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At least 1,621 records · Page 90Linked to original sources
PubMed1998

Differential regulation of extracellular signal-regulated kinase and nuclear factor-kappa B signal transduction pathways by hydrogen peroxide and tumor necrosis factor.

Reactive oxygen metabolites are increasingly recognized for their ability to stimulate signal transduction pathways. This is important because these oxidants are frequently generated at sites of inflammation. However, little is known about the manner in which reactive oxygen species may selectively stimulate distinct signaling pathways. We have examined this question by stimulating mesothelial cells with hydrogen peroxide (H2O2) as a model oxidant stimulus. The response to H2O2 was examined by measuring the activation of the extracellular signal-regulated kinase (ERK1/2) and the nuclear factor-kappa B (NF-kappa B) signal transduction pathways. We found that H2O2 stimulated activity of the ERK1/2 pathway in a dose- and time-dependent manner. The ability of H2O2 to activate ERK1/2 was similar to that found with tumor necrosis factor (TNF) stimulation. The oxidant effect was inhibited by various reactive oxygen scavengers. An inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase, the upstream kinase that activates ERK1/2, inhibited the oxidant effect. The superoxide anion (O2-) also stimulated ERK1/2 activity. In contrast, H2O2 did not stimulate proteolysis of I kappa B-alpha and induced only a small degree of NF-kappa B nuclear translocation. Stimulation of the cells with O2- also induced a minimal degree of NF-kappa B activation. TNF was a potent stimulus for I kappa B-alpha proteolysis and NF-kappa B activation, demonstrating that the cells did have a functional NF-kappa B pathway. These results suggest that oxidants may selectively stimulate certain pathways, thereby preserving some specificity of the signaling process. Furthermore, different cell types and distinct signaling pathways within cells may demonstrate unique profiles in the manner in which they respond to oxidant stimulation.

Animals↗
PubMed2000

Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells.

Here we show that vascular endothelial growth factor (VEGF) mRNA expression is up-regulated in oncogene transformed rat liver epithelial (RLE) cell lines and that the extracellular signal-regulated kinase (ERK) and p38 kinase differentially regulate the oncogene-mediated stimulation of VEGF. The highest level of VEGF mRNA expression was observed in the v-H-ras transformed RLE cell line, followed by the v-raf and v-myc transformed lines. The PD98059 MEK inhibitor was used to block the ERK pathway and SB203580 inhibitor to block the p38 pathway. The parent and the v-H-ras transformed RLE cell lines showed up-regulation of VEGF RNA expression through the ERK pathway and down-regulation of VEGF through the p38 pathway. VEGF was regulated in a comparable manner in a human breast carcinoma cell line. In the v-raf and v-myc transformed RLE lines, positive regulation of VEGF was transduced through the p38 pathway. These findings suggest that (1) oncogenic ras differs from raf and myc in the recruitment of the MAPK signaling pathways for VEGF regulation; (2) that VEGF is regulated in ras transformed and human cancer cell lines in a positive and negative manner by the ERK and p38 signaling pathways.

Animals↗
PubMed2001

Insulin, insulin-like growth factor-I, and platelet-derived growth factor activate extracellular signal-regulated kinase by distinct pathways in muscle cells.

We have investigated the signaling pathways initiated by insulin, insulin-like growth factor-1 (IGF-I), and platelet-derived growth factor (PDGF) leading to activation of the extracellular signal-regulated kinase (ERK) in L6 myotubes. Insulin but not IGF-I or PDGF-induced ERK activation was abrogated by Ras inhibition, either by treatment with the farnesyl transferase inhibitor FTP III, or by actin disassembly by cytochalasin D, previously shown to inhibit Ras activation. The protein kinase C (PKC) inhibitor bisindolylmaleimide abolished PDGF but not IGF-I or insulin-induced ERK activation. ERK activation by insulin, IGF-I, or PDGF was unaffected by the phosphatidylinositol 3-kinase inhibitor wortmannin but was abolished by the MEK inhibitor PD98059. In contrast, activation of the pathway involving phosphatidylinositol 3-kinase (PI3k), protein kinase B, and glycogen synthase kinase 3 (GSK3) was mediated similarly by all three receptors, through a PI 3-kinase-dependent but Ras- and actin-independent pathway. We conclude that ERK activation is mediated by distinct pathways including: (i) a cytoskeleton- and Ras-dependent, PKC-independent, pathway utilized by insulin, (ii) a PKC-dependent, cytoskeleton- and Ras-independent pathway used by PDGF, and (iii) a cytoskeleton-, Ras-, and PKC-independent pathway utilized by IGF-I.

Actins↗
PubMed1997

Immunosensitization of prostate carcinoma cell lines for lymphocytes (CTL, TIL, LAK)-mediated apoptosis via the Fas-Fas-ligand pathway of cytotoxicity.

Several reports suggest that immunotherapy mediated by cytotoxic lymphocytes is beneficial in the destruction of drug-resistant tumor cells. Cytotoxic T lymphocytes kill target cells by two main mechanisms, namely by the perforin pathway and by the Fas-ligand (Fas-L) pathway. The role of the Fas-L pathway in tumor cell killing is not clear because many Fas(+)-expressing tumor cells are resistant to the Fas-L agonist cytotoxic anti-Fas antibody. The human prostate tumor cell lines (PC-3, DU145, and LnCAP) express Fas on the cell surface but are resistant to killing by anti-Fas antibody. This study examined the sensitivity of prostate tumor cells to Fas-L-mediated cytotoxicity and sensitization of the tumor cells by drugs to Fas-L-mediated killing. All three prostate tumor cell lines are resistant to Fas-L killing as determined by the use of the murine CTL hybridoma PMMI that kills only through the Fas-L pathway. However, the addition of subtoxic concentrations of CDDP or VP-16 significantly sensitized the PC-3 and DU145, but not LnCAP, tumor cells to Fas-L killing and apoptosis by PMMI. The sensitization of tumor cells by drugs was inhibited by neutralizing anti-Fas antibody. These findings demonstrate that immunoresistant Fas(+)-expressing DU145 and PC-3 prostate tumor cells can be sensitized by drugs to Fas-L killing. We then examined the role of Fas-L killing by TIL and LAK cells. All three prostate tumor cell lines were sensitive to killing by TIL and LAK and cell killing was primarily mediated through the Ca(2+)-dependent perforin pathway because it was blocked by the addition of EGTA/MgCl2. Sensitization by CDDP or VP-16 did not significantly augment killing of untreated tumor cells by TIL or LAK cells. However, in the presence of EGTA/MgCl2, the addition of CDDP or VP-16 significantly augmented killing of PC-3 and DU145, but not LnCAP, by TIL and LAK, and killing was blocked by neutralizing anti-Fas antibody. These findings demonstrate that both TIL and LAK exhibit a Fas-L-mediated killing pathway that is revealed once the perforin pathway is blocked by the Ca2+ chelator EGTA/MgCl2. Altogether, these findings show that drug-resistant, Fas(+)-expressing PC-3 and DU145 prostate tumor cells can be sensitized by CDDP and VP-16 to killing by Fas-L-bearing CTL, TIL, and LAK cells. Sensitization of tumor cells by drugs may augment the efficacy of immunotherapy in the eradication of tumor cells that are resistant to Fas-L-mediated killing.

Animals↗
PubMed1995

Nematocyte differentiation in hydra: commitment to nematocyte type occurs at the beginning of the pathway.

In hydra the four types of nematocytes arise by differentiation from the multipotent stem cells among the interstitial cells. It has been unclear where along the nematocyte pathway commitment to type occurs. Some evidence suggests that this commitment occurs at the beginning of the pathway, while other data suggest that it occurs at the terminal cell cycle midway through the pathway. Upon reduction of cell population sizes of the interstitial cell lineage by treatment with hydroxyurea, interstitial cells entering nematocyte pathways frequently undergo an amplification division. A nearest-neighbor analysis of pairs of nematoblast nests in such depleted animals has shown that the fraction of the nearest-neighbor pairs that are matched pairs, in which both nests are of the same type, is higher than predicted. A very high fraction of the matched pairs were identical pairs in which the number of cells in each nest was the same. Also, in a large majority of the identical pairs the nests were shown to be in the same stage of development. The simplest interpretation of these results is that the two daughters of the amplification division giving rise to the matched pair were committed to nematocyte type before the division occurred. In another experiment we show that the length of the G2 phase of the next-to-terminal cell cycle differs between desmonemes and stenoteles. This indicates that differences in the differentiation pathways of these two types exist before the terminal cell cycle. This result also supports the idea that commitment to type occurs at the beginning of the pathway. A means of reconciling the view that commitment occurs early with the view that it occurs late in teh differentiation pathway is discussed.

Animals↗
PubMed1996

Two competing pathways for self-splicing by group II introns: a quantitative analysis of in vitro reaction rates and products.

Self-splicing group II introns are found in bacteria and in the organellar genes in plants, fungi, and yeast. The mechanism for the first step of splicing is generally believed to involve attack of a specific intronic 2'-hydroxyl group on a phosphodiester linkage at the 5'-splice site, resulting in the formation of a lariat intron species. In this paper, we present kinetic and enzymatic evidence that in vitro there are two distinct pathways for group II intron self-splicing: one involves 2'-OH attack and another involves attack of water or hydroxide. These two pathways occur in parallel under all reaction conditions, although either can dominate in the presence of particular salts or protein cofactors. Both pathways are followed by a successful second step of splicing, and either pathway can be highly efficient. We find that the hydrolytic pathway prevails under physiological ionic conditions, while branching predominates at molar concentrations of ammonium ion. The intron is observed to adopt two major active conformations. In order to quantify their individual reaction rates, we applied a mechanistic model describing biphasic parallel kinetic behavior. Kinetic analysis throughout the investigation reveals that there is no coupling between the unproductive "spliced-exon-reopening" reaction (SER) and hydrolysis during the first step of splicing. Conditions that stimulate branching can promote the SER reaction just as efficiently as conditions that stimulate the hydrolytic pathway. Although there is little evidence that it exists in vivo, a hydrolytic splicing pathway for group II introns has important implications for the translation of intron-encoded proteins and the inhibition of intron migration into new genomic positions.

Ammonium Chloride↗
PubMed1999

Analysis methods for comparison of multiple molecular dynamics trajectories: applications to protein unfolding pathways and denatured ensembles.

In molecular dynamics simulations of protein unfolding, the pathway of one protein molecule is studied at a time. In contrast, experimental denaturation studies sample from large ensembles of molecules passing from the native to unfolded state. If reasonable comparisons with experiment are to be made, then the generality of the simulations needs to be confirmed by performing multiple unfolding simulations. Given that protein unfolding trajectories are very complicated functions of the proteins and the environment, comparing different trajectories, even under the same conditions, is not straightforward. Several methods are presented here that attempt to accomplish this task at different levels of complexity. The simpler methods are geometry based and make use of the root-mean-squared deviations between structures, while the more complicated methods are based on the time variation of the various properties of the system during the unfolding process. These methods are applied to multiple simulations of three different proteins, bovine pancreatic trypsin inhibitor, chymotrypsin inhibitor 2, and barnase. In general, for these three proteins protein unfolding proceeded via expansion of the core and fraying of secondary structure to yield the major transition state. Once past the transition state, the trajectories for a given protein diverged as the protein lost further secondary and tertiary structure by a variety of mechanisms. Although the unfolding pathways diverged, similar conformations were populated in the denatured state even when the unfolding occurred via different pathways. The multitude of different pathways leading to the denatured state agrees with the funnel description of protein folding. Although the pathways differed in conformational space, the physical properties of the conformations were often similar, highlighting the danger of assuming that similar observed properties imply similar conformations. In fact, there may be many different "conformational pathways" of unfolding that fit within a preferred "property space pathway".

Aprotinin↗
PubMed2001

Flow-induced DNA synthesis requires signaling to a translational control pathway.

BACKGROUND: The mTOR translational control pathway that signals to the P70/P85 S6 kinase (pp70(S6k)) is essential for mitogenesis. We have previously shown that pp70(S6k) is activated by fluid flow. We hypothesized that oscillatory fluid flow in the absence of exogenous mitogens would induce endothelial cells to synthesize DNA via activation of the mTOR pathway. For comparison, we also studied the ERK1/2 transcriptional signaling pathway. METHODS: Confluent human umbilical vein endothelial cells (HUVECs) were exposed to oscillatory flow (12 dyn/cm(2) peak shear stress; 3.3 Hz) or kept static in serum-deprived culture medium. Rapamycin or PD98059 was used to inhibit pp70(S6k) or ERK1/2 activation, respectively. RESULTS: Oscillatory flow activated both the pp70(S6k) and ERK1/2 signaling pathways. Rapamycin blocked activation of pp70(S6k) but not ERK1/2, while PD98059 blocked ERK1/2 but not pp70(S6k). DNA synthesis, as measured by [3H]thymidine uptake, increased by approximately twofold (P < 0.01) in HUVEC cultures exposed to oscillatory flow compared with those kept static. Rapamycin completely abolished the flow-induced increase in DNA synthesis while PD98059 did not. Oscillatory flow upregulated expression of cyclin-dependent kinases 1 and 4 mRNA in a temporal pattern consistent with cell cycle entry; rapamycin also inhibited these changes. CONCLUSIONS: Oscillatory flow activates both the ERK 1/2 and pp70(S6k) signaling pathways in HUVECs and induces DNA synthesis in the absence of other exogenous mitogens. Complete blockade of [3H]thymidine uptake by the mTOR pathway inhibitor rapamycin indicates that separate and distinct signaling to a translational control pathway is necessary to mediate flow-induced DNA synthesis by endothelial cells. Oscillatory flow-induced endothelial proliferation may contribute to atherogenesis.

CDC2 Protein Kinase↗
PubMed2002

Dependence of control coefficient distribution on the boundaries of a metabolic system: a generalized analysis of the effects of additional input and output reactions to a linear pathway.

Both experimental and theoretical studies of metabolism are likely to relate to a segment that has been isolated for analytical purposes. In practice, it will be embedded in the whole of cellular metabolism. Thus, it is necessary to consider how conclusions about the control of an isolated pathway may be modified in this wider context where the input and output metabolites are considered as variables of cellular metabolism. Here, we analyse the effect of expanding a linear metabolic pathway by adding an extra input or an extra output. In particular, we analyse the effect of the elasticities of the extra steps on control coefficients. We derive matrix algebraic relationships for obtaining flux and concentration control coefficients from expressions depending on these extra elasticities and on parameters (elasticities and control coefficients) of the original pathway. These equations can be shown in certain cases to be generalized versions of earlier rescaling relationships and to be related to top-down analysis, but also apply where the new variable metabolite of the expanded pathway is an effector of more than one step of the original pathway. We use our relationships to analyse the dependence or independence of control coefficients upon these extra elasticities for the published analyses of the pathway of mammalian serine biosynthesis (Fell & Snell, 1988) and Escherischia coli threonine biosynthesis (Chassagnole et al., 2001). The same analysis can be applied to determine whether the transport reactions of substrates and products of a pathway in and out of a cell need to be included in estimations of the control coefficients of the enzymes.

Animals↗
PubMed2002

Murine coronavirus-induced apoptosis in 17Cl-1 cells involves a mitochondria-mediated pathway and its downstream caspase-8 activation and bid cleavage.

Mouse hepatitis virus (MHV) infection in murine 17Cl-1 cells results in apoptotic cell death. Inhibition of MHV-induced apoptosis by the pancaspase inhibitor Z-VAD-FMK promoted virus production late in infection, indicating that apoptosis could be a host response to limit the production of viral progeny. Activation of the mitochondria-mediated apoptotic pathway was indicated by the activation of caspase-9 and delay of apoptosis by Bcl-2 overexpression. Analyses of the subcellular distribution of cytochrome c, procaspase-9, and Apaf-1 suggested an aberrant apoptosome formation in the vicinity of the mitochondria, which could be a cell type-specific event. An increase in the amount of Fas (APO-1/CD95), caspase-8 activation, caspase-8-mediated Bid cleavage, and subsequent translocation of truncated Bid to mitochondria, all of which relate to the Fas-mediated pathway, also occurred in MHV-infected 17Cl-1 cells, whereas the formation of the death-inducing signaling complex, a direct indication of the activation of Fas-mediated pathway, was undetectable. Caspase-8 and Bid activation appeared to be downstream of mitochondria, because Bcl-2 overexpression suppressed both events, suggesting that infected 17Cl-1 cells might have activated a receptor-mediated "type II" signaling pathway, in which primary and low levels of receptor-mediated pathway activation lead to the activation of the mitochondria-mediated pathway. All our data indicate that a mitochondria-mediated pathway played a major regulatory role in apoptosis in MHV-infected 17Cl-1 cells.

Animals↗
PubMed2000

Signal transduction pathways activated by CpG-DNA.

While more and more attention has been paid to CpG-DNA with respect to its usefulness as an adjuvant, its molecular mechanism of action is less well defined. Over the last few years, at least two major signalling pathways have been shown to be utilized by CpG-DNA: the NF-kappa B activation pathway and the stress-kinase pathway. Direct downstream events of these pathways are induction of transcriptional activity of NF-kappa B and transcriptional activity of AP-1. As far as investigated, CpG-DNA uses signal transduction pathways originally described for other stimuli, such as LPS, IL-1 or TNF. Therefore, to us, the prime question is: where does CpG-DNA-induced signalling enter these known pathways? This raises questions about the existence of a CpG-DNA-sequence-specific receptor. Several points of evidence support the probability of the existence of a cellular receptor: There is a strong motif (unmethylated CpG) dependency for CpG-DNA-induced signalling. There is cell-type specificity. Dendritic cells, macrophages and B cells respond to CpG-DNA, but other cell types, such as fibroblasts and T cells, do not. In addition, classic signal-transduction pathways are rapidly switched on in a parallel manner, as is known for other receptors. Using competing non-CpG ODNs and inhibitors of endosomal acidification, some evidence has been obtained that CpG ODNs are taken up into endosomes by a CpG-independent receptor, followed by a pH-dependent step before signalling starts. A model based on these findings is proposed in Fig. 4. Nevertheless, other receptor-independent activities of CpG-DNA cannot yet be ruled out. Although unlikely, we should consider the possibility that CpG-DNA directly interacts with cellular nucleic acids either by direct hybridization with complementary nucleotides or by formation of DNA triplexes (VASQUEZ and WILSON 1998). While these possibilities have been explored by antisense technology, using a huge variety of ODNs, there is no experimental evidence that such interactions are important for the activity of CpG-DNA. In this context, it is important to note that DNA, especially phosphothioate-stabilized ODNs with poly-G stretches, have substantial CpG-independent activities, although these activities seem not to depend on specific, antisense-like DNA-DNA interactions (PISETSKY 1996). One good example comes from experiments using ODNs on primary T cells. Co-stimulation of CD3-primed T cells with CpG ODN leads to a significant increase of IL-2 secretion and proliferation; however, these effects are CpG independent (K. Heeg, personal communication). Remarkably, these poly-G stretches seem to be inactive when transferred to double-stranded DNAs, such as plasmid DNA (WLOCH et al. 1998). In contrast, to my knowledge, no immune-stimulatory effect of bacterial DNA has been described that can not be abolished by CpG-specific methylation. Taken together, CpG-dependent and CpG-independent activities must be distinguished from one another. Among these effects, CpG-dependent signalling is better defined. Much effort is going into the investigation of the pharmacological applications of CpG-DNA. Once CpG-receptor-like structures are known, the question of the physiological role of CpG-DNA can be tackled.

Animals↗
PubMed1983

On the nature of the RecBC and RecF pathways of conjugal recombination in Escherichia coli.

The molecular mechanisms of the RecBC and RecF pathways for genetic recombination in E. coli were investigated by studying the kinetics of RecA protein function during conjugation. RecF recombination in recBC sbcB mutants is shown to be a much slower process than RecBC recombination in recBC+ sbcB+ strains, and is blocked by a mutation in lexA that prevents induction of RecA protein. Progress of the RecF pathway is greatly accelerated by a recAoc mutation which increases synthesis of RecA protein, but this does not restore recombination proficiency to a recBC sbcB lexA mutant. These results are interpreted to suggest that the RecF pathway directs integration of single-stranded Hfr DNA into the recipient chromosome whereas the RecBC pathway catalyses the exchange of largely double stranded DNA. This is consistent with the known stoichiometry of RecA protein catalysed heteroduplex DNA formation in vitro and with the delayed replication of RecF pathway recombinants which approximates to the time required for one round of DNA replication to generate homoduplex DNA. The regulation of the RecF pathway by lexA repressor is discussed in relation to the factors that govern the relative utilization of the two recombination pathways in wild-type cells.

Bacterial Proteins↗
PubMed1975

Dual pathways of glycerol assimilation in Klebsiella aerogenes NCIB418: their regulation and possible functional significance.

Klebsiella aerogenes NCIB 418 assimilates glycerol via alternative pathways: one involves a glycerol kinase with a high affinity for glycerol (apparent Km = 1-2x10(-6)M), and the second a glycerol dehydrogenase with a much lower affinity for its substrate (apparent Km=2-4x10(-2)M). In variously-limited chemostat cultures, one or the other pathway predominated. Thus, aerobic carbon-limited organisms contained only the glycerol kinase pathway whereas aerobic sulphate-limited or ammonia-limited organisms (grown on glycerol) used only the glycerol dehydrogenase pathway. Anaerobic cultures invariably contained glycerol dehydrogenase, and glycerol kinase was absent. Washed suspensions of aerobically-grown organisms oxidized glycerol with kinetics similar to that of the particular enzyme (the primary enzyme of the assimilatory pathway) which they possessed, thus indicating a close association between these two enzymes and the uptake process. But a supply of exogenous glycerol was not a prerequisite for the synthesis of either glycerol kinase or glycerol dehydrogenase, and nor was molecular oxygen the key factor in effecting modulation between the alternative pathways of glycerol metabolism, as had been previously suggested. The physiological significance of dual pathways of glycerol assimilation is discussed.

Aerobiosis↗
PubMed1977

Simultaneous operation of three catabolic pathways in the metabolism of glucose by Thiobacillus A2.

Enzymes essential to the operation of the Embden-Meyerhof glycolytic pathway, the Entner-Duodoroff pathway and oxidative pentose phosphate pathway were present in Thiobacillus A2 grown on glucose and other sugars. Radiorespirometry under various conditions with Thiobacillus A2 oxidising glucose specifically labelled with 14C in carbon atoms 1, 2, 3, 3 + 4, 6 or universally labelled demonstrated the simultaneous operation of the Embden-Meyerhof (48%), Entner-Doudoroff (28%), and pentose phosphate (24%) pathways in release of carbon dioxide from glucose. Growth on succinate, or autotrophically on formate or thiosulphate resulted in repression of most enzymes of the pathways, but high aldolase levels were retained indicating its role in gluconeogenesis and the Calvin cycle. Different fructose diphosphatase activities were found in succinate- and thiosulphate-grown organisms. The results indicate that all three major catabolic pathways for glucose function in Thiobacillus A2 grown on sugars. Thiobacillus acidophilus showed a different radiorespirometric pattern and apparently used the Entner-Duodoroff (64.5%) and pentose phosphate (35.5%) pathways, but showed unusually high release of carbon atom 6, as was also found for T. ferrooxidans.

Arsenic↗
PubMed1982

The electrophysiology of rabbit descending colon. II. Current-voltage relations of the apical membrane, the basolateral membrane, and the parallel pathways.

In this paper we employ the data described in the previous paper (I) to derive the current-voltage (I-V) relations of the basolateral membrane, the amiloride-insensitive "leak" pathway across the apical membrane, and the parallel pathways across rabbit descending colon. The results indicated that: a) The resistance of the basolateral membrane is independent of the electrical potential difference across that barrier over the range -8 to 67 mV and averaged 195 omega cm2. The electromotive force across this barrier averaged 50 mV under control conditions and 48 mV in the presence of amiloride. The origin of this difference is discussed. b) The resistance of the parallel pathways averaged 351 omegacm2 and was independent of the transepithelial electrical potential difference over the range -170 to + 90mV. The conductance of these pathways can be reasonably well accounted for by the partial ionic conductances of Na, K and Cl reported previously. c) The resistance of the amiloride-insensitive pathway across the apical membrane averaged 1667 omegacm2 and the electromotive force across this pathway averaged -51 mV. These values are in excellent agreement with those determined by others. The ionic nature of this "leak" pathway remains to be elucidated.

Amiloride↗
PubMed1996

The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution.

The evolutionary origin of the Krebs citric acid cycle has been for a long time a model case in the understanding of the origin and evolution of metabolic pathways: How can the emergence of such a complex pathway be explained? A number of speculative studies have been carried out that have reached the conclusion that the Krebs cycle evolved from pathways for amino acid biosynthesis, but many important questions remain open: Why and how did the full pathway emerge from there? Are other alternative routes for the same purpose possible? Are they better or worse? Have they had any opportunity to be developed in cellular metabolism evolution? We have analyzed the Krebs cycle as a problem of chemical design to oxidize acetate yielding reduction equivalents to the respiratory chain to make ATP. Our analysis demonstrates that although there are several different chemical solutions to this problem, the design of this metabolic pathway as it occurs in living cells is the best chemical solution: It has the least possible number of steps and it also has the greatest ATP yielding. Study of the evolutionary possibilities of each one-taking the available material to build new pathways-demonstrates that the emergence of the Krebs cycle has been a typical case of opportunism in molecular evolution. Our analysis proves, therefore, that the role of opportunism in evolution has converted a problem of several possible chemical solutions into a single-solution problem, with the actual Krebs cycle demonstrated to be the best possible chemical design. Our results also allow us to derive the rules under which metabolic pathways emerged during the origin of life.

Acetates↗
PubMed1998

[High frequency current catheter ablation of accessory conduction pathways].

Radiofrequency catheter ablation has established as the first line therapy for the curative treatment of patients with accessory pathway. Atrioventricular accessory pathways irrespective of the exact localisation can be successfully ablated in more than 90% of all cases. Severe complications associated with the ablation procedure are rare and occur in approximately 2% of patients treated. The recurrence rate after successful ablation is approximately 8 to 10%. Recurrence of accessory pathway conduction occurs almost exclusively within the first 3 months following successful ablation, late recurrences are rare. Patients with variants of accessory pathways such as atriofascicular pathways or retrogradely conducting accessory pathways with decremental conduction properties can also be cured with a high success rate. Because of its well balanced efficacy-risk profile radiofrequency catheter ablation should be recommended as the first line therapy to all symptomatic patients with accessory pathway.

Atrioventricular Node↗
PubMed1999

The stress-activated protein kinase pathways.

Part of the cellular response to toxins, physical stresses and inflammatory cytokines occurs by signalling via the stress-activated protein kinase (SAPK) and p38 reactivating kinase pathways. This results in modification of cellular gene expression. These stress-responsive kinase pathways are structurally similar, but functionally distinct, from the archetypal mitogen-activated protein kinases (MAPKs or ERKs). The ERK pathway is a hierarchical cascade originating at the cell membrane with receptors for mitogens or growth factors, which recruit, via adapter proteins and exchange factors, the small guanosine triphosphatase (GTPase) Ras (see fig. 1). Ras activates raf, a serine threonine kinase, which activates MEK (MAPK/ERK kinase). MEK, in turn, phosphorylates and activates ERK1 and ERK2, which translocate to the nucleus and transactivate transcription factors, changing gene expression to promote growth, differentiation or mitosis. By transducing signals through a cascade of kinases, several options for control are introduced for amplifying and/or modifying the output signal. The SAPK and p38 pathways are also hierarchically arranged, but less is known about the upstream components and the downstream effects of stimulation of these pathways. Among the processes modulated by stress-responsive pathways are apoptosis, transformation, development, immune activation, inflammation and adaptation to environmental changes. This review outlines the upstream componentry of these pathways that interact with a variety of agonists to modify the activity of SAPK and p38, and explores the downstream functions of this activation.

Animals↗