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PubMed2001

Genetic pathways and histogenetic models of AIDS-related lymphomas.

Acquired immunodeficiency syndrome (AIDS)-related lymphomas consistently display a B-cell phenotype and are histogenetically related to germinal centre or post-germinal centre B cells in the overwhelming majority of cases. The pathogenesis of AIDS-related lymphoma is a multistep process involving factors provided by the host as well as alterations intrinsic to the tumour clone. The molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-related lymphomas vary substantially in different clinicopathological categories of the disease and highlight the marked degree of biological heterogeneity of these lymphomas.

Burkitt Lymphoma↗
PubMedDate not supplied

[A model for integrating mental health care resources in the rural population of Mexico].

OBJECTIVE: The purpose of this project was to identify behaviors of health service utilization to solve mental health-related problems among rural inhabitants of Mexico. A model of pathways to mental health services was built. Based on this model, an integration-intervention model is proposed to help improve access to mental health services and their quality. MATERIAL AND METHODS: In 1997, in-depth interviews were conducted among 21 adults (9 men and 12 women) and seven healthcare providers, in a rural community in Jalisco, Mexico. Women's age ranged from 23 to 44 years; ten were married and two single. Men were between 30 and 74 years old; eight were married and one was a widower. Healthcare providers in the same community were: a priest, a general physician, a pharmacy clerk, two nurses, and two traditional healers. RESULTS: The pathways models suggest that the first attempt a person does to solve a symptom is self-care. When such strategies are not sufficient to relief the symptom, the person turns to the members of his/her social network for help, who in addition to providing information about remedies, offer their emotional and instrumental support. If after consulting the social network, the symptom is not relieved, the individual seeks help from other external resources, such as the members of the ethnomedical local system. Inhabitants of rural communities tend to seek help from physicians, only when the symptom persists and the suffering associated with it seems to be out of the individual's control, or if members of the social network or the ethno-medical local system refer the patient to the physician. Seeking help from a specialist in mental health (psychiatrist or psychologist) is quite improbable among the rural inhabitants of Mexico, mostly due to difficulties in accessing these services, such as geographical location, distance, transportation, cost, and cultural distance between the health providers and the patient. CONCLUSIONS: In order to conduct successful intervention programs that are culturally sensitive for rural inhabitants, it is necessary first, to have detailed information derived from research and second, the active participation of all human and institutional resources, from professionals and truly multi-disciplinary researchers, to educators, social, religious, political leaders, and members of the communities and local institutions. The proposed model of integration of personal and community resources for healthcare requires establishing programs that sensitize, inform, and train community members, as well as members the ethno-medical system and the formal heath system.

Adult↗
PubMed2005

A study of kinetic modelling and reaction pathway of 2,4-dichlorophenol transformation by photo-fenton-like oxidation.

The degradation of 2,4-dichlorophenol (2,4-DCP) by the photo-Fenton-like (Fe3+/H2O2/UVC) process under various reaction conditions was investigated. It was interesting to find that the reaction kinetics of 2,4-DCP in Fe3+/H2O2/UVC systems varied depending on the initial [Fe3+] concentration. A pseudo first-order kinetic and a non-conventional kinetic were discovered at low and higher [Fe3+] concentrations, respectively. A model was used to simulate the non-conventional kinetic process, where two character parameters (the initial decay rate and the final decay fraction) were found to be critical in determining the process. The two parameters successfully quantify the photo-Fenton-like oxidation under different concentrations of [Fe3+] and [H2O2] and the corresponding ratios of Fe(III)/H2O2. The reaction intermediates were identified by an LC/MS analysis and a reaction mechanism was proposed.

Chlorophenols↗
PubMed2000

Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis.

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of beta-catenin. Whereas several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPARdelta), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that cotransfection of a constitutively active beta-catenin expression construct causes a threefold increase in gastrin promoter activity. APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number. Gastrin-deficient APC(min-/+) mice, conversely, showed a marked decrease in polyp number and a significantly decreased polyp proliferation rate. Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression. The identification of gastrin as a functionally relevant downstream target of the beta-catenin signaling pathway provides a new target for therapeutic modalities in the treatment of colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed2004

Effects of triflusal on oxidative stress, prostaglandin production and nitric oxide pathway in a model of anoxia-reoxygenation in rat brain slices.

Acetylsalicylic acid (ASA) is the most widely used drug in the prevention of ischemic vascular accidents, mainly because of its antithrombotic effect. Recently, evidence of a neuroprotective effect has appeared. The aim of this study was to evaluate the neuroprotective effect of triflusal, a fluorinated derivative of ASA, in a model of anoxia-reoxygenation in rat brain slices. Rats (n=10 per group) were treated for 7 days with 1, 10 or 50 mg/kg/day p.o. of triflusal or ASA or solvent (control group), then brain slices were obtained and subjected to a period of anoxia followed by 180 min of reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and cell death (lactate dehydrogenase (LDH) efflux). Triflusal decreased cell death in rat brain slices subjected to reoxygenation after anoxia by 21%, 42% and 47% with 1, 10 and 50 mg/kg/day, respectively. This effect was proportionately greater than the effect of ASA (0%, 25% and 24%). The antioxidant effects of triflusal on the biochemical mechanisms of cell damage studied here were also greater than the effects of ASA: lipid peroxidation was reduced by 29%, 35% and 36% with triflusal, and 0%, 19% and 29% with ASA. Inducible NO synthase activity was reduced by 25%, 27% and 30% with triflusal, and 0%, 25% and 24% with ASA. Triflusal can be considered an alternative to ASA as a neuroprotective agent, at least in the experimental model of anoxia-reoxygenation used in the present study.

Analysis of Variance↗
PubMed1998

A retroductive theoretical model of the pathway to chemical dependency in nurses.

Much of the research on chemical dependency in nurses over the past 25 years has been a-theoretical and has tended to focus on descriptive characteristics of nurses. This field of study lacks systematic knowledge building and a useful theoretical base. This article focuses on the development of a middle range theory that begins to explicate the transactions of the chemically dependent nurse with the environment and the process through which nurses become addicted. Steiner's theory models approach using retroductive inference was the method selected to develop the theory. Theoretical work from Bandura, Jessor, and Pender were used as source theories to develop the middle range theory presented.

Female↗
PubMed1989

Cybernetic model of psychophysiological pathways: I. Control functions.

Electrophysiological events carry information, but the signals are not specific for a given bit of information. Therefore, the nervous system is required to extract the information from a multitude of signals. The process of information recognition is achieved by a superization process, i.e., by means of transition from many lower-order signals to a superior-order signal. In this way, a gradual recognition of the respective signal's emitting sources is realized. The recognition is performed with the aid of certain logical circuits representing models of different sources written in the structure of the neuronal network. In this manner, the nervous system passes step by step from control by means of signals to control by means of information. The superior structures can thereby exert much more subtle control and supervise the inferior structures that work by signals. However, because this control cannot refine all the general information of the inferior structures, psychophysiological dysfunction may occur. The nature of the superization process from signals to information is examined in this paper.

Cybernetics↗
PubMed2006

Spectrin functions upstream of ankyrin in a spectrin cytoskeleton assembly pathway.

Prevailing models place spectrin downstream of ankyrin in a pathway of assembly and function in polarized cells. We used a transgene rescue strategy in Drosophila melanogaster to test contributions of four specific functional sites in beta spectrin to its assembly and function. (1) Removal of the pleckstrin homology domain blocked polarized spectrin assembly in midgut epithelial cells and was usually lethal. (2) A point mutation in the tetramer formation site, modeled after a hereditary elliptocytosis mutation in human erythrocyte spectrin, had no detectable effect on function. (3) Replacement of repetitive segments 4-11 of beta spectrin with repeats 2-9 of alpha spectrin abolished function but did not prevent polarized assembly. (4) Removal of the putative ankyrin-binding site had an unexpectedly mild phenotype with no detectable effect on spectrin targeting to the plasma membrane. The results suggest an alternate pathway in which spectrin directs ankyrin assembly and in which some important functions of spectrin are independent of ankyrin.

Animals↗
PubMed2002

Heterotrimeric G-proteins activate Cl- channels through stimulation of a cyclooxygenase-dependent pathway in a model liver cell line.

Circulating hormones produce rapid changes in the Cl(-) permeability of liver cells through activation of plasma membrane receptors coupled to heterotrimeric G-proteins. The resulting effects on intracellular pH, membrane potential, and Cl(-) content are important contributors to the overall metabolic response. Consequently, the purpose of these studies was to evaluate the mechanisms responsible for G-protein-mediated changes in membrane Cl(-) permeability using HTC hepatoma cells as a model. Using patch clamp techniques, intracellular dialysis with 0.3 mm guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) increased membrane conductance from 10 to 260 picosiemens/picofarads due to activation of Ca(2+)-dependent Cl(-) currents that were outwardly rectifying and exhibited slow activation at depolarizing potentials. These effects were mimicked by intracellular AlF(4)(-) (0.03 mm) and inhibited by pertussis toxin (PTX), consistent with current activation through Galpha(i). Studies using defined agonists and inhibitors indicate that Cl(-) channel activation by GTPgammaS occurs through an indomethacin-sensitive pathway involving sequential activation of phospholipase C, mobilization of Ca(2+) from inositol 1,4,5-trisphosphate-sensitive stores, and stimulation of phospholipase A(2) and cyclooxygenase (COX). Accordingly, the conductance responses to GTPgammaS or to intracellular Ca(2+) were inhibited by COX inhibitors. These results indicate that PTX-sensitive G-proteins regulate the Cl(-) permeability of HTC cells through Ca(2+)-dependent stimulation of COX activity. Thus, receptor-mediated activation of Galpha(i) may be essential for hormonal regulation of liver transport and metabolism through COX-dependent opening of a distinct population of plasma membrane Cl(-) channels.

Adenosine Triphosphate↗
PubMed1997

Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution.

Duplicated genes are an important source of new protein functions and novel developmental and physiological pathways. Whereas most models for fate of duplicated genes show that they tend to be rapidly lost, models for pathway evolution suggest that many duplicated genes rapidly acquire novel functions. Little empirical evidence is available, however, for the relative rates of gene loss vs. divergence to help resolve these contradictory expectations. Gene families resulting from genome duplications provide an opportunity to address this apparent contradiction. With genome duplication, the number of duplicated genes in a gene family is at most 2n, where n is the number of duplications. The size of each gene family, e.g., 1, 2, 3, ..., 2n, reflects the patterns of gene loss vs. functional divergence after duplication. We focused on gene families in humans and mice that arose from genome duplications in early vertebrate evolution and we analyzed the frequency distribution of gene family size, i.e., the number of families with two, three or four members. All the models that we evaluated showed that duplicated genes are almost as likely to acquire a new and essential function as to be lost through acquisition of mutations that compromise protein function. An explanation for the unexpectedly high rate of functional divergence is that duplication allows genes to accumulate more neutral than disadvantageous mutations, thereby providing more opportunities to acquire diversified functions and pathways.

Animals↗
PubMed2000

Combined immunodeficiencies due to defects in signal transduction: defects of the gammac-JAK3 signaling pathway as a model.

Combined immune deficiencies comprise a spectrum of genetic disorders characterized by developmental or functional defects of both T and B lymphocytes. Recent progress in cell biology and molecular genetics has unraveled the pathophysiology of most of these defects. In particular, the most common form of severe combined immune deficiency in humans, with lack of circulating T cells, a normal or increased number of B lymphocytes, and an X-linked pattern of inheritance (SCIDXI) has been shown to be due to defects of the IL2RG gene, encoding for the common gamma chain (gammac), shared by several cytokine receptors. Furthermore, defects of the JAK3 gene, encoding for an intracellular tyrosine kinase required for signal transduction through gammac-containing cytokine receptors, have been identified in patients with autosomal recessive T-B+ SCID. Characterization of the functional properties of cytokines that signal through the gammac-JAK3 signaling pathway has been favored by the detailed analysis of SCID patients. Specifically, the key role of IL-7 in promoting T cell development has been substantiated by the identification of rare patients with T-B+ SCID who have a defect in the alpha subunit of the IL-7 receptor (IL7Ralpha). The heterogeneity of genetic defects along the same signaling pathway that may lead to combined immune deficiency is paralleled by the heterogeneity of immunological phenotypes that may associate with defects in the same gene, thus creating a need for detailed immunological and molecular investigations in order to dissect the spectrum of combined immune deficiencies in humans.

Animals↗
PubMed1998

Transition state in the folding of alpha-lactalbumin probed by the 6-120 disulfide bond.

The guanidine hydrochloride concentration dependence of the folding and unfolding rate constants of a derivative of alpha-lactalbumin, in which the 6-120 disulfide bond is selectively reduced and S-carboxymethylated, was measured and compared with that of disulfide-intact alpha-lactalbumin. The concentration dependence of the folding and unfolding rate constants was analyzed on the basis of the two alternative models, the intermediate-controlled folding model and the multiple-pathway folding model, that we had proposed previously. All of the data supported the multiple-pathway folding model. Therefore, the molten globule state that accumulates at an early stage of folding of alpha-lactalbumin is not an obligatory intermediate. The cleavage of the 6-120 disulfide bond resulted in acceleration of unfolding without changing the refolding rate, indicating that the loop closed by the 6-120 disulfide bond is unfolded in the transition state. It is theoretically shown that the chain entropy gain on removing the cross-link from a random coil chain with helical stretches can be comparable to that from an entirely random chain. Therefore, the present result is not inconsistent with the known structure in the molten globule intermediate. Based on this result and other knowledge obtained so far, the structure in the transition state of the folding reaction of alpha-lactalbumin is discussed.

Animals↗
PubMed2004

Hydrolysis of alpha- and beta-glycosides. New experimental data and modeling of reaction pathways.

[reaction: see text] The cyclization of oxocarbenium ion conformers 6alpha and 6beta (from 11E and 11Z) gave only the beta-glycoside 1beta, and the addition of methanol to the oxocarbenium ion 3 yielded mainly the alpha-glycoside 1alpha with both experiments being carried out under kinetically controlled conditions. RHF/6.31G calculations reproduce well these experimental results and show that the endocyclic and the exocyclic C-O bond cleavage processes can compete in the hydrolysis of 1beta, whereas 1alpha gets hydrolyzed by exocyclic C-O bond cleavage only.

Catalysis↗
PubMed2004

Scientiae forum / models and speculations pathways for axonal targeting of membrane proteins.

The distribution of proteins to the correct domains of neurons is crucial for neuronal functioning. Here I discuss possible mechanisms underlying sorting to the axonal plasma membrane which differ with respect to the steps providing selectivity for axonal vs. somatodendritic cargo. Selectivity can be executed at one or more than one step, including sorting into distinct carriers in the Golgi, preferential transport along axonal microtubules, fusion with the plasma membrane, and importantly retrieval by endocytosis. A protein might in fact be sorted multiple times at different places to achieve axonal localization.

Animals↗
PubMed2000

Induction of isoflavonoid pathway in the model legume Lotus japonicus: molecular characterization of enzymes involved in phytoalexin biosynthesis.

Treatment of the seedlings of Lotus japonicus, a model legume for molecular genetic studies, with reduced glutathione (GSH) resulted in the accumulation of an isoflavan phytoalexin, vestitol. Using PCR strategies based on the conserved amino acid sequences, full length P450 cDNAs were obtained from GSH-treated seedling roots. When the clones, LjCYP-1 (CYP93C family) and LjCYP-2 (CYP81E family), were heterologously expressed in yeast, the proteins exhibited 2-hydroxyisoflavanone synthase (IFS) and isoflavone 2'-hydroxylase (I2'H) activities, respectively. The transcription levels of LjCYP-1, LjCYP-2 and isoflavone reductase, which are all involved in vestitol biosynthesis, coordinately increased upon elicitation. Genomic Southern blot analysis indicated that the IFS gene forms a small gene family and a single copy of the I2'H gene is present in the L. japonicus genome. Molecular biological aspects of P450s involved in the isoflavonoid pathway and the genomic approach to flavonoid metabolism in this unique plant are discussed.

Journal Article↗
PubMed2005

Glucocorticoids differentially regulate expression of duodenal and renal calbindin-D9k through glucocorticoid receptor-mediated pathway in mouse model.

Dexamethasone (Dex) is a member of the glucocorticoids (GCs), and is broadly used as an anti-inflammatory medication. Continuous administration with GCs induces adverse effects and suffering in humans (i.e., osteoporosis) due to negative calcium balance derived from low re- and absorption in the duodenum and kidney. A cytosolic calcium-binding protein, calbindin-D9k (CaBP-9k), is dominantly expressed in the renal and intestinal tissues involved in calcium re- and absorption and plays an active role in calcium transport. In the present study, we employed adrenalectomized (ADX) and sham-treated (Sham) male mice to examine the effect of Dex on CaBP-9k gene expression in the duodenum and kidney. Dex significantly reduced the levels of duodenal CaBP-9k mRNA and protein, and it restored ADX-induced decrease in renal CaBP-9k protein compared with the level of Sham control. Dex treatment increased calcium and phosphate levels in the sera of both Sham and ADX mice. In a time course experiment, Dex significantly decreased duodenal CaBP-9k at the transcriptional and translational levels at 3 days, whereas it temporarily increased CaBP-9k mRNA and protein levels at 12 and 24 h. Altered CaBP-9k expression by Dex was completely reversed by mifepristone, an antagonist for the GC receptor (GR). In addition, duodenal CaBP-9k and GR were colocalized on the enterocyte (duodenocyte), supporting a role for GR in regulating CaBP-9k. In ovariectomized (OVX) and ADX female mice daily treated with Dex for 3 days, duodenal CaBP-9k was expressed at the same level as in male mice. Also, no cross-activity of progesterone and Dex on their receptors was observed. Taken together, these results indicate that mouse CaBP-9k gene may be regulated by Dex in a tissue-specific manner, and reduced duodenal CaBP-9k via the GR pathway may take part in negative calcium absorption of GC-induced osteoporosis, whereas renal CaBP-9k may not be involved in the regulation of calcium homeostasis.

Animals↗
PubMed2006

Socio-economic pathways to diet: modelling the association between socio-economic position and food purchasing behaviour.

OBJECTIVES: To examine the association between education level and food purchasing behaviour and the contribution of dietary knowledge to this relationship; and the association between household income and purchasing behaviour and the contribution made by subjective perceptions about the cost of healthy food. DESIGN AND SETTING: The study was conducted in Brisbane City (Australia) in 2000. The sample was selected using a stratified two-stage cluster design. Data were collected by face-to-face interview from residents of private dwellings (n=1003), and the response rate was 66.4%. Dietary knowledge was measured using a 20-item index that assessed general knowledge about food, nutrition, health and their interrelationships. Food-cost concern was measured using a three-item scale derived from principal components analysis (alpha=0.647). Food purchasing was measured using a 16-item index that reflected a household's purchase of grocery items that were consistent (or otherwise) with dietary guideline recommendations. Associations among the variables were analysed using linear regression with adjustment for age and sex. RESULTS: Significant associations were found between education, household income and food purchasing behaviour. Food shoppers with low levels of education, and those residing in low-income households, were least likely to purchase foods that were comparatively high in fibre and low in fat, salt and sugar. Socio-economic differences in dietary knowledge represented part of the pathway through which educational attainment exerts an influence on diet; and food purchasing differences by household income were related to diet in part via food-cost concern. CONCLUSIONS: Our findings suggest that socio-economic differences in food purchasing behaviour may contribute to the relationship between socio-economic position and food and nutrient intakes, and, by extension, to socio-economic health inequalities for diet-related disease. Further, socio-economic differences in dietary knowledge and concerns about the cost of healthy food play an important role in these relationships and hence should form the focus of future health promotion efforts directed at reducing health inequalities and encouraging the general population to improve their diets.

Adult↗