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  • Open Access English
    Authors: 
    R. Thomas Lumbers; Sonia Shah; Honghuang Lin; Tomasz Czuba; Albert Henry; Daniel I. Swerdlow; Anders Mälarstig; Niek Verweij; Michael V. Holmes; Johan Ärnlöv; +157 more
    Countries: Netherlands, France, Sweden, Denmark, United Kingdom, France, Denmark, United Kingdom, Sweden, United Kingdom
    Project: EC | BigData Heart (116074), EC | inHForm (679242)

    Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063 Funder: Swedish National Health Service Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077 Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173 Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748 Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927 Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050 Funder: British Heart Foundation Cardiovascular Biomedicine Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317 Abstract: Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

  • Publication . Preprint . Conference object . Article . 2020 . Embargo End Date: 01 Jan 2020
    Open Access
    Authors: 
    Susanna F. de Rezende; Or Meir; Jakob Nordström; Toniann Pitassi; Robert Robere; Marc Vinyals;
    Publisher: arXiv
    Project: NSERC , EC | UTHOTP (279611)

    We significantly strengthen and generalize the theorem lifting Nullstellensatz degree to monotone span program size by Pitassi and Robere (2018) so that it works for any gadget with high enough rank, in particular, for useful gadgets such as equality and greater-than. We apply our generalized theorem to solve three open problems: •We present the first result that demonstrates a separation in proof power for cutting planes with unbounded versus polynomially bounded coefficients. Specifically, we exhibit CNF formulas that can be refuted in quadratic length and constant line space in cutting planes with unbounded coefficients, but for which there are no refutations in subexponential length and subpolynomial line space if coefficients are restricted to be of polynomial magnitude. •We give the first explicit separation between monotone Boolean formulas and monotone real formulas. Specifically, we give an explicit family of functions that can be computed with monotone real formulas of nearly linear size but require monotone Boolean formulas of exponential size. Previously only a non-explicit separation was known. •We give the strongest separation to-date between monotone Boolean formulas and monotone Boolean circuits. Namely, we show that the classical GEN problem, which has polynomial-size monotone Boolean circuits, requires monotone Boolean formulas of size $2^{\Omega(n/\text{polylog}(n))}$ . An important technical ingredient, which may be of independent interest, is that we show that the Nullstellensatz degree of refuting the pebbling formula over a DAG $G$ over any field coincides exactly with the reversible pebbling price of $G$ . In particular, this implies that the standard decision tree complexity and the parity decision tree complexity of the corresponding falsified clause search problem are equal. This is an extended abstract. The full version of the paper is available at https://arxiv.org/abs/2001.02144.

  • Open Access
    Authors: 
    Wei Lv; Guangming Zhang; Cyril Barinka; James H. Eubanks; Alan P. Kozikowski;
    Publisher: American Chemical Society (ACS)
    Project: CIHR

    A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

  • Publication . Article . 2011
    Open Access
    Authors: 
    Janez Bernik; Mitja Mastnak; Heydar Radjavi;
    Publisher: Elsevier BV

    Abstract We study various aspects of how certain positivity assumptions on complex matrix semigroups affect their structure. Our main result is that every irreducible group of complex matrices with nonnegative diagonal entries is simultaneously similar to a group of weighted permutations. We also consider the corresponding question for semigroups and discuss the effect of the assumption that a fixed linear functional has nonnegative values when restricted to a given semigroup.

  • Open Access
    Authors: 
    Valery Andrushchenko; Hal Wieser; Petr Bour;
    Publisher: American Chemical Society (ACS)

    The cis-platin binding to the d(CCTGGTCC)*d(GGACCAGG) model DNA octamer was monitored with infrared absorption (IR) and vibrational circular dichroism (VCD) spectroscopies. The spectra were modeled with the aid of density functional computations and a Cartesian coordinate-based transfer of molecular property tensors from smaller DNA fragments. Because of the fragmentation, the tensors could be calculated with a higher precision. Environmental effects, such as the presence of the solvent or the cis-platin ligand, could be included in the modeling. The solvent was modeled by an explicit inclusion of hydrogen-bound water molecules, positions of which were estimated from a molecular dynamics simulation, or by the polarized continuum COSMO model. The B3LYP and BPW91 functionals used for the calculations of the spectral parameters were combined with the relativistic LANL2DZ platinum pseudo-potentials. The simulations reproduced the main IR and VCD DNA spectral features and explained most of the changes observed experimentally upon metal binding. The results confirmed that the influence of the ligand on DNA vibrational properties is quite complex; it originates in the geometry deformation and normal mode coupling pattern changes of the platinated octamer, as well as in local perturbations of the electronic structure and force field of the GC base pairs to which the platinum is bound. Many of the local effects could be accounted for by a point charge used in place of the metal in the GC complex.

  • Open Access
    Authors: 
    Andrew Spencer; Suzanne Lentzsch; Katja Weisel; Hervé Avet-Loiseau; Tomer M Mark; Ivan Spicka; Tamás Masszi; Birgitta Lauri; Mark-David Levin; Alberto Bosi; +27 more
    Publisher: Ferrata Storti Foundation (Haematologica)
    Countries: Netherlands, Italy

    Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0–27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease–negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

  • Open Access English
    Authors: 
    Aad, G.; et al., [Unknown]; Aben, R.; Beemster, L.J.; Bentvelsen, S.; Berglund, E.; Bobbink, G.J.; Bos, K.; Boterenbrood, H.; Castelli, A.; +35 more
    Country: Netherlands

    The jet energy scale (JES) and its systematic uncertainty are determined for jets measured with the ATLAS detector using proton-proton collision data with a centre-of-mass energy of √s=7 TeV corresponding to an integrated luminosity of 4.7 fb −1. Jets are reconstructed from energy deposits forming topological clusters of calorimeter cells using the anti-kt algorithm with distance parameters R=0.4 or R=0.6, and are calibrated using MC simulations. A residual JES correction is applied to account for differences between data and MC simulations. This correction and its systematic uncertainty are estimated using a combination of in situ techniques exploiting the transverse momentum balance between a jet and a reference object such as a photon or a Z boson, for 20≤pjetT1 TeV. The calibration of forward jets is derived from dijet pT balance measurements. The resulting uncertainty reaches its largest value of 6 % for low-pT jets at |η|=4.5. Additional JES uncertainties due to specific event topologies, such as close-by jets or selections of event samples with an enhanced content of jets originating from light quarks or gluons, are also discussed. The magnitude of these uncertainties depends on the event sample used in a given physics analysis, but typically amounts to 0.5-3 %.

  • Open Access English
    Authors: 
    Aad, G.; et al., [Unknown]; Aben, R.; Angelozzi, I.; Beemster, L.J.; Bentvelsen, S.; Berge, D.; Bobbink, G.J.; Bos, K.; Boterenbrood, H.; +37 more
    Country: Netherlands

    This article reports on a search for dark matter pair production in association with bottom or top quarks in 20.3 fb−1 of pp collisions collected at s√=8 TeV by the ATLAS detector at the LHC. Events with large missing transverse momentum are selected when produced in association with high-momentum jets of which one or more are identified as jets containing b-quarks. Final states with top quarks are selected by requiring a high jet multiplicity and in some cases a single lepton. The data are found to be consistent with the Standard Model expectations and limits are set on the mass scale of effective field theories that describe scalar and tensor interactions between dark matter and Standard Model particles. Limits on the dark-matter-nucleon cross-section for spin-independent and spin-dependent interactions are also provided. These limits are particularly strong for low-mass dark matter. Using a simplified model, constraints are set on the mass of dark matter and of a coloured mediator suitable to explain a possible signal of annihilating dark matter.

  • Open Access English
    Authors: 
    John Eastwood; Denise E. De Souza; Miranda Shaw; Pankaj Garg; Susan Woolfenden; Ingrid Tyler; Lynn Kemp;
    Publisher: Ubiquity Press
    Country: Singapore

    Introduction: Intergenerational cycles of poverty, violence and crime, poor education and employment opportunities, psychopathology, and poor lifestyle and health behaviours require innovative models of health care delivery to break them. We describe a programme of research informed service development targeting vulnerable families in inner metropolitan Sydney, Australia that is designed to build and confirm a “Theory of Neighbourhood Context, Stress, Depression, and the Developmental Origins of Health and Disease (DOHaD)”. We describe the development of an intervention design and business case that drew on earlier realist causal and programme theoretical work. Methods: Realist causal and programme theory were used to inform the collaborative design of initiatives for vulnerable families. The collaborative design process included: identification of desirable and undesirable outcomes and contextual factors, consultation forums, interagency planning, and development of a service proposal. Results: The design elements included: perinatal coordination, sustained home visiting, integrated service model development, two place-based hubs, health promotion and strengthened research and analysis capability. Conclusions: We demonstrate here the design of interventions for vulnerable families in Sydney utilising translational research from previous realist causal and program theory building to operational service design. We have identified the importance of our earlier analysis of underlying causal mechanisms and related programme mechanisms for identifying the elements for the full intervention design. The application of theory added rigour to the design of the integrated care initiatives. In applying the theory to the local situation the analysis took into account: the role of the local agencies; evidence of program effectiveness; determinants and outcomes for local children and their families; the current deployment of service resources; and insights from front-line staff and interagency partners. Published version

  • Open Access English
    Authors: 
    Ali Azizi; Ashok Kumar; Francisco Diaz-Mitoma; Jiri Mestecky;
    Publisher: Public Library of Science (PLoS)
    Project: CIHR

    The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required. One promising approach is to exploit the potential of microfold (M) cells by mimicking the entry of pathogens into these cells. Targeting specific receptors on the apical surface of M cells might enhance the entry of antigens, initiating the immune response and consequently leading to protection against mucosal pathogens. In this article, we briefly review the challenges associated with current oral vaccine delivery systems and discuss strategies that might potentially target mouse and human intestinal M cells.

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Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
10,941 Research products, page 1 of 1,095
  • Open Access English
    Authors: 
    R. Thomas Lumbers; Sonia Shah; Honghuang Lin; Tomasz Czuba; Albert Henry; Daniel I. Swerdlow; Anders Mälarstig; Niek Verweij; Michael V. Holmes; Johan Ärnlöv; +157 more
    Countries: Netherlands, France, Sweden, Denmark, United Kingdom, France, Denmark, United Kingdom, Sweden, United Kingdom
    Project: EC | BigData Heart (116074), EC | inHForm (679242)

    Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063 Funder: Swedish National Health Service Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077 Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173 Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748 Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927 Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050 Funder: British Heart Foundation Cardiovascular Biomedicine Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317 Abstract: Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

  • Publication . Preprint . Conference object . Article . 2020 . Embargo End Date: 01 Jan 2020
    Open Access
    Authors: 
    Susanna F. de Rezende; Or Meir; Jakob Nordström; Toniann Pitassi; Robert Robere; Marc Vinyals;
    Publisher: arXiv
    Project: NSERC , EC | UTHOTP (279611)

    We significantly strengthen and generalize the theorem lifting Nullstellensatz degree to monotone span program size by Pitassi and Robere (2018) so that it works for any gadget with high enough rank, in particular, for useful gadgets such as equality and greater-than. We apply our generalized theorem to solve three open problems: •We present the first result that demonstrates a separation in proof power for cutting planes with unbounded versus polynomially bounded coefficients. Specifically, we exhibit CNF formulas that can be refuted in quadratic length and constant line space in cutting planes with unbounded coefficients, but for which there are no refutations in subexponential length and subpolynomial line space if coefficients are restricted to be of polynomial magnitude. •We give the first explicit separation between monotone Boolean formulas and monotone real formulas. Specifically, we give an explicit family of functions that can be computed with monotone real formulas of nearly linear size but require monotone Boolean formulas of exponential size. Previously only a non-explicit separation was known. •We give the strongest separation to-date between monotone Boolean formulas and monotone Boolean circuits. Namely, we show that the classical GEN problem, which has polynomial-size monotone Boolean circuits, requires monotone Boolean formulas of size $2^{\Omega(n/\text{polylog}(n))}$ . An important technical ingredient, which may be of independent interest, is that we show that the Nullstellensatz degree of refuting the pebbling formula over a DAG $G$ over any field coincides exactly with the reversible pebbling price of $G$ . In particular, this implies that the standard decision tree complexity and the parity decision tree complexity of the corresponding falsified clause search problem are equal. This is an extended abstract. The full version of the paper is available at https://arxiv.org/abs/2001.02144.

  • Open Access
    Authors: 
    Wei Lv; Guangming Zhang; Cyril Barinka; James H. Eubanks; Alan P. Kozikowski;
    Publisher: American Chemical Society (ACS)
    Project: CIHR

    A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC50, 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

  • Publication . Article . 2011
    Open Access
    Authors: 
    Janez Bernik; Mitja Mastnak; Heydar Radjavi;
    Publisher: Elsevier BV

    Abstract We study various aspects of how certain positivity assumptions on complex matrix semigroups affect their structure. Our main result is that every irreducible group of complex matrices with nonnegative diagonal entries is simultaneously similar to a group of weighted permutations. We also consider the corresponding question for semigroups and discuss the effect of the assumption that a fixed linear functional has nonnegative values when restricted to a given semigroup.

  • Open Access
    Authors: 
    Valery Andrushchenko; Hal Wieser; Petr Bour;
    Publisher: American Chemical Society (ACS)

    The cis-platin binding to the d(CCTGGTCC)*d(GGACCAGG) model DNA octamer was monitored with infrared absorption (IR) and vibrational circular dichroism (VCD) spectroscopies. The spectra were modeled with the aid of density functional computations and a Cartesian coordinate-based transfer of molecular property tensors from smaller DNA fragments. Because of the fragmentation, the tensors could be calculated with a higher precision. Environmental effects, such as the presence of the solvent or the cis-platin ligand, could be included in the modeling. The solvent was modeled by an explicit inclusion of hydrogen-bound water molecules, positions of which were estimated from a molecular dynamics simulation, or by the polarized continuum COSMO model. The B3LYP and BPW91 functionals used for the calculations of the spectral parameters were combined with the relativistic LANL2DZ platinum pseudo-potentials. The simulations reproduced the main IR and VCD DNA spectral features and explained most of the changes observed experimentally upon metal binding. The results confirmed that the influence of the ligand on DNA vibrational properties is quite complex; it originates in the geometry deformation and normal mode coupling pattern changes of the platinated octamer, as well as in local perturbations of the electronic structure and force field of the GC base pairs to which the platinum is bound. Many of the local effects could be accounted for by a point charge used in place of the metal in the GC complex.

  • Open Access
    Authors: 
    Andrew Spencer; Suzanne Lentzsch; Katja Weisel; Hervé Avet-Loiseau; Tomer M Mark; Ivan Spicka; Tamás Masszi; Birgitta Lauri; Mark-David Levin; Alberto Bosi; +27 more
    Publisher: Ferrata Storti Foundation (Haematologica)
    Countries: Netherlands, Italy

    Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0–27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease–negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

  • Open Access English
    Authors: 
    Aad, G.; et al., [Unknown]; Aben, R.; Beemster, L.J.; Bentvelsen, S.; Berglund, E.; Bobbink, G.J.; Bos, K.; Boterenbrood, H.; Castelli, A.; +35 more
    Country: Netherlands

    The jet energy scale (JES) and its systematic uncertainty are determined for jets measured with the ATLAS detector using proton-proton collision data with a centre-of-mass energy of √s=7 TeV corresponding to an integrated luminosity of 4.7 fb −1. Jets are reconstructed from energy deposits forming topological clusters of calorimeter cells using the anti-kt algorithm with distance parameters R=0.4 or R=0.6, and are calibrated using MC simulations. A residual JES correction is applied to account for differences between data and MC simulations. This correction and its systematic uncertainty are estimated using a combination of in situ techniques exploiting the transverse momentum balance between a jet and a reference object such as a photon or a Z boson, for 20≤pjetT1 TeV. The calibration of forward jets is derived from dijet pT balance measurements. The resulting uncertainty reaches its largest value of 6 % for low-pT jets at |η|=4.5. Additional JES uncertainties due to specific event topologies, such as close-by jets or selections of event samples with an enhanced content of jets originating from light quarks or gluons, are also discussed. The magnitude of these uncertainties depends on the event sample used in a given physics analysis, but typically amounts to 0.5-3 %.

  • Open Access English
    Authors: 
    Aad, G.; et al., [Unknown]; Aben, R.; Angelozzi, I.; Beemster, L.J.; Bentvelsen, S.; Berge, D.; Bobbink, G.J.; Bos, K.; Boterenbrood, H.; +37 more
    Country: Netherlands

    This article reports on a search for dark matter pair production in association with bottom or top quarks in 20.3 fb−1 of pp collisions collected at s√=8 TeV by the ATLAS detector at the LHC. Events with large missing transverse momentum are selected when produced in association with high-momentum jets of which one or more are identified as jets containing b-quarks. Final states with top quarks are selected by requiring a high jet multiplicity and in some cases a single lepton. The data are found to be consistent with the Standard Model expectations and limits are set on the mass scale of effective field theories that describe scalar and tensor interactions between dark matter and Standard Model particles. Limits on the dark-matter-nucleon cross-section for spin-independent and spin-dependent interactions are also provided. These limits are particularly strong for low-mass dark matter. Using a simplified model, constraints are set on the mass of dark matter and of a coloured mediator suitable to explain a possible signal of annihilating dark matter.

  • Open Access English
    Authors: 
    John Eastwood; Denise E. De Souza; Miranda Shaw; Pankaj Garg; Susan Woolfenden; Ingrid Tyler; Lynn Kemp;
    Publisher: Ubiquity Press
    Country: Singapore

    Introduction: Intergenerational cycles of poverty, violence and crime, poor education and employment opportunities, psychopathology, and poor lifestyle and health behaviours require innovative models of health care delivery to break them. We describe a programme of research informed service development targeting vulnerable families in inner metropolitan Sydney, Australia that is designed to build and confirm a “Theory of Neighbourhood Context, Stress, Depression, and the Developmental Origins of Health and Disease (DOHaD)”. We describe the development of an intervention design and business case that drew on earlier realist causal and programme theoretical work. Methods: Realist causal and programme theory were used to inform the collaborative design of initiatives for vulnerable families. The collaborative design process included: identification of desirable and undesirable outcomes and contextual factors, consultation forums, interagency planning, and development of a service proposal. Results: The design elements included: perinatal coordination, sustained home visiting, integrated service model development, two place-based hubs, health promotion and strengthened research and analysis capability. Conclusions: We demonstrate here the design of interventions for vulnerable families in Sydney utilising translational research from previous realist causal and program theory building to operational service design. We have identified the importance of our earlier analysis of underlying causal mechanisms and related programme mechanisms for identifying the elements for the full intervention design. The application of theory added rigour to the design of the integrated care initiatives. In applying the theory to the local situation the analysis took into account: the role of the local agencies; evidence of program effectiveness; determinants and outcomes for local children and their families; the current deployment of service resources; and insights from front-line staff and interagency partners. Published version

  • Open Access English
    Authors: 
    Ali Azizi; Ashok Kumar; Francisco Diaz-Mitoma; Jiri Mestecky;
    Publisher: Public Library of Science (PLoS)
    Project: CIHR

    The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required. One promising approach is to exploit the potential of microfold (M) cells by mimicking the entry of pathogens into these cells. Targeting specific receptors on the apical surface of M cells might enhance the entry of antigens, initiating the immune response and consequently leading to protection against mucosal pathogens. In this article, we briefly review the challenges associated with current oral vaccine delivery systems and discuss strategies that might potentially target mouse and human intestinal M cells.