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PubMed1993

Catheter ablation of accessory atrioventricular pathways in young patients: use of long vascular sheaths, the transseptal approach and a retrograde left posterior parallel approach.

OBJECTIVES: This study retrospectively assesses the technical aspects of the catheter techniques used to ablate 83 accessory atrioventricular (AV) pathways during 88 procedures in 71 pediatric and adult patients (median age 14 years, range 1 month to 55 years). A number of catheter approaches and techniques evolved that may have improved success and shortened procedure times. BACKGROUND: Radiofrequency catheter ablation of accessory AV pathways can be highly successful. However, the technical difficulty of many of the procedures is masked by the success rate. METHODS: Left free wall, right free wall and septal accessory pathways were ablated with a variety of approaches. RESULTS: Left free wall pathways were ablated successfully by using a standard retrograde approach through the aortic valve in only 10 (24%) of 43 cases. The remaining 33 (76%) required an approach that was either retrograde through the mitral valve (2 of 33), transseptal (21 of 33) or retrograde where the catheter was advanced behind the posterior mitral leaflet at the point of mitral-aortic continuity, so that the catheter course was parallel rather than perpendicular to the mitral anulus (10 of 33). Nineteen of 20 septal pathways were ablated successfully by using either the parallel approach (2 of 29), a transseptal approach (2 of 19), ablation within the coronary sinus or one of its veins (8 of 19) or ablation on the atrial side of the tricuspid valve (7 of 19). Fifteen of 20 right free wall pathways were ablated successfully with a variety of approaches on both the atrial and the ventricular side of the tricuspid valve. Long vascular sheaths were judged to contribute directly to success in 33 (43%) of 77 pathways. The overall success rate has been 93% (77 of 83 pathways), with 100% success for left free wall (43 of 43), 75% for right free wall (15 of 20) and 95% for septal pathways (19 of 20). CONCLUSIONS: Thus, successful ablation of accessory AV pathways in a mixed group of pediatric and adult patients appears to benefit from a wide range of vascular and catheter approaches.

Adolescent↗
PubMedDate not supplied

Radiofrequency catheter ablation of accessory pathway-mediated tachycardia is a safe and effective long-term therapy.

BACKGROUND: The primary purpose of the study was to evaluate long-term clinical results of radiofrequency catheter ablation of accessory pathway-mediated tachycardia. METHODS: Catheter ablation was performed in 321 patients who were subsequently followed up for an average of 36 months. RESULTS: Accessory pathway-mediated tachycardia was abolished by catheter ablation in 308 patients (96%). Right free wall (10.6%) and right posteroseptal (14.9%) accessory pathway was associated with higher failure rate than left-sided pathways (2.3%, p<0.01). Atrioventricular block occurred in two patients during ablation of anteroseptal pathway. Recurrence of accessory pathway conduction occurred in 13 (4.1%) patients, principally within the first 4 weeks after ablation procedure. Recurrence in right free wall (12.8%) or right posteroseptal (14.2%) pathways was higher than in left-sided pathways (1.8%, p<0.01). CONCLUSIONS: Radiofrequency catheter ablation has high immediate success rate and long-term recurrence of accessory pathway conduction or tachycardia. Right free wall or right posteroseptal pathways are associated with higher incidence of initial ablation failure and short- to medium-term recurrence.

Adolescent↗
PubMed2006

The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development.

The past two decades have led to a tremendous work on the transcription factor NF-kappaB and its molecular mechanisms of activation. The nuclear translocation of NF-kappaB is controlled by two main pathways: the classical and the alternative NF-kappaB pathways. The classical NF-kappaB pathway activates the IKK complex that controls the inducible degradation of most IkappaB family members that are IkappaBalpha, IkappaBbeta, IkappaBvarepsilon and p105. The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. Genetic studies have shown that IKKgamma is dispensable for the alternative pathway, which suggests the existence of an alternative IKKalpha-containing complex. It is noteworthy that activation of particular p52 heterodimers like p52/RelB requires solely the alternative pathway while activation of p52/p65 or p52/c-Rel involves a "hybrid pathway". Among others, LTbetaR, BAFF-R, CD40 and RANK have the ability to induce the alternative pathway. The latter plays some roles in biological functions controlled by these receptors, which are the development of secondary lymphoid organs, the proliferation, survival and maturation of B cell, and the osteoclastogenesis. Exacerbated activation of the alternative pathway is potentially associated to a wide range of disorders like rheumatoid arthritis, ulcerative colitis or B cell lymphomas. Therefore, inhibitors of the alternative pathway could be valuable tools for the treatment of inflammatory disorders and cancers.

Animals↗
PubMed2006

Crosstalk between cAMP-PKA and MAP kinase pathways is a key regulatory design necessary to regulate FLO11 expression.

Signal transduction pathways crosstalk with one another and play a central role in regulation of cellular events. Crosstalk brings complexity to the system, and hence, a systematic analysis of these crosstalks helps in relating the signaling network structure to its function. Here, we present a modular steady state approach to quantify the network comprising of cAMP-PKA and MAP kinase pathways involved in the regulation of FLO11, a gene which is required for pseudohyphae growth in Saccharomyces cerevisiae under nitrogen starvation. These two pathways crosstalk by converging on the same target, i.e., FLO11 and through Ras2p, an upstream activator of both cAMP and MAPK pathway. Analysis of crosstalk at the gene level revealed that cAMP-PKA and MAPK pathways are indispensable to FLO11 expression. The dose response was highly sensitive and primarily controlled by cAMP-PKA pathway. We demonstrate that the highly sensitive response in the cAMP-PKA pathway was due to crosstalk and inhibitor ultrsensitivity, key regulatory designs present at the downstream of cAMP-PKA pathway. The analysis of the role of Ras2p in the crosstalk between the cAMP-PKA and MAPK pathways indicated that crosstalk essentially helped in amplification of the Gpa2p signal, another upstream activator of the cAMP-PKA pathway. However, the effect of crosstalk due to Ras2p on FLO11 expression was minimal under normal activation levels of Ras2p. Whereas, the crosstalk itself can bring about FLO11 expression under the hyperactivated Ras2p conditions thereby eliminating the requirement for the other activator Gpa2p. We also observed the presence of system level properties such as amplification, inhibitor ultrasensitvity and bistability, which can be attributed to the regulatory design present in the FLO11 expression system. These system level properties might help the organism to respond to varying nutritional status.

Adenylyl Cyclases↗
PubMed2004

Negative regulation of gamma-globin gene expression by cyclic AMP-dependent pathway in erythroid cells.

OBJECTIVE: Fetal hemoglobin inducers such as hemin, butyrate, and hydroxyurea stimulate gamma-globin gene expression by activating the cyclic GMP (cGMP)-dependent pathway. Although cGMP activates the cyclic AMP (cAMP)-dependent pathway by suppressing cGMP-inhibited phosphodiesterase 3 (PDE3), the effects of the cAMP-dependent pathway on gamma-globin gene expression are unknown. MATERIALS AND METHODS: The cAMP-dependent pathway was activated in K562 cells using the adenylate cyclase activator forskolin. Expression of gamma-globin mRNA was examined by primer extension, and transcriptional activity of the gamma-globin gene promoter was determined by reporter gene assays. RESULTS: PDE3 was expressed in K562 cells at a high level. The cAMP-dependent pathway was found to be activated in K562 cells in which the cGMP-dependent pathway was activated by hemin. Activation of the cAMP-dependent pathway by forskolin inhibited hemin-induced expression of gamma-globin mRNA and decreased transcriptional activity of the gamma-globin gene promoter. The levels of phosphorylation of mitogen-activated protein kinases (MAPKs) were not affected by the cAMP-dependent pathway. CONCLUSIONS: These results suggested that the cAMP-dependent pathway, which is independent of MAPK pathways, plays a negative role in gamma-globin gene expression in K562 cells. cAMP and cGMP may have differential roles in the regulation of gamma-globin gene expression in erythroid cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

The NO-cGMP-PKG pathway plays an essential role in the acquisition of ethanol resistance by cerebellar granule neurons.

When the developing brain is exposed to alcohol, neuronal death is a prominent pathologic effect. This loss of neurons may underlie many of the behavioral deficits observed in fetal alcohol syndrome (FAS). Previous studies using whole animals and cultured neurons have demonstrated that the vulnerability of neurons to alcohol-induced death changes with development and can diminish markedly over the course of several days. This study examined the possibility that developmental stage-dependent alcohol resistance depends on a unique signaling pathway involving nitric oxide (NO), the NO-cyclic GMP (cGMP)-cGMP-dependent protein kinase (PKG) pathway. Cerebellar granule neuron (CGN) cultures were established from neonatal rats. The cultures were exposed to alcohol (400 mg/dl) either when they were newly established (1 day in vitro, 1-DIV) or when they were more mature (4 days in vitro, 4-DIV). Viable neurons were quantified 24 h later. Although both 1-DIV and 4-DIV cultures were exposed to alcohol for an identical length of time (24 h), the 1-DIV cultures were much more vulnerable to alcohol-induced neuronal death (22.9% neuronal loss) than the 4-DIV cultures (2.3% neuronal loss). Thus, the cultures have a developmental stage-dependent alcohol resistance. To determine the role of the NO-cGMP-PKG pathway in this developmental stage-dependent alcohol resistance, the CGN cultures at 4-DIV were exposed to agents that either activated or inhibited the pathway, either in the presence or in the absence of alcohol. Inhibition of the pathway at its first step with N(G)-nitro-l-arginine-methyl ester (NAME) or at its second step with LY83583 converted the 4-DIV cultures from alcohol resistant to alcohol sensitive. Alcohol-induced neuronal losses were as severe in the 4-DIV cultures treated with pathway inhibitors as they were in the 1-DIV cultures. Treatment of the CGN cultures with agents that activate the NO-cGMP-PKG pathway reduced background cell death, and this neurotrophic effect was not inhibited by the presence of alcohol. Furthermore, activation of the NO-cGMP-PKG pathway at sites downstream from sites of pathway inhibition restored alcohol resistance. Thus, the developmental stage-dependent alcohol resistance acquired by CGN cultures depends on a functional NO-cGMP-PKG pathway.

Aminoquinolines↗
PubMed2005

Evidence for common machinery utilized by the early and late RNA localization pathways in Xenopus oocytes.

In Xenopus, an early and a late pathway exist for the selective localization of RNAs to the vegetal cortex during oogenesis. Previous work has suggested that distinct cellular mechanisms mediate localization during these pathways. Here, we provide several independent lines of evidence supporting the existence of common machinery for RNA localization during the early and late pathways. Data from RNA microinjection assays show that early and late pathway RNAs compete for common localization factors in vivo, and that the same short RNA sequence motifs are required for localization during both pathways. In addition, quantitative filter binding assays demonstrate that the late localization factor Vg RBP/Vera binds specifically to several early pathway RNA localization elements. Finally, confocal imaging shows that early pathway RNAs associate with a perinuclear microtubule network that connects to the mitochondrial cloud of stage I oocytes suggesting that motor driven transport plays a role during the early pathway as it does during the late pathway. Taken together, our data indicate that common machinery functions during the early and late pathways. Thus, RNA localization to the vegetal cortex may be a regulated process such that differential interactions with basal factors determine when distinct RNAs are localized during oogenesis.

Animals↗
PubMed2006

Genomics and expression profiles of the Hedgehog and Notch signaling pathways in sea urchin development.

The Hedgehog (Hh) and Notch signal transduction pathways control a variety of developmental processes including cell fate choice, differentiation, proliferation, patterning and boundary formation. Because many components of these pathways are conserved, it was predicted and confirmed that pathway components are largely intact in the sea urchin genome. Spatial and temporal location of these pathways in the embryo, and their function in development offer added insight into their mechanistic contributions. Accordingly, all major components of both pathways were identified and annotated in the sea urchin Strongylocentrotus purpuratus genome and the embryonic expression of key components was explored. Relationships of the pathway components, and modifiers predicted from the annotation of S. purpuratus, were compared against cnidarians, arthropods, urochordates, and vertebrates. These analyses support the prediction that the pathways are highly conserved through metazoan evolution. Further, the location of these two pathways appears to be conserved among deuterostomes, and in the case of Notch at least, display similar capacities in endomesoderm gene regulatory networks. RNA expression profiles by quantitative PCR and RNA in situ hybridization reveal that Hedgehog is produced by the endoderm beginning just prior to invagination, and signals to the secondary mesenchyme-derived tissues at least until the pluteus larva stage. RNA in situ hybridization of Notch pathway members confirms that Notch functions sequentially in the vegetal-most secondary mesenchyme cells and later in the endoderm. Functional analyses in future studies will embed these pathways into the growing knowledge of gene regulatory networks that govern early specification and morphogenesis.

Amino Acid Sequence↗
PubMed1996

Electrophysiologic significance of discrete slow potentials in dual atrioventricular node physiology: implications for selective radiofrequency ablation of slow pathway conduction.

Atrioventricular (AV) node reentrant tachycardia is now routinely cured by selective radiofrequency ablation of slow AV node pathway conduction. However, debate remains concerning the optimum method for localizing the site at which radiofrequency energy should be delivered to eliminate slow-pathway conduction. Some investigators have proposed simple anatomy-guided ablations posteriorly near the ostium of the coronary sinus, whereas others suggest an electrophysiology-guided ablation using either recorded "slow potentials" or mapping of the retrograde atrial exit site of slow AV note pathway conduction when possible. To examine these issues, we systematically studied slow potentials recorded in the AV junction of patients undergoing radiofrequency catheter ablation for medically refractory AV node reentrant tachycardia. In 67 patients with the slow-fast form of AV note reentrant tachycardia, we performed detailed atrial mapping along the tricuspid annulus within the triangle of Koch. Two types of slow potentials were identified. Low-amplitude, low-frequency potentials, found in 48% of patients, were localized to the mid to posterior portions of the triangle of Koch, whereas high-amplitude, high-frequency potentials, observed in 22% of patients, were located only posteriorly near the ostium of the coronary sinus. In response to a bolus infusion of adenosine or incremental atrial pacing-induced AV node Wenckebach periodicity, the low-amplitude, low-frequency potentials showed an increased duration and further reduction in amplitude and frequency and often totally disappeared. In contrast, in spite of these maneuvers, the high-amplitude and high-frequency potentials remained unchanged. Of the 25 (37%) of 67 patients in whom the earliest retrograde atrial activation during ventriculoatrial slow AV nodal pathway conduction could be recorded, no patient exhibited low-amplitude, low-frequency potentials, and only 7 (28%) of 25 of these patients showed high-amplitude, high-frequency potentials. High-amplitude, high-frequency potentials persisted after successful radiofrequency ablation of slow pathway conduction. Fewer applications of radiofrequency energy were required for successful elimination of slow pathway conduction in patients in whom the retrograde atrial exit site of slow-pathway conduction could be localized, compared with those patients who only exhibited retrograde fast AV nodal pathway conduction. We conclude that high-amplitude, high-frequency potentials are part of atrial activity, whereas the origin of low-amplitude, low-frequency potentials is unclear and may represent either true intranodal biophysical electrical activity or merely artifact or far-field potentials. Regardless, the recording of high-amplitude or low-amplitude potentials is not required for successful ablation of slow-pathway conduction, although the ability to localize the retrograde atrial exit of slow-pathway conduction may assist in the ablation procedure.

Adolescent↗
PubMed2001

Irreversibility in unbranched pathways: preferred positions based on regulatory considerations.

It has been observed experimentally that most unbranched biosynthetic pathways have irreversible reactions near their beginning, many times at the first step. If there were no functional reasons for this fact, then one would expect irreversible reactions to be equally distributed among all positions in such pathways. Since this is not the case, we have attempted to identify functional consequences of having an irreversible reaction early in the pathway. We systematically varied the position of the irreversible reaction in model pathways and compared the resulting systemic behavior according to several criteria for functional effectiveness, using the method of mathematically controlled comparisons. This technique minimizes extraneous differences in systemic behavior and identifies those that are fundamental. Our results show that a pathway with an irreversible reaction located at the first step, and with all other reactions reversible, is on average better than an otherwise equivalent pathway with all reactions reversible, which in turn is on average better than an otherwise equivalent pathway with an irreversible reaction located at any step other than the first. Pathways with an irreversible first reaction and low concentrations of intermediates (one of the primary criteria for functional effectiveness) exhibit the following profile when compared to fully reversible pathways: changes in the concentration of intermediates in response to changes in the level of initial substrate are equally low, the robustness of the intermediate concentrations and of the flux is similar, the margins of stability are similar, flux is more responsive to changes in demand for end product, intermediate concentrations are less responsive to changes in demand for end product, and transient times are shorter. These results provide a functional rationale for the positioning of irreversible reactions at the beginning of unbranched biosynthetic pathways.

Homeostasis↗
PubMed2003

Reconstructing metabolic flux vectors from extreme pathways: defining the alpha-spectrum.

The move towards genome-scale analysis of cellular functions has necessitated the development of analytical (in silico) methods to understand such large and complex biochemical reaction networks. One such method is extreme pathway analysis that uses stoichiometry and thermodynamic irreversibly to define mathematically unique, systemic metabolic pathways. These extreme pathways form the edges of a high-dimensional convex cone in the flux space that contains all the attainable steady state solutions, or flux distributions, for the metabolic network. By definition, any steady state flux distribution can be described as a nonnegative linear combination of the extreme pathways. To date, much effort has been focused on calculating, defining, and understanding these extreme pathways. However, little work has been performed to determine how these extreme pathways contribute to a given steady state flux distribution. This study represents an initial effort aimed at defining how physiological steady state solutions can be reconstructed from a network's extreme pathways. In general, there is not a unique set of nonnegative weightings on the extreme pathways that produce a given steady state flux distribution but rather a range of possible values. This range can be determined using linear optimization to maximize and minimize the weightings of a particular extreme pathway in the reconstruction, resulting in what we have termed the alpha-spectrum. The alpha-spectrum defines which extreme pathways can and cannot be included in the reconstruction of a given steady state flux distribution and to what extent they individually contribute to the reconstruction. It is shown that accounting for transcriptional regulatory constraints can considerably shrink the alpha-spectrum. The alpha-spectrum is computed and interpreted for two cases; first, optimal states of a skeleton representation of core metabolism that include transcriptional regulation, and second for human red blood cell metabolism under various physiological, non-optimal conditions.

Computer Simulation↗
PubMed1984

Sensitivity of pathway rate to activities of substrate-cycle enzymes: application to gluconeogenesis and glycolysis.

In a study of metabolic regulation, it is frequently useful to consider the degree to which an enzyme can influence the rate of its pathway. The most productive expression of rate-controlling influence is the fractional change in pathway rate per fractional change in enzyme activity (called control strength or sensitivity coefficient). We have developed a system for considering how a substrate-cycle enzyme's control strength depends on its flux and reaction order and on related features of other enzymes of its pathway. We have applied this system to the gluconeogenic pathway of rat liver and the glycolytic pathway of bovine sperm, where enough fluxes and reaction orders have been published to allow valid estimates of several control strengths. In normal fed animals where gluconeogenesis is slow and unidirectional substrate-to-product and product-to-substrate fluxes are comparable, all substrate-cycle limbs have very high and similar control strengths regardless of their flux rates and positions in the pathway. The activity of a step affects all substrate-cycle control strengths similarly as it affects unidirectional end-to-end fluxes relative to net rate. Control strengths of non-substrate-cycle enzymes are negligible compared to those of substrate cycles. In fasting animals, on the other hand, where unidirectional Pyr----Glc flux is much greater than Glc----Pyr flux, upstream enzymes (near Pyr) have a regulatory advantage over downstream enzymes (near Glc). In this circumstance, control strength of each substrate-cycle enzyme is inversely related to rate limitingness between its substrate and the pathway substrate. Because the Pyr/PEP cycle is significantly rate limiting, the control strength of the Pyr----PEP limb is much greater than that of pyruvate kinase and all downstream enzymes. In the glycolytic pathway of bovine sperm, strong product inhibition of hexokinase detracts greatly from its rate limitingness and control strength, which are very small despite its position at the beginning of the pathway and its large free energy. Because the glucose-transport-hexokinase segment is not rate limiting, phosphofructo 1-kinase has almost as much control strength as it would have as the first enzyme of the pathway, and because the F6P/FDP cycle is only moderately rate limiting, Fru-1,6-P2ase and enzymes further downstream have substantial control strengths. When glycolysis is accelerated by stimulation of phosphofructo 1-kinase, control strength shifts from phosphofructo-1-kinase and all downstream enzymes to the transporthesokinase segment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Gene expression patterns for metabolic pathway in pgi knockout Escherichia coli with and without phb genes based on RT-PCR.

Metabolic regulations were investigated from the viewpoint of gene expressions for Escherichia coli JM109 and pgi knockout E. coli with and without phb genes using RT-PCR. One of the main features of pgi knockout E. coli is the overproduction of NADPH produced in pentose phosphate (PP) pathway. NADPH overproduction in PP pathway in pgi mutant causes some reducing power imbalance that ultimately affects the cell growth. It was shown that this reducing power imbalance can be recovered to some extent by introducing NADPH absorbing pathway such as PHB synthetic pathway into pgi mutant E. coli. To get insight into the regulation mechanism of pgi mutant E. coli at the transcriptional level, 87 E. coli genes involved in central metabolic pathways and key regulatory mechanisms were investigated by semi-quantitative RT-PCR analysis. The analysis showed that pentose phosphate pathway genes and part of the glycolysis pathway genes were affected significantly by expression of phb genes in pgi mutant E. coli DF11/pAeKG1 as well as in pgi mutant E. coli DF11 as compared with those in E. coli JM109. In contrast, most of the TCA cycle genes except icdA were downregulated in both pgi mutants E. coli. The upregulation of icdA gene may be due to the positive regulation of fruR. Moreover, it was found that ack gene as well as aceA and aceB genes involved in the glyoxylate shunt were upregulated in pgi mutants while ppc gene was downregulated, indicating that pgi inactivation changes the anaplerotic pathway from ppc pathway to glyoxylate shunt. Enzyme activities of glk, zwf, tpiA, fbaA, ldhA, gltA, aceA, mdh and maeB were also measured and compared with the corresponding gene expressions. Most of them are well correlated except for aceA gene indicating that glyoxylate pathway is regulated on the protein level, not on the gene level.

Down-Regulation↗
PubMed1999

KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways.

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) encodes a structural and functional homologue of human IL-6 called viral IL-6 (vIL-6). Expression of vIL-6 in KSHV-related lymphoproliferative disorders has been implicated in their pathogenesis. vIL-6 has been shown to mimic a number of IL-6 activities including stimulating the growth of IL-6 dependent cell lines and activating the JAK1 and STAT1/3 pathway in HepG2 cells. However, IL-6 and vIL-6 display differences in receptor usage that may give rise to underlying qualitative and quantitative differences in the signaling pathways utilized. While IL-6 has an absolute requirement for both the IL-6 Ralpha and the gp130 subunits, vIL-6 appears to require only gp130. In addition to JAK1 and STAT1/3 pathways, IL-6 activates multiple other pathways including the direct activation of STAT 5 by JAK1, the Ras-MAP kinase cascade and a novel H7-sensitive pathway. In this study we examined whether vIL-6 is capable of signaling via distinct IL-6 response elements (IL-6 RE) under the control of these different pathways. We show that vIL-6 activates both STAT1/3- and STAT5-dependent Type II IL-6 REs. In addition, vIL-6 induces transcriptional activation via a Type I IL-6 RE that binds C/EBP, indicative of Ras-MAP kinase pathway induction. Furthermore, vIL-6 is capable of activating the IL-6 response element in the c-jun promoter (RE-IL-6). vIL-6 induced activation of JRE-IL-6 requires both the Ets- and Cre-like sites, suggesting that vIL-6 is capable of stimulating the same novel serine/threonine kinase mediated pathway as IL-6. These results demonstrate that vIL-6 can stimulate all of the known IL-6-induced signaling pathways. Therefore, vIL-6 could potentially contribute to KSHV-related disease progression by continued activation of IL-6-stimulated growth and anti-apoptotic pathways even when cells attempt to protect themselves from IL-6 over-stimulation by downmodulating their IL-6Ralpha subunits.

CCAAT-Enhancer-Binding Proteins↗
PubMed1999

Signaling pathways activated by interferons.

Interferons are pleiotropic cytokines that exhibit negative regulatory effects on the growth of normal and malignant hematopoietic cells in vitro and in vivo. There are two different classes of interferons, Type I (alpha, beta, and omega) and Type II (gamma) interferons. Although the precise mechanisms by which these cytokines exhibit their potent effects on hematopoiesis remain unknown, there has been considerable progress in our understanding of the cellular changes that occur upon engagement of interferon receptors. It is now well established that Type I interferons activate multiple signaling pathways in hematopoietic cells, a finding consistent with their pleiotropic biological effects. One major pathway in Type I IFN signaling involves activation of Stat- proteins and formation of complexes that translocate to the nucleus and bind to specific elements to regulate gene transcription. The activation of this pathway (Jak-Stat pathway) is apparently regulated by members of the Jak-family of kinases, which are constitutively associated with the Type I IFN receptor. In addition to the Jak-Stat pathway, multiple other Jak-kinase-dependent signaling cascades are activated, including the IRS-PI 3'-kinase pathway, a pathway involving the vav proto-oncogene product, and a pathway involving adaptor proteins of the Crk-family (CrkL and CrkII). The only Type II interferon, IFNgamma, also activates multiple Jak-kinase-dependent signaling cascades, including the Stat and Crk pathways. Recent evidence suggests that non-Stat pathways play a critical role in the generation of signals for both Type I and Type II interferons and may be the primary mediators of their growth inhibitory effects on hematopoietic cells.

Animals↗
PubMed2001

Medullary reticulospinal tract mediating the generalized motor inhibition in cats: parallel inhibitory mechanisms acting on motoneurons and on interneuronal transmission in reflex pathways.

The present study was designed to elucidate the spinal interneuronal mechanisms of motor inhibition evoked by stimulating the medullary reticular formation. Two questions were addressed. First, whether there is a parallel motor inhibition to motoneurons and to interneurons in reflex pathways. Second, whether the inhibition is mediated by interneurons interposed in known reflex pathways. We recorded the intracellular activity of hindlimb motoneurons in decerebrate cats and examined the effects of medullary stimulation on these neurons and on interneuronal transmission in reflex pathways to them. Stimuli (three pulses at 10-60microA and 1-10ms intervals) delivered to the nucleus reticularis gigantocellularis evoked inhibitory postsynaptic potentials in alpha-motoneurons (n=147) and gamma-motoneurons (n=5) with both early and late latencies. The early inhibitory postsynaptic potentials were observed in 66.4% of the motoneurons and had a latency of 4.0-5.5ms with a segmental delay of more than 1.4ms. The late inhibitory postsynaptic potentials were observed in 98.0% of the motoneurons and had a latency of 30-35ms, with a peak latency of 50-60ms. Both types of inhibitory postsynaptic potentials were evoked through fibers descending in the ventrolateral quadrant. The inhibitory postsynaptic potentials were not influenced by recurrent inhibitory pathways, but both types were greatly attenuated by volleys in flexor reflex afferents. Conditioning medullary stimulation, which was subthreshold to evoke inhibitory postsynaptic potentials in the motoneurons, neither evoked primary afferent depolarization of dorsal roots nor reduced the input resistance of the motoneurons. However, the conditioning stimulation often facilitated non-reciprocal group I inhibitory pathways (Ib inhibitory pathways) to the motoneurons in early (<20ms) and late (30-80ms) periods. In contrast, it attenuated test postsynaptic potentials evoked through reciprocal Ia inhibitory pathways, and excitatory and inhibitory pathways from flexor reflex afferent and recurrent inhibitory pathways. The inhibitory effects were observed in both early and late periods. The present results provide new information about a parallel inhibitory process from the medullary reticular formation that produces a generalized motor inhibition by acting on alpha- and gamma-motoneurons, and on interneurons in reflex pathways. Interneurons receiving inhibition from flexor reflex afferents and a group of Ib interneurons may mediate the inhibitory effects upon motoneurons.

Animals↗
PubMed1994

Use of Algorithmic Pathways to Develop Quality Care Oriented, Cost Effective Clinical Care

This study analyzed the cost of diagnosis of hydrosalpinges and pelvic adhesions using four pathways. This is an example of the use of algorithmic pathways in developing medical service delivery which provides quality care to women while maintaining cost-effectiveness. The four pathways are: Chlamydia IgG antibody titer -> hysterosalpingogram -> diagnostic laparoscopy; chlamydia IgG titer -> diagnostic laparoscopy, hysterosalpingogram -> diagnostic laparoscopy; and diagnostic laparoscopy with no preliminary studies. These pathways are limited in that they require several assumptions that are not based on biologic data and do not include history, physical, other laboratory finding or other disease processes. However, with these limitations, the least costly approach to the diagnosis of 19 of 26 of the hydrosalpinges was pathway one with a total cost of $103,120. On the other hand, pathway three, with a total cost of $139,440 and a yield of 26 of 27 hydrosalpinges, was less expensive per patient with a cost of $5,363 as compared with the per patient cost of $5,427 using pathway one. In analyzing pelvic adhesions, pathway one was the least expensive at $186,280 but yielded only 13 (42%) of 31 patients with adhesions. Pathway four was the most expensive overall at $332,640 but was the least expensive per patient diagnosis at $10,730. Developing these type pathways will require computer assistance. However, even computer assistance will be inadequate without biologically significant data and without well defined goals and expectations.

Journal Article↗
PubMed2006

Surface proton donors for the D-pathway of cytochrome c oxidase in the absence of subunit III.

The major proton-transfer pathway into the buried active site of cytochrome c oxidase (CcO) is the D-pathway that begins with the subunit I residue Asp-132 on the inner protein surface (the cytoplasmic surface of the aa3-type CcO of Rhodobacter sphaeroides). Asp-132 is surrounded by residues from both subunits I and III. In the absence of subunit III, CcO retains activity, but the functional characteristics of the D-pathway are significantly altered such that the transfer of protons from Asp-132 into the pathway becomes the rate-limiting step. Determination of the pH-dependence of the rate constant for D-pathway proton uptake during the single-turnover of CcO indicates that the pKa of Asp-132 in the absence of subunit III is approximately 7. The removal of subunit III also allows for alternative surface proton donor/acceptors other than Asp-132. With Asp-132 altered to alanine, the rate constant for D-pathway proton uptake is very slow (5 s(-1)) in the presence of subunit III. Once subunit III is removed, the proton uptake rate constant increases 80-fold, to 400 s(-1). The pKa associated with this uptake is >10, and the initial proton donor/acceptor in D132A III (-) is proposed to be a water of the D-pathway rather than an amino acid residue. Arachidonic acid (Aa), which stimulates the activity of several D-pathway mutant CcOs, appears to become the initial proton donor/acceptor in the absence of subunit III, whether or not Asp-132 is altered. Aa shifts the pKa of the initial proton donor to 7.6 for both wild-type (WT) III (-) and D132A III (-). The results indicate that subunit III creates a barrier that helps prevent protons from donors other than Asp-132 from directly accessing the internal waters of the D-pathway, while the subunit also provides an environment that increases the rate at which Asp-132 transfers protons into the D-pathway.

Arachidonic Acid↗