42 research outputs found
The Nondeterministic Waiting Time Algorithm: A Review
We present briefly the Nondeterministic Waiting Time algorithm. Our technique
for the simulation of biochemical reaction networks has the ability to mimic
the Gillespie Algorithm for some networks and solutions to ordinary
differential equations for other networks, depending on the rules of the
system, the kinetic rates and numbers of molecules. We provide a full
description of the algorithm as well as specifics on its implementation. Some
results for two well-known models are reported. We have used the algorithm to
explore Fas-mediated apoptosis models in cancerous and HIV-1 infected T cells
Overexpression of a Minimal Domain of Calpastatin Suppresses IL-6 Production and Th17 Development via Reduced NF-κB and Increased STAT5 Signals
Calpain, a calcium-dependent cysteine protease, is reportedly involved in the pathophysiology of autoimmune diseases such as rheumatoid arthritis (RA). In addition, autoantibodies against calpastatin, a natural and specific inhibitor of calpain, are widely observed in RA. We previously reported that E-64-d, a membrane-permeable cysteine protease inhibitor, is effective in treating experimental arthritis. However, the exact role of the calpastatin-calpain balance in primary inflammatory cells remains unclear. Here we investigated the effect of calpain-specific inhibition by overexpressing a minimal functional domain of calpastatin in primary helper T (Th) cells, primary fibroblasts from RA patients, and fibroblast cell lines. We found that the calpastatin-calpain balance varied during Th1, Th2, and Th17 development, and that overexpression of a minimal domain of calpastatin (by retroviral gene transduction) or the inhibition of calpain by E-64-d suppressed the production of IL-6 and IL-17 by Th cells and the production of IL-6 by fibroblasts. These suppressions were associated with reductions in RORγt expression and STAT3 phosphorylation. Furthermore, inhibiting calpain by silencing its small regulatory subunit (CPNS) suppressed Th17 development. We also confirmed that overexpressing a minimal domain of calpastatin suppressed IL-6 by reducing NF-κB signaling via the stabilization of IκBα, without affecting the upstream signal. Moreover, our findings indicated that calpastatin overexpression suppressed IL-17 production by Th cells by up-regulating the STAT5 signal. Finally, overexpression of a minimal domain of calpastatin suppressed IL-6 production efficiently in primary fibroblasts derived from the RA synovium. These findings suggest that inhibiting calpain by overexpressing a minimal domain of calpastatin could coordinately suppress proinflammatory activities, not only those of Th cells but also of synovial fibroblasts. Thus, this strategy may prove viable as a candidate treatment for inflammatory diseases such as RA
A NMF based approach for integrating multiple data sources to predict HIV-1–human PPIs
PB2000: LESSONS LEARNED FROM CERBA RESEARCH CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR T) MULTIPLE MYELOMA RUNNING TRIALS
IL-15 prolongs CD154 expression on human CD4 T cells via STAT5 binding to the CD154 transcriptional promoter
IgH gene rearrangement by PCR as an adjunct to flow cytometric analysis for the detection of minimal residual disease in patients with B lymphoblastic leukemia
Assistant Editors
Continued overleaf Management of pain in chronic pancreatitis. New solutions to an old problem Management of pain in chronic pancreatitis is a challenging clinical problem. Lack of proper understanding of the mechanisms responsible for pain, high morbidity and mortality rates historically associated with pancreatic surgery, and the long held view that pain will eventually subside when the pancreas "burns itself out " as a result of progressive fibrosis have all contributed to a non-surgical therapeutic approach for decades [1]. Many recent studies have challenged this view, and at present there is a shift from the "wait and see " approach to a more pro-active type of therapeutic approach in the management of pancreatic pain [2]. It is accepted that, at least in a majority of cases, the pain results from pressure increase within the pancreatic duct system from obstruction to the main pancreatic duct by stones or from post-inflammatory strictures [3]