Ames dwarf mice may not be as capable of learning relatively cognitively complex tasks as normal mice. © 2013.

  19. GH and IGF1: roles in energy metabolism of long-living GH mutant mice.

    Science.gov (United States)

    Brown-Borg, Holly M; Bartke, Andrzej

    2012-06-01

    Of the multiple theories to explain exceptional longevity, the most robust of these has centered on the reduction of three anabolic protein hormones, growth hormone (GH), insulin-like growth factor, and insulin. GH mutant mice live 50% longer and exhibit significant differences in several aspects of energy metabolism as compared with wild-type mice. Mitochondrial metabolism is upregulated in the absence of GH, whereas in GH transgenic mice and dwarf mice treated with GH, multiple aspects of these pathways are suppressed. Core body temperature is markedly lower in dwarf mice, yet whole-body metabolism, as measured by indirect calorimetry, is surprisingly higher in Ames dwarf and Ghr-/- mice compared with normal controls. Elevated adiponectin, a key antiinflammatory cytokine, is also very likely to contribute to longevity in these mice. Thus, several important components related to energy metabolism are altered in GH mutant mice, and these differences are likely critical in aging processes and life-span extension.

  20. A Survey on Robustness in Railway Planning

    DEFF Research Database (Denmark)

    Lusby, Richard Martin; Larsen, Jesper; Bull, Simon Henry

    2018-01-01

    Planning problems in passenger railway range from long term strategic decision making to the detailed planning of operations.Operations research methods have played an increasing role in this planning process. However, recently more attention has been given to considerations of robustness...... in the quality of solutions to individual planning problems, and of operations in general. Robustness in general is the capacity for some system to absorb or resist changes. In the context of railway robustness it is often taken to be the capacity for operations to continue at some level when faced...... with a disruption such as delay or failure. This has resulted in more attention given to the inclusion of robustness measures and objectives in individual planning problems, and to the providing of tools to ensure operations continue under disrupted situations. In this paper we survey the literature on robustness...

  1. International Conference on Robust Statistics 2015

    CERN Document Server

    Basu, Ayanendranath; Filzmoser, Peter; Mukherjee, Diganta

    2016-01-01

    This book offers a collection of recent contributions and emerging ideas in the areas of robust statistics presented at the International Conference on Robust Statistics 2015 (ICORS 2015) held in Kolkata during 12–16 January, 2015. The book explores the applicability of robust methods in other non-traditional areas which includes the use of new techniques such as skew and mixture of skew distributions, scaled Bregman divergences, and multilevel functional data methods; application areas being circular data models and prediction of mortality and life expectancy. The contributions are of both theoretical as well as applied in nature. Robust statistics is a relatively young branch of statistical sciences that is rapidly emerging as the bedrock of statistical analysis in the 21st century due to its flexible nature and wide scope. Robust statistics supports the application of parametric and other inference techniques over a broader domain than the strictly interpreted model scenarios employed in classical statis...

  2. Oral lactoferrin protects against experimental candidiasis in mice.

    Science.gov (United States)

    Velliyagounder, K; Alsaedi, W; Alabdulmohsen, W; Markowitz, K; Fine, D H

    2015-01-01

    To determine the role of human lactoferrin (hLF) in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO(-/-)) mice was compared to wild-type (WT) mice. We also aim to determine the protective role of hLF in LFKO(-/-) mice. Antibiotic-treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0·3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO(-/-) I mice showed a 2 log (P = 0·001) higher CFUs of C. albicans in the oral cavity compared to the WT mice infected with C. albicans (WTI). LFKO(-/-) I mice given hLF had a 3 log (P = 0·001) reduction in CFUs in the oral cavity compared to untreated LFKO(-/-) I mice. The severity of infection, observed by light microscopy, revealed that the tongue of the LFKO(-/-) I mice showed more white patches compared to WTI and LFKO(-/-) I + hLF mice. Scanning electron microscopic observations revealed that more filiform papillae were destroyed in LFKO(-/-) I mice when compared to WTI or LFKO(-/-) I + hLF mice. Human LF is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. Human LF, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral healthcare products against C. albicans. © 2014 The Society for Applied Microbiology.

  3. Histone Variant HTZ1 Shows Extensive Epistasis with, but Does Not Increase Robustness to, New Mutations

    Science.gov (United States)

    Richardson, Joshua B.; Uppendahl, Locke D.; Traficante, Maria K.; Levy, Sasha F.; Siegal, Mark L.

    2013-01-01

    Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact) to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA) lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1) to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be caused by loss of

  4. Histone variant HTZ1 shows extensive epistasis with, but does not increase robustness to, new mutations.

    Directory of Open Access Journals (Sweden)

    Joshua B Richardson

    Full Text Available Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1 to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be

  5. A robust image watermarking in contourlet transform domain

    Science.gov (United States)

    Sharma, Rajat; Gupta, Abhishek Kumar; Singh, Deepak; Verma, Vivek Singh; Bhardwaj, Anuj

    2017-10-01

    A lot of work has been done in the field of image watermarking to overcome the problems of rightful ownership, copyright protection etc. In order to provide a robust solution of such issues, the authors propose a hybrid approach that involves contourlet, lifting wavelet, and discrete cosine transform. The first level coefficients of the original image which are obtained using contourlet transform are further decomposed using one level lifting wavelet transform. After that, these coefficients are modified using discrete cosine transform. Whereas, second level subband of contourlet transform coefficients are used to obtain block wise modification parameter based on edge detection and entropy calculations. Watermark bits are embedded by quantizing the discrete cosine transform coefficient blocks obtained using HL sub-band of first level lifting wavelet transform coefficients. The experimental results reveal that the proposed scheme has high robustness and imperceptibility.

  6. Robust Adaptive Speed Control of Induction Motor Drives

    DEFF Research Database (Denmark)

    Bidstrup, N.

    This thesis concerns speed control of current vector controlled induction motor drives (CVC drives). The CVC drive is an existing prototype drive developed by Danfoss A/S, Transmission Division. Practical tests have revealed that the open loop dynamical properties of the CVC drive are highly......, (LS) identification and generalized predictive control (GPC) has been implemented and tested on the CVC drive. Allthough GPC is a robust control method, it was not possible to maintain specified controller performance in the entire operating range. This was the main reason for investigating truly...... and measurement noise in general, were the major reasons for the drifting parameters. Two approaches was proposed to robustify MASTR2 against the output noise. The first approach consists of filtering the output. Output filtering had a significant effect in simulations, but the robustness against the output noise...

  7. Inner ear dysfunction in caspase-3 deficient mice

    Directory of Open Access Journals (Sweden)

    Woo Minna

    2011-10-01

    Full Text Available Abstract Background Caspase-3 is one of the most downstream enzymes activated in the apoptotic pathway. In caspase-3 deficient mice, loss of cochlear hair cells and spiral ganglion cells coincide closely with hearing loss. In contrast with the auditory system, details of the vestibular phenotype have not been characterized. Here we report the vestibular phenotype and inner ear anatomy in the caspase-3 deficient (Casp3-/- mouse strain. Results Average ABR thresholds of Casp3-/- mice were significantly elevated (P Casp3+/- mice and Casp3+/+ mice at 3 months of age. In DPOAE testing, distortion product 2F1-F2 was significantly decreased (P Casp3-/- mice, whereas Casp3+/- and Casp3+/+ mice showed normal and comparable values to each other. Casp3-/- mice were hyperactive and exhibited circling behavior when excited. In lateral canal VOR testing, Casp3-/- mice had minimal response to any of the stimuli tested, whereas Casp3+/- mice had an intermediate response compared to Casp3+/+ mice. Inner ear anatomical and histological analysis revealed gross hypomorphism of the vestibular organs, in which the main site was the anterior semicircular canal. Hair cell numbers in the anterior- and lateral crista, and utricle were significantly smaller in Casp3-/- mice whereas the Casp3+/- and Casp3+/+ mice had normal hair cell numbers. Conclusions These results indicate that caspase-3 is essential for correct functioning of the cochlea as well as normal development and function of the vestibule.

  8. Robustness Analysis of Dynamic Watermarks

    Directory of Open Access Journals (Sweden)

    Ivan V. Nechta

    2017-06-01

    Full Text Available In this paper we consider previously known scheme of dynamic watermarks embedding (Ra- dix-n that is used for preventing illegal use of software. According to the scheme a watermark is dynamic linked data structure (graph, which is created in memory during program execution. Hidden data, such as information about author, can be represented in a different type of graph structure. This data can be extracted and demonstrated in judicial proceedings. This paper declared that the above mentioned scheme was previously one of the most reliable, has a number of features that allows an attacker to detect a stage of watermark construction in the program, and therefore it can be corrupted or deleted. The author of this article shows the weakness of Radix-N scheme, which consists in the fact that we can reveal dynamic data structures of a program by using information received from some API-functions hooker which catches function calls of dynamic memory allocation. One of these data structures is the watermark. Pointers on dynamically created objects (arrays, variables, class items, etc. of a program can be detected by content analysis of computer's RAM. Different dynamic objects in memory interconnected by pointers form dynamic data structures of a program such as lists, stacks, trees and other graphs (including the watermark. Our experiment shows that in the vast majority of cases the amount of data structure in programs is small, which increases probability of a successful attack. Also we present an algorithm for finding connected components of a graph with linear time-consuming in cases where the number of nodes is about 106. On the basis of the experimental findings the new watermarking scheme has been presented, which is resistant to the proposed attack. It is offered to use different graph structure representation of a watermark, where edges are implemented using unique signatures. Our scheme uses content encrypting of graph nodes (except signature

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

    International Nuclear Information System (INIS)

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

    2015-01-01

    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. (paper)

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

    Science.gov (United States)

    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.

  11. Robust optimization based upon statistical theory.

    Science.gov (United States)

    Sobotta, B; Söhn, M; Alber, M

    2010-08-01

    Organ movement is still the biggest challenge in cancer treatment despite advances in online imaging. Due to the resulting geometric uncertainties, the delivered dose cannot be predicted precisely at treatment planning time. Consequently, all associated dose metrics (e.g., EUD and maxDose) are random variables with a patient-specific probability distribution. The method that the authors propose makes these distributions the basis of the optimization and evaluation process. The authors start from a model of motion derived from patient-specific imaging. On a multitude of geometry instances sampled from this model, a dose metric is evaluated. The resulting pdf of this dose metric is termed outcome distribution. The approach optimizes the shape of the outcome distribution based on its mean and variance. This is in contrast to the conventional optimization of a nominal value (e.g., PTV EUD) computed on a single geometry instance. The mean and variance allow for an estimate of the expected treatment outcome along with the residual uncertainty. Besides being applicable to the target, the proposed method also seamlessly includes the organs at risk (OARs). The likelihood that a given value of a metric is reached in the treatment is predicted quantitatively. This information reveals potential hazards that may occur during the course of the treatment, thus helping the expert to find the right balance between the risk of insufficient normal tissue sparing and the risk of insufficient tumor control. By feeding this information to the optimizer, outcome distributions can be obtained where the probability of exceeding a given OAR maximum and that of falling short of a given target goal can be minimized simultaneously. The method is applicable to any source of residual motion uncertainty in treatment delivery. Any model that quantifies organ movement and deformation in terms of probability distributions can be used as basis for the algorithm. Thus, it can generate dose

  12. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Science.gov (United States)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  13. Salmonella enterica serovar Typhimurium ΔmsbB triggers exacerbated inflammation in Nod2 deficient mice.

    Directory of Open Access Journals (Sweden)

    Anne-Kathrin Claes

    Full Text Available The intracellular pathogen Salmonella enterica serovar Typhimurium causes intestinal inflammation characterized by edema, neutrophil influx and increased pro-inflammatory cytokine expression. A major bacterial factor inducing pro-inflammatory host responses is lipopolysaccharide (LPS. S. Typhimurium ΔmsbB possesses a modified lipid A, has reduced virulence in mice, and is being considered as a potential anti-cancer vaccine strain. The lack of a late myristoyl transferase, encoded by MsbB leads to attenuated TLR4 stimulation. However, whether other host receptor pathways are also altered remains unclear. Nod1 and Nod2 are cytosolic pattern recognition receptors recognizing bacterial peptidoglycan. They play important roles in the host's immune response to enteric pathogens and in immune homeostasis. Here, we investigated how deletion of msbB affects Salmonella's interaction with Nod1 and Nod2. S. Typhimurium Δ msbB-induced inflammation was significantly exacerbated in Nod2-/- mice compared to C57Bl/6 mice. In addition, S. Typhimurium ΔmsbB maintained robust intestinal colonization in Nod2-/- mice from day 2 to day 7 p.i., whereas colonization levels significantly decreased in C57Bl/6 mice during this time. Similarly, infection of Nod1-/- and Nod1/Nod2 double-knockout mice revealed that both Nod1 and Nod2 play a protective role in S. Typhimurium ΔmsbB-induced colitis. To elucidate why S. Typhimurium ΔmsbB, but not wild-type S. Typhimurium, induced an exacerbated inflammatory response in Nod2-/- mice, we used HEK293 cells which were transiently transfected with pathogen recognition receptors. Stimulation of TLR2-transfected cells with S. Typhimurium ΔmsbB resulted in increased IL-8 production compared to wild-type S. Typhimurium. Our results indicate that S. Typhimurium ΔmsbB triggers exacerbated colitis in the absence of Nod1 and/or Nod2, which is likely due to increased TLR2 stimulation. How bacteria with "genetically detoxified" LPS

  14. Robust recognition via information theoretic learning

    CERN Document Server

    He, Ran; Yuan, Xiaotong; Wang, Liang

    2014-01-01

    This Springer Brief represents a comprehensive review of information theoretic methods for robust recognition. A variety of information theoretic methods have been proffered in the past decade, in a large variety of computer vision applications; this work brings them together, attempts to impart the theory, optimization and usage of information entropy.The?authors?resort to a new information theoretic concept, correntropy, as a robust measure and apply it to solve robust face recognition and object recognition problems. For computational efficiency,?the brief?introduces the additive and multip

  15. Robust statistics and geochemical data analysis

    International Nuclear Information System (INIS)

    Di, Z.

    1987-01-01

    Advantages of robust procedures over ordinary least-squares procedures in geochemical data analysis is demonstrated using NURE data from the Hot Springs Quadrangle, South Dakota, USA. Robust principal components analysis with 5% multivariate trimming successfully guarded the analysis against perturbations by outliers and increased the number of interpretable factors. Regression with SINE estimates significantly increased the goodness-of-fit of the regression and improved the correspondence of delineated anomalies with known uranium prospects. Because of the ubiquitous existence of outliers in geochemical data, robust statistical procedures are suggested as routine procedures to replace ordinary least-squares procedures

  16. Design Robust Controller for Rotary Kiln

    Directory of Open Access Journals (Sweden)

    Omar D. Hernández-Arboleda

    2013-11-01

    Full Text Available This paper presents the design of a robust controller for a rotary kiln. The designed controller is a combination of a fractional PID and linear quadratic regulator (LQR, these are not used to control the kiln until now, in addition robustness criteria are evaluated (gain margin, phase margin, strength gain, rejecting high frequency noise and sensitivity applied to the entire model (controller-plant, obtaining good results with a frequency range of 0.020 to 90 rad/s, which contributes to the robustness of the system.

  17. Towards distortion-free robust image authentication

    International Nuclear Information System (INIS)

    Coltuc, D

    2007-01-01

    This paper investigates a general framework for distortion-free robust image authentication by multiple marking. First, by robust watermarking a subsampled version of image edges is embedded. Then, by reversible watermarking the information needed to recover the original image is inserted, too. The hiding capacity of the reversible watermarking is the essential requirement for this approach. Thus in case of no attacks not only image is authenticated but also the original is exactly recovered. In case of attacks, reversibility is lost, but image can still be authenticated. Preliminary results providing very good robustness against JPEG compression are presented

  18. An Overview of the Adaptive Robust DFT

    Directory of Open Access Journals (Sweden)

    Djurović Igor

    2010-01-01

    Full Text Available Abstract This paper overviews basic principles and applications of the robust DFT (RDFT approach, which is used for robust processing of frequency-modulated (FM signals embedded in non-Gaussian heavy-tailed noise. In particular, we concentrate on the spectral analysis and filtering of signals corrupted by impulsive distortions using adaptive and nonadaptive robust estimators. Several adaptive estimators of location parameter are considered, and it is shown that their application is preferable with respect to non-adaptive counterparts. This fact is demonstrated by efficiency comparison of adaptive and nonadaptive RDFT methods for different noise environments.

  19. A robust interpretation of duration calculus

    DEFF Research Database (Denmark)

    Franzle, M.; Hansen, Michael Reichhardt

    2005-01-01

    We transfer the concept of robust interpretation from arithmetic first-order theories to metric-time temporal logics. The idea is that the interpretation of a formula is robust iff its truth value does not change under small variation of the constants in the formula. Exemplifying this on Duration...... Calculus (DC), our findings are that the robust interpretation of DC is equivalent to a multi-valued interpretation that uses the real numbers as semantic domain and assigns Lipschitz-continuous interpretations to all operators of DC. Furthermore, this continuity permits approximation between discrete...

  20. REINA at CLEF 2007 Robust Task

    OpenAIRE

    Zazo Rodríguez, Ángel Francisco; Figuerola, Carlos G.; Alonso Berrocal, José Luis

    2007-01-01

    This paper describes our work at CLEF 2007 Robust Task. We have participated in the monolingual (English, French and Portuguese) and the bilingual (English to French) subtask. At CLEF 2006 our research group obtained very good results applying local query expansion using windows of terms in the robust task. This year we have used the same expansion technique, but taking into account some criteria of robustness: MAP, GMAP, MMR, GS@10, P@10, number of failed topics, number of topics bellow 0.1 ...

  1. REINA at CLEF 2007 Robust Track (2007)

    OpenAIRE

    Zazo, Ángel F.; G.-Figuerola, Carlos; Alonso-Berrocal, José-Luis

    2007-01-01

    This paper describes our work at CLEF 2007 Robust Task. We have participated in the monolingual (English, French and Portuguese) and the bilingual (English to French) subtask. At CLEF 2006 our research group obtained very good results applying local query expansion using windows of terms in the robust task. This year we have used the same expansion technique, but taking into account some criteria of robustness: MAP, GMAP, MMR, GS@10, P@10, number of failed topics, number of topics bellow 0.1 ...

  2. Danish Requirements for Robustness of Structures

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard; Christensen, H. H.

    2006-01-01

    . This paper describes the background of the revised robustness requirements implemented in the Danish Code of Practice for Safety of Structures in 2003 [1, 2, 3]. According to the Danish design rules robustness shall be documented for all structures where consequences of failure are serious. This paper...... describes the background of the design procedure in the Danish codes, which shall be followed in order to document sufficient robustness in the following steps: Step 1: review of loads and possible failure modes/scenarios and determination of acceptable collapse extent. Step 2: review of the structural...

  3. Robustness-related issues in speaker recognition

    CERN Document Server

    Zheng, Thomas Fang

    2017-01-01

    This book presents an overview of speaker recognition technologies with an emphasis on dealing with robustness issues. Firstly, the book gives an overview of speaker recognition, such as the basic system framework, categories under different criteria, performance evaluation and its development history. Secondly, with regard to robustness issues, the book presents three categories, including environment-related issues, speaker-related issues and application-oriented issues. For each category, the book describes the current hot topics, existing technologies, and potential research focuses in the future. The book is a useful reference book and self-learning guide for early researchers working in the field of robust speech recognition.

  4. Robustness and structure of complex networks

    Science.gov (United States)

    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

  5. Robust Structured Control Design via LMI Optimization

    DEFF Research Database (Denmark)

    Adegas, Fabiano Daher; Stoustrup, Jakob

    2011-01-01

    This paper presents a new procedure for discrete-time robust structured control design. Parameter-dependent nonconvex conditions for stabilizable and induced L2-norm performance controllers are solved by an iterative linear matrix inequalities (LMI) optimization. A wide class of controller...... structures including decentralized of any order, fixed-order dynamic output feedback, static output feedback can be designed robust to polytopic uncertainties. Stability is proven by a parameter-dependent Lyapunov function. Numerical examples on robust stability margins shows that the proposed procedure can...

  6. Robustness of Greenberger-Horne-Zeilinger and W states for teleportation in external environments

    Energy Technology Data Exchange (ETDEWEB)

    Hu Mingliang, E-mail: mingliang0301@163.co [School of Science, Xi' an University of Posts and Telecommunications, Xi' an 710061 (China)

    2011-01-31

    By solving analytically a master equation in the Lindblad form, we study quantum teleportation of the one-qubit state under the influence of different surrounding environments, and compared the robustness between Greenberger-Horne-Zeilinger (GHZ) and W states in terms of their teleportation capacity. The results revealed that when subject to zero temperature environment, the GHZ state is always more robust than the W state, while the reverse situation occurs when the channel is subject to infinite temperature or dephasing environment.

  7. Robustness of Greenberger-Horne-Zeilinger and W states for teleportation in external environments

    International Nuclear Information System (INIS)

    Hu Mingliang

    2011-01-01

    By solving analytically a master equation in the Lindblad form, we study quantum teleportation of the one-qubit state under the influence of different surrounding environments, and compared the robustness between Greenberger-Horne-Zeilinger (GHZ) and W states in terms of their teleportation capacity. The results revealed that when subject to zero temperature environment, the GHZ state is always more robust than the W state, while the reverse situation occurs when the channel is subject to infinite temperature or dephasing environment.

  8. Principles of Economic Rationality in Mice.

    Science.gov (United States)

    Rivalan, Marion; Winter, York; Nachev, Vladislav

    2017-12-12

    Humans and non-human animals frequently violate principles of economic rationality, such as transitivity, independence of irrelevant alternatives, and regularity. The conditions that lead to these violations are not completely understood. Here we report a study on mice tested in automated home-cage setups using rewards of drinking water. Rewards differed in one of two dimensions, volume or probability. Our results suggest that mouse choice conforms to the principles of economic rationality for options that differ along a single reward dimension. A psychometric analysis of mouse choices further revealed that mice responded more strongly to differences in probability than to differences in volume, despite equivalence in return rates. This study also demonstrates the synergistic effect between the principles of economic rationality and psychophysics in making quantitative predictions about choices of healthy laboratory mice. This opens up new possibilities for the analyses of multi-dimensional choice and the use of mice with cognitive impairments that may violate economic rationality.

  9. Robust synthesis for real-time systems

    DEFF Research Database (Denmark)

    Larsen, Kim Guldstrand; Legay, Axel; Traonouez, Luois-Marie

    2014-01-01

    Specification theories for real-time systems allow reasoning about interfaces and their implementation models, using a set of operators that includes satisfaction, refinement, logical and parallel composition. To make such theories applicable throughout the entire design process from an abstract...... of introducing small perturbations into formal models. We address this problem of robust implementations in timed specification theories. We first consider a fixed perturbation and study the robustness of timed specifications with respect to the operators of the theory. To this end we synthesize robust...... specification to an implementation, we need to reason about the possibility to effectively implement the theoretical specifications on physical systems, despite their limited precision. In the literature, this implementation problem has been linked to the robustness problem that analyzes the consequences...

  10. Robust adaptive synchronization of general dynamical networks ...

    Indian Academy of Sciences (India)

    Robust adaptive synchronization; dynamical network; multiple delays; multiple uncertainties. ... Networks such as neural networks, communication transmission networks, social rela- tionship networks etc. ..... a very good effect. Pramana – J.

  11. Technical Challenges Hindering Development of Robust Wireless ...

    African Journals Online (AJOL)

    PROF. OLIVER OSUAGWA

    2015-12-01

    Dec 1, 2015 ... challenges remain to be resolved, in designing robust wireless networks that can deliver the performance ... demonstrated the first radio transmission from the Isle of ... distances with better quality, less power, and smaller ...

  12. Multifidelity Robust Aeroelastic Design, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — Nielsen Engineering & Research (NEAR) proposes a new method to generate mathematical models of wind-tunnel models and flight vehicles for robust aeroelastic...

  13. The structural robustness of multiprocessor computing system

    Directory of Open Access Journals (Sweden)

    N. Andronaty

    1996-03-01

    Full Text Available The model of the multiprocessor computing system on the base of transputers which permits to resolve the question of valuation of a structural robustness (viability, survivability is described.

  14. Design principles for robust oscillatory behavior.

    Science.gov (United States)

    Castillo-Hair, Sebastian M; Villota, Elizabeth R; Coronado, Alberto M

    2015-09-01

    Oscillatory responses are ubiquitous in regulatory networks of living organisms, a fact that has led to extensive efforts to study and replicate the circuits involved. However, to date, design principles that underlie the robustness of natural oscillators are not completely known. Here we study a three-component enzymatic network model in order to determine the topological requirements for robust oscillation. First, by simulating every possible topological arrangement and varying their parameter values, we demonstrate that robust oscillators can be obtained by augmenting the number of both negative feedback loops and positive autoregulations while maintaining an appropriate balance of positive and negative interactions. We then identify network motifs, whose presence in more complex topologies is a necessary condition for obtaining oscillatory responses. Finally, we pinpoint a series of simple architectural patterns that progressively render more robust oscillators. Together, these findings can help in the design of more reliable synthetic biomolecular networks and may also have implications in the understanding of other oscillatory systems.

  15. Robust and Efficient Parametric Face Alignment

    NARCIS (Netherlands)

    Tzimiropoulos, Georgios; Zafeiriou, Stefanos; Pantic, Maja

    2011-01-01

    We propose a correlation-based approach to parametric object alignment particularly suitable for face analysis applications which require efficiency and robustness against occlusions and illumination changes. Our algorithm registers two images by iteratively maximizing their correlation coefficient

  16. Framework for Robustness Assessment of Timber Structures

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard

    2011-01-01

    This paper presents a theoretical framework for the design and analysis of robustness of timber structures. This is actualized by a more4 frequent use of advanced types of timber structures with limited redundancy and serious consequences in the case of failure. Combined with increased requirements...... to efficiency in design and execution followed by increased risk of human errors has made the need of requirements to robustness of new structures essential. Further, the collapse of the Ballerup Super Arena, the bad Reichenhall Ice-Arena and a number of other structural systems during the last 10 years has...... increased the interest in robustness. Typically, modern structural design codes require that ‘the consequence of damages to structures should not be disproportional to the causes of the damages’. However, although the importance of robustness for structural design is widely recognized, the code requirements...

  17. Robust Analysis and Design of Multivariable Systems

    National Research Council Canada - National Science Library

    Tannenbaum, Allen

    1998-01-01

    In this Final Report, we will describe the work we have performed in robust control theory and nonlinear control, and the utilization of techniques in image processing and computer vision for problems in visual tracking...

  18. Robust Tracking Control for a Piezoelectric Actuator

    National Research Council Canada - National Science Library

    Salah, M; McIntyre, M; Dawson, D; Wagner, J

    2006-01-01

    In this paper, a hysteresis model-based nonlinear robust controller is developed for a piezoelectric actuator, utilizing a Lyapunov-based stability analysis, which ensures that a desired displacement...

  19. Robustness studies on coal gasification process variables

    African Journals Online (AJOL)

    coal before feeding to the gasification process [1]. .... to-control variables will make up the terms in the response surface model for the ... Montgomery (1999) explained that all the Taguchi engineering objectives for a robust ..... software [3].

  20. Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

    Science.gov (United States)

    Ruud, Johan; Nilsson, Anna; Engström Ruud, Linda; Wang, Wenhua; Nilsberth, Camilla; Iresjö, Britt-Marie; Lundholm, Kent; Engblom, David; Blomqvist, Anders

    2013-03-01

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Antecedents and Dimensions of Supply Chain Robustness

    OpenAIRE

    Durach, Christian F.; Wieland, Andreas; Machuca, Jose A.D.

    2015-01-01

    Purpose – The purpose of this paper is to provide groundwork for an emerging theory of supply chain robustness – which has been conceptualized as a dimension of supply chain resilience – through reviewing and synthesizing related yet disconnected studies. The paper develops a formal definition of supply chain robustness to build a framework that captures the dimensions, antecedents and moderators of the construct as discussed in the literature. Design/methodology/approach – The...

  2. 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

    Science.gov (United States)

    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

  3. Adaptive Critic Nonlinear Robust Control: A Survey.

    Science.gov (United States)

    Wang, Ding; He, Haibo; Liu, Derong

    2017-10-01

    Adaptive dynamic programming (ADP) and reinforcement learning are quite relevant to each other when performing intelligent optimization. They are both regarded as promising methods involving important components of evaluation and improvement, at the background of information technology, such as artificial intelligence, big data, and deep learning. Although great progresses have been achieved and surveyed when addressing nonlinear optimal control problems, the research on robustness of ADP-based control strategies under uncertain environment has not been fully summarized. Hence, this survey reviews the recent main results of adaptive-critic-based robust control design of continuous-time nonlinear systems. The ADP-based nonlinear optimal regulation is reviewed, followed by robust stabilization of nonlinear systems with matched uncertainties, guaranteed cost control design of unmatched plants, and decentralized stabilization of interconnected systems. Additionally, further comprehensive discussions are presented, including event-based robust control design, improvement of the critic learning rule, nonlinear H ∞ control design, and several notes on future perspectives. By applying the ADP-based optimal and robust control methods to a practical power system and an overhead crane plant, two typical examples are provided to verify the effectiveness of theoretical results. Overall, this survey is beneficial to promote the development of adaptive critic control methods with robustness guarantee and the construction of higher level intelligent systems.

  4. Robust reflective ghost imaging against different partially polarized thermal light

    Science.gov (United States)

    Li, Hong-Guo; Wang, Yan; Zhang, Rui-Xue; Zhang, De-Jian; Liu, Hong-Chao; Li, Zong-Guo; Xiong, Jun

    2018-03-01

    We theoretically study the influence of degree of polarization (DOP) of thermal light on the contrast-to-noise ratio (CNR) of the reflective ghost imaging (RGI), which is a novel and indirect imaging modality. An expression for the CNR of RGI with partially polarized thermal light is carefully derived, which suggests a weak dependence of CNR on the DOP, especially when the ratio of the object size to the speckle size of thermal light has a large value. Different from conventional imaging approaches, our work reveals that RGI is much more robust against the DOP of the light source, which thereby has advantages in practical applications, such as remote sensing.

  5. Median Robust Extended Local Binary Pattern for Texture Classification.

    Science.gov (United States)

    Liu, Li; Lao, Songyang; Fieguth, Paul W; Guo, Yulan; Wang, Xiaogang; Pietikäinen, Matti

    2016-03-01

    Local binary patterns (LBP) are considered among the most computationally efficient high-performance texture features. However, the LBP method is very sensitive to image noise and is unable to capture macrostructure information. To best address these disadvantages, in this paper, we introduce a novel descriptor for texture classification, the median robust extended LBP (MRELBP). Different from the traditional LBP and many LBP variants, MRELBP compares regional image medians rather than raw image intensities. A multiscale LBP type descriptor is computed by efficiently comparing image medians over a novel sampling scheme, which can capture both microstructure and macrostructure texture information. A comprehensive evaluation on benchmark data sets reveals MRELBP's high performance-robust to gray scale variations, rotation changes and noise-but at a low computational cost. MRELBP produces the best classification scores of 99.82%, 99.38%, and 99.77% on three popular Outex test suites. More importantly, MRELBP is shown to be highly robust to image noise, including Gaussian noise, Gaussian blur, salt-and-pepper noise, and random pixel corruption.

  6. Robust Visual Tracking Using the Bidirectional Scale Estimation

    Directory of Open Access Journals (Sweden)

    An Zhiyong

    2017-01-01

    Full Text Available Object tracking with robust scale estimation is a challenging task in computer vision. This paper presents a novel tracking algorithm that learns the translation and scale filters with a complementary scheme. The translation filter is constructed using the ridge regression and multidimensional features. A robust scale filter is constructed by the bidirectional scale estimation, including the forward scale and backward scale. Firstly, we learn the scale filter using the forward tracking information. Then the forward scale and backward scale can be estimated using the respective scale filter. Secondly, a conservative strategy is adopted to compromise the forward and backward scales. Finally, the scale filter is updated based on the final scale estimation. It is effective to update scale filter since the stable scale estimation can improve the performance of scale filter. To reveal the effectiveness of our tracker, experiments are performed on 32 sequences with significant scale variation and on the benchmark dataset with 50 challenging videos. Our results show that the proposed tracker outperforms several state-of-the-art trackers in terms of robustness and accuracy.

  7. Meta-analysis of melanin-concentrating hormone signaling-deficient mice on behavioral and metabolic phenotypes.

    Directory of Open Access Journals (Sweden)

    Kenkichi Takase

    Full Text Available The demand for meta-analyses in basic biomedical research has been increasing because the phenotyping of genetically modified mice does not always produce consistent results. Melanin-concentrating hormone (MCH has been reported to be involved in a variety of behaviors that include feeding, body-weight regulation, anxiety, sleep, and reward behavior. However, the reported behavioral and metabolic characteristics of MCH signaling-deficient mice, such as MCH-deficient mice and MCH receptor 1 (MCHR1-deficient mice, are not consistent with each other. In the present study, we performed a meta-analysis of the published data related to MCH-deficient and MCHR1-deficient mice to obtain robust conclusions about the role of MCH signaling. Overall, the meta-analysis revealed that the deletion of MCH signaling enhanced wakefulness, locomotor activity, aggression, and male sexual behavior and that MCH signaling deficiency suppressed non-REM sleep, anxiety, responses to novelty, startle responses, and conditioned place preferences. In contrast to the acute orexigenic effect of MCH, MCH signaling deficiency significantly increased food intake. Overall, the meta-analysis also revealed that the deletion of MCH signaling suppressed the body weight, fat mass, and plasma leptin, while MCH signaling deficiency increased the body temperature, oxygen consumption, heart rate, and mean arterial pressure. The lean phenotype of the MCH signaling-deficient mice was also confirmed in separate meta-analyses that were specific to sex and background strain (i.e., C57BL/6 and 129Sv. MCH signaling deficiency caused a weak anxiolytic effect as assessed with the elevated plus maze and the open field test but also caused a weak anxiogenic effect as assessed with the emergence test. MCH signaling-deficient mice also exhibited increased plasma corticosterone under non-stressed conditions, which suggests enhanced activity of the hypothalamic-pituitary-adrenal axis. To the best of our

  8. Measure of robustness for complex networks

    Science.gov (United States)

    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

  9. Multivariate Regression of Liver on Intestine of Mice: A ...

    African Journals Online (AJOL)

    Multivariate Regression of Liver on Intestine of Mice: A Chemotherapeutic Evaluation of Plant ... Using an analysis of covariance model, the effects ... The findings revealed, with the aid of likelihood-ratio statistic, a marked improvement in

  10. Prolongation of chemically-induced methemoglobinemia in mice lacking α-synuclein: A novel pharmacologic and toxicologic phenotype

    Directory of Open Access Journals (Sweden)

    Yien-Ming Kuo

    2015-01-01

    Full Text Available The protein α-synuclein is considered central to the pathogenesis of Parkinson disease (PD on genetic and histopathological grounds. It is widely expressed in fetal life and continues to be highly expressed in adult neural tissues, red blood cells and platelets, while the remainder of adult tissues are reported to have little or no expression. Despite cellular and molecular evidence for a role in neuronal function including synaptic vesicle trafficking, neurotransmitter release, mitochondrial function, lipid metabolism, neurogenesis, neuroprotection, and neuromelanin biosynthesis, mice ablated for the gene encoding α-synuclein (Snca have little or no neurological phenotype. Thus, nearly 20 years of intensive study have yet to reveal conclusively what the normal function of this highly abundant protein is in the nervous system. Interestingly, α-synuclein has also been shown to have enzymatic activity as a ferrireductase capable of reducing Fe+3 to Fe+2. Given its abundant expression in red blood cells, we set out to explore the role of α-synuclein in converting chemically-induced Fe+3 methemoglobin to normal Fe+2 hemoglobin. Initial in vivo experiments with the potent methemoglobin inducer, para-aminopropiophenone and its active metabolite, 4-hydroxy para-aminopropiophenone, demonstrated significantly greater and more prolonged methemoglobinemia in Snca−/− mice compared to Snca+/+ mice. In vitro experiments with red blood cells, however, and in vivo experiments in genetically engineered mouse strains that differ in their α-synuclein expression in various tissues, including the nervous system, red blood cells and liver, revealed that contrary to the initial hypothesis, a lack of expression of α-synuclein in red blood cells did not correlate with higher levels or more prolonged duration of methemoglobinemia. Instead, the greater sensitivity to chemically induced methemoglobinemia correlated with the absence of hepatic

  11. Masking Responses to Light in Period Mutant Mice

    Science.gov (United States)

    Pendergast, Julie S.; Yamazaki, Shin

    2013-01-01

    Masking is an acute effect of an external signal on an overt rhythm and is distinct from the process of entrainment. In the current study, we investigated the phase dependence and molecular mechanisms regulating masking effects of light pulses on spontaneous locomotor activity in mice. The circadian genes, Period1 (Per1) and Per2, are necessary components of the timekeeping machinery and entrainment by light appears to involve the induction of the expression of Per1 and Per2 mRNAs in the suprachiasmatic nuclei (SCN). We assessed the roles of the Per genes in regulating masking by assessing the effects of light pulses on nocturnal locomotor activity in C57BL/6J Per mutant mice. We found that Per1−/− and Per2−/− mice had robust negative masking responses to light. In addition, the locomotor activity of Per1−/−/Per2−/− mice appeared to be rhythmic in the light-dark (LD) cycle, and the phase of activity onset was advanced (but varied among individual mice) relative to lights off. This rhythm persisted for 1 to 2 days in constant darkness in some Per1−/−/Per2−/− mice. Furthermore, Per1−/−/Per2−/− mice exhibited robust negative masking responses to light. Negative masking was phase dependent in wild-type mice such that maximal suppression was induced by light pulses at zeitgeber time 14 (ZT14) and gradually weaker suppression occurred during light pulses at ZT16 and ZT18. By measuring the phase shifts induced by the masking protocol (light pulses were administered to mice maintained in the LD cycle), we found that the phase responsiveness of Per mutant mice was altered compared to wild-types. Together, our data suggest that negative masking responses to light are robust in Per mutant mice and that the Per1−/−/Per2−/− SCN may be a light-driven, weak/damping oscillator. PMID:21793695

  12. A Comparative Theoretical and Computational Study on Robust Counterpart Optimization: I. Robust Linear Optimization and Robust Mixed Integer Linear Optimization

    Science.gov (United States)

    Li, Zukui; Ding, Ran; Floudas, Christodoulos A.

    2011-01-01

    Robust counterpart optimization techniques for linear optimization and mixed integer linear optimization problems are studied in this paper. Different uncertainty sets, including those studied in literature (i.e., interval set; combined interval and ellipsoidal set; combined interval and polyhedral set) and new ones (i.e., adjustable box; pure ellipsoidal; pure polyhedral; combined interval, ellipsoidal, and polyhedral set) are studied in this work and their geometric relationship is discussed. For uncertainty in the left hand side, right hand side, and objective function of the optimization problems, robust counterpart optimization formulations induced by those different uncertainty sets are derived. Numerical studies are performed to compare the solutions of the robust counterpart optimization models and applications in refinery production planning and batch process scheduling problem are presented. PMID:21935263

  13. Network properties of robust immunity in plants.

    Directory of Open Access Journals (Sweden)

    Kenichi Tsuda

    2009-12-01

    Full Text Available Two modes of plant immunity against biotrophic pathogens, Effector Triggered Immunity (ETI and Pattern-Triggered Immunity (PTI, are triggered by recognition of pathogen effectors and Microbe-Associated Molecular Patterns (MAMPs, respectively. Although the jasmonic acid (JA/ethylene (ET and salicylic acid (SA signaling sectors are generally antagonistic and important for immunity against necrotrophic and biotrophic pathogens, respectively, their precise roles and interactions in ETI and PTI have not been clear. We constructed an Arabidopsis dde2/ein2/pad4/sid2-quadruple mutant. DDE2, EIN2, and SID2 are essential components of the JA, ET, and SA sectors, respectively. The pad4 mutation affects the SA sector and a poorly characterized sector. Although the ETI triggered by the bacterial effector AvrRpt2 (AvrRpt2-ETI and the PTI triggered by the bacterial MAMP flg22 (flg22-PTI were largely intact in plants with mutations in any one of these genes, they were mostly abolished in the quadruple mutant. For the purposes of this study, AvrRpt2-ETI and flg22-PTI were measured as relative growth of Pseudomonas syringae bacteria within leaves. Immunity to the necrotrophic fungal pathogen Alternaria brassicicola was also severely compromised in the quadruple mutant. Quantitative measurements of the immunity levels in all combinatorial mutants and wild type allowed us to estimate the effects of the wild-type genes and their interactions on the immunity by fitting a mixed general linear model. This signaling allocation analysis showed that, contrary to current ideas, each of the JA, ET, and SA signaling sectors can positively contribute to immunity against both biotrophic and necrotrophic pathogens. The analysis also revealed that while flg22-PTI and AvrRpt2-ETI use a highly overlapping signaling network, the way they use the common network is very different: synergistic relationships among the signaling sectors are evident in PTI, which may amplify the signal

  14. Robust adaptive control for Unmanned Aerial Vehicles

    Science.gov (United States)

    Kahveci, Nazli E.

    anti-windup compensation. Our analysis on the indirect adaptive scheme reveals that the perturbation terms due to parameter errors do not cause any unbounded signals in the closed-loop. The stability of the adaptive system is established, and the properties of the proposed control scheme are demonstrated through simulations on a UAV model with input magnitude saturation constraints. The robust adaptive control design is further developed to extend our results to rate-saturated systems.

  15. Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin

    DEFF Research Database (Denmark)

    Nasser, Arafat; Birk Møller, Lisbeth; Olesen, Jess Have

    2014-01-01

    as determine hippocampal monoamine and plasma nitric oxide levels. In the elevated zero maze test, hph mice displayed increased anxiety-like responses compared to wild-type mice, while the marble burying test revealed decreased anxiety-like behaviour. This was particularly observed in male mice. In the tail...

  16. Robustness analysis of chiller sequencing control

    International Nuclear Information System (INIS)

    Liao, Yundan; Sun, Yongjun; Huang, Gongsheng

    2015-01-01

    Highlights: • Uncertainties with chiller sequencing control were systematically quantified. • Robustness of chiller sequencing control was systematically analyzed. • Different sequencing control strategies were sensitive to different uncertainties. • A numerical method was developed for easy selection of chiller sequencing control. - Abstract: Multiple-chiller plant is commonly employed in the heating, ventilating and air-conditioning system to increase operational feasibility and energy-efficiency under part load condition. In a multiple-chiller plant, chiller sequencing control plays a key role in achieving overall energy efficiency while not sacrifices the cooling sufficiency for indoor thermal comfort. Various sequencing control strategies have been developed and implemented in practice. Based on the observation that (i) uncertainty, which cannot be avoided in chiller sequencing control, has a significant impact on the control performance and may cause the control fail to achieve the expected control and/or energy performance; and (ii) in current literature few studies have systematically addressed this issue, this paper therefore presents a study on robustness analysis of chiller sequencing control in order to understand the robustness of various chiller sequencing control strategies under different types of uncertainty. Based on the robustness analysis, a simple and applicable method is developed to select the most robust control strategy for a given chiller plant in the presence of uncertainties, which will be verified using case studies

  17. Information theory perspective on network robustness

    International Nuclear Information System (INIS)

    Schieber, Tiago A.; Carpi, Laura; Frery, Alejandro C.; Rosso, Osvaldo A.; Pardalos, Panos M.; Ravetti, Martín G.

    2016-01-01

    A crucial challenge in network theory is the study of the robustness of a network when facing a sequence of failures. In this work, we propose a dynamical definition of network robustness based on Information Theory, that considers measurements of the structural changes caused by failures of the network's components. Failures are defined here as a temporal process defined in a sequence. Robustness is then evaluated by measuring dissimilarities between topologies after each time step of the sequence, providing a dynamical information about the topological damage. We thoroughly analyze the efficiency of the method in capturing small perturbations by considering different probability distributions on networks. In particular, we find that distributions based on distances are more consistent in capturing network structural deviations, as better reflect the consequences of the failures. Theoretical examples and real networks are used to study the performance of this methodology. - Highlights: • A novel methodology to measure the robustness of a network to component failure or targeted attacks is proposed. • The use of the network's distance PDF allows a precise analysis. • The method provides a dynamic robustness profile showing the response of the topology to each failure event. • The measure is capable to detect network's critical elements.

  18. On the robustness of Herlihy's hierarchy

    Science.gov (United States)

    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.

  19. Replication and robustness in developmental research.

    Science.gov (United States)

    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).

  20. Emergence of robustness in networks of networks

    Science.gov (United States)

    Roth, Kevin; Morone, Flaviano; Min, Byungjoon; Makse, Hernán A.

    2017-06-01

    A model of interdependent networks of networks (NONs) was introduced recently [Proc. Natl. Acad. Sci. (USA) 114, 3849 (2017), 10.1073/pnas.1620808114] in the context of brain activation to identify the neural collective influencers in the brain NON. Here we investigate the emergence of robustness in such a model, and we develop an approach to derive an exact expression for the random percolation transition in Erdös-Rényi NONs of this kind. Analytical calculations are in agreement with numerical simulations, and highlight the robustness of the NON against random node failures, which thus presents a new robust universality class of NONs. The key aspect of this robust NON model is that a node can be activated even if it does not belong to the giant mutually connected component, thus allowing the NON to be built from below the percolation threshold, which is not possible in previous models of interdependent networks. Interestingly, the phase diagram of the model unveils particular patterns of interconnectivity for which the NON is most vulnerable, thereby marking the boundary above which the robustness of the system improves with increasing dependency connections.

  1. Primal and dual approaches to adjustable robust optimization

    NARCIS (Netherlands)

    de Ruiter, Frans

    2018-01-01

    Robust optimization has become an important paradigm to deal with optimization under uncertainty. Adjustable robust optimization is an extension that deals with multistage problems. This thesis starts with a short but comprehensive introduction to adjustable robust optimization. Then the two

  2. Hyperalgesic activity of kisspeptin in mice

    Directory of Open Access Journals (Sweden)

    Spampinato Simona

    2011-11-01

    Full Text Available Abstract Background Kisspeptin is a neuropeptide known for its role in the hypothalamic regulation of the reproductive axis. Following the recent description of kisspeptin and its 7-TM receptor, GPR54, in the dorsal root ganglia and dorsal horns of the spinal cord, we examined the role of kisspeptin in the regulation of pain sensitivity in mice. Results Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol, caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone. Conclusion These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain.

  3. Robust Object Tracking Using Valid Fragments Selection.

    Science.gov (United States)

    Zheng, Jin; Li, Bo; Tian, Peng; Luo, Gang

    Local features are widely used in visual tracking to improve robustness in cases of partial occlusion, deformation and rotation. This paper proposes a local fragment-based object tracking algorithm. Unlike many existing fragment-based algorithms that allocate the weights to each fragment, this method firstly defines discrimination and uniqueness for local fragment, and builds an automatic pre-selection of useful fragments for tracking. Then, a Harris-SIFT filter is used to choose the current valid fragments, excluding occluded or highly deformed fragments. Based on those valid fragments, fragment-based color histogram provides a structured and effective description for the object. Finally, the object is tracked using a valid fragment template combining the displacement constraint and similarity of each valid fragment. The object template is updated by fusing feature similarity and valid fragments, which is scale-adaptive and robust to partial occlusion. The experimental results show that the proposed algorithm is accurate and robust in challenging scenarios.

  4. Occupant behaviour and robustness of building design

    DEFF Research Database (Denmark)

    Buso, Tiziana; Fabi, Valentina; Andersen, Rune Korsholm

    2015-01-01

    in a dynamic building energy simulation tool (IDA ICE). The analysis was carried out by simulating 15 building envelope designs in different thermal zones of an Office Reference Building in 3 climates: Stockholm, Frankfurt and Athens.In general, robustness towards changes in occupants' behaviour increased......Occupant behaviour can cause major discrepancies between the designed and the real total energy use in buildings. A possible solution to reduce the differences between predictions and actual performances is designing robust buildings, i.e. buildings whose performances show little variations...... with alternating occupant behaviour patterns. The aim of this work was to investigate how alternating occupant behaviour patterns impact the performance of different envelope design solutions in terms of building robustness. Probabilistic models of occupants' window opening and use of shading were implemented...

  5. Robust Mediation Analysis Based on Median Regression

    Science.gov (United States)

    Yuan, Ying; MacKinnon, David P.

    2014-01-01

    Mediation analysis has many applications in psychology and the social sciences. The most prevalent methods typically assume that the error distribution is normal and homoscedastic. However, this assumption may rarely be met in practice, which can affect the validity of the mediation analysis. To address this problem, we propose robust mediation analysis based on median regression. Our approach is robust to various departures from the assumption of homoscedasticity and normality, including heavy-tailed, skewed, contaminated, and heteroscedastic distributions. Simulation studies show that under these circumstances, the proposed method is more efficient and powerful than standard mediation analysis. We further extend the proposed robust method to multilevel mediation analysis, and demonstrate through simulation studies that the new approach outperforms the standard multilevel mediation analysis. We illustrate the proposed method using data from a program designed to increase reemployment and enhance mental health of job seekers. PMID:24079925

  6. Robustness of Distance-to-Default

    DEFF Research Database (Denmark)

    Jessen, Cathrine; Lando, David

    2013-01-01

    Distance-to-default is a remarkably robust measure for ranking firms according to their risk of default. The ranking seems to work despite the fact that the Merton model from which the measure is derived produces default probabilities that are far too small when applied to real data. We use...... simulations to investigate the robustness of the distance-to-default measure to different model specifications. Overall we find distance-to-default to be robust to a number of deviations from the simple Merton model that involve different asset value dynamics and different default triggering mechanisms....... A notable exception is a model with stochastic volatility of assets. In this case both the ranking of firms and the estimated default probabilities using distance-to-default perform significantly worse. We therefore propose a volatility adjustment of the distance-to-default measure, that significantly...

  7. Handling Occlusions for Robust Augmented Reality Systems

    Directory of Open Access Journals (Sweden)

    Maidi Madjid

    2010-01-01

    Full Text Available Abstract In Augmented Reality applications, the human perception is enhanced with computer-generated graphics. These graphics must be exactly registered to real objects in the scene and this requires an effective Augmented Reality system to track the user's viewpoint. In this paper, a robust tracking algorithm based on coded fiducials is presented. Square targets are identified and pose parameters are computed using a hybrid approach based on a direct method combined with the Kalman filter. An important factor for providing a robust Augmented Reality system is the correct handling of targets occlusions by real scene elements. To overcome tracking failure due to occlusions, we extend our method using an optical flow approach to track visible points and maintain virtual graphics overlaying when targets are not identified. Our proposed real-time algorithm is tested with different camera viewpoints under various image conditions and shows to be accurate and robust.

  8. Robust Portfolio Optimization using CAPM Approach

    Directory of Open Access Journals (Sweden)

    mohsen gharakhani

    2013-08-01

    Full Text Available In this paper, a new robust model of multi-period portfolio problem has been developed. One of the key concerns in any asset allocation problem is how to cope with uncertainty about future returns. There are some approaches in the literature for this purpose including stochastic programming and robust optimization. Applying these techniques to multi-period portfolio problem may increase the problem size in a way that the resulting model is intractable. In this paper, a novel approach has been proposed to formulate multi-period portfolio problem as an uncertain linear program assuming that asset return follows the single-index factor model. Robust optimization technique has been also used to solve the problem. In order to evaluate the performance of the proposed model, a numerical example has been applied using simulated data.

  9. Robustness of quantum correlations against linear noise

    International Nuclear Information System (INIS)

    Guo, Zhihua; Cao, Huaixin; Qu, Shixian

    2016-01-01

    Relative robustness of quantum correlations (RRoQC) of a bipartite state is firstly introduced relative to a classically correlated state. Robustness of quantum correlations (RoQC) of a bipartite state is then defined as the minimum of RRoQC of the state relative to all classically correlated ones. It is proved that as a function on quantum states, RoQC is nonnegative, lower semi-continuous and neither convex nor concave; especially, it is zero if and only if the state is classically correlated. Thus, RoQC not only quantifies the endurance of quantum correlations of a state against linear noise, but also can be used to distinguish between quantum and classically correlated states. Furthermore, the effects of local quantum channels on the robustness are explored and characterized. (paper)

  10. Parametric uncertainty modeling for robust control

    DEFF Research Database (Denmark)

    Rasmussen, K.H.; Jørgensen, Sten Bay

    1999-01-01

    The dynamic behaviour of a non-linear process can often be approximated with a time-varying linear model. In the presented methodology the dynamics is modeled non-conservatively as parametric uncertainty in linear lime invariant models. The obtained uncertainty description makes it possible...... to perform robustness analysis on a control system using the structured singular value. The idea behind the proposed method is to fit a rational function to the parameter variation. The parameter variation can then be expressed as a linear fractional transformation (LFT), It is discussed how the proposed...... point changes. It is shown that a diagonal PI control structure provides robust performance towards variations in feed flow rate or feed concentrations. However including both liquid and vapor flow delays robust performance specifications cannot be satisfied with this simple diagonal control structure...

  11. Catalase deletion promotes prediabetic phenotype in mice.

    Science.gov (United States)

    Heit, Claire; Marshall, Stephanie; Singh, Surrendra; Yu, Xiaoqing; Charkoftaki, Georgia; Zhao, Hongyu; Orlicky, David J; Fritz, Kristofer S; Thompson, David C; Vasiliou, Vasilis

    2017-02-01

    Hydrogen peroxide is produced endogenously and can be toxic to living organisms by inducing oxidative stress and cell damage. However, it has also been identified as a signal transduction molecule. By metabolizing hydrogen peroxide, catalase protects cells and tissues against oxidative damage and may also influence signal transduction mechanisms. Studies suggest that acatalasemic individuals (i.e., those with very low catalase activity) have a higher risk for the development of diabetes. We now report catalase knockout (Cat -/- ) mice, when fed a normal (6.5% lipid) chow, exhibit an obese phenotype that manifests as an increase in body weight that becomes more pronounced with age. The mice demonstrate altered hepatic and muscle lipid deposition, as well as increases in serum and hepatic triglycerides (TGs), and increased hepatic transcription and protein expression of PPARγ. Liver morphology revealed steatosis with inflammation. Cat -/- mice also exhibited pancreatic morphological changes that correlated with impaired glucose tolerance and increased fasting serum insulin levels, conditions consistent with pre-diabetic status. RNA-seq analyses revealed a differential expression of pathways and genes in Cat -/- mice, many of which are related to metabolic syndrome, diabetes, and obesity, such as Pparg and Cidec. In conclusion, the results of the present study show mice devoid of catalase develop an obese, pre-diabetic phenotype and provide compelling evidence for catalase (or its products) being integral in metabolic regulation. Copyright © 2016. Published by Elsevier Inc.

  12. Tumor radiation responses and tumor oxygenation in aging mice

    International Nuclear Information System (INIS)

    Rockwell, S.

    1989-01-01

    EMT6 mouse mammary tumors transplanted into aging mice are less sensitive to radiation than tumors growing in young adult animals. The experiments reported here compare the radiation dose-response curves defining the survivals of tumor cells in aging mice and in young adult mice. Cell survival curves were assessed in normal air-breathing mice and in mice asphyxiated with N 2 to produce uniform hypoxia throughout the tumors. Analyses of survival curves revealed that 41% of viable malignant cells were severely hypoxic in tumors in aging mice, while only 19% of the tumor cells in young adult animals were radiobiologically hypoxic. This did not appear to reflect anaemia in the old animals. Treatment of aging animals with a perfluorochemical emulsion plus carbogen (95% O 2 /5% CO 2 ) increased radiation response of the tumors, apparently by improving tumor oxygenation and decreasing the number of severely hypoxic, radiation resistant cells in the tumors. (author)

  13. Competition improves robustness against loss of information

    Directory of Open Access Journals (Sweden)

    Arash eKermani Kolankeh

    2015-03-01

    Full Text Available A substantial number of works aimed at modeling the receptive field properties of the primary visual cortex (V1. Their evaluation criterion is usually the similarity of the model response properties to the recorded responses from biological organisms. However, as several algorithms were able to demonstrate some degree of similarity to biological data based on the existing criteria, we focus on the robustness against loss of information in the form of occlusions as an additional constraint for better understanding the algorithmic level of early vision in the brain. We try to investigate the influence of competition mechanisms on the robustness. Therefore, we compared four methods employing different competition mechanisms, namely, independent component analysis, non-negative matrix factorization with sparseness constraint, predictive coding/biased competition, and a Hebbian neural network with lateral inhibitory connections. Each of those methods is known to be capable of developing receptive fields comparable to those of V1 simple-cells. Since measuring the robustness of methods having simple-cell like receptive fields against occlusion is difficult, we measure the robustness using the classification accuracy on the MNIST hand written digit dataset. For this we trained all methods on the training set of the MNIST hand written digits dataset and tested them on a MNIST test set with different levels of occlusions. We observe that methods which employ competitive mechanisms have higher robustness against loss of information. Also the kind of the competition mechanisms plays an important role in robustness. Global feedback inhibition as employed in predictive coding/biased competition has an advantage compared to local lateral inhibition learned by an anti-Hebb rule.

  14. Return Predictability, Model Uncertainty, and Robust Investment

    DEFF Research Database (Denmark)

    Lukas, Manuel

    Stock return predictability is subject to great uncertainty. In this paper we use the model confidence set approach to quantify uncertainty about expected utility from investment, accounting for potential return predictability. For monthly US data and six representative return prediction models, we...... find that confidence sets are very wide, change significantly with the predictor variables, and frequently include expected utilities for which the investor prefers not to invest. The latter motivates a robust investment strategy maximizing the minimal element of the confidence set. The robust investor...... allocates a much lower share of wealth to stocks compared to a standard investor....

  15. Three Contributions to Robust Regression Diagnostics

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2015-01-01

    Roč. 11, č. 2 (2015), s. 69-78 ISSN 1336-9180 Grant - others:GA ČR(CZ) GA13-01930S; Nadační fond na podporu vědy(CZ) Neuron Institutional support: RVO:67985807 Keywords : robust regression * robust econometrics * hypothesis test ing Subject RIV: BA - General Mathematics http://www.degruyter.com/view/j/jamsi.2015.11.issue-2/jamsi-2015-0013/jamsi-2015-0013.xml?format=INT

  16. Robust Inference with Multi-way Clustering

    OpenAIRE

    A. Colin Cameron; Jonah B. Gelbach; Douglas L. Miller; Doug Miller

    2009-01-01

    In this paper we propose a variance estimator for the OLS estimator as well as for nonlinear estimators such as logit, probit and GMM. This variance estimator enables cluster-robust inference when there is two-way or multi-way clustering that is non-nested. The variance estimator extends the standard cluster-robust variance estimator or sandwich estimator for one-way clustering (e.g. Liang and Zeger (1986), Arellano (1987)) and relies on similar relatively weak distributional assumptions. Our...

  17. Robust control synthesis for uncertain dynamical systems

    Science.gov (United States)

    Byun, Kuk-Whan; Wie, Bong; Sunkel, John

    1989-01-01

    This paper presents robust control synthesis techniques for uncertain dynamical systems subject to structured parameter perturbation. Both QFT (quantitative feedback theory) and H-infinity control synthesis techniques are investigated. Although most H-infinity-related control techniques are not concerned with the structured parameter perturbation, a new way of incorporating the parameter uncertainty in the robust H-infinity control design is presented. A generic model of uncertain dynamical systems is used to illustrate the design methodologies investigated in this paper. It is shown that, for a certain noncolocated structural control problem, use of both techniques results in nonminimum phase compensation.

  18. Robustness of multiparty nonlocality to local decoherence

    International Nuclear Information System (INIS)

    Jang, Sung Soon; Cheong, Yong Wook; Kim, Jaewan; Lee, Hai-Woong

    2006-01-01

    We investigate the robustness of multiparty nonlocality under local decoherence, acting independently and equally on each subsystem. To be specific, we consider an N-qubit Greenberger-Horne-Zeilinger (GHZ) state under a depolarization, dephasing, or dissipation channel, and examine nonlocality by testing violation of the Mermin-Klyshko inequality, which is one of Bell's inequalities for multiqubit systems. The results show that the robustness of nonlocality increases with the number of qubits, and that the nonlocality of an N-qubit GHZ state with even N is extremely persistent against dephasing

  19. Robust speaker recognition in noisy environments

    CERN Document Server

    Rao, K Sreenivasa

    2014-01-01

    This book discusses speaker recognition methods to deal with realistic variable noisy environments. The text covers authentication systems for; robust noisy background environments, functions in real time and incorporated in mobile devices. The book focuses on different approaches to enhance the accuracy of speaker recognition in presence of varying background environments. The authors examine: (a) Feature compensation using multiple background models, (b) Feature mapping using data-driven stochastic models, (c) Design of super vector- based GMM-SVM framework for robust speaker recognition, (d) Total variability modeling (i-vectors) in a discriminative framework and (e) Boosting method to fuse evidences from multiple SVM models.

  20. Robust Parametric Control of Spacecraft Rendezvous

    Directory of Open Access Journals (Sweden)

    Dake Gu

    2014-01-01

    Full Text Available This paper proposes a method to design the robust parametric control for autonomous rendezvous of spacecrafts with the inertial information with uncertainty. We consider model uncertainty of traditional C-W equation to formulate the dynamic model of the relative motion. Based on eigenstructure assignment and model reference theory, a concise control law for spacecraft rendezvous is proposed which could be fixed through solving an optimization problem. The cost function considers the stabilization of the system and other performances. Simulation results illustrate the robustness and effectiveness of the proposed control.

  1. Robust cluster analysis and variable selection

    CERN Document Server

    Ritter, Gunter

    2014-01-01

    Clustering remains a vibrant area of research in statistics. Although there are many books on this topic, there are relatively few that are well founded in the theoretical aspects. In Robust Cluster Analysis and Variable Selection, Gunter Ritter presents an overview of the theory and applications of probabilistic clustering and variable selection, synthesizing the key research results of the last 50 years. The author focuses on the robust clustering methods he found to be the most useful on simulated data and real-time applications. The book provides clear guidance for the varying needs of bot

  2. Robust median estimator in logisitc regression

    Czech Academy of Sciences Publication Activity Database

    Hobza, T.; Pardo, L.; Vajda, Igor

    2008-01-01

    Roč. 138, č. 12 (2008), s. 3822-3840 ISSN 0378-3758 R&D Projects: GA MŠk 1M0572 Grant - others:Instituto Nacional de Estadistica (ES) MPO FI - IM3/136; GA MŠk(CZ) MTM 2006-06872 Institutional research plan: CEZ:AV0Z10750506 Keywords : Logistic regression * Median * Robustness * Consistency and asymptotic normality * Morgenthaler * Bianco and Yohai * Croux and Hasellbroeck Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 0.679, year: 2008 http://library.utia.cas.cz/separaty/2008/SI/vajda-robust%20median%20estimator%20in%20logistic%20regression.pdf

  3. Introduction to Robust Estimation and Hypothesis Testing

    CERN Document Server

    Wilcox, Rand R

    2012-01-01

    This revised book provides a thorough explanation of the foundation of robust methods, incorporating the latest updates on R and S-Plus, robust ANOVA (Analysis of Variance) and regression. It guides advanced students and other professionals through the basic strategies used for developing practical solutions to problems, and provides a brief background on the foundations of modern methods, placing the new methods in historical context. Author Rand Wilcox includes chapter exercises and many real-world examples that illustrate how various methods perform in different situations.Introduction to R

  4. Robust-mode analysis of hydrodynamic flows

    Science.gov (United States)

    Roy, Sukesh; Gord, James R.; Hua, Jia-Chen; Gunaratne, Gemunu H.

    2017-04-01

    The emergence of techniques to extract high-frequency high-resolution data introduces a new avenue for modal decomposition to assess the underlying dynamics, especially of complex flows. However, this task requires the differentiation of robust, repeatable flow constituents from noise and other irregular features of a flow. Traditional approaches involving low-pass filtering and principle components analysis have shortcomings. The approach outlined here, referred to as robust-mode analysis, is based on Koopman decomposition. Three applications to (a) a counter-rotating cellular flame state, (b) variations in financial markets, and (c) turbulent injector flows are provided.

  5. Myosin heavy chain isoform expression in adult and juvenile mini-muscle mice bred for high-voluntary wheel running.

    Science.gov (United States)

    Talmadge, Robert J; Acosta, Wendy; Garland, Theodore

    2014-11-01

    The myosin heavy chain (MyHC) isoform composition of locomotor and non-locomotor muscles of mini-muscle mice were assessed at the protein and mRNA levels in both adult and juvenile (21 day old) mice. Mini-muscle mice are one outcome of a replicated artificial selection experiment in which four lines of mice were bred for high voluntary wheel running (HR lines). Two of the lines responded with an increase in frequency of a single nucleotide polymorphism in an intron in the MyHC-2b gene (myh4) that when homozygous causes a dramatic reduction in triceps surae mass. We found that both locomotor and non-locomotor muscles of adult mini-muscle mice displayed robust reductions, but not elimination, of the MyHC-2b isoform at both the protein and mRNA levels, with commensurate increases in MyHC-2x and sometimes MyHC-2a, as compared with either a line of HR mice that does not display the mini-muscle phenotype or inbred C57Bl6 mice. Immunohistochemical analyses revealed that locomotor muscles of mini-muscle mice contain fibers that express the MyHC-2b isoform, which migrates normally in SDS-PAGE gels. However, these MyHC-2b positive fibers are generally smaller than the surrounding fibers and smaller than the MyHC-2b positive fibers of non-mini-muscle mice, resulting in characteristically fast muscles that lack a substantial MyHC-2b positive (superficial) region. In contrast, the masseter, a non-locomotor muscle of mini-muscle mice contained MyHC-2b positive fibers that stained more lightly for MyHC-2b, but appeared normal in size and distribution. In adults, many of the MyHC-2b positive fibers in the mini-muscle mice also display central nuclei. Only a small proportion of small MyHC-2b fibers in mini-muscle mice stained positive for the neural cell adhesion molecule, suggesting that anatomical innervation was not compromised. In addition, weanling (21 day old), but not 5 day old mice, displayed alterations in MyHC isoform content at both the protein and mRNA levels, including

  6. Robust dynamic classes revealed by measuring the response function of a social system.

    Science.gov (United States)

    Crane, Riley; Sornette, Didier

    2008-10-14

    We study the relaxation response of a social system after endogenous and exogenous bursts of activity using the time series of daily views for nearly 5 million videos on YouTube. We find that most activity can be described accurately as a Poisson process. However, we also find hundreds of thousands of examples in which a burst of activity is followed by an ubiquitous power-law relaxation governing the timing of views. We find that these relaxation exponents cluster into three distinct classes and allow for the classification of collective human dynamics. This is consistent with an epidemic model on a social network containing two ingredients: a power-law distribution of waiting times between cause and action and an epidemic cascade of actions becoming the cause of future actions. This model is a conceptual extension of the fluctuation-dissipation theorem to social systems [Ruelle, D (2004) Phys Today 57:48-53] and [Roehner BM, et al., (2004) Int J Mod Phys C 15:809-834], and provides a unique framework for the investigation of timing in complex systems.

  7. Changepoint detection in base-resolution methylome data reveals a robust signature of methylated domain landscape.

    Science.gov (United States)

    Yokoyama, Takao; Miura, Fumihito; Araki, Hiromitsu; Okamura, Kohji; Ito, Takashi

    2015-08-12

    Base-resolution methylome data generated by whole-genome bisulfite sequencing (WGBS) is often used to segment the genome into domains with distinct methylation levels. However, most segmentation methods include many parameters to be carefully tuned and/or fail to exploit the unsurpassed resolution of the data. Furthermore, there is no simple method that displays the composition of the domains to grasp global trends in each methylome. We propose to use changepoint detection for domain demarcation based on base-resolution methylome data. While the proposed method segments the methylome in a largely comparable manner to conventional approaches, it has only a single parameter to be tuned. Furthermore, it fully exploits the base-resolution of the data to enable simultaneous detection of methylation changes in even contrasting size ranges, such as focal hypermethylation and global hypomethylation in cancer methylomes. We also propose a simple plot termed methylated domain landscape (MDL) that globally displays the size, the methylation level and the number of the domains thus defined, thereby enabling one to intuitively grasp trends in each methylome. Since the pattern of MDL often reflects cell lineages and is largely unaffected by data size, it can serve as a novel signature of methylome. Changepoint detection in base-resolution methylome data followed by MDL plotting provides a novel method for methylome characterization and will facilitate global comparison among various WGBS data differing in size and even species origin.

  8. Metabolic characteristics of long-lived mice

    Directory of Open Access Journals (Sweden)

    Andrzej eBartke

    2012-12-01

    Full Text Available Genetic suppression of insulin/insulin-like growth factor signaling (IIS can extend longevity in worms, insects, and mammals. In laboratory mice, mutations with the greatest, most consistent, and best documented positive impact on lifespan are those that disrupt growth hormone (GH release or actions. These mutations lead to major alterations in IIS but also have a variety of effects that are not directly related to the actions of insulin or insulin-like growth factor (IGF-1. Long-lived GH-resistant GHRKO mice with targeted disruption of the GH receptor gene, as well as Ames dwarf (Prop1df and Snell dwarf (Pit1dw mice lacking GH (along with prolactin and TSH, are diminutive in size and have major alterations in body composition and metabolic parameters including increased subcutaneous adiposity, increased relative brain weight, small liver, hypoinsulinemia, mild hypoglycemia, increased adiponectin levels and insulin sensitivity, and reduced serum lipids. Body temperature is reduced in Ames, Snell, and female GHRKO mice. Indirect calorimetry revealed that both Ames dwarf and GHRKO mice utilize more oxygen per gram (g of body weight than sex- and age-matched normal animals from the same strain. They also have reduced respiratory quotient (RQ, implying greater reliance on fats, as opposed to carbohydrates, as an energy source. Differences in oxygen consumption (VO2 were seen in animals fed or fasted during the measurements as well as in animals that had been exposed to 30% calorie restriction or every-other-day feeding. However, at the thermoneutral temperature of 30°C, VO2 did not differ between GHRKO and normal mice. Thus, the increased metabolic rate of the GHRKO mice, at a standard animal room temperature of 23°C, is apparently related to increased energy demands for thermoregulation in these diminutive animals. We suspect that increased oxidative metabolism combined with enhanced fatty acid oxidation contribute to the extended longevity of

  9. Of mice and men

    CERN Multimedia

    1973-01-01

    At the end of March , sixty mice were irradiated at the synchro-cyclotron in the course of an experimental programme studying radiation effects on mice and plants (Vicia faba bean roots) being carried out by the CERN Health Physics Group.

  10. Analysis of mice radiosensitivity depending on age

    International Nuclear Information System (INIS)

    Bogatyrev, A.V.; Timoshenko, S.I.; Nikanorova, N.G.; Sverdlov, A.G.

    1979-01-01

    In order to elucidate mechanisms of age variations in radiosensitivity of mice a study was made of the sensitivity of in vitro irradiated bone marrow stem cells, taken from animals of different age, and postradiation recovery of leukocyte content of peripheral blood and cellularity of bone marrow and spleen. Using the method of spleen colonies similar affections were revealed in bone marrow cells of animals of different age. The degree of recovery of the hemopoietic cell pool was significantly lower in newborn mice than in adults after exposure to a dose (LDsub(50/30)) equally effective with respect to mortality

  11. Action of apilite on radiosensitivity of mice

    International Nuclear Information System (INIS)

    Artemov, N.M.; Kon'kova, L.G.; Sergeyeva, L.I.

    1975-01-01

    A preparation of bee venom - apilite - has been administered to mice in different periods prior to and after the exposure to 600 and 500 r (6 and 10 μg/g, respectively). This preparation is freed from allergizating proteins and enzymes of the venom. Its basic active substance is polypeptid melittine. Apilite has been found to exert a protective effect: the survival of the experimental groups of mice is 27-44 per cent higher than that of the controls. It has also been revealed that apilite has a positive action on a number of indices of the peripheral blood of irradiated animals

  12. Robust giant magnetoresistive effect type multilayer sensor

    NARCIS (Netherlands)

    Lenssen, K.M.H.; Kuiper, A.E.T.; Roozeboom, F.

    2002-01-01

    A robust Giant Magneto Resistive effect type multilayer sensor comprising a free and a pinned ferromagnetic layer, which can withstand high temperatures and strong magnetic fields as required in automotive applications. The GMR multi-layer has an asymmetric magneto-resistive curve and enables

  13. New solutions for NPP robustness improvement

    International Nuclear Information System (INIS)

    Wolski, Alexander

    2013-01-01

    Fukushima accident has triggered a major re-assessment of robustness of nuclear stations. First round of evaluations has been Finished. Improvement areas and strategies have been identified. Implementation of upgrades has started world-wide. New solutions can provide substantial benefits

  14. Robust inference in sample selection models

    KAUST Repository

    Zhelonkin, Mikhail; Genton, Marc G.; Ronchetti, Elvezio

    2015-01-01

    The problem of non-random sample selectivity often occurs in practice in many fields. The classical estimators introduced by Heckman are the backbone of the standard statistical analysis of these models. However, these estimators are very sensitive to small deviations from the distributional assumptions which are often not satisfied in practice. We develop a general framework to study the robustness properties of estimators and tests in sample selection models. We derive the influence function and the change-of-variance function of Heckman's two-stage estimator, and we demonstrate the non-robustness of this estimator and its estimated variance to small deviations from the model assumed. We propose a procedure for robustifying the estimator, prove its asymptotic normality and give its asymptotic variance. Both cases with and without an exclusion restriction are covered. This allows us to construct a simple robust alternative to the sample selection bias test. We illustrate the use of our new methodology in an analysis of ambulatory expenditures and we compare the performance of the classical and robust methods in a Monte Carlo simulation study.

  15. Robust inference in sample selection models

    KAUST Repository

    Zhelonkin, Mikhail

    2015-11-20

    The problem of non-random sample selectivity often occurs in practice in many fields. The classical estimators introduced by Heckman are the backbone of the standard statistical analysis of these models. However, these estimators are very sensitive to small deviations from the distributional assumptions which are often not satisfied in practice. We develop a general framework to study the robustness properties of estimators and tests in sample selection models. We derive the influence function and the change-of-variance function of Heckman\\'s two-stage estimator, and we demonstrate the non-robustness of this estimator and its estimated variance to small deviations from the model assumed. We propose a procedure for robustifying the estimator, prove its asymptotic normality and give its asymptotic variance. Both cases with and without an exclusion restriction are covered. This allows us to construct a simple robust alternative to the sample selection bias test. We illustrate the use of our new methodology in an analysis of ambulatory expenditures and we compare the performance of the classical and robust methods in a Monte Carlo simulation study.

  16. Highly Robust Methods in Data Mining

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2013-01-01

    Roč. 8, č. 1 (2013), s. 9-24 ISSN 1452-4864 Institutional support: RVO:67985807 Keywords : data mining * robust statistics * high-dimensional data * cluster analysis * logistic regression * neural networks Subject RIV: BB - Applied Statistics, Operational Research

  17. Robust Utility Maximization Under Convex Portfolio Constraints

    International Nuclear Information System (INIS)

    Matoussi, Anis; Mezghani, Hanen; Mnif, Mohamed

    2015-01-01

    We study a robust maximization problem from terminal wealth and consumption under a convex constraints on the portfolio. We state the existence and the uniqueness of the consumption–investment strategy by studying the associated quadratic backward stochastic differential equation. We characterize the optimal control by using the duality method and deriving a dynamic maximum principle

  18. Robust diamond meshes with unique wettability properties.

    Science.gov (United States)

    Yang, Yizhou; Li, Hongdong; Cheng, Shaoheng; Zou, Guangtian; Wang, Chuanxi; Lin, Quan

    2014-03-18

    Robust diamond meshes with excellent superhydrophobic and superoleophilic properties have been fabricated. Superhydrophobicity is observed for water with varying pH from 1 to 14 with good recyclability. Reversible superhydrophobicity and hydrophilicity can be easily controlled. The diamond meshes show highly efficient water-oil separation and water pH droplet transference.

  19. Robustness of dynamic systems with parameter uncertainties

    CERN Document Server

    Balemi, S; Truöl, W

    1992-01-01

    Robust Control is one of the fastest growing and promising areas of research today. In many practical systems there exist uncertainties which have to be considered in the analysis and design of control systems. In the last decade methods were developed for dealing with dynamic systems with unstructured uncertainties such as HOO_ and £I-optimal control. For systems with parameter uncertainties, the seminal paper of V. L. Kharitonov has triggered a large amount of very promising research. An international workshop dealing with all aspects of robust control was successfully organized by S. P. Bhattacharyya and L. H. Keel in San Antonio, Texas, USA in March 1991. We organized the second international workshop in this area in Ascona, Switzer­ land in April 1992. However, this second workshop was restricted to robust control of dynamic systems with parameter uncertainties with the objective to concentrate on some aspects of robust control. This book contains a collection of papers presented at the International W...

  20. Robust predictions of the interacting boson model

    International Nuclear Information System (INIS)

    Casten, R.F.; Koeln Univ.

    1994-01-01

    While most recognized for its symmetries and algebraic structure, the IBA model has other less-well-known but equally intrinsic properties which give unavoidable, parameter-free predictions. These predictions concern central aspects of low-energy nuclear collective structure. This paper outlines these ''robust'' predictions and compares them with the data

  1. Robust keyword retrieval method for OCRed text

    Science.gov (United States)

    Fujii, Yusaku; Takebe, Hiroaki; Tanaka, Hiroshi; Hotta, Yoshinobu

    2011-01-01

    Document management systems have become important because of the growing popularity of electronic filing of documents and scanning of books, magazines, manuals, etc., through a scanner or a digital camera, for storage or reading on a PC or an electronic book. Text information acquired by optical character recognition (OCR) is usually added to the electronic documents for document retrieval. Since texts generated by OCR generally include character recognition errors, robust retrieval methods have been introduced to overcome this problem. In this paper, we propose a retrieval method that is robust against both character segmentation and recognition errors. In the proposed method, the insertion of noise characters and dropping of characters in the keyword retrieval enables robustness against character segmentation errors, and character substitution in the keyword of the recognition candidate for each character in OCR or any other character enables robustness against character recognition errors. The recall rate of the proposed method was 15% higher than that of the conventional method. However, the precision rate was 64% lower.

  2. Robust Algebraic Multilevel Methods and Algorithms

    CERN Document Server

    Kraus, Johannes

    2009-01-01

    This book deals with algorithms for the solution of linear systems of algebraic equations with large-scale sparse matrices, with a focus on problems that are obtained after discretization of partial differential equations using finite element methods. Provides a systematic presentation of the recent advances in robust algebraic multilevel methods. Can be used for advanced courses on the topic.

  3. Replication and Robustness in Developmental Research

    Science.gov (United States)

    Duncan, Greg J.; Engel, Mimi; Claessens, Amy; Dowsett, Chantelle J.

    2014-01-01

    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…

  4. A Robust Alternative to the Normal Distribution.

    Science.gov (United States)

    1982-07-07

    for any Purpose of the United States Governuent DEPARTMENT OF STATISTICS t -, STANFORD UIVERSITY I STANFORD, CALIFORNIA A Robust Alternative to the...Stanford University Technical Report No. 3. [5] Bhattacharya, S. K. (1966). A Modified Bessel Function lodel in Life Testing. Metrika 10, 133-144

  5. Robust bayesian inference of generalized Pareto distribution ...

    African Journals Online (AJOL)

    En utilisant une etude exhaustive de Monte Carlo, nous prouvons que, moyennant une fonction perte generalisee adequate, on peut construire un estimateur Bayesien robuste du modele. Key words: Bayesian estimation; Extreme value; Generalized Fisher information; Gener- alized Pareto distribution; Monte Carlo; ...

  6. Robust balance shift control with posture optimization

    NARCIS (Netherlands)

    Kavafoglu, Z.; Kavafoglu, Ersan; Egges, J.

    2015-01-01

    In this paper we present a control framework which creates robust and natural balance shifting behaviours during standing. Given high-level features such as the position of the center of mass projection and the foot configurations, a kinematic posture satisfying these features is synthesized using

  7. Finite Algorithms for Robust Linear Regression

    DEFF Research Database (Denmark)

    Madsen, Kaj; Nielsen, Hans Bruun

    1990-01-01

    The Huber M-estimator for robust linear regression is analyzed. Newton type methods for solution of the problem are defined and analyzed, and finite convergence is proved. Numerical experiments with a large number of test problems demonstrate efficiency and indicate that this kind of approach may...

  8. Robust network design for multispecies conservation

    Science.gov (United States)

    Ronan Le Bras; Bistra Dilkina; Yexiang Xue; Carla P. Gomes; Kevin S. McKelvey; Michael K. Schwartz; Claire A. Montgomery

    2013-01-01

    Our work is motivated by an important network design application in computational sustainability concerning wildlife conservation. In the face of human development and climate change, it is important that conservation plans for protecting landscape connectivity exhibit certain level of robustness. While previous work has focused on conservation strategies that result...

  9. Neuromorphic Configurable Architecture for Robust Motion Estimation

    Directory of Open Access Journals (Sweden)

    Guillermo Botella

    2008-01-01

    Full Text Available The robustness of the human visual system recovering motion estimation in almost any visual situation is enviable, performing enormous calculation tasks continuously, robustly, efficiently, and effortlessly. There is obviously a great deal we can learn from our own visual system. Currently, there are several optical flow algorithms, although none of them deals efficiently with noise, illumination changes, second-order motion, occlusions, and so on. The main contribution of this work is the efficient implementation of a biologically inspired motion algorithm that borrows nature templates as inspiration in the design of architectures and makes use of a specific model of human visual motion perception: Multichannel Gradient Model (McGM. This novel customizable architecture of a neuromorphic robust optical flow can be constructed with FPGA or ASIC device using properties of the cortical motion pathway, constituting a useful framework for building future complex bioinspired systems running in real time with high computational complexity. This work includes the resource usage and performance data, and the comparison with actual systems. This hardware has many application fields like object recognition, navigation, or tracking in difficult environments due to its bioinspired and robustness properties.

  10. Robust control charts in statistical process control

    NARCIS (Netherlands)

    Nazir, H.Z.

    2014-01-01

    The presence of outliers and contaminations in the output of the process highly affects the performance of the design structures of commonly used control charts and hence makes them of less practical use. One of the solutions to deal with this problem is to use control charts which are robust

  11. Some Diagnostic Tools in Robust Econometrics

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2011-01-01

    Roč. 50, č. 2 (2011), s. 55-67 ISSN 0231-9721 Grant - others:GA ČR(CZ) GA402/09/0557 Institutional research plan: CEZ:AV0Z10300504 Keywords : robust regression * autocorrelated errors * heteroscedastic regression * instrumental variables * least weighted squares Subject RIV: BB - Applied Statistics, Operational Research http://dml.cz/handle/10338.dmlcz/141754

  12. Robust estimation for ordinary differential equation models.

    Science.gov (United States)

    Cao, J; Wang, L; Xu, J

    2011-12-01

    Applied scientists often like to use ordinary differential equations (ODEs) to model complex dynamic processes that arise in biology, engineering, medicine, and many other areas. It is interesting but challenging to estimate ODE parameters from noisy data, especially when the data have some outliers. We propose a robust method to address this problem. The dynamic process is represented with a nonparametric function, which is a linear combination of basis functions. The nonparametric function is estimated by a robust penalized smoothing method. The penalty term is defined with the parametric ODE model, which controls the roughness of the nonparametric function and maintains the fidelity of the nonparametric function to the ODE model. The basis coefficients and ODE parameters are estimated in two nested levels of optimization. The coefficient estimates are treated as an implicit function of ODE parameters, which enables one to derive the analytic gradients for optimization using the implicit function theorem. Simulation studies show that the robust method gives satisfactory estimates for the ODE parameters from noisy data with outliers. The robust method is demonstrated by estimating a predator-prey ODE model from real ecological data. © 2011, The International Biometric Society.

  13. Chromatin regulators, phenotypic robustness and autism risk

    Directory of Open Access Journals (Sweden)

    Reut eSuliman

    2014-04-01

    Full Text Available Though extensively characterized clinically, the causes of autism spectrum disorder (ASD remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD.

  14. Robust and Adaptive Control With Aerospace Applications

    CERN Document Server

    Lavretsky, Eugene

    2013-01-01

    Robust and Adaptive Control shows the reader how to produce consistent and accurate controllers that operate in the presence of uncertainties and unforeseen events. Driven by aerospace applications the focus of the book is primarily on continuous-dynamical systems.  The text is a three-part treatment, beginning with robust and optimal linear control methods and moving on to a self-contained presentation of the design and analysis of model reference adaptive control (MRAC) for nonlinear uncertain dynamical systems. Recent extensions and modifications to MRAC design are included, as are guidelines for combining robust optimal and MRAC controllers. Features of the text include: ·         case studies that demonstrate the benefits of robust and adaptive control for piloted, autonomous and experimental aerial platforms; ·         detailed background material for each chapter to motivate theoretical developments; ·         realistic examples and simulation data illustrating key features ...

  15. Robust Pedestrian Navigation for Challenging Applications

    OpenAIRE

    Gilliéron, PY; Renaudin, V

    2009-01-01

    Presentation of a concept for robust indoor navigation. The concept is based on three key elements: - the use of an absolute geographical reference - the hybridisation of complementary technologies - specific motion models. This concept is illustrated by the means of two applications: the urban displacement of blind people and the indoor guidance of fire-fighters

  16. Robust online face tracking-by-detection

    NARCIS (Netherlands)

    Comaschi, F.; Stuijk, S.; Basten, T.; Corporaal, H.

    2016-01-01

    The problem of online face tracking from unconstrained videos is still unresolved. Challenges range from coping with severe online appearance variations to coping with occlusion. We propose RFTD (Robust Face Tracking-by-Detection), a system which combines tracking and detection into a single

  17. Robust control investigations for equipment loaded panels

    DEFF Research Database (Denmark)

    Aglietti, G.S.; Langley, R.S.; Rogers, E.

    1998-01-01

    This paper develops a modelling technique for equipment load panels which directly produces (adequate) models of the underlying dynamics on which to base robust controller design/evaluations. This technique is based on the use of the Lagrange's equations of motion and the resulting models...

  18. Robust Design of Sounds in Mechanical Mechanisms

    DEFF Research Database (Denmark)

    Boegedal Jensen, Annemette; Munch, Natasja; Howard, Thomas J.

    2015-01-01

    mechanism consisting of a toothed rack and a click arm. First several geometries of the teeth and the click arm’s head were investigated to identify the most robust and repeatable design. It was found that a flat surface in the valleys between the teeth is very beneficial in relation to repeatability...

  19. Robust glint detection through homography normalization

    DEFF Research Database (Denmark)

    Hansen, Dan Witzner; Roholm, Lars; García Ferreiros, Iván

    2014-01-01

    A novel normalization principle for robust glint detection is presented. The method is based on geometric properties of corneal reflections and allows for simple and effective detection of glints even in the presence of several spurious and identically appearing reflections. The method is tested...

  20. Robust power spectral estimation for EEG data.

    Science.gov (United States)

    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.

  1. Chance constrained uncertain classification via robust optimization

    NARCIS (Netherlands)

    Ben-Tal, A.; Bhadra, S.; Bhattacharayya, C.; Saketha Nat, J.

    2011-01-01

    This paper studies the problem of constructing robust classifiers when the training is plagued with uncertainty. The problem is posed as a Chance-Constrained Program (CCP) which ensures that the uncertain data points are classified correctly with high probability. Unfortunately such a CCP turns out

  2. Robust Geometric Control of a Distillation Column

    DEFF Research Database (Denmark)

    Kymmel, Mogens; Andersen, Henrik Weisberg

    1987-01-01

    A frequency domain method, which makes it possible to adjust multivariable controllers with respect to both nominal performance and robustness, is presented. The basic idea in the approach is that the designer assigns objectives such as steady-state tracking, maximum resonance peaks, bandwidth, m...... is used to examine and improve geometric control of a binary distillation column....

  3. Quantifying the robustness of metro networks

    NARCIS (Netherlands)

    Wang, X.; Koç, Y.; Derrible, S.; Nasir Ahmad, Sk.; Kooij, R.E.

    2015-01-01

    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 network topological entities,

  4. Robust Refinement as Implemented in TOPAS

    Energy Technology Data Exchange (ETDEWEB)

    Stone, K.; Stephens, P

    2010-01-01

    A robust refinement procedure is implemented in the program TOPAS through an iterative reweighting of the data. Examples are given of the procedure as applied to fitting partially overlapped peaks by full and partial models and also of the structures of ibuprofen and acetaminophen in the presence of unmodeled impurity contributions

  5. Robust Satisfiability of Systems of Equations

    Czech Academy of Sciences Publication Activity Database

    Franek, Peter; Krčál, M.

    2015-01-01

    Roč. 62, č. 4 (2015), Article 26 ISSN 0004-5411 R&D Projects: GA ČR GBP202/12/G061 Grant - others:GA MŠk(CZ) LL1201 Institutional support: RVO:67985807 Keywords : nonlinear equations * satisfability * undecibility * topological extensions * uncertainty * robustness Subject RIV: IN - Informatics, Computer Science Impact factor: 1.803, year: 2015

  6. Robust fitting of diurnal brightness temperature cycle

    CSIR Research Space (South Africa)

    Udahemuka, G

    2007-11-01

    Full Text Available for a pixel concerned. Robust fitting of observed Diurnal Temperature Cycle (DTC) taken over a day of a given pixel without cloud cover and other abnormally conditions such as fire can give a data based brightness temperature model for a given pixel...

  7. The MICE Online Systems

    CERN Multimedia

    CERN. Geneva

    2012-01-01

    The Muon Ionization Cooling Experiment (MICE) is designed to test transverse cooling of a muon beam, demonstrating an important step along the path toward creating future high intensity muon beam facilities. Protons in the ISIS synchrotron impact a titanium target, producing pions which decay into muons that propagate through the beam line to the MICE cooling channel. Along the beam line, particle identification (PID) detectors, scintillating fiber tracking detectors, and beam diagnostic tools identify and measure individual muons moving through the cooling channel. The MICE Online Systems encompass all tools; including hardware, software, and documentation, within the MLCR (MICE Local Control Room) that allow the experiment to efficiently record high quality data. Controls and Monitoring (C&M), Data Acquisition (DAQ), Online Monitoring and Reconstruction, Data Transfer, and Networking all fall under the Online Systems umbrella. C&M controls all MICE systems including the target, conventional an...

  8. Effects of methodology and analysis strategy on robustness of pestivirus phylogeny.

    Science.gov (United States)

    Liu, Lihong; Xia, Hongyan; Baule, Claudia; Belák, Sándor; Wahlberg, Niklas

    2010-01-01

    Phylogenetic analysis of pestiviruses is a useful tool for classifying novel pestiviruses and for revealing their phylogenetic relationships. In this study, robustness of pestivirus phylogenies has been compared by analyses of the 5'UTR, and complete N(pro) and E2 gene regions separately and combined, performed by four methods: neighbour-joining (NJ), maximum parsimony (MP), maximum likelihood (ML), and Bayesian inference (BI). The strategy of analysing the combined sequence dataset by BI, ML, and MP methods resulted in a single, well-supported tree topology, indicating a reliable and robust pestivirus phylogeny. By contrast, the single-gene analysis strategy resulted in 12 trees of different topologies, revealing different relationships among pestiviruses. These results indicate that the strategies and methodologies are two vital aspects affecting the robustness of the pestivirus phylogeny. The strategy and methodologies outlined in this paper may have a broader application in inferring phylogeny of other RNA viruses.

  9. Robustness of Linear Systems towards Multi-Dissipative Pertubations

    DEFF Research Database (Denmark)

    Thygesen, Uffe Høgsbro; Poulsen, Niels Kjølstad

    1997-01-01

    We consider the question of robust stability of a linear time invariant plant subject to dynamic perturbations, which are dissipative in the sense of Willems with respect to several quadratic supply rates. For instance, parasitic dynamics are often both small gain and passive. We reduce several...... robustness analysis questions to linear matrix inequalities: robust stability, robust H2 performance and robust performance in presence of disturbances with finite signal-to-noise ratios...

  10. Robust Parameter Coordination for Multidisciplinary Design

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    This paper introduced a robust parameter coordination method to analyze parameter uncertainties so as to predict conflicts and coordinate parameters in multidisciplinary design. The proposed method is based on constraints network, which gives a formulated model to analyze the coupling effects between design variables and product specifications. In this model, interval boxes are adopted to describe the uncertainty of design parameters quantitatively to enhance the design robustness. To solve this constraint network model, a general consistent algorithm framework is designed and implemented with interval arithmetic and the genetic algorithm, which can deal with both algebraic and ordinary differential equations. With the help of this method, designers could infer the consistent solution space from the given specifications. A case study involving the design of a bogie dumping system demonstrates the usefulness of this approach.

  11. Robust lyapunov controller for uncertain systems

    KAUST Repository

    Laleg-Kirati, Taous-Meriem

    2017-02-23

    Various examples of systems and methods are provided for Lyapunov control for uncertain systems. In one example, a system includes a process plant and a robust Lyapunov controller configured to control an input of the process plant. The robust Lyapunov controller includes an inner closed loop Lyapunov controller and an outer closed loop error stabilizer. In another example, a method includes monitoring a system output of a process plant; generating an estimated system control input based upon a defined output reference; generating a system control input using the estimated system control input and a compensation term; and adjusting the process plant based upon the system control input to force the system output to track the defined output reference. An inner closed loop Lyapunov controller can generate the estimated system control input and an outer closed loop error stabilizer can generate the system control input.

  12. Communicating via robust synchronization of chaotic lasers

    International Nuclear Information System (INIS)

    Lopez-Gutierrez, R.M.; Posadas-Castillo, C.; Lopez-Mancilla, D.; Cruz-Hernandez, C.

    2009-01-01

    In this paper, the robust synchronization problem for coupled chaotic Nd:YAG lasers is addressed. We resort to complex systems theory to achieve chaos synchronization. Based on stability theory, it is shown that the state trajectories of the perturbed error synchronization are ultimately bounded, provided the unperturbed synchronization error system is exponentially stable, and some conditions on the bounds of the perturbation terms are satisfied. So that, encoding, transmission, and decoding in chaotic optical communications are presented. We analyze the transmission and recovery of encrypted information when parameter mismatches are considered. Computer simulations are provided to show the effectiveness of this robustness synchronization property, we present the encrypted transmission of image messages, and we show that, the transmitted image is faithfully recovered.

  13. Communicating via robust synchronization of chaotic lasers

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Gutierrez, R.M. [Engineering Faculty, Baja California Autonomous University (UABC), Km. 103 Carret. Tij-Ens., 22860 Ensenada, B.C. (Mexico); Posadas-Castillo, C. [Engineering Faculty, Baja California Autonomous University (UABC), Km. 103 Carret. Tij-Ens., 22860 Ensenada, B.C. (Mexico); FIME, Autonomous University of Nuevo Leon (UANL), Pedro de Alba, S.N., Cd. Universitaria, San Nicolas de los Garza, NL (Mexico); Lopez-Mancilla, D. [Departamento de Ciencias Exactas y Tecnologicas, Centro Universitario de los Lagos, Universidad de Guadalajara (CULagos-UdeG), Enrique Diaz de Leon s/n, 47460 Lagos de Moreno, Jal. (Mexico); Cruz-Hernandez, C. [Electronics and Telecommunications Department, Scientific Research and Advanced Studies of Ensenada (CICESE), Km. 107 Carret. Tij-Ens., 22860 Ensenada, B.C. (Mexico)], E-mail: ccruz@cicese.mx

    2009-10-15

    In this paper, the robust synchronization problem for coupled chaotic Nd:YAG lasers is addressed. We resort to complex systems theory to achieve chaos synchronization. Based on stability theory, it is shown that the state trajectories of the perturbed error synchronization are ultimately bounded, provided the unperturbed synchronization error system is exponentially stable, and some conditions on the bounds of the perturbation terms are satisfied. So that, encoding, transmission, and decoding in chaotic optical communications are presented. We analyze the transmission and recovery of encrypted information when parameter mismatches are considered. Computer simulations are provided to show the effectiveness of this robustness synchronization property, we present the encrypted transmission of image messages, and we show that, the transmitted image is faithfully recovered.

  14. Robust small area prediction for counts.

    Science.gov (United States)

    Tzavidis, Nikos; Ranalli, M Giovanna; Salvati, Nicola; Dreassi, Emanuela; Chambers, Ray

    2015-06-01

    A new semiparametric approach to model-based small area prediction for counts is proposed and used for estimating the average number of visits to physicians for Health Districts in Central Italy. The proposed small area predictor can be viewed as an outlier robust alternative to the more commonly used empirical plug-in predictor that is based on a Poisson generalized linear mixed model with Gaussian random effects. Results from the real data application and from a simulation experiment confirm that the proposed small area predictor has good robustness properties and in some cases can be more efficient than alternative small area approaches. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  15. Robust quantum optimizer with full connectivity.

    Science.gov (United States)

    Nigg, Simon E; Lörch, Niels; Tiwari, Rakesh P

    2017-04-01

    Quantum phenomena have the potential to speed up the solution of hard optimization problems. For example, quantum annealing, based on the quantum tunneling effect, has recently been shown to scale exponentially better with system size than classical simulated annealing. However, current realizations of quantum annealers with superconducting qubits face two major challenges. First, the connectivity between the qubits is limited, excluding many optimization problems from a direct implementation. Second, decoherence degrades the success probability of the optimization. We address both of these shortcomings and propose an architecture in which the qubits are robustly encoded in continuous variable degrees of freedom. By leveraging the phenomenon of flux quantization, all-to-all connectivity with sufficient tunability to implement many relevant optimization problems is obtained without overhead. Furthermore, we demonstrate the robustness of this architecture by simulating the optimal solution of a small instance of the nondeterministic polynomial-time hard (NP-hard) and fully connected number partitioning problem in the presence of dissipation.

  16. Robust haptic large distance telemanipulation for ITER

    International Nuclear Information System (INIS)

    Heck, D.J.F.; Heemskerk, C.J.M.; Koning, J.F.; Abbasi, A.; Nijmeijer, H.

    2013-01-01

    Highlights: • ITER remote handling maintenance can be controlled safely over a large distance. • Bilateral teleoperation experiments were performed in a local network. • Wave variables make the controller robust against constant communication delays. • Master and slave position synchronization guaranteed by proportional action. -- Abstract: During shutdowns, maintenance crews are expected to work in 24/6 shifts to perform critical remote handling maintenance tasks on the ITER system. In this article, we investigate the possibility to safely perform these haptic maintenance tasks remotely from control stations located anywhere around the world. To guarantee stability in time delayed bilateral teleoperation, the symmetric position tracking controller using wave variables is selected. This algorithm guarantees robustness against communication delays, can eliminate wave reflections and provide position synchronization of the master and slave devices. Experiments have been conducted under realistic local network bandwidth, latency and jitter constraints. They show sufficient transparency even for substantial communication delays

  17. Design of Robust Neural Network Classifiers

    DEFF Research Database (Denmark)

    Larsen, Jan; Andersen, Lars Nonboe; Hintz-Madsen, Mads

    1998-01-01

    This paper addresses a new framework for designing robust neural network classifiers. The network is optimized using the maximum a posteriori technique, i.e., the cost function is the sum of the log-likelihood and a regularization term (prior). In order to perform robust classification, we present...... a modified likelihood function which incorporates the potential risk of outliers in the data. This leads to the introduction of a new parameter, the outlier probability. Designing the neural classifier involves optimization of network weights as well as outlier probability and regularization parameters. We...... suggest to adapt the outlier probability and regularisation parameters by minimizing the error on a validation set, and a simple gradient descent scheme is derived. In addition, the framework allows for constructing a simple outlier detector. Experiments with artificial data demonstrate the potential...

  18. Robustness and modular structure in networks

    DEFF Research Database (Denmark)

    Bagrow, James P.; Lehmann, Sune; Ahn, Yong-Yeol

    2015-01-01

    -12]. Many complex systems, from power grids and the Internet to the brain and society [13-15], can be modeled using modular networks comprised of small, densely connected groups of nodes [16, 17]. These modules often overlap, with network elements belonging to multiple modules [18, 19]. Yet existing work...... on robustness has not considered the role of overlapping, modular structure. Here we study the robustness of these systems to the failure of elements. We show analytically and empirically that it is possible for the modules themselves to become uncoupled or non-overlapping well before the network disintegrates....... If overlapping modular organization plays a role in overall functionality, networks may be far more vulnerable than predicted by conventional percolation theory....

  19. Track filtering by robust neural network

    International Nuclear Information System (INIS)

    Baginyan, S.A.; Kisel', I.V.; Konotopskaya, E.V.; Ososkov, G.A.

    1993-01-01

    In the present paper we study the following problems of track information extraction by the artificial neural network (ANN) rotor model: providing initial ANN configuration by an algorithm general enough to be applicable for any discrete detector in- or out of a magnetic field; robustness to heavy contaminated raw data (up to 100% signal-to-noise ratio); stability to the growing event multiplicity. These problems were carried out by corresponding innovations of our model, namely: by a special one-dimensional histogramming, by multiplying weights by a specially designed robust multiplier, and by replacing the simulated annealing schedule by ANN dynamics with an optimally fixed temperature. Our approach is valid for both circular and straight (non-magnetic) tracks and tested on 2D simulated data contaminated by 100% noise points distributed uniformly. To be closer to some reality in our simulation, we keep parameters of the cylindrical spectrometer ARES. 12 refs.; 9 figs

  20. Robustness analysis method for orbit control

    Science.gov (United States)

    Zhang, Jingrui; Yang, Keying; Qi, Rui; Zhao, Shuge; Li, Yanyan

    2017-08-01

    Satellite orbits require periodical maintenance due to the presence of perturbations. However, random errors caused by inaccurate orbit determination and thrust implementation may lead to failure of the orbit control strategy. Therefore, it is necessary to analyze the robustness of the orbit control methods. Feasible strategies which are tolerant to errors of a certain magnitude can be developed to perform reliable orbit control for the satellite. In this paper, first, the orbital dynamic model is formulated by Gauss' form of the planetary equation using the mean orbit elements; the atmospheric drag and the Earth's non-spherical perturbations are taken into consideration in this model. Second, an impulsive control strategy employing the differential correction algorithm is developed to maintain the satellite trajectory parameters in given ranges. Finally, the robustness of the impulsive control method is analyzed through Monte Carlo simulations while taking orbit determination error and thrust error into account.

  1. The Robustness of High Danish National Happiness

    DEFF Research Database (Denmark)

    Hussain, M. Azhar

    2014-01-01

    Denmark’s top position in various rankings of country happiness is well-documented. This study goes beyond the national average comparisons and investigates whether Denmark’s top position is also found when we disaggregate data in line with social categories often used within the social sciences....... The central measure is the empirical probability that a given population subgroup in Denmark has significantly higher happiness compared to another country’s similar subgroup in a given year. All five rounds of the European Social Survey are used but only the sixteen countries that were surveyed in each...... of the five rounds are included in this study. The results show that Denmark’s position at the top of the happiness scale is also robust when we look at population subgroups, but not in the sense that Denmark dominates all countries for all years. Instead, a modified version of robustness is necessary...

  2. Reliability and Robustness Evaluation of Timber Structures

    DEFF Research Database (Denmark)

    Cizmar, Dean; Sørensen, John Dalsgaard; Kirkegaard, Poul Henning

    In the last few decades there have been intensely research concerning reliability of timber structures. This is primarily because there is an increased focus on society on sustainability and environmental aspects. Modern timber as a building material is also being competitive compared to concrete...... and steel. However, reliability models applied to timber were always related to individual components but not the systems. as any real structure is a complex system, system behaviour must be of a particular interest. In the chapter 1 of this document an overview of stochastic models for strength and loads...... (deterministic, probabilistic and risk based approaches) of the robustness are given. Chapter 3 deals more detailed with the robustness of timber structures....

  3. Robust haptic large distance telemanipulation for ITER

    Energy Technology Data Exchange (ETDEWEB)

    Heck, D.J.F., E-mail: d.j.f.heck@tue.nl [Eindhoven University of Technology, Department of Mechanical Engineering, Eindhoven (Netherlands); Heemskerk, C.J.M.; Koning, J.F. [Heemskerk Innovative Technologies, Sassenheim (Netherlands); Abbasi, A.; Nijmeijer, H. [Eindhoven University of Technology, Department of Mechanical Engineering, Eindhoven (Netherlands)

    2013-10-15

    Highlights: • ITER remote handling maintenance can be controlled safely over a large distance. • Bilateral teleoperation experiments were performed in a local network. • Wave variables make the controller robust against constant communication delays. • Master and slave position synchronization guaranteed by proportional action. -- Abstract: During shutdowns, maintenance crews are expected to work in 24/6 shifts to perform critical remote handling maintenance tasks on the ITER system. In this article, we investigate the possibility to safely perform these haptic maintenance tasks remotely from control stations located anywhere around the world. To guarantee stability in time delayed bilateral teleoperation, the symmetric position tracking controller using wave variables is selected. This algorithm guarantees robustness against communication delays, can eliminate wave reflections and provide position synchronization of the master and slave devices. Experiments have been conducted under realistic local network bandwidth, latency and jitter constraints. They show sufficient transparency even for substantial communication delays.

  4. Robust blood-glucose control using Mathematica.

    Science.gov (United States)

    Kovács, Levente; Paláncz, Béla; Benyó, Balázs; Török, László; Benyó, Zoltán

    2006-01-01

    A robust control design on frequency domain using Mathematica is presented for regularization of glucose level in type I diabetes persons under intensive care. The method originally proposed under Mathematica by Helton and Merino, --now with an improved disturbance rejection constraint inequality--is employed, using a three-state minimal patient model. The robustness of the resulted high-order linear controller is demonstrated by nonlinear closed loop simulation in state-space, in case of standard meal disturbances and is compared with H infinity design implemented with the mu-toolbox of Matlab. The controller designed with model parameters represented the most favorable plant dynamics from the point of view of control purposes, can operate properly even in case of parameter values of the worst-case scenario.

  5. Model predictive control classical, robust and stochastic

    CERN Document Server

    Kouvaritakis, Basil

    2016-01-01

    For the first time, a textbook that brings together classical predictive control with treatment of up-to-date robust and stochastic techniques. Model Predictive Control describes the development of tractable algorithms for uncertain, stochastic, constrained systems. The starting point is classical predictive control and the appropriate formulation of performance objectives and constraints to provide guarantees of closed-loop stability and performance. Moving on to robust predictive control, the text explains how similar guarantees may be obtained for cases in which the model describing the system dynamics is subject to additive disturbances and parametric uncertainties. Open- and closed-loop optimization are considered and the state of the art in computationally tractable methods based on uncertainty tubes presented for systems with additive model uncertainty. Finally, the tube framework is also applied to model predictive control problems involving hard or probabilistic constraints for the cases of multiplic...

  6. Robust facility location: Hedging against failures

    International Nuclear Information System (INIS)

    Hernandez, Ivan; Emmanuel Ramirez-Marquez, Jose; Rainwater, Chase; Pohl, Edward; Medal, Hugh

    2014-01-01

    While few companies would be willing to sacrifice day-to-day operations to hedge against disruptions, designing for robustness can yield solutions that perform well before and after failures have occurred. Through a multi-objective optimization approach this paper provides decision makers the option to trade-off total weighted distance before and after disruptions in the Facility Location Problem. Additionally, this approach allows decision makers to understand the impact on the opening of facilities on total distance and on system robustness (considering the system as the set of located facilities). This approach differs from previous studies in that hedging against failures is done without having to elicit facility failure probabilities concurrently without requiring the allocation of additional hardening/protections resources. The approach is applied to two datasets from the literature

  7. Robust photometric stereo using structural light sources

    Science.gov (United States)

    Han, Tian-Qi; Cheng, Yue; Shen, Hui-Liang; Du, Xin

    2014-05-01

    We propose a robust photometric stereo method by using structural arrangement of light sources. In the arrangement, light sources are positioned on a planar grid and form a set of collinear combinations. The shadow pixels are detected by adaptive thresholding. The specular highlight and diffuse pixels are distinguished according to their intensity deviations of the collinear combinations, thanks to the special arrangement of light sources. The highlight detection problem is cast as a pattern classification problem and is solved using support vector machine classifiers. Considering the possible misclassification of highlight pixels, the ℓ1 regularization is further employed in normal map estimation. Experimental results on both synthetic and real-world scenes verify that the proposed method can robustly recover the surface normal maps in the case of heavy specular reflection and outperforms the state-of-the-art techniques.

  8. Energy metabolism in BPH/2J genetically hypertensive mice.

    Science.gov (United States)

    Jackson, Kristy L; Nguyen-Huu, Thu-Phuc; Davern, Pamela J; Head, Geoffrey A

    2014-05-01

    Recent evidence indicates that genetic hypertension in BPH/2J mice is sympathetically mediated, but these mice also have lower body weight (BW) and elevated locomotor activity compared with BPN/3J normotensive mice, suggestive of metabolic abnormalities. The aim of the present study was to determine whether hypertension in BPH/2J mice is associated with metabolic differences. Whole-body metabolic and cardiovascular parameters were measured over 24 h by indirect calorimetry and radiotelemetry respectively, in conscious young (10-13 weeks) and older (22-23 weeks) BPH/2J, normotensive BPN/3J and C57Bl6 mice. Blood pressure (BP) was greater in BPH/2J compared with both normotensive strains at both ages (PBPH/2J compared with BPN/3J mice (PBPH/2J and normotensive mice when adjusted for activity (P>0.1) suggesting differences in this relationship are not responsible for hypertension. EchoMRI revealed that percentage body composition was comparable in BPN/3J and BPH/2J mice (P>0.1) and both strains gained weight similarly with age (P=0.3). Taken together, the present findings indicate that hypertension in BPH/2J mice does not appear to be related to altered energy metabolism.

  9. COA based robust output feedback UPFC controller design

    Energy Technology Data Exchange (ETDEWEB)

    Shayeghi, H., E-mail: hshayeghi@gmail.co [Technical Engineering Department, University of Mohaghegh Ardabili, Ardabil (Iran, Islamic Republic of); Shayanfar, H.A. [Center of Excellence for Power System Automation and Operation, Electrical Engineering Department, Iran University of Science and Technology, Tehran (Iran, Islamic Republic of); Jalilzadeh, S.; Safari, A. [Technical Engineering Department, Zanjan University, Zanjan (Iran, Islamic Republic of)

    2010-12-15

    In this paper, a novel method for the design of output feedback controller for unified power flow controller (UPFC) using chaotic optimization algorithm (COA) is developed. Chaotic optimization algorithms, which have the features of easy implementation, short execution time and robust mechanisms of escaping from the local optimum, is a promising tool for the engineering applications. The selection of the output feedback gains for the UPFC controllers is converted to an optimization problem with the time domain-based objective function which is solved by a COA based on Lozi map. Since chaotic mapping enjoys certainty, ergodicity and the stochastic property, the proposed chaotic optimization problem introduces chaos mapping using Lozi map chaotic sequences which increases its convergence rate and resulting precision. To ensure the robustness of the proposed stabilizers, the design process takes into account a wide range of operating conditions and system configurations. The effectiveness of the proposed controller for damping low frequency oscillations is tested and demonstrated through non-linear time-domain simulation and some performance indices studies. The results analysis reveals that the designed COA based output feedback UPFC damping controller has an excellent capability in damping power system low frequency oscillations and enhance greatly the dynamic stability of the power systems.

  10. 2D Vector Field Simplification Based on Robustness

    KAUST Repository

    Skraba, Primoz

    2014-03-01

    Vector field simplification aims to reduce the complexity of the flow by removing features in order of their relevance and importance, to reveal prominent behavior and obtain a compact representation for interpretation. Most existing simplification techniques based on the topological skeleton successively remove pairs of critical points connected by separatrices, using distance or area-based relevance measures. These methods rely on the stable extraction of the topological skeleton, which can be difficult due to instability in numerical integration, especially when processing highly rotational flows. These geometric metrics do not consider the flow magnitude, an important physical property of the flow. In this paper, we propose a novel simplification scheme derived from the recently introduced topological notion of robustness, which provides a complementary view on flow structure compared to the traditional topological-skeleton-based approaches. Robustness enables the pruning of sets of critical points according to a quantitative measure of their stability, that is, the minimum amount of vector field perturbation required to remove them. This leads to a hierarchical simplification scheme that encodes flow magnitude in its perturbation metric. Our novel simplification algorithm is based on degree theory, has fewer boundary restrictions, and so can handle more general cases. Finally, we provide an implementation under the piecewise-linear setting and apply it to both synthetic and real-world datasets. © 2014 IEEE.

  11. Robust gates for holonomic quantum computation

    International Nuclear Information System (INIS)

    Florio, Giuseppe; Pascazio, Saverio; Facchi, Paolo; Fazio, Rosario; Giovannetti, Vittorio

    2006-01-01

    Non-Abelian geometric phases are attracting increasing interest because of possible experimental application in quantum computation. We study the effects of the environment (modeled as an ensemble of harmonic oscillators) on a holonomic transformation and write the corresponding master equation. The solution is analytically and numerically investigated and the behavior of the fidelity analyzed: fidelity revivals are observed and an optimal finite operation time is determined at which the gate is most robust against noise

  12. Heteroscedasticity resistant robust covariance matrix estimator

    Czech Academy of Sciences Publication Activity Database

    Víšek, Jan Ámos

    2010-01-01

    Roč. 17, č. 27 (2010), s. 33-49 ISSN 1212-074X Grant - others:GA UK(CZ) GA402/09/0557 Institutional research plan: CEZ:AV0Z10750506 Keywords : Regression * Covariance matrix * Heteroscedasticity * Resistant Subject RIV: BB - Applied Statistics, Operational Research http://library.utia.cas.cz/separaty/2011/SI/visek-heteroscedasticity resistant robust covariance matrix estimator.pdf

  13. Robust motion estimation using connected operators

    OpenAIRE

    Salembier Clairon, Philippe Jean; Sanson, H

    1997-01-01

    This paper discusses the use of connected operators for robust motion estimation The proposed strategy involves a motion estimation step extracting the dominant motion and a ltering step relying on connected operators that remove objects that do not fol low the dominant motion. These two steps are iterated in order to obtain an accurate motion estimation and a precise de nition of the objects fol lowing this motion This strategy can be applied on the entire frame or on individual connected c...

  14. Muscle Synergy-Driven Robust Motion Control.

    Science.gov (United States)

    Min, Kyuengbo; Iwamoto, Masami; Kakei, Shinji; Kimpara, Hideyuki

    2018-04-01

    Humans are able to robustly maintain desired motion and posture under dynamically changing circumstances, including novel conditions. To accomplish this, the brain needs to optimize the synergistic control between muscles against external dynamic factors. However, previous related studies have usually simplified the control of multiple muscles using two opposing muscles, which are minimum actuators to simulate linear feedback control. As a result, they have been unable to analyze how muscle synergy contributes to motion control robustness in a biological system. To address this issue, we considered a new muscle synergy concept used to optimize the synergy between muscle units against external dynamic conditions, including novel conditions. We propose that two main muscle control policies synergistically control muscle units to maintain the desired motion against external dynamic conditions. Our assumption is based on biological evidence regarding the control of multiple muscles via the corticospinal tract. One of the policies is the group control policy (GCP), which is used to control muscle group units classified based on functional similarities in joint control. This policy is used to effectively resist external dynamic circumstances, such as disturbances. The individual control policy (ICP) assists the GCP in precisely controlling motion by controlling individual muscle units. To validate this hypothesis, we simulated the reinforcement of the synergistic actions of the two control policies during the reinforcement learning of feedback motion control. Using this learning paradigm, the two control policies were synergistically combined to result in robust feedback control under novel transient and sustained disturbances that did not involve learning. Further, by comparing our data to experimental data generated by human subjects under the same conditions as those of the simulation, we showed that the proposed synergy concept may be used to analyze muscle synergy

  15. Optimal interdependence enhances robustness of complex systems

    OpenAIRE

    Singh, R. K.; Sinha, Sitabhra

    2017-01-01

    While interdependent systems have usually been associated with increased fragility, we show that strengthening the interdependence between dynamical processes on different networks can make them more robust. By coupling the dynamics of networks that in isolation exhibit catastrophic collapse with extinction of nodal activity, we demonstrate system-wide persistence of activity for an optimal range of interdependence between the networks. This is related to the appearance of attractors of the g...

  16. Stability Constraints for Robust Model Predictive Control

    Directory of Open Access Journals (Sweden)

    Amanda G. S. Ottoni

    2015-01-01

    Full Text Available This paper proposes an approach for the robust stabilization of systems controlled by MPC strategies. Uncertain SISO linear systems with box-bounded parametric uncertainties are considered. The proposed approach delivers some constraints on the control inputs which impose sufficient conditions for the convergence of the system output. These stability constraints can be included in the set of constraints dealt with by existing MPC design strategies, in this way leading to the “robustification” of the MPC.

  17. Automatic Mode Transition Enabled Robust Triboelectric Nanogenerators.

    Science.gov (United States)

    Chen, Jun; Yang, Jin; Guo, Hengyu; Li, Zhaoling; Zheng, Li; Su, Yuanjie; Wen, Zhen; Fan, Xing; Wang, Zhong Lin

    2015-12-22

    Although the triboelectric nanogenerator (TENG) has been proven to be a renewable and effective route for ambient energy harvesting, its robustness remains a great challenge due to the requirement of surface friction for a decent output, especially for the in-plane sliding mode TENG. Here, we present a rationally designed TENG for achieving a high output performance without compromising the device robustness by, first, converting the in-plane sliding electrification into a contact separation working mode and, second, creating an automatic transition between a contact working state and a noncontact working state. The magnet-assisted automatic transition triboelectric nanogenerator (AT-TENG) was demonstrated to effectively harness various ambient rotational motions to generate electricity with greatly improved device robustness. At a wind speed of 6.5 m/s or a water flow rate of 5.5 L/min, the harvested energy was capable of lighting up 24 spot lights (0.6 W each) simultaneously and charging a capacitor to greater than 120 V in 60 s. Furthermore, due to the rational structural design and unique output characteristics, the AT-TENG was not only capable of harvesting energy from natural bicycling and car motion but also acting as a self-powered speedometer with ultrahigh accuracy. Given such features as structural simplicity, easy fabrication, low cost, wide applicability even in a harsh environment, and high output performance with superior device robustness, the AT-TENG renders an effective and practical approach for ambient mechanical energy harvesting as well as self-powered active sensing.

  18. Matlab as a robust control design tool

    Science.gov (United States)

    Gregory, Irene M.

    1994-01-01

    This presentation introduces Matlab as a tool used in flight control research. The example used to illustrate some of the capabilities of this software is a robust controller designed for a single stage to orbit air breathing vehicles's ascent to orbit. The global requirements of the controller are to stabilize the vehicle and follow a trajectory in the presence of atmospheric disturbances and strong dynamic coupling between airframe and propulsion.

  19. Adding query privacy to robust DHTs

    DEFF Research Database (Denmark)

    Backes, Michael; Goldberg, Ian; Kate, Aniket

    2012-01-01

    intermediate peers that (help to) route the queries towards their destinations. In this paper, we satisfy this requirement by presenting an approach for providing privacy for the keys in DHT queries. We use the concept of oblivious transfer (OT) in communication over DHTs to preserve query privacy without...... privacy over robust DHTs. Finally, we compare the performance of our privacy-preserving protocols with their more privacy-invasive counterparts. We observe that there is no increase in the message complexity...

  20. Sparse alignment for robust tensor learning.

    Science.gov (United States)

    Lai, Zhihui; Wong, Wai Keung; Xu, Yong; Zhao, Cairong; Sun, Mingming

    2014-10-01

    Multilinear/tensor extensions of manifold learning based algorithms have been widely used in computer vision and pattern recognition. This paper first provides a systematic analysis of the multilinear extensions for the most popular methods by using alignment techniques, thereby obtaining a general tensor alignment framework. From this framework, it is easy to show that the manifold learning based tensor learning methods are intrinsically different from the alignment techniques. Based on the alignment framework, a robust tensor learning method called sparse tensor alignment (STA) is then proposed for unsupervised tensor feature extraction. Different from the existing tensor learning methods, L1- and L2-norms are introduced to enhance the robustness in the alignment step of the STA. The advantage of the proposed technique is that the difficulty in selecting the size of the local neighborhood can be avoided in the manifold learning based tensor feature extraction algorithms. Although STA is an unsupervised learning method, the sparsity encodes the discriminative information in the alignment step and provides the robustness of STA. Extensive experiments on the well-known image databases as well as action and hand gesture databases by encoding object images as tensors demonstrate that the proposed STA algorithm gives the most competitive performance when compared with the tensor-based unsupervised learning methods.

  1. Distributed redundancy and robustness in complex systems

    KAUST Repository

    Randles, Martin

    2011-03-01

    The uptake and increasing prevalence of Web 2.0 applications, promoting new large-scale and complex systems such as Cloud computing and the emerging Internet of Services/Things, requires tools and techniques to analyse and model methods to ensure the robustness of these new systems. This paper reports on assessing and improving complex system resilience using distributed redundancy, termed degeneracy in biological systems, to endow large-scale complicated computer systems with the same robustness that emerges in complex biological and natural systems. However, in order to promote an evolutionary approach, through emergent self-organisation, it is necessary to specify the systems in an \\'open-ended\\' manner where not all states of the system are prescribed at design-time. In particular an observer system is used to select robust topologies, within system components, based on a measurement of the first non-zero Eigen value in the Laplacian spectrum of the components\\' network graphs; also known as the algebraic connectivity. It is shown, through experimentation on a simulation, that increasing the average algebraic connectivity across the components, in a network, leads to an increase in the variety of individual components termed distributed redundancy; the capacity for structurally distinct components to perform an identical function in a particular context. The results are applied to a specific application where active clustering of like services is used to aid load balancing in a highly distributed network. Using the described procedure is shown to improve performance and distribute redundancy. © 2010 Elsevier Inc.

  2. Effect of smoothing on robust chaos.

    Science.gov (United States)

    Deshpande, Amogh; Chen, Qingfei; Wang, Yan; Lai, Ying-Cheng; Do, Younghae

    2010-08-01

    In piecewise-smooth dynamical systems, situations can arise where the asymptotic attractors of the system in an open parameter interval are all chaotic (e.g., no periodic windows). This is the phenomenon of robust chaos. Previous works have established that robust chaos can occur through the mechanism of border-collision bifurcation, where border is the phase-space region where discontinuities in the derivatives of the dynamical equations occur. We investigate the effect of smoothing on robust chaos and find that periodic windows can arise when a small amount of smoothness is present. We introduce a parameter of smoothing and find that the measure of the periodic windows in the parameter space scales linearly with the parameter, regardless of the details of the smoothing function. Numerical support and a heuristic theory are provided to establish the scaling relation. Experimental evidence of periodic windows in a supposedly piecewise linear dynamical system, which has been implemented as an electronic circuit, is also provided.

  3. Robustness of inflation to inhomogeneous initial conditions

    Energy Technology Data Exchange (ETDEWEB)

    Clough, Katy; Lim, Eugene A. [Theoretical Particle Physics and Cosmology Group, Physics Department, Kings College London, Strand, London WC2R 2LS (United Kingdom); DiNunno, Brandon S.; Fischler, Willy; Flauger, Raphael; Paban, Sonia, E-mail: katy.clough@kcl.ac.uk, E-mail: eugene.a.lim@gmail.com, E-mail: bsd86@physics.utexas.edu, E-mail: fischler@physics.utexas.edu, E-mail: flauger@physics.utexas.edu, E-mail: paban@physics.utexas.edu [Department of Physics, The University of Texas at Austin, Austin, TX, 78712 (United States)

    2017-09-01

    We consider the effects of inhomogeneous initial conditions in both the scalar field profile and the extrinsic curvature on different inflationary models. In particular, we compare the robustness of small field inflation to that of large field inflation, using numerical simulations with Einstein gravity in 3+1 dimensions. We find that small field inflation can fail in the presence of subdominant gradient energies, suggesting that it is much less robust to inhomogeneities than large field inflation, which withstands dominant gradient energies. However, we also show that small field inflation can be successful even if some regions of spacetime start out in the region of the potential that does not support inflation. In the large field case, we confirm previous results that inflation is robust if the inflaton occupies the inflationary part of the potential. Furthermore, we show that increasing initial scalar gradients will not form sufficiently massive inflation-ending black holes if the initial hypersurface is approximately flat. Finally, we consider the large field case with a varying extrinsic curvature K , such that some regions are initially collapsing. We find that this may again lead to local black holes, but overall the spacetime remains inflationary if the spacetime is open, which confirms previous theoretical studies.

  4. Mutational robustness of gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Aalt D J van Dijk

    Full Text Available Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive. In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence.

  5. TAO-robust backpropagation learning algorithm.

    Science.gov (United States)

    Pernía-Espinoza, Alpha V; Ordieres-Meré, Joaquín B; Martínez-de-Pisón, Francisco J; González-Marcos, Ana

    2005-03-01

    In several fields, as industrial modelling, multilayer feedforward neural networks are often used as universal function approximations. These supervised neural networks are commonly trained by a traditional backpropagation learning format, which minimises the mean squared error (mse) of the training data. However, in the presence of corrupted data (outliers) this training scheme may produce wrong models. We combine the benefits of the non-linear regression model tau-estimates [introduced by Tabatabai, M. A. Argyros, I. K. Robust Estimation and testing for general nonlinear regression models. Applied Mathematics and Computation. 58 (1993) 85-101] with the backpropagation algorithm to produce the TAO-robust learning algorithm, in order to deal with the problems of modelling with outliers. The cost function of this approach has a bounded influence function given by the weighted average of two psi functions, one corresponding to a very robust estimate and the other to a highly efficient estimate. The advantages of the proposed algorithm are studied with an example.

  6. Engineering Robustness of Microbial Cell Factories.

    Science.gov (United States)

    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.

  7. A robust nonlinear filter for image restoration.

    Science.gov (United States)

    Koivunen, V

    1995-01-01

    A class of nonlinear regression filters based on robust estimation theory is introduced. The goal of the filtering is to recover a high-quality image from degraded observations. Models for desired image structures and contaminating processes are employed, but deviations from strict assumptions are allowed since the assumptions on signal and noise are typically only approximately true. The robustness of filters is usually addressed only in a distributional sense, i.e., the actual error distribution deviates from the nominal one. In this paper, the robustness is considered in a broad sense since the outliers may also be due to inappropriate signal model, or there may be more than one statistical population present in the processing window, causing biased estimates. Two filtering algorithms minimizing a least trimmed squares criterion are provided. The design of the filters is simple since no scale parameters or context-dependent threshold values are required. Experimental results using both real and simulated data are presented. The filters effectively attenuate both impulsive and nonimpulsive noise while recovering the signal structure and preserving interesting details.

  8. UNIX-based operating systems robustness evaluation

    Science.gov (United States)

    Chang, Yu-Ming

    1996-01-01

    Robust operating systems are required for reliable computing. Techniques for robustness evaluation of operating systems not only enhance the understanding of the reliability of computer systems, but also provide valuable feed- back to system designers. This thesis presents results from robustness evaluation experiments on five UNIX-based operating systems, which include Digital Equipment's OSF/l, Hewlett Packard's HP-UX, Sun Microsystems' Solaris and SunOS, and Silicon Graphics' IRIX. Three sets of experiments were performed. The methodology for evaluation tested (1) the exception handling mechanism, (2) system resource management, and (3) system capacity under high workload stress. An exception generator was used to evaluate the exception handling mechanism of the operating systems. Results included exit status of the exception generator and the system state. Resource management techniques used by individual operating systems were tested using programs designed to usurp system resources such as physical memory and process slots. Finally, the workload stress testing evaluated the effect of the workload on system performance by running a synthetic workload and recording the response time of local and remote user requests. Moderate to severe performance degradations were observed on the systems under stress.

  9. Interlinked bistable mechanisms generate robust mitotic transitions.

    Science.gov (United States)

    Hutter, Lukas H; Rata, Scott; Hochegger, Helfrid; Novák, Béla

    2017-10-18

    The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit, 1 and the mitotic checkpoint. 2 Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states.

  10. Tension and robustness in multitasking cellular networks.

    Directory of Open Access Journals (Sweden)

    Jeffrey V Wong

    Full Text Available Cellular networks multitask by exhibiting distinct, context-dependent dynamics. However, network states (parameters that generate a particular dynamic are often sub-optimal for others, defining a source of "tension" between them. Though multitasking is pervasive, it is not clear where tension arises, what consequences it has, and how it is resolved. We developed a generic computational framework to examine the source and consequences of tension between pairs of dynamics exhibited by the well-studied RB-E2F switch regulating cell cycle entry. We found that tension arose from task-dependent shifts in parameters associated with network modules. Although parameter sets common to distinct dynamics did exist, tension reduced both their accessibility and resilience to perturbation, indicating a trade-off between "one-size-fits-all" solutions and robustness. With high tension, robustness can be preserved by dynamic shifting of modules, enabling the network to toggle between tasks, and by increasing network complexity, in this case by gene duplication. We propose that tension is a general constraint on the architecture and operation of multitasking biological networks. To this end, our work provides a framework to quantify the extent of tension between any network dynamics and how it affects network robustness. Such analysis would suggest new ways to interfere with network elements to elucidate the design principles of cellular networks.

  11. Hyperspectral Unmixing with Robust Collaborative Sparse Regression

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    Chang Li

    2016-07-01

    Full Text Available Recently, sparse unmixing (SU of hyperspectral data has received particular attention for analyzing remote sensing images. However, most SU methods are based on the commonly admitted linear mixing model (LMM, which ignores the possible nonlinear effects (i.e., nonlinearity. In this paper, we propose a new method named robust collaborative sparse regression (RCSR based on the robust LMM (rLMM for hyperspectral unmixing. The rLMM takes the nonlinearity into consideration, and the nonlinearity is merely treated as outlier, which has the underlying sparse property. The RCSR simultaneously takes the collaborative sparse property of the abundance and sparsely distributed additive property of the outlier into consideration, which can be formed as a robust joint sparse regression problem. The inexact augmented Lagrangian method (IALM is used to optimize the proposed RCSR. The qualitative and quantitative experiments on synthetic datasets and real hyperspectral images demonstrate that the proposed RCSR is efficient for solving the hyperspectral SU problem compared with the other four state-of-the-art algorithms.

  12. Robustness of airline alliance route networks

    Science.gov (United States)

    Lordan, Oriol; Sallan, Jose M.; Simo, Pep; Gonzalez-Prieto, David

    2015-05-01

    The aim of this study is to analyze the robustness of the three major airline alliances' (i.e., Star Alliance, oneworld and SkyTeam) route networks. Firstly, the normalization of a multi-scale measure of vulnerability is proposed in order to perform the analysis in networks with different sizes, i.e., number of nodes. An alternative node selection criterion is also proposed in order to study robustness and vulnerability of such complex networks, based on network efficiency. And lastly, a new procedure - the inverted adaptive strategy - is presented to sort the nodes in order to anticipate network breakdown. Finally, the robustness of the three alliance networks are analyzed with (1) a normalized multi-scale measure of vulnerability, (2) an adaptive strategy based on four different criteria and (3) an inverted adaptive strategy based on the efficiency criterion. The results show that Star Alliance has the most resilient route network, followed by SkyTeam and then oneworld. It was also shown that the inverted adaptive strategy based on the efficiency criterion - inverted efficiency - shows a great success in quickly breaking networks similar to that found with betweenness criterion but with even better results.

  13. Impact of self-healing capability on network robustness

    Science.gov (United States)

    Shang, Yilun

    2015-04-01

    A wide spectrum of real-life systems ranging from neurons to botnets display spontaneous recovery ability. Using the generating function formalism applied to static uncorrelated random networks with arbitrary degree distributions, the microscopic mechanism underlying the depreciation-recovery process is characterized and the effect of varying self-healing capability on network robustness is revealed. It is found that the self-healing capability of nodes has a profound impact on the phase transition in the emergence of percolating clusters, and that salient difference exists in upholding network integrity under random failures and intentional attacks. The results provide a theoretical framework for quantitatively understanding the self-healing phenomenon in varied complex systems.

  14. Cardiovascular phenotype in Smad3 deficient mice with renovascular hypertension.

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    Sonu Kashyap

    Full Text Available Renovascular hypertension (RVH has deleterious effects on both the kidney and the heart. TGF-β signaling through Smad3 directs tissue fibrosis in chronic injury models. In the 2-kidney 1-clip (2K1C model of RVH, employing mice on the 129 genetic background, Smad3 deficiency (KO protects the stenotic kidney (STK from development of interstitial fibrosis. However, these mice have an increased incidence of sudden cardiac death following 2K1C surgery. The purpose of this study was to characterize the cardiovascular phenotype of these mice. Renal artery stenosis (RAS was established in Wild-type (WT and Smad3 KO mice (129 genetic background by placement of a polytetrafluoroethylene cuff on the right renal artery. Mortality was 25.5% for KO mice with RAS, 4.1% for KO sham mice, 1.2% for WT with RAS, and 1.8% for WT sham mice. Myocardial tissue of mice studied at 3 days following surgery showed extensive myocyte necrosis in KO but not WT mice. Myocyte necrosis was associated with a rapid induction of Ccl2 expression, macrophage influx, and increased MMP-9 activity. At later time points, both KO and WT mice developed myocardial fibrosis. No aortic aneurysms or dissections were observed at any time point. Smad3 KO mice were backcrossed to the C57BL/6J strain and subjected to RAS. Sudden death was observed at 10-14 days following surgery in 62.5% of mice; necropsy revealed aortic dissections as the cause of death. As observed in the 129 mice, the STK of Smad3 KO mice on the C57BL/6J background did not develop significant chronic renal damage. We conclude that the cardiovascular manifestations of Smad3 deficient mice are strain-specific, with myocyte necrosis in 129 mice and aortic rupture in C57BL/6J mice. Future studies will define mechanisms underlying this strain-specific effect on the cardiovascular system.

  15. The cellular robustness by genetic redundancy in budding yeast.

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    Jingjing Li

    2010-11-01

    Full Text Available The frequent dispensability of duplicated genes in budding yeast is heralded as a hallmark of genetic robustness contributed by genetic redundancy. However, theoretical predictions suggest such backup by redundancy is evolutionarily unstable, and the extent of genetic robustness contributed from redundancy remains controversial. It is anticipated that, to achieve mutual buffering, the duplicated paralogs must at least share some functional overlap. However, counter-intuitively, several recent studies reported little functional redundancy between these buffering duplicates. The large yeast genetic interactions released recently allowed us to address these issues on a genome-wide scale. We herein characterized the synthetic genetic interactions for ∼500 pairs of yeast duplicated genes originated from either whole-genome duplication (WGD or small-scale duplication (SSD events. We established that functional redundancy between duplicates is a pre-requisite and thus is highly predictive of their backup capacity. This observation was particularly pronounced with the use of a newly introduced metric in scoring functional overlap between paralogs on the basis of gene ontology annotations. Even though mutual buffering was observed to be prevalent among duplicated genes, we showed that the observed backup capacity is largely an evolutionarily transient state. The loss of backup capacity generally follows a neutral mode, with the buffering strength decreasing in proportion to divergence time, and the vast majority of the paralogs have already lost their backup capacity. These observations validated previous theoretic predictions about instability of genetic redundancy. However, departing from the general neutral mode, intriguingly, our analysis revealed the presence of natural selection in stabilizing functional overlap between SSD pairs. These selected pairs, both WGD and SSD, tend to have decelerated functional evolution, have higher propensities of co

  16. Of mice and (Viking?) men: phylogeography of British and Irish house mice.

    Science.gov (United States)

    Searle, Jeremy B; Jones, Catherine S; Gündüz, Islam; Scascitelli, Moira; Jones, Eleanor P; Herman, Jeremy S; Rambau, R Victor; Noble, Leslie R; Berry, R J; Giménez, Mabel D; Jóhannesdóttir, Fríoa

    2009-01-22

    The west European subspecies of house mouse (Mus musculus domesticus) has gained much of its current widespread distribution through commensalism with humans. This means that the phylogeography of M. m. domesticus should reflect patterns of human movements. We studied restriction fragment length polymorphism (RFLP) and DNA sequence variations in mouse mitochondrial (mt) DNA throughout the British Isles (328 mice from 105 localities, including previously published data). There is a major mtDNA lineage revealed by both RFLP and sequence analyses, which is restricted to the northern and western peripheries of the British Isles, and also occurs in Norway. This distribution of the 'Orkney' lineage fits well with the sphere of influence of the Norwegian Vikings and was probably generated through inadvertent transport by them. To form viable populations, house mice would have required large human settlements such as the Norwegian Vikings founded. The other parts of the British Isles (essentially most of mainland Britain) are characterized by house mice with different mtDNA sequences, some of which are also found in Germany, and which probably reflect both Iron Age movements of people and mice and earlier development of large human settlements. MtDNA studies on house mice have the potential to reveal novel aspects of human history.

  17. Desensitization of delayed-type hypersensitivity in mice: suppressive environment

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    Takashi Katsura

    1993-01-01

    Full Text Available The systemic injection of high doses of antigen into a preimmunized animal results in transient unresponsiveness of cell-mediated immune responses. This phenomenon is known as desensitization. Serum interleukin 2 (IL-2 activity was found transiently in desensitized mice at 3 h after the antigen challenge. These mice could not reveal antigen nonspecific delayed-type hypersensitivity (DTH 1 d after the challenge. Specific suppression of DTH was observed at later stages. Sera from 3 h desensitized mice showed suppressive effects on DTH in preo immunized mice. Administration of recombinant IL-2 into preimmunized mice led to the failure of development of DTH to antigens. These observations suggest that IL-2 plays an important role in the suppressive environment.

  18. Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice.

    Science.gov (United States)

    Carr, Michael I; Roderick, Justine E; Zhang, Hong; Woda, Bruce A; Kelliher, Michelle A; Jones, Stephen N

    2016-12-27

    The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2 S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present study, we have generated an Mdm2 mutant mouse (Mdm2 Y393F ) to determine whether c-Abl phosphorylation of Mdm2 regulates the p53-mediated DNA damage response or p53 tumor suppression in vivo. The Mdm2 Y393F mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Although apoptosis is unaltered in these mice, they recover more rapidly from radiation-induced bone marrow ablation and are more resistant to whole-body radiation-induced lethality. These data reveal an in vivo role for c-Abl phosphorylation of Mdm2 in regulation of p53 tumor suppression and bone marrow failure. However, c-Abl phosphorylation of Mdm2 Tyr393 appears to play a lesser role in governing Mdm2-p53 signaling than ATM phosphorylation of Mdm2 Ser394. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2 Y393F/S394A mice and Mdm2 S394A mice display similar phenotypes.

  19. Diminished responsiveness to dobutamine as an inotrope in mice with cecal ligation and puncture-induced sepsis: attribution to phosphodiesterase 4 upregulation.

    Science.gov (United States)

    Sakai, Mari; Suzuki, Tokiko; Tomita, Kengo; Yamashita, Shigeyuki; Palikhe, Sailesh; Hattori, Kohshi; Yoshimura, Naoki; Matsuda, Naoyuki; Hattori, Yuichi

    2017-06-01

    Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of β 1 -adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support. NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis

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

    Energy Technology Data Exchange (ETDEWEB)

    Voort, Sebastian van der [Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam (Netherlands); Section of Nuclear Energy and Radiation Applications, Department of Radiation, Science and Technology, Delft University of Technology, Delft (Netherlands); Water, Steven van de [Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam (Netherlands); Perkó, Zoltán [Section of Nuclear Energy and Radiation Applications, Department of Radiation, Science and Technology, Delft University of Technology, Delft (Netherlands); Heijmen, Ben [Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam (Netherlands); Lathouwers, Danny [Section of Nuclear Energy and Radiation Applications, Department of Radiation, Science and Technology, Delft University of Technology, Delft (Netherlands); Hoogeman, Mischa, E-mail: m.hoogeman@erasmusmc.nl [Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam (Netherlands)

    2016-05-01

    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 the 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 that can