[590] INHIBITION OF HCV REPLICATION BY PSI-6130: MECHANISM OF BIOCHEMICAL ACTIVATION AND INHIBITION

2007 ◽  
Vol 46 ◽  
pp. S224 ◽  
Author(s):  
P.A. Furman ◽  
E. Murakami ◽  
H. Bao ◽  
J. Symons ◽  
M.J. Otto
Planta ◽  
1997 ◽  
Vol 204 (1) ◽  
pp. 16-26 ◽  
Author(s):  
M. U. F. Kirschbaum ◽  
M. Küppers ◽  
H. Schneider ◽  
C. Giersch ◽  
S. Noe

1986 ◽  
Vol 108 (4) ◽  
pp. 301-305 ◽  
Author(s):  
A. To¨zeren

In the present study, an analytical method is developed to deduce the constitutive equations of fibers embedded in a thick shell from the time-variant pressure volume curves obtained by experimental procedures. It is assumed that the spherical shell under consideration is composed of a fiber reinforced material and undergoes radial deflection, modeling the behavior of some biological shells such as urinary bladder. The fiber stress is expressed as a function of fiber strain, rate of strain and the degree of biochemical activation. The function form is chosen such that equations of mechanical equilibrium can be integrated analytically to yield chamber pressure as a function of chamber volume, time rate of change of volume and activation. Arbitrary coefficients appearing in the fiber stress-equation are also present in the resultant time-variant pressure-volume relation. These coefficients can be determined by curve-fitting commonly used clinical data such as cystometry measurements.


2001 ◽  
Vol 281 (2) ◽  
pp. C524-C531 ◽  
Author(s):  
Rennolds S. Ostrom ◽  
Caroline Gregorian ◽  
Ryan M. Drenan ◽  
Kathryn Gabot ◽  
Brinda K. Rana ◽  
...  

Madin-Darby canine kidney (MDCK) cells release ATP upon mechanical or biochemical activation, initiating P2Y receptor signaling that regulates basal levels of multiple second messengers, including cAMP ( J Biol Chem 275: 11735–11739, 2000). Data shown here document inhibition of cAMP formation by Gd3+ and niflumic acid, channel inhibitors that block ATP release. cAMP production is stimulated via Ca2+-dependent activation of cytosolic phospholipase A2, release of arachidonic acid (AA), and cyclooxygenase (COX)-dependent production of prostaglandins, which activate prostanoid receptors coupled to Gs and adenylyl cyclase. In the current investigation, we assessed the expression and functional role of the two known isoforms of COX, COX-1 and COX-2. Treatment of cells with either a COX-1-selective inhibitor, SC-560, or COX-2-selective inhibitors, SC-58125 or NS-398, inhibited basal and UTP-stimulated cAMP levels. COX inhibitors also decreased forskolin-stimulated cAMP formation, implying this response is in part attributable to an action of AA metabolites. These findings imply an important role for the inducible form of COX, COX-2, under basal conditions. Indeed, COX-2 expression was readily detectable by immunoblot, and treatments that induce or reduce COX-2 expression in other cells (interleukin-1β, tumor necrosis factor-α, phorbol ester, or dexamethasone) had minimal or no effect on the levels of COX-2 immunoreactivity. RT-PCR using isoform-specific primers detected COX-2 mRNA. We conclude that COX-2 is constitutively expressed in MDCK-D1 cells and participates in basal and P2Y2-mediated signaling, implying a key role for COX-2 in regulation of epithelial cell function.


1987 ◽  
Author(s):  
L J Wurzinger ◽  
R Opitz ◽  
H Schmid-Schönbein

High shear forces are suspected to play a triggering role in the initiation of arterial thrombosis, by activating platelets and the coagulation system. In an earlier study a shear stress of 170 N/m2 acting for only 7 milliseconds (ms) on platelet rich plasma (PRP) was found to induce a significant increase in platelet factor 3 availability (Thromb. Haemost. 54: 381-386; 1985). To clarify the question whether platelets can be activated directly by mechanical forces in analogy to smooth muscle cells, electron micrographs of platelets subjected to laminar shear stress were analysed with morphometric methods. The level of activation of platelet suspensions was quantified by assessing 1) the elongation of platelet profiles giving a measure for the “flatness” of the discoid resting platelets, and 2) the centralization of granules.Exposure to a shear stress of 170 N/m2 for 113 ms leaves ca. 15 % of the platelets irreversibly damaged, featuring degenerative ballooning, with break-down of internal structure and cell membrane defects. The remaining 85 % appear typically activated with rounded shape, extension of pseudopods and centralization of granules. Addition of “ADP-scavengers” to the suspension medium totally changes the appearance of sheared platelets: still a comparable proportion of them has undergone irreversible degenerative changes, but the “surviving” population lacks ultrastructural signs of platelet activation. This is reflected in values of the morphometric parameters which are close to the level of unsheared control samples.It is therefore concluded that “shear-induced platelet activation” cannot be ascribed to a direct stimulating effect of shear forces, but rather to secondary biochemical activation by adenine nucleotides leaking from a small percentage of shear destroyed platelets. The latter process, however, requires a well stirred though undiluted environment, as it is provided in vortices and eddies.


Author(s):  
Sangyoon J. Han ◽  
Nathan J. Sniadecki

Cells rely on traction forces in order to crawl across a substrate. These traction forces come from dynamic changes in focal adhesions, cytoskeletal structures, and chemical and mechanical signals from the extracellular matrix. Several computational models have been developed that help explain the trajectory or accumulation of cells during migration, but little attention has been placed on traction forces during this process. Here, we investigated the spatial and temporal dynamics of traction forces by using a multiphysics model that describes the cycle of steps for a migrating cell on an array of posts. The migration cycle includes extension of the leading edge, formation of new adhesions at the front, contraction of the cytoskeleton, and the release of adhesions at the rear. In the model, an activation signal triggers the assembly of actin and myosin into a stress fiber, which generates a cytoskeletal tension in a manner similar to Hill’s muscle model. In addition, the role that adhesion dynamics has in regulating cytoskeletal tension has been added to the model. The multiphysics model was simulated in Matlab for 1-D simulations, and in Comsol for 2-D simulations. The model was able to predict the spatial distribution of traction forces observed with previous experiments in which large forces were seen at the leading and trailing edges. The large traction force at the trailing edge during the extension phase likely contributes to detachment of the focal adhesion by overcoming its adhesion strength with the post. Moreover, the model found that the mechanical work of a migrating cell underwent a cyclic relationship that rose with the formation of a new adhesion and fell with the release of an adhesion at its rear. We applied a third activation signal at the time of release and found it helped to maintain a more consistent level of work during migration. Therefore, the results from both our 1-D and 2-D migration simulations strongly suggest that cells use biochemical activation to supplement the loss in cytoskeletal tension upon adhesion release.


2004 ◽  
Vol 324 (1) ◽  
pp. 401-408 ◽  
Author(s):  
Taehyun Kim ◽  
Juhyun Choi ◽  
Sunoh Kim ◽  
Ohyeun Kwon ◽  
Seung-Yeol Nah ◽  
...  

2021 ◽  
Author(s):  
Jonathan B Estrada ◽  
Harry C Cramer ◽  
Mark T Scimone ◽  
Selda Buyukozturk ◽  
Christian Franck

Successful detection and prevention of brain injuries relies on the quantitative identification of cellular injury thresholds associated with the underlying pathology. Here, by combining a recently developed inertial microcavitation rheology technique with a 3D in vitro neural tissue model, we quantify and resolve the structural pathology and critical injury strain thresholds of neural cells occurring at high loading rates such as encountered in blast exposures or cavitation-based medical procedures. We find that neuronal dendritic spines characterized by MAP2 displayed the lowest physical failure strain at 7.3%, whereas microtubules and filamentous actin were able to tolerate appreciably higher strains (14%) prior to injury. Interestingly, while these critical injury thresholds were similar to previous literature values reported for moderate and lower strain rates (<100 1/s), the pathology of primary injury reported here was distinctly different by being purely physical in nature as compared to biochemical activation during apoptosis or necrosis.


1989 ◽  
Vol 169 (1) ◽  
pp. 291-296 ◽  
Author(s):  
R Fava ◽  
N Olsen ◽  
J Keski-Oja ◽  
H Moses ◽  
T Pincus

We have evaluated the possible involvement of TGF-beta in rheumatoid arthritis by assay of 16 cell-free synovial fluids for the presence of its active and "latent" forms. Evidence has been obtained for TGF-beta-like activity in synovial effusions by four criteria: (a) TGF-beta receptor competition, (b) soft-agar colony formation of AKR-2B and NRK-49F indicator cells, (c) immunological neutralization of the biological activity, and (d) biochemical activation of a latent form.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1431-1431 ◽  
Author(s):  
Suzanne Schubbert ◽  
Oddmund Sovik ◽  
Gideon Bollag ◽  
Hoa Nguyen ◽  
Sara L. Rowe ◽  
...  

Abstract Noonan syndrome is characterized by short stature, facial dysmorphism, and cardiac defects. We and our colleagues discovered novel de novo germline KRAS mutations that introduce V14I, T58I, or D153V amino acid substitutions in individuals with NS and a P34R alteration in an individual with cardio-facio-cutaneous (CFC) syndrome, which has overlapping phenotypic features with NS. Recombinant V14I and T58I K-Ras proteins display defective intrinsic GTP hydrolysis and impaired responsiveness to the GTPase activating proteins (GAPs) p120 GAP and neurofibromin. We also found that V14I and T58I K-Ras render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage specific manner (Nature Genetics38, 331, 2006). We recently began interrogating the P34R and D153V K-Ras mutant proteins and a novel CFC-associated F156L K-Ras mutant protein. Both P34R and D153V K-Ras display normal levels of intrinsic GTP hydrolysis. In contrast, F156L K-Ras displays defective intrinsic GTP hydrolysis that resembles oncogenic G12D K-Ras. P34R K-Ras is completely resistant to both GAPs, which is intriguing as these data suggest that the ability of GAPs to down-regulate Ras-GTP levels is dispensible for development. In contrast, D153V K-Ras is responsive to both GAPs. We expressed mutant Ras proteins in COS-7 monkey kidney cells to investigate activation of Ras and downstream effectors. Cells expressing P34R, D153V, F156L, and G12D K-Ras demonstrate elevated levels of Ras-GTP and phospho-MEK in basal and serum-starved conditions. We conclude that germline KRAS mutations that cause human disease encode proteins with distinct mechanisms of biochemical activation. Further investigation of this allele series will provide insights about the relative importance of the intrinsic Ras GTPase, GAPs, and other biochemical mechanisms in controlling the growth of different cell lineages.


Blood ◽  
2014 ◽  
Vol 123 (12) ◽  
pp. 1810-1817 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Kelly Smucker ◽  
Lisa L. Smith ◽  
Arletta Lozanski ◽  
Yiming Zhong ◽  
...  

Key Points Persistent CLL cells during ibrutinib therapy show evidence of biochemical activation, but inhibited BCR and no proliferation. Long lymphocytosis during ibrutinib therapy is not associated with adverse progression-free survival.


Sign in / Sign up

Export Citation Format

Share Document