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Sökning: WFRF:(O'Hare P.)

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  • Kos, K., et al. (författare)
  • DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue : DPP-IV inhibition in human adipose tissue
  • 2009
  • Ingår i: Diabetes Obes Metab. - 1463-1326. ; 11:4, s. 285-92
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY(1-36)) which is truncated by DPP-IV to NPY(3-36), as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways. AIMS: To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT). METHODS: Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean +/- s.d.) +/- 5 kg/m2, age: 43.7 +/- 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1-100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects. RESULTS AND CONCLUSION: rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean +/- s.e.) +/- 37 micromol/l; NPY, 100 nM: 161 +/- 27 micromol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 +/- 14 micromol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 +/- 6 signal units (SU)] vs. lean subjects (186 +/- 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 +/- 111 SU vs. lean: 711 +/- 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors.
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3.
  • Zabriskie, Matthew S., et al. (författare)
  • BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
  • 2014
  • Ingår i: Cancer Cell. - 1535-6108 .- 1878-3686. ; 26:3, s. 428-442
  • Tidskriftsartikel (refereegranskat)abstract
    • Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
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4.
  • Amato, Giuseppe, et al. (författare)
  • Robotic UBIquitous COgnitive Network
  • 2012
  • Ingår i: Ambient Intelligence. - : Springer-Verlag New York. - 9783642287824 - 9783642287831 ; , s. 191-195
  • Konferensbidrag (refereegranskat)abstract
    • Robotic ecologies are networks of heterogeneous robotic devices pervasively embedded in everyday environments, where they cooperate to perform complex tasks. While their potential makes them increasingly popular, one fundamental problem is how to make them self-adaptive, so as to reduce the amount of preparation, pre-programming and human supervision that they require in real world applications. The EU FP7 project RUBICON develops self-sustaining learning solutions yielding cheaper, adaptive and efficient coordination of robotic ecologies. The approach we pursue builds upon a unique combination of methods from cognitive robotics, agent control systems, wireless sensor networks and machine learning. This paper briefly illustrates how these techniques are being extended, integrated, and applied to AAL applications.
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  • Arboleda-Velasquez, Joseph F, et al. (författare)
  • Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.
  • 2019
  • Ingår i: Nature medicine. - 1546-170X. ; 25:11, s. 1680-1683
  • Tidskriftsartikel (refereegranskat)abstract
    • We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.
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  • Bodda, C., et al. (författare)
  • HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
  • 2020
  • Ingår i: The Journal of experimental medicine. - 1540-9538. ; 217:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain. © 2020 Bodda et al.
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  • Dragone, Mauro, et al. (författare)
  • A cognitive robotic ecology approach to self-configuring and evolving AAL systems
  • 2015
  • Ingår i: Engineering applications of artificial intelligence. - : Pergamon-Elsevier Science. - 0952-1976 .- 1873-6769. ; 45, s. 269-280
  • Tidskriftsartikel (refereegranskat)abstract
    • Robotic ecologies are systems made out of several robotic devices, including mobile robots, wireless sensors and effectors embedded in everyday environments, where they cooperate to achieve complex tasks. This paper demonstrates how endowing robotic ecologies with information processing algorithms such as perception, learning, planning, and novelty detection can make these systems able to deliver modular, flexible, manageable and dependable Ambient Assisted Living (AAL) solutions. Specifically, we show how the integrated and self-organising cognitive solutions implemented within the EU project RUBICON (Robotic UBIquitous Cognitive Network) can reduce the need of costly pre-programming and maintenance of robotic ecologies. We illustrate how these solutions can be harnessed to (i) deliver a range of assistive services by coordinating the sensing & acting capabilities of heterogeneous devices, (ii) adapt and tune the overall behaviour of the ecology to the preferences and behaviour of its inhabitants, and also (iii) deal with novel events, due to the occurrence of new user's activities and changing user's habits.
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9.
  • Dragone, Mauro, et al. (författare)
  • A Programming Framework for Multi-agent Coordination of Robotic Ecologies
  • 2013
  • Ingår i: Programming Multi-Agent Systems. - : Springer Publishing Company. - 9783642387005 ; , s. 72-89
  • Konferensbidrag (refereegranskat)abstract
    • Building smart environments with Robotic ecologies, comprising of distributed sensors, actuators and mobile robot devices facilitates and extends the nature and form of smart environments that can be developed, and reduces the complexity and cost of such solutions. While the potentials of such an approach makes robotic ecologies increasingly popular, many fundamental research questions remain open. One such question is how to make a robotic ecology self-adaptive, so as to adapt to changing conditions and evolving requirements, and consequently reduce the amount of preparation and pre-programming required for their deployment in real world applications. This paper presents a framework for the specification and the programming of robotic ecologies. The framework extends an existing agent system and integrates it with the pre-existing and dominant traditional robotic and middleware approach to the development of robotic ecologies. We illustrate how these technologies complement each other and offer a candidate technology to pursue adaptive robotic ecologies.
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