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PubMed1992

Analysis of intraarticular fibrinolytic pathways in patients with inflammatory and noninflammatory joint diseases.

OBJECTIVE: Intraarticular activation of the fibrinolytic system has been suspected to occur in patients with arthritis. We undertook the present study to investigate the relation of this activation to clinical symptoms, and the molecular pathways involved. METHODS: We quantitatively assessed levels of plasmin-alpha 2-antiplasmin (PAP) complexes in synovial fluid (SF) from 25 patients with rheumatoid arthritis (RA), 7 with seronegative spondylarthropathy (SSA), and 10 with osteoarthritis (OA), and conducted an analysis to determine the plasminogen-activating pathway via which these complexes were generated. In addition, we studied the relationship of intraarticular fibrinolysis to clinical and biochemical parameters. RESULTS: All patients studied had increased SF levels of PAP complexes. Levels in patients with RA and SSA were slightly higher than those in patients with OA. These complexes were probably formed by activation of urokinase-type plasminogen activator (u-PA), and not tissue-type plasminogen activator (t-PA), since SF levels of both u-PA antigen and u-PA-plasminogen activator inhibitor (PAI) complexes were increased in 27 of the 42 patients. Conversely, SF levels of t-PA were below normal in all but 1 patient. In some patients, activation of factor XII presumably also contributed to plasminogen activation in SF, since levels of factor XIIa-C1 inhibitor in SF were increased in 8 of the 42 patients and correlated, as did u-PA-PAI levels, with levels of PAP complexes. Several of the parameters of fibrinolysis in SF, particularly u-PA antigen and u-PA-PAI-1 complexes, were found to correlate with clinical and biochemical parameters. CONCLUSION: Our results suggest that plasminogen is frequently activated in the joints of patients with inflammatory or noninflammatory arthropathy and that this activation mainly occurs via a u-PA-, and in some cases also via a factor XII-, dependent pathway. The possible relation of this activation process to stimulation of synovial cells by cytokines is discussed.

Adult↗
PubMed2005

A novel gnd mutation leading to increased L-lysine production in Corynebacterium glutamicum.

Toward more efficient L-lysine production, we have been challenging genome-based strain breeding by the approach of assembling only relevant mutations in a single wild-type background. Following the creation of a new L-lysine producer Corynebacterium glutamicum AHP-3 that carried three useful mutations (lysC311, hom59, and pyc458) on the relevant downstream pathways, we shifted our target to the pentose phosphate pathway. Comparative genomic analysis for the pathway between a classically derived L-lysine producer and its parental wild-type identified several mutations. Among these mutations, a Ser-361-->Phe mutation in the 6-phosphogluconate dehydrogenase gene (gnd) was defined as a useful mutation for L-lysine production. Introduction of the gnd mutation into strain AHP-3 by allelic replacement led to approximately 15% increased L-lysine production. Enzymatic analysis revealed that the mutant enzyme was less sensitive than the wild-type enzyme to allosteric inhibition by intracellular metabolites, such as fructose 1,6-bisphosphate, D-glyceraldehyde 3-phosphate, phosphoribosyl pyrophosphate, ATP, and NADPH, which were known to inhibit this enzyme. Isotope-based metabolic flux analysis demonstrated that the gnd mutation resulted in 8% increased carbon flux through the pentose phosphate pathway during L-lysine production. These results indicate that the gnd mutation is responsible for diminished allosteric regulation and contributes to redirection of more carbon to the pentose phosphate pathway that was identified as the primary source for NADPH essential for L-lysine biosynthesis, thereby leading to improved product formation.

Corynebacterium↗
PubMed2004

Analysis on a cooperative pathway involving multiple cations in hammerhead reactions.

The hammerhead ribozyme reaction is more complex than might have been expected, perhaps because of the flexibility of RNA, which would have enhanced the potential of RNA during evolution of and in the RNA world. Divalent Mg(2+) ions can increase the rate of the ribozyme-catalyzed reaction by approximately 10(9)-fold as compared to the background rate under standard conditions. However, the role of Mg(2+) ions is controversial since the reaction can proceed in the presence of high concentrations of monovalent ions, such as Li(+), Na(+), and NH(4)(+) ions, in the absence of divalent ions. We thus carried out ribozyme reactions under various conditions, and we obtained parameters that explain the experimental data. On the basis of the analysis, we propose a new pathway in the hammerhead ribozyme reaction in which divalent metal ions and monovalent ions act cooperatively.

Base Sequence↗
PubMed2003

The glutathione-mediated detoxification pathway in yeast: an analysis using the red pigment that accumulates in certain adenine biosynthetic mutants of yeasts reveals the involvement of novel genes.

The glutathione-mediated pathway for the detoxification of endogenously and exogenously derived toxic compounds was investigated using a pigment that accumulates in certain adenine biosynthetic mutants of yeasts. The ade1 / ade2 mutants of Saccharomyces cerevisiae, when grown on adenine-limiting medium, accumulate a characteristic red pigment (ade pigment) in their vacuoles. The precursors of the ade pigments are toxic intermediates that form conjugates with glutathione, followed by their transport inside the vacuole. In this study, this red pigment was used as a phenotypic screen to obtain insight regarding new genes involved in the three phases of this detoxification pathway: the activation phase (phase I), the conjugation phase (phase II), and the efflux phase (phase III). Components of the phase III (efflux) pathway which includes, in addition to the previously characterized Ycf1p and Bpt1p, another member of the 'Ycf1p family', Bat1p, as well as a vacuolar H(+)-ATPase-dependent transport were identified. In the investigation of phase II (conjugation), it was found that glutathione S-transferases, encoded by GTT1 and GTT2,do not appear to play a role in this process. By contrast, two other previously characterized genes, the oxidative stress transcription factor gene, SKN7, and the yeast caesin protein kinase gene, YCK1, of S. cerevisiae do participate in this pathway.

Adenine↗
PubMed2025

HEPARIN AND DNase I TREAT MYOCARDIAL INJURY IN SEPTIC MICE.

Background: Sepsis is a life-threatening clinical condition often seen in intensive care units, leading to multi-organ dysfunction. Myocardial injury is a prevalent complication, significantly increasing mortality among sepsis patients. Although heparin is used in sepsis management, its specific effects on myocardial injury and the role of neutrophil extracellular traps (NETs) in this context remain insufficiently understood. Aim: This study investigates the role of unfractionated heparin (UFH) combined with DNase I in reducing myocardial injury in a septic mouse model. Methods: A cecal ligation and puncture (CLP)-induced sepsis model was established in C57BL/6 mice to study myocardial injury. The experimental groups included treatments with UFH, UFH with DNase I, and NETs introduction. Myocardial injury was assessed using hematoxylin and eosin staining, enzyme linked immunosorbent assay for injury markers (creatine kinase MB [CK-MB] and lactate dehydrogenase [LDH]), and Western blotting for inflammatory proteins (TNF-α and IL-6). Differential proteomic analysis using data independent acquisition mass spectrometry and pathway enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) were conducted to identify molecular pathways and key proteins affected by the treatments. Results: Single UFH treatment increased the formation of NETs, upregulated TNF-α and IL-6, and increased CK-MB and LDH, worsening myocardial injury. The combination of UFH and DNase I significantly reduced myocardial injury, suppressing NETs formation and inflammation. Proteomic analysis identified crucial pathways related to NETs, metabolism, and complement and coagulation cascades, with proteins Ccn1 and Tagln highlighted as potential therapeutic targets. Conclusion: UFH combined with DNase I effectively alleviates myocardial injury in septic mice by modulating NETs formation and associated inflammatory processes. This study may provide new insights and options for the early use of heparin in the treatment of septic patients, particularly in cases with a higher risk of myocardial injury.

Animals↗
PubMed2005

Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs.

Mycobacterium tuberculosis is the focus of several investigations for design of newer drugs, as tuberculosis remains a major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualities to mycolic acids, which are known to be important for their growth, survival, and pathogenicity. Mycolic acid biosynthesis has therefore been the focus of a number of biochemical and genetic studies. It also turns out to be the pathway inhibited by front-line anti-tubercular drugs such as isoniazid and ethionamide. Recent years have seen the emergence of systems-based methodologies that can be used to study microbial metabolism. Here, we seek to apply insights from flux balance analyses of the mycolic acid pathway (MAP) for the identification of anti-tubercular drug targets. We present a comprehensive model of mycolic acid synthesis in the pathogen M. tuberculosis involving 197 metabolites participating in 219 reactions catalysed by 28 proteins. Flux balance analysis (FBA) has been performed on the MAP model, which has provided insights into the metabolic capabilities of the pathway. In silico systematic gene deletions and inhibition of InhA by isoniazid, studied here, provide clues about proteins essential for the pathway and hence lead to a rational identification of possible drug targets. Feasibility studies using sequence analysis of the M. tuberculosis H37Rv and human proteomes indicate that, apart from the known InhA, potential targets for anti-tubercular drug design are AccD3, Fas, FabH, Pks13, DesA1/2, and DesA3. Proteins identified as essential by FBA correlate well with those previously identified experimentally through transposon site hybridisation mutagenesis. This study demonstrates the application of FBA for rational identification of potential anti-tubercular drug targets, which can indeed be a general strategy in drug design. The targets, chosen based on the critical points in the pathway, form a ready shortlist for experimental testing.

Algorithms↗
PubMed2006

Proteomic analysis identifies alterations in cellular morphology and cell death pathways in mouse brain after chronic corticosterone treatment.

Some patients with Major Depression and other neurological afflictions display hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. HPA hyperactivity may be due to impaired feedback inhibition and manifested as increased levels of circulating cortisol. Subcutaneous implants of corticosterone pellets were used to mimic this situation in mice to gain insight into any effects on brain function by comparative proteomic analysis using two-dimensional Differential In-Gel Electrophoresis. A total of 150 different protein spots were altered by corticosterone treatment in the hypothalamus, hippocampus and cerebral cortex. Of these, 117 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass fingerprinting equating to 51 different proteins. Association of these corticosterone-modulated proteins with biological functions using the Ingenuity Pathways Analysis tool showed that cell morphology was significantly altered in the hippocampus and cerebral cortex, whereas the hypothalamus showed significant changes in cell death. Ingenuity Pathways Analysis of the canonical signaling pathways showed that glycolysis and gluconeogenesis were altered in the hypothalamus and the hippocampus and all three brain regions showed changes in phenylalanine, glutamate and nitrogen metabolism. Further elucidation of these pathways could lead to identification of biomarkers for the development of pharmacological therapies targeted at neuropsychiatric disorders.

Animals↗
PubMed2002

Variance analysis applied to a stroke pathway: how this can improve efficiency of healthcare delivery.

INTRODUCTION: Stroke is a complicated disease that requires a multidisciplinary approach for its management. We postulated that variance analysis applied to a stroke pathway, by identifying major problem areas and encouraging timely corrective actions, would lead to more efficient healthcare delivery to hospitalised stroke patients. MATERIALS AND METHODS: Prospectively collected variance data from consecutive stroke patients discharged from a tertiary hospital in Singapore during a 3-month period in 2000 were used to identify the major variances causing increased length of stay. These were compared and contrasted to variance data collected during the same 3-month period in the subsequent year (2001), after the implementation of stroke pathway and the availability of monthly variance analysis reports. Patient characteristics and outcome measures were also compared between the two study periods. RESULTS: The four major variances that accounted for increased length of stay were, in descending order of the number of patients affected, awaiting bed availability in step-down facilities, delay in head computed tomographic scan performance, awaiting family's decision on discharge plan and incomplete application submitted to step-down facilities. After implementation of the stroke pathway with ongoing variance analysis, all four variances showed different extent of improvements. There were no significant differences in patient characteristics between the two study periods, whereas the average length of stay significantly diminished in the late study period with a trend for decreased in-hospital mortality, compared to the early study period. CONCLUSION: Variance analysis applied in the context of a stroke pathway was effective in identifying major variances causing increased length of stay. This allowed targeted intervention to improve efficiency of healthcare delivery to stroke patients.

Aged↗
PubMed2004

Identification and analysis of vocal communication pathways in birds through inducible gene expression.

The immediate-early gene zenk is an activity-dependent gene highly induced in auditory processing or vocal motor control brain areas when birds engage in hearing or producing song, respectively. Studies of the expression of zenk in songbirds and other avian groups will be reviewed here briefly, with a focus on how this analysis has generated new insights on the brain pathways and mechanisms involved in perceptual and motor aspects of vocal communication and vocal learning.

Animals↗
PubMed2006

New insights into gene positional clustering and its properties supported by large-scale analysis of various differentiation pathways.

To understand how genes are distributed on chromosomes we bring new insights into gene positional clustering and its properties. We have made a large-scale analysis of three types of differentiation and we observed that genes that subsequently enter into different cell processes are positionally clustered on chromosomes. Genes from the clusters are transcribed subsequently with respect to time kinetics and also to position. This means that the genes related to a cellular process are clustered together, independent of the period of time during which they are active and important for the process. Our results also demonstrate not only that there are general regions of increased or decreased levels of gene expression, but also that, in fact, in some chromosome regions we can find clustering of genes related to specific cell processes. The results provided in this paper also support the theory of "transcription factories" and show that transcription of genes from the clusters is managed by softer epigenetic mechanisms.

Base Sequence↗
PubMed2006

Nonparametric pathway-based regression models for analysis of genomic data.

High-throughout genomic data provide an opportunity for identifying pathways and genes that are related to various clinical phenotypes. Besides these genomic data, another valuable source of data is the biological knowledge about genes and pathways that might be related to the phenotypes of many complex diseases. Databases of such knowledge are often called the metadata. In microarray data analysis, such metadata are currently explored in post hoc ways by gene set enrichment analysis but have hardly been utilized in the modeling step. We propose to develop and evaluate a pathway-based gradient descent boosting procedure for nonparametric pathways-based regression (NPR) analysis to efficiently integrate genomic data and metadata. Such NPR models consider multiple pathways simultaneously and allow complex interactions among genes within the pathways and can be applied to identify pathways and genes that are related to variations of the phenotypes. These methods also provide an alternative to mediating the problem of a large number of potential interactions by limiting analysis to biologically plausible interactions between genes in related pathways. Our simulation studies indicate that the proposed boosting procedure can indeed identify relevant pathways. Application to a gene expression data set on breast cancer distant metastasis identified that Wnt, apoptosis, and cell cycle-regulated pathways are more likely related to the risk of distant metastasis among lymph-node-negative breast cancer patients. Results from analysis of other two breast cancer gene expression data sets indicate that the pathways of Metalloendopeptidases (MMPs) and MMP inhibitors, as well as cell proliferation, cell growth, and maintenance are important to breast cancer relapse and survival. We also observed that by incorporating the pathway information, we achieved better prediction for cancer recurrence.

Adult↗
PubMed2006

Novel retrotransposon analysis reveals multiple mobility pathways dictated by hosts.

Autonomous non-long-terminal-repeat retrotransposons (NLRs) proliferate by retrotransposition via coordinated reactions of target DNA cleavage and reverse transcription by a mechanism called target-primed reverse transcription (TPRT). Whereas this mechanism guarantees the covalent attachment of the NLR and its target site at the 3' junction, mechanisms for the joining at the 5' junction have been conjectural. To better understand the retrotransposition pathways, we analyzed target-NLR junctions of zebrafish NLRs with a new method of identifying genomic copies that reside within other transposons, termed "target analysis of nested transposons" (TANT). Application of the TANT method revealed various features of the zebrafish NLR integrants; for example, half of the integrants carry extra nucleotides at the 5' junction, which is in stark contrast to the major human NLR, LINE-1. Interestingly, in a cell culture assay, retrotransposition of the zebrafish NLR in heterologous human cells did not bear extra 5' nucleotides, indicating that the choice of the 5' joining pathway is affected by the host. Our results suggest that several pathways exist for NLR retrotransposition and argue in favor of host protein involvement. With genomic sequence information accumulating exponentially, our data demonstrate the general applicability of the TANT method for the analysis of a wide variety of retrotransposons.

Animals↗
PubMed2007

Pathway mapping tools for analysis of high content data.

The complexity of human biology requires a systems approach that uses computational approaches to integrate different data types. Systems biology encompasses the complete biological system of metabolic and signaling pathways, which can be assessed by measuring global gene expression, protein content, metabolic profiles, and individual genetic, clinical, and phenotypic data. High content screening assays can also be used to generate systems biology knowledge. In this review, we will summarize the pathway databases and describe biological network tools used predominantly with this genomics, proteomics, and metabolomics data but which are equally as applicable for high content screening data analysis. We describe in detail the integrated data-mining tools applicable to building biological networks developed by GeneGo, namely, MetaCore and MetaDrug.

Computational Biology↗
PubMed1994

Separate neural pathways for the visual analysis of object shape in perception and prehension.

BACKGROUND: Earlier work with neurological patients has shown that the visual perception of object size and orientation depends on visual pathways in the cerebral cortex that are separate from those mediating the use of these same object properties in the control of goal-directed grasping. We present evidence suggesting that the same dissociation between perception and action is evident in the visual processing of object shape. In other words, discrimination between objects on the basis of their shape appears to be mediated by visual mechanisms that are functionally and neurally distinct from those controlling the pre-shaping of the hand during grasping movements directed at those same objects. RESULTS: We studied two patients with lesions in different parts of the cerebral visual pathways. One patient (RV), who had sustained bilateral lesions of the occipitoparietal cortex, was unable to use visual information to place her fingers correctly on the circumference of irregularly shaped objects when asked to pick them up, even though she had no difficulty in visually discriminating one such object from another. Conversely, a second patient (DF), who had bilateral damage in the ventrolateral occipital region, had no difficulty in placing her fingers on appropriate opposition points during grasping, even though she was unable to discriminate visually amongst such objects. CONCLUSIONS: This double dissociation lends strong support to the idea that the visual mechanisms mediating the perception of objects are functionally and neurally distinct from those mediating the control of skilled actions directed at those objects. It also supports the recent proposal of Goodale and Milner that visual perception depends on a ventral stream of projections from the primary visual cortex to the inferotemporal cortex, whereas the visual control of skilled actions depends on a dorsal stream from the primary visual cortex to the posterior parietal cortex.

Adult↗
PubMed1995

Arabidopsis phosphoribosylanthranilate isomerase: molecular genetic analysis of triplicate tryptophan pathway genes.

Phosphoribosylanthranilate isomerase (PAI) catalyzes the third step of the tryptophan biosynthetic pathway. Arabidopsis PAI cDNAs were cloned from a cDNA expression library by complementation of an Escherichia coli trpC- PAI deficiency mutation. Genomic DNA blot hybridization analysis detected three nonallelic genes encoding PAI in the Arabidopsis genome. DNA sequence analysis of cDNA and genomic clones indicated that the PAI1 and PAI2. All three PAI polypeptides possess an N-terminal putative plastid target sequence, suggesting that these enzymes all function in plastids. The PAI1 gene is flanked by nearly identical direct repeats of approximately 350 nucleotides. Our results indicate that, in contrast to most microorganisms, the Arabidopsis PAI protein is not fused with indole-3-glycerolphosphate synthase, which catalyzes the next step in the pathway. Yeast artificial chromosome hybridization studies indicated that the PAI2 gene is tightly linked to the anthranilate synthase alpha subunit 1 (ASA1) gene on chromosome 5. PAI1 was mapped to the top of chromosome 1 using recombinant inbred lines, and PAI3 is loosely linked to PAI1. cDNA restriction mapping and sequencing and RNA gel blot hybridization analysis indicated that all three genes are transcribed in wild-type plants. The expression of antisense PAI1 RNA significantly reduced the immunologically observable PAI protein and enzyme activity in transgenic plants. The plants expressing antisense RNA also showed two phenotypes consistent with a block early in the pathway: blue fluorescence under UV light and resistance to the anthranilate analog 6-methylanthranilate. The extreme nucleotide conservation between the unlinked PAI1 and PAI2 loci suggests that this gene family is actively evolving.

Aldose-Ketose Isomerases↗
PubMed2006

Whole genome expression analysis for biologic rational pathway modeling: application in cancer prognosis and therapy prediction.

Using semi-quantitative microarray technology, almost every one of the approximately 30 000 human genes can be analyzed simultaneously with a low rate of false-positives, a high specificity, and a high quantification accuracy. This is supported by data from comparative studies of microarrays and reverse-transcription PCR for established cancer genes including those for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2/ERBB2), estrogen receptor (ESR1), progesterone receptor (PGR), urokinase-type plasminogen activator (PLAU), and plasminogen activator inhibitor-1 (SERPINE1). As such, semi-quantitative expression data provide an almost completely comprehensive background of biological knowledge that can be applied to cancer diagnostics. In clinical terms, expression profiling may be able to provide significant information regarding (i) the identification of high-risk patients requiring aggressive chemotherapy; (ii) the pathway control of therapy predictive parameters (e.g. ESR1 and HER2); (iii) the discovery of targets for biologically rational therapeutics (e.g. capecitabine and trastuzumab); (iv) additional support for decisions about switching therapy; (v) target discovery; and (vi) the prediction of the course of new therapies in clinical trials. In conclusion, whole genome expression analysis might be able to determine important genes related to cancer progression and adjuvant chemotherapy resistance, especially in the context of new approaches involving primary systemic chemotherapy. In this review, we will survey the current progress in whole genome expression analyses for cancer prognosis and prediction. Special emphasis is given to the approach of combining biostatistical analysis of expression data with knowledge of biochemical and genetic pathways.

Cluster Analysis↗
PubMed2003

[Treatment of atrioventricular accessory pathways using catheter ablation: analysis of immediate and long-term results at the end of the learning curve period].

UNLABELLED: Immediate and long-term results of catheter ablation of atrioventricular accessory pathways (AP) are presented. METHOD: One hundred and seventy-one patients aged 41.8 +/- 14.4 years underwent catheter ablation of 179 AP. Right and left AP occurred simultaneously in 3 patients; thus 65 ablation procedures for 57 rights AP in 57 patients were compared with 125 ablation procedures for 122 left AP in 117 patients. RESULTS: Including repeated procedures ablation was successful in 116 (99%) patients with left AP and in 57 (100%) patients with right AP. First catheter ablation failed in 4 (7%) patients with right AP and in 4 (3.4%) patients with left AP (p = NS). Two of these patients with left AP and all 4 pts with right AP had successful reablation. AP conduction recurred after successful ablation in 7 (12.3%) patients with right AP and in u 5 (4.1%) patients with left AP (p = 0.1). Three patients with right AP did not undergo another ablation, other 9 patients with AP recurrence had successful reablation. Procedure time during left AP ablation was shorter (159.6 +/- 70.7 vs. 183.4 +/- 75.6 min.; p = 0.02) and number of RF current deliveries was lower during left AP ablation (9.3 +/- 8.5 vs. 13.3 +/- 11.8; p = 0.008) compared to right AP ablation. Fluoroscopy time during left AP ablation (22.4 +/- 19.1 min.) did not significantly differ from that during right AP ablation (20.9 +/- 17.1 min.). Concealed AP was present in 13 (22.8%) patients with right AP and in 59 (48.4%) patients with left AP (p = 0.002). Anatomico-functional variant of AP occurred in 5 (8.8%) patients with right AP and in 4 (3.3%) patients with left AP (p = NS). Atrial fibrillation complicated ablation procedure in 9 (15.8%) patients with right AP and in 7 (5.7%) patients with left AP (p = NS). During 30.3 +/- 17 (2-60) months follow-up period tachyarrhythmia associated with the presence of an AP occurred in 3 patients with right AP and in 1 patient with unsuccessful ablation of left AP. None of these patients underwent repeated ablation. CONCLUSION: Successful ablation of AP can be achieved successfully in 100%. Catheter ablation of right AP is generally more difficult and primary ablation failure and AP conduction recurrence is nonsignificantly more often. Irregularity of the tricuspid annulus, instability of the ablation catheter, presence of the conduction system, higher occurrence of anatomico-functional AP variants and sustained atrial fibrillation during the ablation procedure represent the main causes of this finding.

Adolescent↗