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PubMedDate not supplied

Excess haemoglobin digestion by malaria parasites: a strategy to prevent premature host cell lysis.

To understand the osmotic stability of a Plasmodium falciparum-infected red blood cell, whose membrane permeability becomes highly increased during parasite growth, we developed an integrated mathematical model of the homeostasis of an infected red cell. The model encoded the known time courses of red cell membrane permeabilisation and of haemoglobin digestion, as well as alternative options for parasite volume growth. Model simulations revealed that excess haemoglobin digestion, by reducing the colloid-osmotic pressure within the host red cell, is essential to preserve the osmotic stability of the infected cell for the duration of the parasite asexual cycle. We present here experimental tests of the model predictions and discuss the available evidence in the context of the interpretations provided by the model.

Animals↗

PubMed2004

In silico prediction of central nervous system activity of compounds. Identification of potential pharmacophores by the TOPS-MODE approach.

The central nervous system (CNS) activity has been investigated by using a topological substructural molecular approach (TOPS-MODE). A discriminant analysis to classify CNS and non-CNS drugs was developed on a data set (302 compounds) of great structural variability where more than 81% (247/302) were well classified. Randic's orthogonalization procedures was carried out to allow the interpretation of the model and to avoid the collinearity among descriptors. The discriminant model was assessed by a leave-n-out (when n varies from 2 to 20) cross-validation procedure (79.94% of correct classification), an external prediction set composed by 78 CNS/non-CNS drugs (80.77% of correct classification) and a 5-fold full cross-validation (removing 78 compounds in each cycle, 80.00% of good classification). With this methodology was demonstrated that the hydrophobicity increase the CNS activity, while the dipole moment and the polar surface area decrease it; evidencing the capacity of the TOPS-MODE descriptors to estimate CNS activity for new drug candidates. The structural contributions to the CNS activity for two compounds are presented on the basis of fragment contributions. The model has also been able to identify potential structural pharmacophore, showing its possibilities in the lead generation and optimization processes.

Central Nervous System↗

PubMed2006

Epidemiology: a foundation for dairy production medicine.

Epidemiology in dairy production medicine strives to optimize production through the elimination and control of disease and the implementation of management practices that promote animal health, welfare, productivity, and profitability. Epidemiology in dairy production medicine is a broad discipline that encompasses many inter-related areas of activity. Quantitative epidemiology includes a range of activities, from counting clinical cases to the development of complex hierarchic decision models. Evaluation and interpretation of "tests" applied at various levels of the health management cycle serve as the basis for diagnostic and monitoring systems. Critical evaluation of the published scientific literature in the practice of evidence-based veterinary medicine facilitates the appropriate use of knowledge in support of health management decisions.

Animal Welfare↗

PubMed2004

Brca1 expression is regulated by a bidirectional promoter that is shared by the Nbr1 gene in mouse.

The lack of functionally disrupting mutations of BRCA1 in sporadic breast tumours has suggested that other mechanisms, including dysregulation of gene expression, might be important in tumour development. We have analysed the control of expression of murine Brca1 and the adjacent gene, Nbr1, which lie head-to-head and are separated by less than 300 bp. Our results show that the expression of these two genes is under complex regulation, through a bidirectional promoter. Brca1 expression is driven by this single promoter, whereas Nbr1 expression is driven by this and one additional promoter, which generate two distinct transcripts, differing by the alternate use of the first exons. By comparison of mRNA transcription in adult murine tissues and also in the mammary gland during pregnancy and lactation, we show that Brca1 and Nbr1 expression is coordinately regulated in a spatial and temporal manner to produce quite different patterns of expression, even from the same promoter. The analysis of the murine and human syntenic region and its control has important implications for the regulation of human and murine BRCA1/NBR1 expression and the interpretation of animal models of disease.

3T3 Cells↗

PubMed2006

Uses and issues of biomonitoring.

In the last two decades, an explosion in information and literature on human biomonitoring data has occurred. Symposia, workshops, and workgroups have been formed to discuss all issues surrounding biomonitoring. One such workgroup, formed by the International Life Sciences Institute's Health and Environmental Sciences Institute (HESI), developed a wheel which has biomonitoring at its hub; its spokes depict the uses of biomonitoring. As it rolls and picks up speed, the biomonitoring wheel will no doubt gain additional spokes. In this manuscript, we describe and give examples of these biomonitoring uses and some of their further applications as well as some of the issues surrounding biomonitoring. Special emphasis is placed on the uses and limitations of large-scale representative cross sectional studies such as the National Health and Nutrition Examination Surveys in the United States. Priority setting, improved modeling methods for interpreting the biomonitoring data, and an increase in studies designed to associate health indicators and health risks to selected environmental chemicals are needed to increase the power of biomonitoring.

Biomarkers↗

PubMed2004

An assessment of relative transcriptional availability from nonviral vectors.

To design better delivery systems that enhance transfection efficiency of nonviral vectors, we need to improve our understanding of the mechanisms governing both the amounts of plasmid delivered to the nucleus and gene expression. What is needed is a measure of transcriptional availability (TA): the average level of gene expression per plasmid delivered to the nucleus over the course of an experiment. We describe a method to measure TA and demonstrate its application. The chloramphenicol acetyltransferase reporter gene was transfected into NIH/3T3 cells using either cationic liposomes (TFL-3; O,O'-ditetradecanoyl-N-(alpha-trimethylammonioacetyl) diethanolamine chloride (DC-6-14), dioleoylphosphatidylethanolamine (DOPE) and cholesterol, molar ratio 1/0.75/0.75) or cationic polymer (PEI; polyethylenimine). The time courses of both nuclear delivery of plasmids and reporter gene expression were measured for 4 h thereafter. For the conditions used, time courses of gene expression and plasmid nuclear delivery for the two vectors were different. To understand the origins of those differences, we applied a simple pharmacokinetic model, used the data to estimate the values of the model parameters, and interpret differences in estimated parameter values. The rate constant of delivery of plasmids into the nucleus for the TFL-3 vector was twice that of the PEI vector, whereas rate constant of elimination of plasmids in the nucleus for the PEI vector was four times that for the TFL-3 vector. The gene expression rate constant for the TFL-3 vector was estimated to be seven times larger than that of the PEI vector for the conditions used. The pharmacokinetically determined average exposure of a nucleus to plasmid was about 17 times larger for the TFL-3 vector, relative to the PEI vector. That greater exposure resulted in increased relative gene expression. Overall, the TA from the TFL-3 vector was about 13 times greater than from the PEI vector. The experimental design combined with the adoption of pharmacokinetic concepts and principles provide a method to measure TA along with detailed insights into the mechanisms governing gene delivery and expression.

Animals↗

PubMed2005

Evaluation of the reticulocyte micronucleus assay in patients treated with radioiodine for thyroid cancer.

In the case of accidental radiation exposure, biological dosimetry has an important role. Previous studies have indicated that the flow cytometric micronucleus (MN) assay in human transferrin receptor positive reticulocytes (Tf-Ret) in blood could be a sensitive biomarker for chromosome damage. In the present investigation, the utility and sensitivity of this method was studied in 44 young patients from Belarus, who were treated with 131I for thyroid cancer. Red marrow (RM) is the critical organ in radioiodine therapy (RIT). In our patients, it was exposed to 100-700 mSv low-dose rate irradiation within 2-4 days. About 3 days after 131I administration, the frequency of micronucleated-Tf-Ret (f(MN-Tf-Ret)) increases within 1 day to a maximum and declines in the following 2-5 days to its value before treatment. A total dose of 100 mSv was easily detectable. The sensitivity of the assay after acute irradiation may be 50 mSv. The method should be useful for monitoring individuals after a radiation accident, provided blood samples can be obtained within a few days after exposure. The time-course of f(MN-Tf-Ret) is interpreted using a model, which considers the exponential exposure of red marrow in RIT as well as the kinetics of erythroblast maturation and reticulocyte migration into the peripheral circulation. Similar modelling was done on published data of MN in immature mouse erythrocytes. Striking similarities in the kinetic and in the yield of MN-induction were found between these two species. This lends support for the use of the mouse as a model for the MN-induction in humans.

Adult↗

PubMed2005

Behavioural and physiological aspects of stress and aggression in nonhuman primates.

There is considerable interest in the study of stress and aggression in primates as a model for their interpretation in humans. Despite methodological and interpretational problems associated with behavioural and physiological measurement and definition, a considerable body of literature exists on these phenomena in primates. In the course of reviewing this literature we examine examples of many of the sources of variation in stress and aggression, including species identity, sex, age, breeding and social status, individual temperament, background, learning and resource distribution. This is followed by an examination of the interaction between stress and aggression before reviewing the most important areas in which changes in both stress and aggression are measured. In particular we examine those studies covering social aspects of an animal's life, specifically relating to social isolation, crowding as well as group formation, composition and instability. This review reveals the complex and often contradictory nature of relationships, not just between an animal's physiology and its behaviour, but between its stress status and display or receipt of aggression.

Aggression↗

PubMed2006

Application of a semi-dependent latent model in the Bayesian estimation of the sensitivity and specificity of two faecal culture methods for diagnosis of paratuberculosis in sub-clinically infected Greek dairy sheep and goats.

In this study, we compared the frequency of isolation of Mycobacterium avium subsp. paratuberculosis (MAP) from faecal samples grown on Herrold's egg-yolk medium (HEYM) or on Lowenstein-Jensen (LJ) medium and estimated the sensitivity (Se) and specificity (Sp) of the methods separately in sub-clinically infected Greek dairy sheep and goats, using latent-class models and Bayesian estimation procedures. Faecal and blood samples were collected from 400 animals > or =1 year old in April-May 2002. The HEYM supported growth of MAP better than the LJ method and their agreement was very poor (weighted kappa=0.062 (95% CI: -0.098, 0.222)). There was no evidence of dependence between the Ses whereas the Sps were positively correlated. Thus, a semi-dependent model that assumed independence of Ses and accounted for the dependence of Sps was adopted. Under this model, the parallel interpretation of the results of the two methods gave median estimates and 95% credible intervals (CrIs) for Se(par), Sp(par) of 15% (CrIs: 3, 45%), 96% (92, 98%) in sheep and 16% (6, 36%) and 97% (94, 99%) in goats.

Animals↗

PubMed2005

Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease.

Although hyperuricemia has long been associated with renal disease, uric acid has not been considered as a true mediator of progression of renal disease. The observation that hyperuricemia commonly is associated with other risk factors of cardiovascular and renal disease, especially hypertension, has made it difficult to dissect the effect of uric acid itself. However, recent epidemiologic evidence suggests a significant and independent association between the level of serum uric acid and renal disease progression with beneficial effect of decreasing uric acid levels. Furthermore, our experimental data using hyperuricemic animals and cultured cells have provided robust evidence regarding the role of uric acid on progression of renal disease. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Although we must be cautious in the interpretation of animal models to human disease, these studies provide a mechanism to explain epidemiologic data that show uric acid is an independent risk factor for renal progression. Although there is no concrete evidence yet that uric acid bears a causal or reversible relationship to progressive renal disease in humans, it is time to reevaluate the implication of hyperuricemia as an important player for progression of renal disease and to try to find safe and reasonable therapeutic modalities in individual patients based on their clinical data, medication history, and the presence of cardiovascular complications.

Animals↗

PubMed2005

Multi-level modelling in health research: a caution and rejoinder on temporally mismatched data.

In a review of the multilevel modelling literature (MLM) we find that data on individuals and their social environment contexts (neighbourhoods, municipalities) are often drawn from different years/time periods. This temporal mismatch has scarcely attracted any attention though it can significantly influence modelling results and interpretation. We demonstrate the influence of temporal mismatch first by outlining the degree of neighbourhood mobility in large metropolitan areas in Britain, Canada and the United States and second with a brief MLM example. We conclude that researchers ought to provide more study context when such mismatch is unavoidable.

Bias↗

PubMed2005

The NADPH oxidase inhibitor apocynin (acetovanillone) induces oxidative stress.

Apocynin (acetovanillone) is often used as a specific inhibitor of NADPH oxidase. In N11 glial cells, apocynin induced, in a dose-dependent way, a significant increase of both malonyldialdehyde level (index of lipid peroxidation) and lactate dehydrogenase release (index of a cytotoxic effect). Apocynin evoked also, in a significant way, an increase of H(2)O(2) concentration and a decrease of the intracellular glutathione/glutathione disulfide ratio, accompanied by augmented efflux of glutathione and glutathione disulfide. Apocynin induced the activation of both pentose phosphate pathway and tricarboxylic acid cycle, which was blocked when the cells were incubated with glutathione together with apocynin. The cell incubation with glutathione prevented also the apocynin-induced increase of malonyldialdehyde generation and lactate dehydrogenase leakage. Apocynin exerted an oxidant effect also in a cell-free system: indeed, in aqueous solution, it evoked a faster oxidation of the thiols glutathione and dithiothreitol, and elicited the generation of reactive oxygen species, mainly superoxide anions. Our results suggest that apocynin per se can induce an oxidative stress and exert a cytotoxic effect in N11 cells and other cell types, and that some effects of apocynin in in vitro and in vivo experimental models should be interpreted with caution.

Acetophenones↗

PubMed2004

Modulated angle beam ultrasonic spectroscopy for evaluation of imperfect interfaces and adhesive bonds.

An experimental method incorporating high frequency pulsed angle beam ultrasonic measurements modulated by low frequency vibrations of a bonded structure is described. This method uses parametric/nonlinear mixing between high and low frequencies to characterize adhesive degradation. It is demonstrated that good quality (undamaged) bonds exhibit little dependence of ultrasonic signature on the overlay of low frequency vibration loads; however, environmentally degraded or imperfect bonds exhibit strong modulation of the resonance frequency of the ultrasonic signal reflected from the bond. The results are interpreted using a model for normal and oblique wave interaction with two nonlinear interfaces separated by an adhesive layer under quasi-static stress modulation.

Journal Article↗

PubMed2004

alpha-Synuclein A53T substitution associated with Parkinson disease also marks the divergence of Old World and New World primates.

The alpha-synuclein mutation Ala53Thr is associated with increased oligomerization, toxicity, and early onset Parkinson disease in humans, but 53Thr is the normal residue in other species. Comparative sequencing of SNCA genes shows that 53Ala marks the divergence of Old World and New World primates, in an otherwise constrained protein region. These results have implications for interpreting Parkinson disease models and suggest that other long-lived mammals have different mechanisms to forestall alpha-synucleinopathy.

Alleles↗

PubMed1999

Prolonged exposure to glare and driving time: effects on performance in a driving simulator.

Twelve experienced truck drivers drove a fixed-base driving simulator for two 8 h sessions, including: (1) no glare and (2) intermittent glare presented in the exterior rear-view mirrors to simulate headlights from following vehicles. The driving task combined vehicle control on straight and curved road segments with detection of pedestrians appearing alongside the road and targets appearing in the rear-view mirrors. The results provided no evidence to support the hypothesis that prolonged exposure to glare impairs driving performance. However, we found time-related changes in target-detection and critical tracking performance, some of which were consistent with established patterns of diurnal variation. Subjective sleepiness ratings also increased over time. The results were interpreted within a model according to which drivers are able to maintain effective performance at early levels of impairment, thus compensating for increasing feelings of subjective tiredness.

Adult↗

PubMed2000

Molecular contacts in the transmembrane c-subunit oligomer of F-ATPases identified by tryptophan substitution mutagenesis.

When isolated in its monomeric form, subunit c of the proton transporting ATP synthase of Escherichia coli was shown to fold in a hairpin-like structure consisting of two hydrophobic membrane spanning helices and a short connecting hydrophilic loop. In the plasma membrane of Escherichia coli, however, about 9-12 c-subunit monomers form an oligomeric complex that functions in transmembrane proton conduction and in energy transduction to the catalytic F1 domain. The arrangement of the monomers and the molecular architecture of the complex were studied by tryptophan scanning mutagenesis and restrained MD simulations. Residues 12-24 of the N-terminal transmembrane segment of subunit c were individually substituted by the large and moderately hydrophobic tryptophan side chain. Effects on the activity of the mutant proteins were studied in selective growth experiments and various ATP synthase specific activity assays. The results identify potential intersubunit contacts and structurally non-distorted, accessible residues in the c-oligomer and add constraints to the arrangement of monomers in the oligomeric complex. Results from our mutagenesis experiments were interpreted in structural models of the c-oligomer that have been obtained by restrained MD simulations. Different stoichiometries and monomer orientations were applied in these calculations. A cylindrical complex consisting of 10 monomers that are arranged in two concentric rings with the N-terminal helices of the monomers located at the periphery shows the best match with the experimental data.

Adenosine Triphosphate↗

PubMed1997

The involvement of the two acidic patches of spinach plastocyanin in the reaction with photosystem I.

Six different spinach plastocyanin mutants have been constructed by site-directed mutagenesis and expressed in Escherichia coli to probe the importance of the two acidic patches in the interaction with photosystem I. The mutants were: Asp42Lys, Glu43Asn, Glu43Lys, Glu43Gln/Asp44Asn, Glu59Lys/Glu60Gln and Glu43Asn/Glu59Lys/Glu60Gln and they have been characterised by optical absorption and EPR spectroscopy, redox titrations and isoelectric focusing. The electron transfer to photosystem I was investigated by flash-induced time-resolved absorption measurements at 830 nm. The kinetics were interpreted with a model that incorporates a rate-limiting conformational change from inactive to active forms of the plastocyanin-photosystem I complex. All mutations resulted in a displacement of the equilibrium towards the inactive conformation. The strongest impairment of the electron transfer was found for mutations in the larger acidic patch, in particular upon modification of residues 43 or 44. However, mutations of residues 59 and 60 in the smaller acidic patch also resulted in a lower reactivity.

Electron Transport↗

PubMed2000

Differential limbic--cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders.

BACKGROUND: Affective disorders are associated with comorbidity of depression and anxiety symptoms. Positron emission tomography resting-state studies in affective disorders have generally failed to isolate specific symptom effects. Emotion provocation studies in healthy volunteers have produced variable results, due to differences in experimental paradigm and instructions. METHODS: To better delineate the neural correlates of sad mood and anxiety, this study used autobiographical memory scripts in eight healthy women to generate sadness, anxiety, or a neutral relaxed state in a within-subject design. RESULTS: Sadness and anxiety, when contrasted to a neutral emotional state, engaged a set of distinct paralimbic-cortical regions, with a limited number of common effects. Sadness was accompanied by specific activations of the subgenual cingulate area (BA) 25 and dorsal insula, specific deactivation of the right prefrontal cortex BA 9, and more prominent deactivation of the posterior parietal cortex BAs 40/7. Anxiety was associated with specific activations of the ventral insula, the orbitofrontal and anterior temporal cortices, specific deactivation of parahippocampal gyri, and more prominent deactivation of the inferior temporal cortex BAs 20/37. CONCLUSIONS: These findings are interpreted within a model in which sadness and anxiety are represented by segregated corticolimbic pathways, where a major role is played by selective dorsal cortical deactivations during sadness, and ventral cortical deactivations in anxiety.

Adult↗