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Inflammation and Alzheimer disease.

Inflammatory mechanisms are active in patients with Alzheimer disease. Serum elevations of acute phase proteins such as alpha 1-antichymotrypsin, along with deposition of inflammatory cytokines in the brain, suggest a "cerebral acute phase response" contributing to amyloid deposition and tissue destruction. Activated microglia possessing HLA-DR surface markers accumulate around amyloid plaques. The complement cascade leads to generation of the membrane attack complex, which may directly damage neuronal membranes. This growing body of evidence suggests that empirical trials of anti-inflammatory drugs are now appropriate to test the hypothesis that suppression of these mechanisms will slow the rate of progression of Alzheimer disease. Several drugs useful in the treatment of rheumatic diseases are candidates for study in Alzheimer disease, including glucocorticoids, antimalarial drugs, and colchicine. Pilot studies of the synthetic glucocorticoid prednisone indicate that treatment with a moderate dose is well tolerated in patients with Alzheimer disease, and suppresses serum levels of acute phase proteins. Based on this experience, a multicenter parallel-design placebo-controlled trial has been initiated with Alzheimer's Disease Cooperative Study to determine whether treatment with prednisone can slow the rate of progression of Alzheimer disease.

Acute-Phase Proteins↗
PubMed2003

Complement therapeutics; history and current progress.

Complement (C) performs vital roles in immune surveillance, from killing of bacteria to generation of an optimal antibody response. However, the mediators responsible for this protective role can inappropriately target self tissues and cause pathology in many inflammatory diseases, in ischaemia-reperfusion injuries and also as a result of therapeutic intervention, such as in cardiopulmonary bypass. Here we review the history of anti-complement therapeutics and describe the plethora of reagents that have evolved to treat complement-mediated pathologies. These agents range from small compounds, including natural products isolated from plants and synthetic peptides designed to target and inhibit the complement cascade, to large, intricately engineered biological reagents. Recombinant, humanised antibody fragments which inhibit at specific points in the complement cascade have been generated and used successfully in man. Other reagents, mimicking the action of the natural complement regulatory proteins present on the surface of self cells, have also been developed and extensively tested. We discuss the pros and cons of these different reagents and describe recent advances in the field, such as specific targeting of drugs to sites of inflammation, which have opened the door to the use of anti-complement therapy in both acute and chronic inflammatory conditions.

Animals↗
PubMed2004

NADH augments blood flow in physiologically activated retina and visual cortex.

The mechanism(s) that increase retinal and visual cortex blood flows in response to visual stimulation are poorly understood. We tested the hypothesis that increased transfer of electrons and protons from glucose to cytosolic free NAD(+), reducing it to NADH, evoked by increased energy metabolism, fuels redox-signaling pathways that augment flow. The near-equilibrium between free cytosolic NADH/NAD(+) and lactate/pyruvate ratios established by lactate dehydrogenase predicts that transfer of additional electrons and protons from injected lactate to NAD(+) will augment the elevated blood flows in stimulated retina and cortex, whereas transfer of electrons and protons from NADH to injected pyruvate will attenuate the elevated flows. These predictions were tested and confirmed in rats. Increased flows evoked by stimulation also were prevented by inhibition of nitric oxide synthase. These findings support an important role for cytosolic free NADH in fueling a signaling cascade that increases *NO production, which augments blood flow in photostimulated retina and visual cortex.

Animals↗
PubMed2002

Stimulation of Cl- secretion via membrane-restricted Ca2+ signaling mediated by P2Y receptors in polarized epithelia.

Extracellular nucleotides such as ATP have been shown to regulate ion transport processes in a variety of epithelia. This effect is mediated by the activation of plasma membrane P2Y receptors, which leads to Ca(2+) signaling cascade. Ion transport processes (e.g. activation of apical calcium-dependent Cl(-) channels) are then stimulated via an increase in [Ca(2+)](i). Many polarized epithelia express apical and/or basolateral P2Y receptors. To test whether apical and basolateral stimulation of P2Y receptors elicit polarized Ca(2+) signaling and anion secretion, we simultaneously measured the two parameters in polarized epithelia. Although activation of P2Y receptors located at both apical and basolateral membranes evoked an increase in [Ca(2+)](i), only apical P2Y receptors-coupled Ca(2+) release stimulated an increase in anion secretion. Moreover, the calcium influx evoked by apical and basolateral P2Y receptor stimulation is predominately via the basolateral membrane domain. It appears that the apical P2Y receptor-regulated Ca(2+) release and activation of apical Cl(-) channels is compartmentalized in polarized epithelia with basolateral P2Y-stimulated Ca(2+) release failing to activate anion secretion. These data suggest that there may be two distinct ATP-releasable Ca(2+) pools, each coupled to apical and basolateral membrane receptor but linked to the same calcium influx pathway located at the basolateral membrane.

Adenosine Triphosphate↗
PubMed2006

An experimental study on pedestrian classification.

Detecting people in images is key for several important application domains in computer vision. This paper presents an in-depth experimental study on pedestrian classification; multiple feature-classifier combinations are examined with respect to their ROC performance and efficiency. We investigate global versus local and adaptive versus nonadaptive features, as exemplified by PCA coefficients, Haar wavelets, and local receptive fields (LRFs). In terms of classifiers, we consider the popular Support Vector Machines (SVMs), feed-forward neural networks, and k-nearest neighbor classifier. Experiments are performed on a large data set consisting of 4,000 pedestrian and more than 25,000 nonpedestrian (labeled) images captured in outdoor urban environments. Statistically meaningful results are obtained by analyzing performance variances caused by varying training and test sets. Furthermore, we investigate how classification performance and training sample size are correlated. Sample size is adjusted by increasing the number of manually labeled training data or by employing automatic bootstrapping or cascade techniques. Our experiments show that the novel combination of SVMs with LRF features performs best. A boosted cascade of Haar wavelets can, however, reach quite competitive results, at a fraction of computational cost. The data set used in this paper is made public, establishing a benchmark for this important problem.

Algorithms↗
PubMed1987

Possible existence of a novel amphipathic immunostimulator in the phenol-water extracts of Mycobacteriaceae.

The extracts having diverse immunostimulating activities were obtained as a water-phase fraction from four bacterial species representing the 4 genera (Mycobacterium, Nocardia, Gordona, and Rhodococcus) of Mycobacteriaceae by the phenol-water method, which is commonly used for extraction of endotoxic lipopolysaccharides (LPS) from gram-negative bacteria and amphipathic substances from gram-positives. These fractions, especially those of G. aurantiaca and R. terrae, showed strong stimulatory effects on murine splenocytes, macrophages of mice and guinea pigs, the immunoadjuvant activities in guinea pigs and mice, and the distinct activities inducing a tumor necrosis factor and interferons alpha/beta and gamma in primed mice. The fractions from G. aurantiaca and R. terrae exhibited potent pyrogenicity and the ability to activate the clotting enzyme cascade of the horseshoe crab (Tachypleus tridentatus). Some of these biological activities were not very different from the potency of the reference endotoxic LPS derived from Escherichia coli or Fusobacterium nucleatum. But the test fractions neither showed the activity to prepare rabbit skin to the local Shwartzman reaction, nor reacted with anti-lipid A conventional and monoclonal antibodies. Furthermore, unlike LPS, these fractions stimulated the splenocytes of C3H/HeJ mice (LPS-Nonresponder). Although the fractions showing the above biological activities have not yet been adequately purified, they contained polysaccharides, whose main constituent sugar is mannose with a smaller amount of arabinose, fatty acids consisting primarily of palmitic, stearic, and tuberculostearic acids, and small amounts of peptides and amino sugars. Since components characteristic of known immunomodulators of bacterial origin, namely endotoxins (lipid A's), cell wall peptidoglycans, lipoteichoic acids, cord factors (trehalose dimycolates), or deoxyribonucleic acids, were practically not detected in these fractions, the agent responsible for the above bioactivities is considered to be a novel substance different from the known, bacterial immunomodulators.

Adjuvants, Immunologic↗
PubMed2002

D-dimer correlates with proinflammatory cytokine levels and outcomes in critically ill patients.

STUDY OBJECTIVES: To determine the relationship between d-dimer (DD) and both proinflammatory and anti-inflammatory cytokine levels, and to confirm the association between DD status and outcomes in critically ill patients. DESIGN: Prospective observational study. SETTING: Medical ICU (MICU) of a tertiary care, academic medical center. PATIENTS: Individuals admitted to the MICU. INTERVENTIONS: Within 24 h of MICU admission, patients had DD status determined and interleukin (IL) levels (IL-6, IL-8, and IL-10) and tumor necrosis factor (TNF)-alpha measured. The strength of the DD level was also noted. Subjects were then monitored prospectively to determine mortality rate and the incidence of organ failure. MEASUREMENT AND RESULTS: The study cohort included 79 patients (mean age, 65.2 years; 54.5% male patients). DD was present in 53.2% of subjects. The DD reaction was weak (1+) in 15 patients and strong (2+) in 27 patients. The TNF-alpha, IL-6, and IL-8 levels all increased in parallel with the increasing strength of the DD level. IL-10 levels did not differ based on DD status. Similarly, the severity of illness as measured by the APACHE (acute physiology and chronic health evaluation) II score was highest among those with higher DD levels: 24.7 +/- 6.2 for those with 2+ DD vs 17.2 +/- 3.1 and 11.5 +/- 2.7 for those with 1+ DD and no circulating DD, respectively (p < 0.001). For patients lacking DD, the mortality rate was 8.1%, compared to 13.3% and 55.6% for those with 1+ and 2+ DD levels, respectively (p < 0.001). No patient without DD had multisystem organ failure (MSOF) develop, while the incidence of MSOF also increased with increasing DD levels. As a screening test for mortality, the DD performed as well as the APACHE II system. CONCLUSIONS: The coagulation system is active in critically ill patients, and DD levels correlate with activation of the proinflammatory cytokine cascade. The absence of a relationship between DD and anti-inflammatory cytokines (IL-10) suggests that the presence of DD may reflect the imbalance between proinflammatory and anti-inflammatory cytokines. DD identifies patients at increased risk for both MSOF and death.

APACHE↗
PubMed2003

Spontaneous antibiotic resistance mutation associated pleiotropic changes in Escherichia coli O157:H7.

Besides the well-known O157:H7 clone causing enterohaemorrhagic colitis and haemolytic uraemic syndrome in Europe, Japan and North America, the number of Escherichia coli isolates with non-motile (NM) phenotype has considerably increased. We supposed that spontaneous antibiotic resistance mutation could cause this phenotypic change. To model our hypothesis we isolated rifampicin--(Rif) and ampicillin--(Amp) resistant mutants from E. coli O157:H7 prototype strains 7785 and EDL933. Among Rifr mutants we could isolate strains with no or reduced motility, while the Ampr mutants became hypermotile. The biochemical profile of the mutants had not changed but phage sensitivity and generation time of the mutants were altered. Among the representative strains we did not find polymorphism with Southern blot analysis and no polymorphism was found in the fliC gene of the mutants. The described characteristics have proven to be stable. In a mice virulence assay by intravenous infections the virulence of the derivatives was also found to be changed. In summary, we found that the antibiotic-resistant phenotype in E. coli O157:H7 was coexpressed with several other phenotypic changes including motility and virulence. It can be assumed that expression of the involved phenotypes may be under the influence of a common regulatory cascade. Further work is needed to identify the components and mechanism of this regulatory system.

Agglutination Tests↗
PubMed1994

Pharmacologic evidence that spinal muscarinic analgesia is mediated by an L-arginine/nitric oxide/cyclic GMP cascade in rats.

This study was designed to determine if the antinociception produced by intrathecally (i.t.) administered muscarinic agonists in male Sprague-Dawley rats is mediated by an L-arginine/nitric oxide/cyclic GMP cascade. Seven days after implantation of intrathecal catheters, antinociception was produced with graded doses of (+)-cis-methyldioxolane (CD). The ED50 values for CD in the hot-plate and tail-flick tests were 2.6 and 2.0 nmol, respectively. The corneal and righting reflexes, as well as stepping and negative geotaxic responses, were not affected by CD. Six-minute pretreatment with 50 nmol of the nitric oxide synthase inhibitor L-NG-nitroarginine (NNR) significantly inhibited CD-produced hot-plate and tail-flick antinociception as evidenced by 6-fold shifts to the right of the CD dose-response curves. Coadministration of 150 nmol of L-arginine with NNR reversed the NNR-induced inhibition of the antinociception produced by CD. D-Arginine was without effect. Pretreatment with 500 nmol of the guanylyl cyclase inhibitor methylene blue also antagonized the antinociception produced by CD in both the hot-plate and tail-flick tests. In parallel with CD, coadministration of L-arginine with NMR reversed the NMR-induced inhibition of (+)-muscarine-produced antinociception in both nociceptive tests. Intrathecal administration of buffer, 50 nmol of NNR, 150 nmol of L- or D-arginine or 500 nmol of methylene blue, did not alter nociceptive responses when injected alone. In contrast, i.t. administration of the membrane-permeable cyclic GMP analogs, dibutyryl cyclic GMP and 8-bromo cyclic GMP, produced antinociception in both nociceptive tests when injected alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1998

[The modulating action of serotonin on single calcium channels in the neurons of the snail Helix pomatia].

The influence of a neurotransmitter serotonin (5-hydroxytriptamine, 5-HT) on single Ca2+ channel activity was studied on unidentified neurons of the snail Helix pomatia. Our findings showed that 5-HT influences the channel molecule in indirect manner, as it appeared effective at its application by adding to the bath solution, that had no contact with the tested membrane fragment. This finding excludes the possibility of direct binding of 5-HT to the channel molecule and shows that the effect is really mediated through a cytoplasmic messenger, cAMP-dependent cascade of phosphorylation. Also our investigations shows, that only one type of Ca2+ channel with the unitary conductance of 5 pS was identified in this kind of neurons.

Animals↗
PubMed2006

Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys.

OBJECTIVE: We tested the hypothesis that gene delivery of the trophic factor neurturin could preserve motor function and protect nigrostriatal circuitry in hemiparkinsonian monkeys. METHODS: An adeno-associated virus-based vector encoding human neurturin (AAV2-NTN; also called CERE-120) was injected into the striatum and substantia nigra of monkeys 4 days after a unilateral intracarotid injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rendered them hemiparkinsonian. Control hemiparkinsonian monkeys received either AAV2 encoding green fluorescent protein or formulation buffer. RESULTS: Although stable deficits were seen in all control monkeys, AAV2-NTN significantly improved MPTP-induced motor impairments by 80 to 90% starting at approximately month 4 and lasting until the end of the experiment (month 10). AAV2-NTN significantly preserved nigral neurons, significantly preserved striatal dopaminergic innervation, and activated phospho-extracellular signal-regulated kinase, consistent with a mechanism involving a trophic factor-initiated molecular cascade. Histological analyses of numerous brain regions, including the cerebellum, showed normal cytoarchitecture and no aberrant pathology. INTERPRETATION: These data demonstrate that AAV2-NTN (CERE-120) can preserve function and anatomy in degenerating nigrostriatal neurons and are supportive of ongoing clinical tests in Parkinson's disease patients.

Animals↗
PubMed1998

Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40.

Accumulating evidence suggests that beta-amyloid (Abeta)-induced inflammatory reactions may partially drive the pathogenesis of Alzheimer's disease (AD). Recent data also implicate similar inflammatory processes in cerebral amyloid angiopathy (CAA). To evaluate the roles of Abeta in the inflammatory processes in vascular tissues, we have tested the ability of Abeta to trigger inflammatory responses in cultured human vascular cells. We found that stimulation with Abeta dose-dependently increased the expression of CD40, and secretion of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in endothelial cells. Abeta also induced expression of IFN-gamma receptor (IFN-gammaR) both in endothelial and smooth muscle cells. Characterization of the Abeta-induced inflammatory responses in the vascular cells showed that the ligation of CD40 further increased cytokine production and/or the expression of IFN-gammaR. Moreover, IL-1beta and IFN-gamma synergistically increased the Abeta-induced expression of CD40 and IFN-gammaR. We have recently found that Abeta induces expression of adhesion molecules, and that cytokine production and interaction of CD40-CD40 ligand (CD40L) further increase the Abeta-induced expression of adhesion molecules in these same cells. These results suggest that Abeta can function as an inflammatory stimulator to activate vascular cells and induces an auto-amplified inflammatory molecular cascade, through interactions among adhesion molecules, CD40-CD40L and cytokines. Additionally, Abeta1-42, the more pathologic form of Abeta, induces much stronger effects in endothelial cells than in smooth muscle cells, while the reverse is true for Abeta1-40. Collectively, these findings support the hypothesis that the Abeta-induced inflammatory responses in vascular cells may play a significant role in the pathogenesis of CAA and AD.

Alzheimer Disease↗
PubMed1998

Role of reactive oxygen species in the signalling cascade of cyclosporine A-mediated up-regulation of eNOS in vascular endothelial cells.

1. Cyclosporine A (CsA) increases eNOS mRNA expression in bovine cultured aortic endothelial cells (BAEC). As some effects of CsA may be mediated by reactive oxygen species (ROS), present experiments were devoted to test the hypothesis that the CsA-induced eNOS up-regulation could be dependent on an increased synthesis of ROS. 2. CsA induced a dose-dependent increase of ROS synthesis, with the two fluorescent probes used, DHR123 (CsA 1 microM: 305+/-7% over control) and H2DCFDA (CsA 1 microM: 178+/-6% over control). 3. Two ROS generating systems, xanthine plus xanthine oxidase (XXO) and glucose oxidase (GO), increased the expression of eNOS mRNA in BAEC, an effect which was maximal after 8 h of incubation (XXO: 168+/-21% of control values. GO: 208+/-18% of control values). The ROS-dependent increased eNOS mRNA expression was followed by an increase in eNOS activity. 4. The effect of CsA on eNOS mRNA expression was abrogated by catalase, and superoxide dismutase (SOD). In contrast, the antioxidant PDTC augmented eNOS mRNA expression, both in basal conditions and in the presence of CsA. 5. The potential participation of the transcription factor AP-1 was explored. Electrophoretic mobility shift assays were consistent with an increase in AP-1 DNA-binding activity in BAEC treated with CsA or glucose oxidase. 6. The present results support a role for ROS, particularly superoxide anion and hydrogen peroxide, as mediators of the CsA-induced eNOS mRNA up-regulation. Furthermore, they situate ROS as potential regulators of gene expression in endothelial cells, both in physiological and pathophysiological situations.

Animals↗
PubMed2001

Interallelic complementation at the Drosophila melanogaster gastrulation defective locus defines discrete functional domains of the protein.

The gastrulation defective (gd) locus encodes a novel serine protease that is involved in specifying the dorsal-ventral axis during embryonic development. Mutant alleles of gd have been classified into three complementation groups, two of which exhibit strong interallelic (intragenic) complementation. To understand the molecular basis of this interallelic complementation, we examined the complementation behavior of additional mutant alleles and sequenced alleles in all complementation groups. The data suggest that there are two discrete functional domains of Gd. A two-domain model of Gd suggesting that it is structurally similar to mammalian complement factors C2 and B has been previously proposed. To test this model we performed SP6 RNA microinjection to assay for activities associated with various domains of Gd. The microinjection data are consistent with the complement factor C2/B-like model. Site-directed mutagenesis suggests that Gd functions as a serine protease. An allele-specific interaction between an autoactivating form of Snake (Snk) and a gd allele altered in the protease domain suggests that Gd directly activates Snk in a protease activation cascade. We propose a model in which Gd is expressed during late oogenesis and bound within the perivitelline space but only becomes catalytically active during embryogenesis.

Alleles↗
PubMed2005

VeloceGenomics: an accelerated in vivo drug discovery approach to rapidly predict the biologic, drug-like activity of compounds, proteins, or genes.

PURPOSE: The aim of this study is to test the predictive power of in vivo multiorgan RNA expression profiling in identifying the biologic activity of molecules. METHODS: Animals were treated with compound A or B. At the end of the treatment period, in vivo multiorgan microarray-based gene expression data were collected. Investigators masked to the identity of the compounds analyzed the transcriptome signatures to define the molecular pathways affected by treatment and to hypothesize the biologic activity and potential therapeutic indications of the blinded compounds. RESULTS: For compound A, G-protein-coupled receptors and factors associated with cell growth were affected-growth hormone/insulin-like growth factor-1, glucagon/insulin axes, and general somatomedin-like activity. Deblinding showed the compound to be a somatostatin analog, SOM230, confirming the accuracy of the predicted biologic activity. For compound B, components of the inflammatory cascade potentially mediated by lipopolysaccharide, tumor necrosis factor, or proinflammatory cytokines were affected. The gene expression signatures were most consistent with an interleukin-6 family activity. Deblinding revealed that compound B was leukemia inhibitory factor. CONCLUSIONS: VeloceGenomics is a strategy of coupling in vivo compound testing with genomic technologies. The process enables prediction of the mechanism of action and, coupled with other relevant data, prediction of the suitability of compounds for advancement in the drug development process.

Animals↗
PubMed2004

Neuronal MEK is important for normal fear conditioning in mice.

The extracellular signal-regulated kinase (ERK) cascade has received much attention for its possible role in neuronal synaptic plasticity. Although ERK activation has been linked to learning behaviors and activity-dependent neuronal function, much of the acquired data has relied upon pharmacological agents that suppress ERK function in both neurons and nonneuronal cells. To determine the function of neuronal ERK activity in learning, a new line of transgenic mice was generated wherein dominant-negative MEK1, the upstream obligate activator of ERK1/2, was expressed by using a neuronal-specific and pan-neuronal Talpha1 alpha-tubulin promoter element. Mice expressing this construct exhibited decreased ERK1/2 activity in the hippocampus and thus were tested for learning impairments. In a battery of control tests, including open field, rotarod, and shock threshold, the transgenic mice displayed no deficits and performed as well as their wild-type littermate counterparts. However, the mice displayed a significant impairment in contextual fear conditioning compared with the wild-type littermates. These findings indicate that the MEK1/ERK1/2 cascade within neurons plays an important role in the processes of learning and memory.

Animals↗
PubMed2006

Predators have large effects on ecosystem properties by changing plant diversity, not plant biomass.

Cascading effects of predators on total plant trophic-level biomass tend to be weaker in terrestrial than in aquatic systems. Accordingly, it is hypothesized that top predator effects on terrestrial plant diversity and on ecosystem function should likewise be weak or unimportant. This report presents a test of this hypothesis using data from a long-term field experiment. The five-year experiment manipulated the trophic structure of an old field ecosystem by excluding either predators or predators and herbivores relative to an unmanipulated, natural control. Long-term manipulations led to systematic treatment effects on community properties (plant trophic-level biomass, plant species biomass, plant species evenness) and on ecosystem properties (supply rate of solar radiation, N mineralization rate). The strengths of top predator effects on community properties were modest compared with nonterrestrial systems. But, predator-caused changes in plant community structure via alteration of plant dominance, and hence plant species evenness, strengthened effects on ecosystem properties. Counter to the hypothesis, weak trophic cascades do not necessarily lead to weak indirect effects of predators on ecosystem properties.

Animals↗
PubMed1993

Evolutionary conservation of Xenopus laevis mitogen-activated protein kinase activation and function.

Saccharomyces cerevisiae possesses at least four mitogen-activated protein (MAP) kinase family members, encoded by the FUS3, KSS1, HOG1, and MPK1 genes, that participate in three distinct signaling pathways. We have tested whether a MAP kinase from Xenopus laevis (Xp42) can function in budding yeast, by expressing wild-type and mutant forms of Xp42 in different strains of S. cerevisiae. In Xenopus cells, Xp42 is phosphorylated on threonine188 and tyrosine190 when activated by a MAP kinase kinase (MAPKK). In S. cerevisiae, Xp42 is constitutively phosphorylated on tyrosine190. Since a kinase-inactive mutant of Xp42 is also phosphorylated, this phosphorylation is presumably due to activation by an endogenous MAPKK. Xp42 phosphorylation and kinase activity are dependent on yeast Bck1p, a putative MAPKK kinase (MAPKKK) and indirect upstream activator of Mpk1p. The loss of either Ste7p or Pbs2p, the upstream activators of Fus3p, Kss1p, and Hog1p, does not decrease the phosphorylation stoichiometry of Xp42. We also show that expression of Xenopus MAP kinase permits an mpk1::TRP1 deletion strain to grow at 37 degrees C. We conclude that S. cerevisiae and X. laevis possess evolutionarily conserved cascades, where biochemical activation and substrate specificity of MAP kinase have been maintained.

Animals↗