5,452 research outputs found
Predicting the contribution of rat cytochrome P-450 3A1, 3A2 and human cytochrome P-450 3A4, 3A5 to territrem A 4 beta-C hydroxylation using the relative activity factor.
No full textMetabolism of territrem A by liver microsomes of Wistar rats: Sex differences and regulation with gonadal hormones and phenobarbital.
No full textStudies investigating peripheral blood derived cells that express the high affinity receptor for immunoglobulin E (Fc?RI) In Allergic Disorders
No full textIt is just forty years since the identification of immunoglobulin E (IgE) as the reagin responsible for allergen induced immediate hypersensitivity reactions. IgE exerts its biological actions through the binding of its Fc fragment to specific Fc receptors on effector cells. There are two predominant Fc receptors for IgE – Fc?RI, which has a very high affinity for IgE and Fc?RII, which shows less avid binding. For much of the first two decades after the identification of IgE, it was thought that Fc?RI expression was limited to mast cells and basophils and that IgE binding to other cell types such as Blymphocytes and antigen presenting cells (APCs) was mainly due to Fc?RII. However with major advances in characterisation and functional knowledge of Fc?RI, particularly in the last fifteen years, it has become apparent that Fc?RI can be expressed on several more cell types that may be involved in initiation and maintenance of allergic inflammation – including APCs (monocytes and dendritic cells)and possibly eosinophils.The research described in the four papers forming this thesis was completed during this period and evaluated Fc?RI expression on different cell types, their potential roles in allergen induced inflammatory responses and whether successful therapeutic strategies for allergic disorders may involve actions on Fc?RI+ cells. The relative expression of Fc?RI on peripheral blood basophils, monocytes and eosinophils from atopic and non-atopic subjects and any relationship with serum IgE concentrations was assessed in the first paper. The second study examined a potentially important role for basophils as a cellular source of rapidly releasable IL-4 which may help initiate allergen induced TH2 responses. The next study investigated the possible effects on allergen induced early and late asthmatic responses of the immunosuppressive drug cyclosporin A which had been shown both to inhibit mast cell and basophil degranulation and cytokine secretion (particularly by CD4+ T-cells). The final study evaluated Fc?RI expression on these cell types as well humoral factors (e.g. seasonal changes in allergen specific IgG and IgE) in subjects who, after 3 to 4 years of grass pollen immunotherapy, had continued on either active or placebo immunotherapy for a further 3 years. A historical perspective explaining some of the reasons the studies were done is provided in the introductory chapter whilst the discussion chapter at the end reviews how many of the findings of the study have evolved in subsequent years right up to the present day and finishes off with a brief synopsis of how rapidly increasing knowledge of the regulatory functions of dendritic cells (expressing Fc?RI and often monocyte derived) has resulted in better understanding of the mechanisms of allergen specific immunotherapy and is leading to more effective treatment modalities
NEW ROLES FOR FC RECEPTORS IN NEURODEGENERATION-THE IMPACT ON IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE
No full textThere are an estimated 18 million Alzheimer’s disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterised by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterised by deposits of amyloid beta (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunisation or passive immunisation against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. This clearance is associated with reversal of associated cognitive deficits, but these results have failed to translate to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fcγ) are a family of immunoglobulin like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking Fc receptors by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc receptor expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. We propose that increased expression and ligation of Fc receptors in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of Fc receptors in the healthy and diseased brain
Metabolism of territrem A by liver microsomes of Wistar rats: Cytochrome P450 isoforms catalyzing TRA metabolism.
No full textMetabolism of territrem A by liver microsomes of Wistar rats: identification of the metabolites and their metabolic pathway.
No full textTwo-machine flow-shop scheduling to minimize total late work
No full text[[abstract]]This article considers a two-machine flow-shop scheduling problem of minimizing total late work. Unlike tardiness, which is based upon the difference between the job completion time and the due date, the late work of a job is defined as the amount of work not completed by its due date. This article first shows that the problem remains non-deterministic polynomial time (NP) hard even if all jobs share a common due date. A lower bound and a dominance property are developed to design branch-and-bound algorithms. Computational experiments are conducted to assess the performance of the proposed algorithms. Numerical results demonstrate that the lower bound and dominance rule can help to reduce the computational efforts required by exploring the enumeration tree. The average deviation between the solution found by tabu search and the proposed lower bound is less than 3%, suggesting that the proposed lower bound is close to the optimal solution.[[note]]SC
A two-machine flowshop problem with processing time-dependent buffer constraints-An application in multimedia presentations
No full text[[abstract]]To have a quality multimedia presentation through networks, its presentation lag needs to be controlled. One way to reduce the lag is to prefetch the media objects before their due dates. This paper explores techniques for optimizing the object sequence in a prefetch-enabled TV-like presentation. An optimal solution is the one with which the presentation lag is minimized. We formulate the problem into a two-machine flowshop scheduling problem with a single chain precedence constraint and a player-side buffer constraint. The player-side buffer is "processing time-dependent" and distinguished from the conventional item-based intermediate buffer constraints discussed in previous flowshop studies. We prove the problem to he strongly NP-hard. A branch and bound algorithm equipped with four lower bounds and an NEH-based upper bound is developed. The simulation results show that the average gaps between the overall lower bounds and the NEH-based upper bound are less than 3% for problems with a large buffer size, and less than 13% for problems with a small buffer size and high density of precedence constraints. For applications where the media objects are delivered through extremely busy servers with which only very restricted CPU resources can be allocated for computation, the CDS-based algorithm provides better sequences than the NEH-based algorithm. (C) 2008 Elsevier Ltd. All rights reserved.[[note]]SC
Studies investigating peripherial blood derived cells that express the high affinity receptor for immunoglobulin E (FceRI) in allergic disorders
No full textIt is just forty years since the identification of immunoglobulin E (IgE) as the reagin responsible for
allergen induced immediate hypersensitivity reactions. IgE exerts its biological actions through the
binding of its Fc fragment to specific Fc receptors on effector cells. There are two predominant Fc
receptors for IgE – Fc?RI, which has a very high affinity for IgE and Fc?RII, which shows less avid
binding. For much of the first two decades after the identification of IgE, it was thought that Fc?RI
expression was limited to mast cells and basophils and that IgE binding to other cell types such as Blymphocytes
and antigen presenting cells (APCs) was mainly due to Fc?RII . However with major
advances in characterisation and functional knowledge of Fc?RI, particularly in the last fifteen years, it
has become apparent that Fc?RI can be expressed on several more cell types that may be involved in
initiation and maintenance of allergic inflammation – including APCs (monocytes and dendritic cells)
and possibly eosinophils.The research described in the four papers forming this thesis was completed during this period and
evaluated Fc?RI expression on different cell types, their potential roles in allergen induced
inflammatory responses and whether successful therapeutic strategies for allergic disorders may
involve actions on Fc?RI+ cells. The relative expression of Fc?RI on peripheral blood basophils,
monocytes and eosinophils from atopic and non-atopic subjects and any relationship with serum IgE
concentrations was assessed in the first paper. The second study examined a potentially important role
for basophils as a cellular source of rapidly releasable IL-4 which may help initiate allergen induced
TH2 responses. The next study investigated the possible effects on allergen induced early and late
asthmatic responses of the immunosuppressive drug cyclosporin A which had been shown both to
inhibit mast cell and basophil degranulation and cytokine secretion (particularly by CD4+ T-cells). The
final study evaluated Fc?RI expression on these cell types as well humoral factors (e.g. seasonal
changes in allergen specific IgG and IgE) in subjects who, after 3 to 4 years of grass pollen
immunotherapy, had continued on either active or placebo immunotherapy for a further 3 years.A historical perspective explaining some of the reasons the studies were done is provided in the
introductory chapter whilst the discussion chapter at the end reviews how many of the findings of the
study have evolved in subsequent years right up to the present day and finishes off with a brief
synopsis of how rapidly increasing knowledge of the regulatory functions of dendritic cells (expressing
Fc?RI and often monocyte derived) has resulted in better understanding of the mechanisms of allergen
specific immunotherapy and is leading to more effective treatment modalities
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