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At least 217 records · Page 12Linked to original sources

PubMed2001

A CCR5/CXCR4-independent coreceptor pathway on human macrophages supports efficient SIV env-mediated fusion but not infection: implications for alternative pathways of viral entry.

Several coreceptors in addition to CCR5 and CXCR4 support immunodeficiency virus entry in transfected cells, but whether they could play a role in HIV-1 pathogenesis is uncertain. To probe whether human macrophages express potentially functional alternative entry pathways, we analyzed cell-cell fusion and infection of primary macrophage by several SIVmac Envs. All Envs fused with normal macrophages. One, SIVmac316, also fused efficiently with macrophages lacking CCR5. CCR5-independent fusion was not mediated by CXCR4 and was CD4 dependent, while CCR5-mediated fusion was partly independent of CD4. However, pseudotype virions carrying the SIVmac316 Env and HIV-1 core could not infect macrophages through the CCR5-independent pathway, although they did infect wild-type macrophages. Thus, human macrophages possess an alternative coreceptor pathway that mediates SIV Env fusion but does not support infection. Macrophage entry pathways other than CCR5 and CXCR4 may have limited potential in pathogenesis given their restricted capacity for infection despite efficient fusion.

DNA Primers↗

PubMed1978

Pathways for movement of ions and water across toad urinary bladder. III. Physiologic significance of the paracellular pathway.

Hypertonicity of the mucosal bathing medium increases the electrical conductance of toad urinary bladder by osmotic distension of the epithelial "tight" or limiting junctions. However, toad urine is not normally hypertonic to plasma. In this study, the transmural osmotic gradient was varied strictly within the physiologic range; initially hypotonic mucosal bathing media were made isotonic by addition of a variety of solutes. Mucosal NaCl increased tissue conductance substantially. This phenomenon could not have reflected soley an altered conductance of the transcellular active transport pathway since mucosal KCl also increased tissue conductance, whether or not Na+ was present in the bathing media. The effect of mucosal NaCl could not have been mediated solely by a parallel transepithelial pathway formed by damaged tissue since mucosal addition of certain nonelectrolytes also increased tissue conductance. Finally, the osmotically-induced increase in conductance could not have occurred soley in transcellular transepithelial channels in parallel with the active pathway for Na+, since the permeability to 22Na from serosa to mucosa (s to m) was also increased by mucosal addition of NaCl; a number of lines of evidence suggest that s-to-m movement of Na+ proceeds largely through paracellular transepithelial pathways. The results thus establish that the permeability of the limiting junctions is physiologically dependent on the magnitude of the transmural osmotic gradient. A major role is proposed for this mechanism, serving to conserve the body stores of NaCl from excessive urinary excretion.

Animals↗

PubMed1982

Perforant pathway activation of hippocampal CA1 stratum pyramidale neurons: electrophysiological evidence for a direct pathway.

Electrophysiological techniques were used to investigate the effect of stimulating the perforant pathway (PP) on pyramidal neurons in the CA1 region of the hippocampal slice. Stimulation of the PP evoked both field potentials and single unit discharges in the pyramidal cell layer of the CA1 region. Several lines of experimental evidence suggest that the CA1 response does not involve granule or CA3 neurons: (i) movement of the recording electrode in the CA1 region away from the site of stimulation in the PP and closer to the CA3 region increased the latency of the evoked potential; (ii) the sum of latencies of the individual pathways in a trisynaptic circuit - from the PP to granule cells to CA3 neurons to CA1 neurons - was 2-3 times longer than the latency of the PP evoked response recorded in the CA1 region: (iii) lesioning the mossy fiber pathway or excising the CA3 region did not inhibit the CA1 response to PP stimulation. Other experimental results suggest that the PP activation of CA1 pyramidal neurons involves a direct synaptic pathway: (i) PP stimulation evoked potentials with similar latencies in the dentate gyrus and the CA1 region; (ii) the CA1 response was abolished in a Krebs' solution containing low calcium/high magnesium; (iii) excising a portion of the CA1 region between the stimulating electrode in the PP and the CA1 recording electrode, but sparing the PP, did not abolish the CA1 response; (iv) electrolytic lesions of the PP abolished the CA1 response to PP stimulation, but did not affect the CA1 response to stimulation of the CA3 region. The data suggest that fibers in the PP make direct synaptic connection with pyramidal neurons in the CA1 region of the hippocampus.

Animals↗

PubMed2005

Novel Daple-like protein positively regulates both the Wnt/beta-catenin pathway and the Wnt/JNK pathway in Xenopus.

Wnt signaling pathways are essential in various developmental processes including differentiation, proliferation, cell migration, and cell polarity. Wnt proteins execute their multiple functions by activating distinct intracellular signaling cascades, although the mechanisms underlying this activation are not fully understood. We identified a novel Daple-like protein in Xenopus and named it xDal (Xenopus Daple-like). As with Daple, xDal contains several leucine zipper-like regions (LZLs) and a putative PDZ domain-binding motif, and can interact directly with the dishevelled protein. In contrast to mDaple, injection of xDal mRNA into the dorso-vegetal blastomere does not induce ventralization and acted synergistically with xdsh in secondary axis induction. XDal also induced expression of siamois and xnr-3, suggesting that XDal functions as a positive regulator of the Wnt/beta-catenin pathway. Injection of xDal mRNA into the dorso-animal blastomere, however, induced gastrulation-defective phenotypes in a dose-dependent manner. In addition, xDal inhibited activin-induced elongation of animal caps and enhanced c-jun phosphorylation. Based on these findings, xDal is also thought to function in the Wnt/JNK pathway. Moreover, functional domain analysis with several deletion mutants indicated that xDal requires both a putative PDZ domain-binding motif and at least one LZL for its activity. These findings with xDal will provide new information on the Wnt signaling pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Arachidonic acid synthetic pathways of the oyster protozoan parasite, Perkinsus marinus: evidence for usage of a delta-8 pathway.

The meront stage of the oyster protozoan parasite, Perkinsus marinus, is capable of synthesizing saturated and unsaturated fatty acids including the essential fatty acid, arachidonic acid [20:4(n-6)]. Eukaryotes employ either delta-6 (Delta-6) or delta-8 (Delta-8) desaturase pathway or both to synthesize arachidonic acid. To elucidate the arachidonic acid synthetic pathways in P. marinus, meronts were incubated with deuterium-labeled precursors [18:1(n-9)-d6, 18:2(n-6)-d4, 18:3(n-3)-d4, and 20:3(n-3)-d8]. The lipids were extracted, converted to fatty acid methyl esters, and analyzed using gas chromatography/mass spectrometry and gas chromatography/flame ionization detection. Deuterium-labeled 18:2(n-6), 20:2(n-6), 20:3(n-6), and 20:4(n-6) were detected in meront lipids after 1-, 3-, 5-, and 10-day incubation with 18:1(n-9)-d6. Deuterium-labeled 20:2(n-6), 20:3(n-6) and 20:4(n-6) were found in lipids from meronts after incubation with 18:2(n-6)-d4 methyl ester. No labeled 18:3(n-6) was detected in either incubation. Apparently, when incubated with 18:1(n-9)-d6, the parasite first desaturated 18:1(n-9)-d6 to 18:2(n-6)-d6 by Delta-12 desaturase, then to 20:2(n-6)-d6 by elongation, and ultimately desaturated to 20:3(n-6)-d6 and 20:4(n-6)-d6 using the sequential Delta-8 and Delta-5 desaturation. Similarly, when incubated with 18:2(n-6)-d4, P. marinus converted the 18:2(n-6)-d4 to 20:2(n-6)-d4 by elongation and 20:2(n-6)-d4 to 20:3(n-6)-d4 by Delta-8 desaturase then by Delta-5 desaturase to 20:4(n-6)-d4. These results provide evidence that P. marinus employed the Delta-8 rather Delta-6 pathway for arachidonic acid synthesis. Additional support for the presence of a Delta-8 pathway was the demonstrated ability of the parasite to metabolize 18:3(n-3)-d4 to 20:3(n-3)-d4 and 20:4(n-3)-d4, and 20:3(n-3)-d8 to 20:4(n-3)-d6 and 20:5(n-3)-d6 using the sequential position-specific Delta-8 and Delta-5 desaturases.

Animals↗

PubMed2003

To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways.

After a severe episode of ischemia, traumatic brain injury (TBI) or epilepsy, it is typical to find necrotic cell death within the injury core. In addition, a substantial number of neurons in regions surrounding the injury core have been observed to die via the programmed cell death (PCD) pathways due to secondary effects derived from the various types of insults. Apart from the cell loss in the injury core, cell death in regions surrounding the injury core may also contribute to significant losses in neurological functions. In fact, it is the injured neurons in these regions around the injury core that treatments are targeting to preserve. In this review, we present our cumulated understanding of stress-activated signaling pathways and apoptotic pathways in the research areas of ischemic injury, TBI and epilepsy and that gathered from concerted research efforts in oncology and other diseases. However, it is obvious that our understanding of these pathways in the context of acute brain injury is at its infancy stage and merits further investigation. Hopefully, this added research effort will provide a more detailed knowledge from which better therapeutic strategies can be developed to treat these acute brain injuries.

Animals↗

PubMed2002

The porphyrin pathway: the final common pathway?

When I was learning pathology a wise and knowledgeable mentor described a final common pathway that allows many diseases to overlap in their presentation. This pathway was never identified for it was unknown. Recent books by physicians have suggested that maintaining body balance and/or treatment by a substance could halt or repair damage caused by a wide array of diseases, once again suggesting a common thread amongst diseases. Again no mention was made regarding what was this common denominator. I have been interested in people who have more than one disease, feeling that there must be a link. My interest in the porphyrin pathway has strengthened that impression. Since finding Doss's list of diseases having porphyrin abnormalities unrelated to a porphyria, I have worked on models that would allow me to show a way where porphyrin abnormalities may be a part of the final common pathway for all disease. I have finally decided that a spider's web is that model. The following discussion will attempt to demonstrate that this hypothesis could be true.

Diabetes Mellitus↗

PubMed1988

"Nodoventricular" accessory pathway: evidence for a distinct accessory atrioventricular pathway with atrioventricular node-like properties.

Two patients are described with recurrent pre-excited tachycardia and electrophysiologic characteristics typically ascribed to a nodoventricular accessory connection. The accessory pathway in each case demonstrated rate-dependent prolongation of conduction time and a low right ventricular insertion site; it was associated with a left bundle branch block configuration during pre-excitation. Intraoperatively, the pathway was demonstrated to originate at the anterior right atrioventricular (AV) anulus and not at the AV node. These data suggest that a "typical" nodoventricular pathway, by electrophysiologic criteria, may in fact be an AV pathway with AV node-like conduction properties and a distal right ventricular insertion site.

Adult↗

PubMed2003

Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway.

Bisphosphonates have been used for the treatment of hypercalcemia associated with malignancies and osteoporosis. It was previously reported that the mevalonate pathway is involved in nitrogen-containing bisphosphonate-induced apoptosis in osteoclasts and myeloma cells. The aim of this study was to determine the effects of two bisphosphonates, incadronate, and newly developed bisphosphonate YM529 on human myeloma cells, U266, RPMI-8226, and HS-Sultan. Both incadronate and YM529 induced S-phase cell cycle arrest and apoptosis in these myeloma cells. Treatment of the myeloma cells with cell-permeable substrates for mevalonate pathways, geranylgeraniol, and farnesol prevented bisphosphonate-mediated growth suppression. Checkpoint kinases, Chk1/2, and MAPK became phosphorylated after stimulation with bisphosphonates in the myeloma cells. Bisphosphonate-induced apoptosis was partially prevented by the pretreatment with MAPK inhibitor. These results demonstrate that incadronate and YM529 suppress the proliferation of myeloma cells through mevalonate pathway and MAPK pathway.

Apoptosis↗

PubMed2003

Elucidation of the metabolic pathway of fluorene and cometabolic pathways of phenanthrene, fluoranthene, anthracene and dibenzothiophene by Sphingomonas sp. LB126.

The metabolic pathway of the PAH fluorene and the cometabolic pathway of the PAHs phenanthrene, fluoranthene, anthracene and dibenzothiophene in Sphingomonas sp. LB126 were examined. To our knowledge this is the first study on the cometabolic degradation of the three-ring PAHs phenanthrene, anthracene and the four-ring PAH fluoranthene by a fluorene-utilizing species. Metabolism of fluorene was shown to proceed via the 9-fluorenone pathway to form o-phthalic acid and protocatechuic acid. The cometabolic mono-hydroxylation found for phenanthrene, fluoranthene and anthracene shows similarity with the hydroxylation of fluorene. Several mono- and dihydroxy products and ring-cleavage products were identified for phenanthrene, fluoranthene and anthracene. It appeared that the cometabolism of those three compounds is a non-specific process, in contrast to the metabolism of fluorene. For dibenzothiophene the metabolites dibenzothiophene-5-oxide and dibenzothiophene-5,5-dioxide were identified; these compounds appeared to be the products of a dead-end pathway. Since apart from dibenzothiophene no metabolites were found in very high concentrations for any of the other substrates, complete degradation is suggested, even for the cometabolic degradation of phenanthrene, fluoranthene and anthracene.

Anthracenes↗

PubMed2001

Importance of the cytochrome pathway of mitochondrial electron transport over the alternative pathway during the Kok effect in leaf discs of pea (Pisum sativum).

The Kok effect refers to the progressive light-induced inhibition of dark respiration at low light intensities, which saturates around the light compensation point. This appears as a sudden break around the light compensation point in the plot of photosynthesis versus light intensity. The magnitude of the break can be considered as a measure of the Kok effect. In the present work, the importance of different components of dark respiration during the Kok effect was investigated by using low concentrations of mitochondrial inhibitors in leaf discs of pea (Pisum sativum L. cv. Azad P1). The effects of glucose (stimulates respiration) and 0.8 M sorbitol (imposes osmotic stress and inhibits photosynthesis) were also studied for comparison. The magnitude of the break decreased significantly in the presence of antimycin A or oligomycin (inhibitors of cytochrome pathway of mitochondrial electron transport and ATP synthase, respectively). In contrast, there was no significant change with salicylhydroxamic acid (SHAM; an inhibitor of alternative pathway of mitochondrial electron transport). The magnitude of the break increased significantly with glucose, and decreased on exposure to osmotic stress. Our results suggest that the Kok effect (inhibition of dark respiration in light) is modulated by inhibitors of cytochrome pathway and ATP synthesis, but not that of the alternative pathway.

Journal Article↗

PubMed2006

A model of the ethylene signaling pathway and its gene response in Arabidopsis thaliana: pathway cross-talk and noise-filtering properties.

Dynamic models of molecular networks and pathways enable in silico evaluations of the consistency of proposed interactions and the outcomes of perturbations as well as of hypotheses on system-level structure and function. We postulate a continuous model of the activation dynamics of the ethylene response factor 1 (ERF1) gene in response to ethylene signaling. This activation elicits the response of the plant defensin 1 (PDF1) gene, which also responds to jasmonic acid, and the inhibition of the putative auxin responsive factor 2 (ARF2) gene, that also responds to auxin. Our model allows the effect of different ethylene concentrations in eliciting contrasting genetic and phenotypic responses to be evaluated allows the effect of different ethylene concentrations in eliciting contrasting genetic and phenotypic responses to be evaluated and seems to consider key components of the ethylene pathway because the ERF1 dose-response curve that we predict has the same qualitative form as the phenotypic dose-response curves obtained experimentally. Therefore, our model suggests that the phenotypic dose-response curves obtained experimentally could be due, at least in part, to ERF1 changes to different ethylene concentrations. Stability analyses show that the model's results are robust to parameter estimates. Of interest is that our model predicts that the ethylene pathway may filter stochastic and rapid chaotic fluctuations in ethylene availability. This novel approach may be applied to any cellular signaling and response pathway in plants and animals.

Arabidopsis↗

PubMed2002

Phi value analysis of heterogeneity in pathways of allosteric transitions: Evidence for parallel pathways of ATP-induced conformational changes in a GroEL ring.

What are the mechanisms of ligand-induced allosteric transitions in proteins? A powerful method to characterize pathways and transition states of reactions is phi value analysis. A phi value is the ratio between the changes on a perturbation (e.g., mutation) in the activation and equilibrium free energies of a reaction. Here, phi value analysis is used to characterize the ATP-induced allosteric transitions of GroEL by using changes in ATP concentration as perturbations. GroEL consists of two stacked back-to-back heptameric rings that bind ATP with positive cooperativity within rings and negative cooperativity between rings. Evidence is presented for the existence of parallel pathways for the allosteric transition of each ring. In both allosteric transitions, there is an abrupt ATP-dependent switch from a pathway with ATP-binding sites in the transition state that are very similar to those of the initial T state (phi = 0) to a pathway with a phi value of approximately 0.3. The phi value procedure outlined here should be useful in mapping the energy landscape of allosteric transitions of other proteins.

Adenosine Triphosphate↗

PubMed1997

Antisense repression of proto-oncogene c-Cbl enhances activation of the JAK-STAT pathway but not the ras pathway in epidermal growth factor receptor signaling.

Many growth factors including epidermal growth factor (EGF) induce tyrosine phosphorylation of the c-Cbl proto-oncogene product, whose function, however, remains unclear. Recently, Sli-1, a Caenorhabditis elegans homologue of c-Cbl, was found to be a negative regulator of let-23-mediated vulval induction pathway, suggesting that c-Cbl may negatively regulate EGF receptor (EGFR)-mediated signaling. In this study, by an antisense RNA approach, we examined the effects of expression level of c-Cbl on EGFR signaling and showed that overexpression of c-Cbl reduces and antisense repression of c-Cbl enhances autophosphorylation of EGF receptors and activation of the JAK-STAT pathway. However, in contrast to the Sli-1 protein, the expressed amount of c-Cbl does not affect activation of the Ras pathway, suggesting that the EGFR-mediated signaling pathways are differently regulated by c-Cbl among nematodes and mammals.

3T3 Cells↗

PubMed1999

Evidence for a beta2-adrenergic/arachidonic acid pathway in ventricular cardiomyocytes. Regulation by the beta1-adrenergic/camp pathway.

The signaling pathway mediating the contractile effect of beta2-adrenergic receptors (beta2-AR) in the heart is still matter of debate. By using embryonic chick ventricular cardiomyocytes that express both functional beta1-and beta2-ARs, we show here that the specific beta2-AR agonist, zinterol, increases the amplitude of Ca2+ transients and cell contraction of electrically stimulated cells. Zinterol, up to 10 microM, did not stimulate adenylyl cyclase activity, and its effect on Ca2+ transients was unmodified by the specific cAMP antagonist, (Rp)-cAMPS. In contrast, zinterol (10-100 nM) triggered arachidonic acid (AA) release from [3H]AA-loaded cells via the activation of the cytosolic phospholipase A2 (cPLA2). Stimulation of the Ca2+ transients by zinterol was abolished by the cPLA2 inhibitor, AACOCF3, and was mimicked by AA (0.3-3 microM). Both stimulations of [3H]AA release and of [Ca2+]i cycling by zinterol were abolished after treatment of the cardiomyocytes with pertussis toxin. Although cell responses to beta2-AR stimulation were mediated by AA, they were under cAMP control as follows: (i) the beta1-AR stimulation exerted a cAMP-mediated negative constraint on the beta2-AR/cPLA2 pathway; (ii) cAMP potentiated AA action downstream beta-AR stimulation. We conclude that, in cardiomyocytes, beta2-AR is coupled to cPLA2 activation via a pertussis toxin-sensitive G protein. These results demonstrate the involvement of the cPLA2/AA pathway in mediating positive inotropic effects, which could potentially compensate for a defective cAMP pathway.

Adenylyl Cyclases↗

PubMed2000

Tumor necrosis factor-alpha activation of the c-Jun N-terminal kinase pathway in human neutrophils. Integrin involvement in a pathway leading from cytoplasmic tyrosine kinases apoptosis.

The intensity and duration of an inflammatory response depends on the balance of factors that favor perpetuation versus resolution. At sites of inflammation, neutrophils adherent to other cells or matrix components are exposed to tumor necrosis factor-alpha (TNFalpha). Although TNFalpha has been implicated in induction of pro-inflammatory responses, it may also inhibit the intensity of neutrophilic inflammation by promoting apoptosis. Since TNFalpha is not only an important activator of the stress-induced pathways leading to p38 MAPk and c-Jun N-terminal kinase (JNK) but also a potent effector of apoptosis, we investigated the effects of TNFalpha on the JNK pathway in adherent human neutrophils and the potential involvement of this pathway in neutrophil apoptosis. Stimulation with TNFalpha was found to result in beta2 integrin-mediated activation of the cytoplasmic tyrosine kinases Pyk2 and Syk, and activation of a three-part MAPk module composed of MEKK1, MKK7, and/or MKK4 and JNK1. JNK activation was attenuated by blocking antibodies to beta2 integrins, the tyrosine kinase inhibitors, genistein, and tyrphostin A9, a Pyk2-specific inhibitor, and piceatannol, a Syk-specific inhibitor. Exposure of adherent neutrophils to TNFalpha led to the rapid onset of apoptosis that was demonstrated by augmented annexin V binding and caspase-3 cleavage. TNFalpha-induced increases in annexin V binding to neutrophils were attenuated by blocking antibodies to beta2 integrins, and the caspase-3 cleavage was attenuated by tyrphostin A9. Hence, exposure of adherent neutrophils to TNFalpha leads to utilization of the JNK-signaling pathways that may contribute to diverse functional responses including induction of apoptosis and subsequent resolution of the inflammatory response.

Apoptosis↗

PubMed2002

The ERK/MAPK pathway regulates the activity of the human tissue factor pathway inhibitor-2 promoter.

Human tissue factor pathway inhibitor-2 (hTFPI-2) is a 32-kDa serine protease inhibitor that is associated with the extracellular matrix. hTFPI-2 inhibits several extracellular matrix-degrading serine proteases and may play a role in tumor invasion and metastasis. To study the signal transduction pathway that leads to the activation of the hTFPI-2, we cloned the potential promoter region of this gene adjacent to a heterologous luciferase reporter gene. Phorbol 12-myristate 13-acetate (PMA) induced the luciferase reporter gene in HEK293 cells and other epithelial cell lines, such as the human lung carcinoma A549 cells, the breast carcinoma MCF7 cells, and the cervical HeLa cells. This PMA induction was blocked with the MEK inhibitor UO126, suggesting that the PMA-induced activation of the hTFPI-2 promoter is mediated through MEK. Furthermore, epidermal growth factor induced the luciferase reporter gene in HeLa cells. Cotransfection of the luciferase construct with constitutively active components of the Ras/Raf/MEK/ERK pathway in EcR-293 cells lead to a 7- to 92-fold induction of the luciferase reporter gene, indicating that regulation of hTFPI-2 is mediated through this pathway. A series of luciferase reporter gene constructs with progressive deletions of the 5'-flanking region suggested that the minimal basal promoter activity is located between nucleotide positions -89 and -384, whereas the minimal inducible promoter activity is between -89 and -222. We have used the computer program TFSEARCH and mutagenesis to analyze potential transcription factor binding sites. We identified an AP-1 binding site at nucleotide position -156 (inducible activity) and a Sp1 site at position -134 (basal activity) as potential cis-acting elements in the promoter region of the hTFPI-2.

Binding Sites↗

PubMed2004

Formation of factors IXa and Xa by the extrinsic pathway: differential regulation by tissue factor pathway inhibitor and antithrombin III.

The activation of factor X by VIIa/TF and the Xa-dependent inhibition of the enzyme complex by tissue factor pathway inhibitor (TFPI) are considered primary steps in the initiation of coagulation. IX activation by VIIa/TF is considered to contribute catalyst necessary for further Xa production in the ensuing amplification phase. We have investigated Xa and IXabeta production by VIIa-TF in a system reconstituted with both X and IX and the principal physiologic inhibitors of this pathway TFPI and antithrombin III (AT). Kinetic studies without inhibitors established that IX and X functioned as competitive alternate substrates for VIIa/TF with similar kinetic constants. When both IX and X were present, TFPI significantly inhibited the extent of formation of either IXabeta or Xa. In contrast, AT rapidly depleted active Xa with a small effect on IXabeta formation. When both AT and TFPI were present, active IXabeta formation significantly exceeded the formation of active Xa regardless of the VIIa/TF concentration. These findings could be quantitatively accounted for by a model encompassing the kinetics of the individual activation and inhibition steps. Active Xa formation by this pathway is regulated in a principal way by its rapid inactivation by AT. In contrast, the Xa-dependent inhibitory reactions of TFPI play a primary role in limiting zymogen consumption and the formation of active IXabeta. These regulatory phenomena yield active IXabeta as a major rather than secondary product of VIIa/TF. Our findings raise the possibility that IXabeta produced by the extrinsic pathway, and its ability to function within the intrinsic Xase complex to activate X may play a significant role in producing Xa necessary for both the initiation and sustained phases of the procoagulant response following vascular damage.

Animals↗