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Modeling Reviews: 2003
(29 References)
Andersen, M. E. (2003). "Toxicokinetic modeling and its applications in chemical risk assessment." Toxicol Lett 138(1-2): 9-27.
In recent years physiologically based pharmacokinetic (PBPK) modeling has found frequent application in risk assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. In this regard, studies on mode of action provide insight into both the sites/mechanisms of action and the form of the xenobiotic associated with toxic responses. Validated PBPK models permit calculation of tissue doses of xenobiotics and metabolites for a variety of conditions, i.e. at low-doses, in different animal species, and in different members of a human population. In this manner, these PBPK models support the low-dose and interspecies extrapolations that are important components of current risk assessment methodologies. PBPK models are sometimes referred to as physiological toxicokinetic (PT) models to emphasize their application with compounds causing toxic responses. Pharmacokinetic (PK) modeling in general has a rich history. Data-based PK compartmental models were developed in the 1930's when only primitive tools were available for solving sets of differential equations. These models were expanded in the 1960's and 1970's to accommodate new observations on dose-dependent elimination and flow-limited metabolism. The application of clearance concepts brought many new insights about the disposition of drugs in the body. In the 1970's PBPK/PT models were developed to evaluate metabolism of volatile compounds of occupational importance, and, for the first time, dose-dependent processes in toxicology were included in PBPK models in order to assess the conditions under which saturation of metabolic and elimination processes lead to non-linear dose response relationships. In the 1980's insights from chemical engineers and occupational toxicology were combined to develop PBPK/PT models to support risk assessment with methylene chloride and other solvents. The 1990's witnessed explosive growth in risk assessment applications of PBPK/PT models and in applying sensitivity and variability methods to evaluate model performance. Some of the compounds examined in detail include butadiene, styrene, glycol ethers, dioxins and organic esters/aids. This paper outlines the history of PBPK/PT modeling, emphasizes more recent applications of PBPK/TK models in health risk assessment, and discusses the risk assessment perspective provided by modern uses of these modeling approaches.
Archer, E., B. Maigret, et al. (2003). "Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors?" Trends Pharmacol Sci 24(1): 36-40.
Molecular modelling is of major help to understand structure-function data on G-protein-coupled receptors (GPCRs). Since the first determination of the structure of rhodopsin, at high resolution, the view has emerged that it will be now easy to automatically obtain realistic models for any GPCR by homology modeling. Our experience on cholecystokinin CCK(1) receptor modelling together with available data on other GPCRs leads us to rule out this opinion. We believe that construction of realistic models of certain GPCRs still remains time-consuming and requires many refinements of the models in close association with experiments. This conclusion has important consequences for modelling orphan GPCRs.
Bhalla, U. S. (2003). "Understanding complex signaling networks through models and metaphors." Prog Biophys Mol Biol 81(1): 45-65.
Signaling networks are complex both in terms of the chemical and biophysical events that underlie them, and in the sheer number of interactions. Computer models are powerful tools to deal with both aspects of complexity, but their utility goes beyond simply replicating signaling events in silicon. Their great advantage is as a tool to understanding. The completeness of the description demanded by computer models highlights gaps in knowledge. The quantitative description in models facilitates a mapping between different kinds of analysis methods for complex systems. Systems analysis methods can highlight stable states of signaling networks and describe the transitions between them. Modeling also reveals functional similarities between signaling network properties and other well-understood systems such as electronic devices and neural networks. These suggest various metaphors as a tool to understanding. Based on such descriptions, it is possible to regard signaling networks as systems that decode complex inputs in time, space and chemistry into combinatorial output patterns of signaling activity. This would provide a natural interface to the combinatorial input patterns required by genetic circuits. Thus, a combination of computer modeling methods to capture the complexity and details, and useful abstractions revealed by these models, is necessary to achieve both rigorous description as well as human understanding.
Bogdanffy, M. S. and R. Sarangapani (2003). "Physiologically-based kinetic modeling of vapours toxic to the respiratory tract." Toxicol Lett 138(1-2): 103-17.
The respiratory tract is frequently identified as a site of toxicity for inhaled xenobiotic chemicals. Usually, these observations come from controlled animal studies. For these studies to be of quantitative value to human health risk assessment, species-specific factors governing dosimetry of inhaled substances must be taken into account. Toxicokinetics of vapours in the respiratory tract are defined by absorption, distribution, metabolism, and excretion, as they are in other tissues; however, these concepts take on new dimensions when considering respiratory tract toxicants, especially those that elicit portal of entry effects by directly interacting with the tissue lining the respiratory tract. Species-specific factors related to anatomy, physiology and biochemistry govern inter-species extrapolation of toxicokinetics. This article discusses critical factors of respiratory tract kinetics that should be considered when developing physiological-based toxicokinetic (PBTK) models for inhaled vapours. Important considerations such as impact of regional airflow-delivery, water solubility, reactivity, and rates of local biotransformation on respiratory tract tissue dosimetry are highlighted. These factors can be accounted for only to a limited extent when using default approaches to extrapolate dosimetry of inhaled substances across species. On the other hand, PBTK modeling has the flexibility to accommodate many of the critical determinants of respiratory tract toxicity. PBTK models can also help identify the most critical toxicokinetic data necessary to replace defaults. PBTK approaches have led to more informed estimates of human target tissue dose, and therefore human health risk, especially where these risk assessments have been based on extrapolation of animal dosimetry studies. Experience derived from the development of more intensive case studies have, in turn, enabled simplified approaches to the use of PBTK modeling for respiratory tract toxicants. Whether simplified or highly complex, PBTK modeling approaches are proven to be of great utility to risk assesors interested in applying quantitative information to informed risk assessment evaluations.
Colombo, P., A. Bonura, et al. (2003). "The allergens of Parietaria." Int Arch Allergy Immunol 130(3): 173-9.
Parietaria is a genus of dicotyledonous weeds of the Urticaceae family including several species and its pollen grain is one of the most important allergenic sources in the Mediterranean area. Species belonging to this genus induce IgE responses in approximately 10 million people. Identification of allergens by means of independent strategies suggest that the allergens of the two more common species, Parietaria judaica and Parietaria Officinalis, show molecular weights ranging between 10 and 14 kD and that the allergens of the two extracts are highly cross-reactive. Biochemical analysis and molecular cloning allowed the isolation and immunological characterization of the two major allergens of the P. judaica pollen, Par j 1 and Par j 2. Sequence comparison suggests that the P j major allergens of P. Judaica belong to the nonspecific lipid transfer protein family, and three-dimensional modeling by homology has revealed that both proteins present a very conserved structural motif composed of four alpha-helices. Immunological analysis has shown that Par j 1 and Par j 2 are able to bind most of the P. Judaica-specific IgE and some of their IgE determinants have been mapped. Recombinant Par j 1 and Par j 2 allergens have been shown to possess immunological properties equivalent to their natural counterpart and their availability represents a fundamental tool for the diagnosis and therapy of Parietaria pollen allergy.
Colonna, M. (2003). "DAP12 signaling: from immune cells to bone modeling and brain myelination." J Clin Invest 111(3): 313-4.
Coughlin, M. T. and D. C. Angus (2003). "Economic evaluation of new therapies in critical illness." Crit Care Med 31(1 Suppl): S7-16.
The recent Food and Drug Administration approval of drotrecogin alfa (activated) and the potential of several other new therapies may represent the beginning of a breakthrough in the management of critical illness in the intensive care unit. However, their use in clinical practice will likely be dependent on a rigorous appraisal not only of their effects, but also of their costs. Novel therapies can no longer be judged simply by their effectiveness in treating illness, but must also be evaluated on an institutional and societal level on the basis of their cost. These considerations have important implications for the practicing intensivist, who will need to better understand the conduct and design of economic evaluations, including their strengths and weaknesses. In this article, we review the rationale behind economic evaluations of new therapies and the alternative economic approaches available. We then discuss in more detail the elements contained in a cost-effectiveness analysis, the preferred approach to pharmacoeconomic evaluation today.
Dubnau, J., A. S. Chiang, et al. (2003). "Neural substrates of memory: from synapse to system." J Neurobiol 54(1): 238-53.
One of the fundamental challenges of modern neuroscience is to understand how memories are acquired, stored, and retrieved by the brain. In the broadest terms, attempts to dissect memory can be broken down into four experimental disciplines: (1) identification of molecular components, (2) ex vivo and in vivo cellular analysis of neuronal function, (3) theoretical modeling approaches of neural systems, and (4) organismal-level behavioral analyses. Our objective here is to offer a conceptually unifying perspective and to discuss this perspective in relation to an experiment analysis of memory in Drosophila.
Dwyer, J., M. F. Picciano, et al. (2003). "Estimation of usual intakes: What We Eat in America-NHANES." J Nutr 133(2): 609S-23S.
Usual intakes of nutrients are reliable indicators for making associations between diet and health or disease risks. Estimates of consumption of specific foods and food groups are also important for evaluating the progress in meeting key objectives in such national public health initiatives as Healthy People 2010. Reliable and valid estimates of intakes of particular foods, food ingredients, dietary supplements and other bioactive substances are also needed for dietary assessment and regulatory purposes. The ability to generate useful estimates of these constituents often requires much larger sample sizes than are needed for estimating nutrient intakes. Statistical methods recommended by the National Academy of Sciences are described that provide estimates of distributions of usual nutrient intakes and permit dietary assessment and planning at the population level. Statistical and modeling approaches for estimating intakes of foods, dietary supplements and other bioactive substances are also summarized. Based on the deliberations of discussion groups consisting of members of key stakeholder groups involved in the planning, implementation and utilization of national survey data, a high priority was placed on the need for more research to determine the best approaches for applying these methods to dietary data in the integrated What We Eat in America-National Health and Nutrition Examination Survey (NHANES).
Elias, J. A., T. Zheng, et al. (2003). "Transgenic modeling of interleukin-13 in the lung." Chest 123(3 Suppl): 339S-45S.
Interleukin (IL)-13 is a key cytokine in asthma pathogenesis. We used constitutive and inducible overexpression transgenic mice to characterize the mechanisms by which IL-13 causes phenotypic alterations in the lung. These studies demonstrated that chemokine receptor-2, transforming growth factor-beta(1), and IL-11 play an important role in the regulation of inflammation and remodeling in the IL-13-treated lung. The study results also demonstrated that IL-13 induces vascular endothelial growth factor, which causes bronchial circulation neovascularization in the murine airway. Last, it was demonstrated that IL-13 induces adenosine accumulation and that adenosine in turn stimulates IL-13 elaboration. These approaches validated in vivo genetic targets against which therapies can be directed to selectively regulate aspects of the IL-13 phenotype.
Hamilton, D. R. and D. R. Hardten (2003). "Cataract surgery in patients with prior refractive surgery." Curr Opin Ophthalmol 14(1): 44-53.
As the number and types of keratorefractive procedures increase and as the baby boomer population moves into the "cataractous decades," the number of patients requiring cataract surgery following refractive surgery grows larger each year. While technological advances in surgical instrumentation and intraocular lens (IOL) design allow us to perform cleaner, faster, and more reliable cataract extractions, the ultimate postoperative refraction depends primarily on calculations performed before surgery. Third-generation IOL formulas ( Haigis, Hoffer Q, Holladay 2, or SRK/T) provide outstanding accuracy when used for eyes with physiologic, prolate corneas. In addition, most instruments used today for measuring corneal curvature and power were designed before the era of refractive surgery. These formulas and instruments make assumptions about the anatomy and refractive properties of the cornea that are no longer valid following most keratorefractive procedures. These breakdowns in IOL calculation often result in a "refractive surprise" after cataract surgery, which may require subsequent surgical correction. This article examines recent publications of modeling studies of various methods for estimating effective K values for IOL calculation, cataract surgery case series following refractive surgery, new corneal topography technologies and methods for correcting "refractive surprises" postoperatively.
Kelley, G. A., K. S. Kelley, et al. (2003). "The effects of exercise on resting blood pressure in children and adolescents: a meta-analysis of randomized controlled trials." Prev Cardiol 6(1): 8-16.
Resting blood pressure in children and adolescents can track into adulthood. The purpose of this study was to use the meta-analytic approach to examine the effects of exercise on resting systolic and diastolic blood pressure in children and adolescents. Twelve randomized, controlled trials representing 16 outcomes in 1,266 subjects met the inclusion criteria. Reductions in blood pressure were approximately 1% and 3% for resting systolic and diastolic blood pressures, respectively. However, random-effects modeling using 5000 bootstrap confidence intervals revealed that neither result was statistically significant (systolic, x-bar (x);+/-SEM=-1+/-2; 95% bootstrap confidence intervals=-2 to 0 mm Hg; diastolic, x+/-SEM=-2+/-1; 95% bootstrap confidence intervals=-3 to 0 mm Hg). The results of this study suggest that short-term exercise does not appear to reduce resting systolic and diastolic blood pressure in children and adolescents. However, a need exists for additional studies, especially in hypertensive children and adolescents.
Krieger, E., S. B. Nabuurs, et al. (2003). "Homology modeling." Methods Biochem Anal 44: 509-23.
Lakatta, E. G., V. A. Maltsev, et al. (2003). "Cyclic variation of intracellular calcium: a critical factor for cardiac pacemaker cell dominance." Circ Res 92(3): e45-50.
While a diversity of cell types and distribution within the sinoatrial node and cell-cell interactions add complexity to a complete elucidation of the heart's pacemaker function, it has become clear that cyclic variation of submembrane [Ca2+] and activation of the Na+-Ca2+ exchanger during diastolic depolarization (DD) act in concert with ion channels to confer on sinoatrial node cells (SANCs) their status of dominance with respect to pacemaker function. Studies using confocal microscopy indicate that subsarcolemmal Ca2+ release via ryanodine receptors occurs not only in response to the action potential (AP) upstroke, but also during the DD, and this is augmented by beta-adrenergic receptor (beta-AR) stimulation. Spontaneous APs simulated by mathematical SANC models beat at a faster rate when this subsarcolemmal Ca2+ waveform measured under beta-AR stimulation is introduced into the modeling scheme. Thus, in future investigation of pacemaker functioning in health, disease, and disease therapies the "bar ought to be raised" to embrace the impact of cyclic variation in submembrane [Ca2+] on pacemaker function. The full text of this article is available at http://www.circresaha.org.
Lio, P. (2003). "Statistical bioinformatic methods in microbial genome analysis." Bioessays 25(3): 266-73.
It is probable that, increasingly, genome investigations are going to be based on statistical formalization. This review summarizes the state of art and potentiality of using statistics in microbial genome analysis. First, I focus on recent advances in functional genomics, such as finding genes and operons, identifying gene conversion events, detecting DNA replication origins and analysing regulatory sites. Then I describe how to use phylogenetic methods in genome analysis and methods for genome-wide scanning for positively selected amino acids. I conclude with speculations on the future course of genome statistical modeling.
Liteplo, R. G. and M. E. Meek (2003). "Inhaled formaldehyde: exposure estimation, hazard characterization, and exposure-response analysis." J Toxicol Environ Health B Crit Rev 6(1): 85-114.
Formaldehyde has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Probabilistic estimates of exposure of the general population in Canada to formaldehyde in ambient and indoor air are presented. Critical health effects include sensory irritation and the potential to induce tumors in the upper respiratory tract (the nasal region in rodents and potentially the lungs of humans). The majority of the general population is exposed to airborne concentrations of formaldehyde less than those typically associated with sensory irritation (i.e., 0.1 mg/m3). Based primarily upon data derived from laboratory studies, the inhalation of formaldehyde under conditions that induce cytotoxicity and sustained regenerative proliferation within the respiratory tract is considered to present a carcinogenic hazard to humans. At airborne levels for which the prevalence of sensory irritation is minimal (i.e., 0.1 mg/m3), risks of respiratory-tract cancers for the general population estimated on the basis of a biologically motivated case-specific model are exceedingly low. This biologically motivated case-specific model incorporates two-stage clonal expansion and is supported by dosimetry calculations from computational fluid dynamics analyses of formaldehyde flux in various regions of the nose and single-path modeling for the lower respiratory tract. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.
Meek, B., A. Renwick, et al. (2003). "Practical application of kinetic data in risk assessment--an IPCS initiative." Toxicol Lett 138(1-2): 151-60.
In this paper, guidance developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals is considered in the context of its application in the assessment of the adequacy of physiological-toxicokinetic (PTK) modeling to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment. This guidance was developed in the context of a framework, which permits the incorporation of quantitative chemical-specific data, relating to either toxicokinetics or toxicodynamics to replace part or all of the usual 100-fold default uncertainty factor for interspecies differences or human variability in the development of tolerable or reference doses or concentrations. However, since the guidance relates specifically to adequacy of kinetic or dynamic data to replace default for interspecies and human variability, it is also applicable to other approaches of dose-response analyses such as estimation of cancer potency or risk. The framework also supports probabilistic characterization, where data are sufficient. This guidance has been developed and refined through a series of planning and technical meetings and larger workshops, in which a broad range of participants from academia, government agencies, and the private sector have prepared and gained experience in application through case studies. The guidance for adequacy of kinetic data to replace default is presented in the context of several categories, including determination of the active chemical species, choice of the appropriate kinetic parameter and experimental data, the latter which includes reference to relevance of population, relevance of route, relevance of dose/concentration, and adequacy of number of subjects/samples. The principal objective of this guidance, which has been developed primarily as a resource for risk assessors, is to foster better understanding of the criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics, including PTK models. It is anticipated that the guidance will also encourage generation of appropriate data and models, and facilitate their incorporation in dose/concentration-response assessment for regulatory purposes. In this paper, the application of the guidance is considered primarily through reference to examples, with emphasis on those where PTK models have been informative.
Papadopoulo, V. (2003). "Peripheral benzodiazepine receptor: structure and function in health and disease." Ann Pharm Fr 61(1): 30-50.
In vitro studies using biochemical, pharmacological and molecular approaches demonstrated that the peripheral-type benzodiazepine receptor (PBR) is a mitochondrial protein, involved in the regulation of cholesterol transport from the outer to the inner mitochondrial membrane, the rate-determining step in steroid biosynthesis. In vivo animal models and ontogeny studies validated the role of PBR in steroidogenesis. Targeted disruption of the PBR gene in Leydig cells resulted in the arrest of cholesterol transport into mitochondria and steroid formation. Molecular modeling of PBR suggested that it might function as a channel for cholesterol. Indeed, cholesterol uptake and transport by bacteria cells was induced upon PBR expression. Amino acid deletion and site-directed mutagenesis studies identified a cholesterol recognition/interaction amino acid consensus sequence in the cytoplasmic carboxy-terminus of the receptor. In vitro reconstitution experiments demonstrated that the 18 kDa PBR protein binds with high affinity both drug ligands and cholesterol, suggesting that this protein might serve numerous functions considering the critical role of cholesterol in membrane biogenesis and human pathology. In this context, PBR expression correlated with the quality of kidney preservation, indicating that it might serve as an index of kidney and mitochondrial viability during ischemia-reperfusion injury. PBR overexpression was also found to be a prognostic indicator of the aggressive phenotype in breast, colorectal and prostate cancers. Moreover, in Alzheimer's disease brain specimens, PBR levels were increased and paralleled the elevated neurosteroid synthesis observed in specific brain areas. The role for PBR in these pathological conditions remains to be elucidated. paralleled the elevated neurosteroid synthesis observed in specific brain areas. The role for PBR in these pathological conditions remains to be elucidated.
Pfefferle, W., B. Mockel, et al. (2003). "Biotechnological manufacture of lysine." Adv Biochem Eng Biotechnol 79: 59-112.
L-Lysine has been manufactured using Corynebacterium glutamicum for more than 40 years. Nowadays production exceeds 600,000 tons per year. Based on conventionally bred strains, further improvement of lysine productivity has been achieved by genetic engineering. Pyruvate carboxylase, aspartate kinase, dihydrodipicolinate synthase, homoserine dehydrogenase and the specific lysine exporter were shown to be key enzymes for lysine production and were characterized in detail. Their combined engineering led to a striking increase in lysine formation. Pathway modeling with data emerging from 13C-isotope experiments revealed a coordinated flux through pentose phosphate cycle and tricarboxylic acid cycle and intensive futile cycling between C3 compounds of glycolysis and C4 compounds of tricarboxylic acid cycle. Process economics have been optimized by developing repeated fed-batch techniques and technical continuous fermentations. In addition, on-line metabolic pathway analysis or flow cytometry may help to improve the fermentation performance. Finally, the availability of the Corynebacterium glutamicum genome sequence has a major impact on the improvement of the biotechnological manufacture of lysine. In this context, all genes of the carbon flow from sugar uptake to lysine secretion have been identified and are accessible to manipulation. The whole sequence information gives access to post genome technologies such as transcriptome analysis, investigation of the proteome and the active metabolic network. These multi-parallel working technologies will accelerate the generation of knowledge. For the first time there is a chance of understanding the overall picture of the physiological state of lysine overproduction in a technical environment.
Rassovsky, Y. and M. G. Kushner (2003). "Carbon dioxide in the study of panic disorder: issues of definition, methodology, and outcome." J Anxiety Disord 17(1): 1-32.
The carbon dioxide (CO(2)) challenge paradigm has been useful for modeling panic in the laboratory. While showing promise as a technique able to promote a better understanding of the etiology of panic disorder (PD), this goal has been impeded by the lack of standardization of the challenge methodology and by uncertainty concerning the optimal definition and assessment of laboratory panic. The purpose of this paper is to highlight the impact of method variance on laboratory findings and to present recommendations for future challenge research. We begin by reviewing studies that have employed CO(2) as a stimulus for panic provocation focusing on the status of key methodological parameters between the studies and the relationship of these parameters to findings. We then make pragmatic and theoretically-based recommendations concerning approaches to methodological standardization, the establishment of a valid laboratory panic definition and the desirability of using of additional outcome measures. We conclude that although further work is needed to improve the CO(2) challenge laboratory model of panic, this paradigm can play an important role in understanding the psychopathology of PD.
Sappington, J. Y. (2003). "Nurturance. The spirit of holistic nursing." J Holist Nurs 21(1): 8-19.
In the theory of modeling and role modeling, the concept of nurturance is connected to holistic nursing practice. As nurturance is given and received within a context of unconditional acceptance, clients' needs are fulfilled and they can move toward a healthier state. An exploration of the literature revealed several defining attributes that clarify the definition of the concept as it is used by Erickson, Tomlin, and Swain. Model, borderline, related, and contrary cases further illustrate the meaning of nurturance and its relationship to holistic care. In addition, methods of measuring nurturance are discussed. An analysis of the concept brings an increased understanding of how nurses can care for clients in a manner that respects the uniqueness and value of each individual. The result is a client who experiences growth and renewal of of strength, allowing optimal healing to occur.
Scriver, C. R., M. Hurtubise, et al. (2003). "PAHdb 2003: what a locus-specific knowledgebase can do." Hum Mutat 21(4): 333-44.
PAHdb, a legacy of and resource in genetics, is a relational locus-specific database (http://www.pahdb.mcgill.ca). It records and annotates both pathogenic alleles (n = 439, putative disease-causing) and benign alleles (n = 41, putative untranslated polymorphisms) at the human phenylalanine hydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) and their trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typical for mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites are interconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of the allele (submitter, publication, or population); polymorphic haplotype background; and effect of the allele as predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.16.1) or by in vitro expression analysis. The majority (63%) of the putative pathogenic PAH alleles are point mutations causing missense in translation of which few have a primary effect on PAH enzyme kinetics. Most apparently have a secondary effect on its function through misfolding, aggregation, and intracellular degradation of the protein. Some point mutations create new splice sites. A subset of primary PAH mutations that are tetrahydrobiopterin-responsive is highlighted on a Curators' Page. A clinical module describes the corresponding human clinical disorders (hyperphenylalaninemia [HPA] and phenylketonuria [PKU]), their inheritance, and their treatment. PAHdb contains data on the mouse gene (Pah) and on four orthologous mutant mouse models and their use (for example, in research on oral treatment of PKU with the enzyme phenylalanine ammonia lyase [EC 4.3.1.5]).
Solomon, K. R., X. Tang, et al. (2003). "Changes in tropospheric composition and air quality due to stratospheric ozone depletion." Photochem Photobiol Sci 2(1): 62-7.
Increased UV-B through stratospheric ozone depletion leads to an increased chemical activity in the lower atmosphere (the troposphere). The effect of stratospheric ozone depletion on tropospheric ozone is small (though significant) compared to the ozone generated anthropogenically in areas already experiencing air pollution. Modeling and experimental studies suggest that the impacts of stratospheric ozone depletion on tropospheric ozone are different at different altitudes and for different chemical regimes. As a result the increase in ozone due to stratospheric ozone depletion may be greater in polluted regions. Attributable effects on concentrations are expected only in regions where local emissions make minor contributions. The vertical distribution of NOx (NO + NO2), the emission of volatile organic compounds and the abundance of water vapor, are important influencing factors. The long-term nature of stratospheric ozone depletion means that even a small increase in tropospheric ozone concentration can have a significant impact on human health and the environment. Trifluoroacetic acid (TFA) and chlorodifluoroacetic acid (CDFA) are produced by the atmospheric degradation of hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs). TFA has been measured in rain, rivers, lakes, and oceans, the ultimate sink for these and related compounds. Significant anthropogenic sources of TFA other than degradation HCFCs and HFCs have been identified. Toxicity tests under field conditions indicate that the concentrations of TFA and CDFA currently produced by the atmospheric degradation of HFCs and HCFCs do not present a risk to human health and the environment. The impact of the interaction between ozone depletion and future climate change is complex and a significant area of current research. For air quality and tropospheric composition, a range of physical parameters such as temperature, cloudiness and atmospheric transport will modify the impact of UV-B. Changes in the chemical composition of the atmosphere including aerosols will also have an impact. For example, tropospheric OH is the 'cleaning' agent of the troposphere. While increased UV-B increases the OH concentration, increases in concentration of gases like methane, carbon monoxide and volatile organic compounds will act as sinks for OH in troposphere and hence change air quality and chemical composition in the troposphere. Also, changes in the aerosol content of the atmosphere resulting from global climate change may affect ozone photolysis rate coefficients and hence reduce or increase tropospheric ozone concentrations.
Stark, J. D. and J. E. Banks (2003). "Population-level effects of pesticides and other toxicants on arthropods." Annu Rev Entomol 48: 505-19.
New developments in ecotoxicology are changing the way pesticides and other toxicants are evaluated. An emphasis on life histories and population fitness through the use of demography, other measures of population growth rate, field studies, and modeling are being exploited to derive better estimates of pesticide impacts on both target and nontarget species than traditional lethal dose estimates. We review the state of the art in demographic toxicology, an approach to the evaluation of toxicity that uses life history parameters and other measures of population growth rate. A review of the literature revealed that 75 studies on the use of demography and similar measures of population growth rate in toxicology have been published since 1962. Of these 75 studies, the majority involved arthropods. Recent evaluations have indicated that ecotoxicological analysis based on population growth rate results in more accurate assessments of the impacts of pesticides and other toxicants because measures of population growth rate combine lethal and sublethal effects, which lethal dose/concentration estimates (LD/LC50) cannot do. We contend that to advance our knowledge of toxicant impacts on arthropods, the population growth rate approach should be widely adopted.
Swanson, K. R., L. D. True, et al. (2003). "On the use of quantitative modeling to help understand prostate-specific antigen dynamics and other medical problems." Am J Clin Pathol 119(1): 14-7.
Takigawa, M., T. Nakanishi, et al. (2003). "Role of CTGF/HCS24/ecogenin in skeletal growth control." J Cell Physiol 194(3): 256-66.
Connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) is a multifunctional growth factor for chondrocytes, osteoblasts, and vascular endothelial cells. CTGF/Hcs24 promotes the proliferation and maturation of growth cartilage cells and articular cartilage cells in culture and hypertrophy of growth cartilage cells in culture. The factor also stimulates the proliferation and differentiation of cultured osteoblastic cells. Moreover, CTGF/Hcs24 promotes the adhesion, proliferation, and migration of vascular endothelial cells, as well as induces tube formation by the cells and strong angiogenesis in vivo. Because angiogenesis is critical for the replacement of cartilage with bone at the final stage of endochondral ossification and because gene expression of CTGF/Hcs24 predominates in hypertrophic chondrocytes in the physiological state, a major physiological role for this factor should be the promotion of the entire process of endochondral ossification, with the factor acting on the above three types of cells as a paracrine factor. Thus, CTGF/Hcs24 should be called "ecogenin: endochondral ossification genetic factor." In addition to hypertrophic chondrocytes, osteoblasts activated by various stimuli including wounding also express a significantly high level of CTGF/Hcs24. These findings in conjunction with in vitro findings about osteoblasts mentioned above suggest the involvement of CTGF/Hcs24 in intramembranous ossification and bone modeling/remodeling. Because angiogenesis is also critical for intramembranous ossification and bone remodeling, CTGF/Hcs24 expressed in endothelial cells activated by various stimuli including wounding may also play important roles in direct bone formation. In conclusion, although the most important physiological role of CTGF/Hcs24 is ecogenin action, the factors also play important roles in skeletal growth and modeling/remodeling via its direct action on osteoblasts under both physiological and pathological conditions.
Theil, F. P., T. W. Guentert, et al. (2003). "Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection." Toxicol Lett 138(1-2): 29-49.
The present paper proposes a modeling and simulation strategy for the prediction of pharmacokinetics (PK) of drug candidates by using currently available in silico and in vitro based prediction tools for absorption, distribution, metabolism and excretion (ADME). These methods can be used to estimate specific ADME parameters (such as rate and extent of absorption into portal vein, volume of distribution, metabolic clearance in the liver). They can also be part of a physiologically based pharmacokinetic (PBPK) model to simulate concentration-time profiles in tissues and plasma resulting from the overall PK after intravenous or oral administration. Since the ADME prediction tools are built only on commonly generated in silico and in vitro data, they can be applied already in early drug discovery, prior to any in vivo study. With the suggested methodology, the following advantages of the mechanistic PBPK modeling framework can now be utilized to explore potential clinical candidates already in drug discovery: (i) prediction of plasma (blood) and tissue PK of drug candidates prior to in vivo experiments, (ii) supporting a better mechanistic understanding of PK properties, as well as helping the development of more rationale PK-PD relationships from tissue kinetic data predicted, and hence facilitating a more rational decision during clinical candidate selection, and (iii) the extrapolation across species, routes of administration and dose levels.
Weiss, J. N., Z. Qu, et al. (2003). "Understanding biological complexity: lessons from the past." Faseb J 17(1): 1-6.
Advances in molecular biology now permit complex biological systems to be tracked at an exquisite level of detail. The information flow is so great, however, that using intuition alone to draw connections is unrealistic. Thus, the need to integrate mathematical biology with experimental biology is greater than ever. To achieve this integration, obstacles that have traditionally prevented effective communication between theoreticians and experimentalists must be overcome, so that experimentalists learn the language of mathematics and dynamical modeling and theorists learn the language of biology. Fifty years ago Alan Hodgkin and Andrew Huxley published their quantitative model of the nerve action potential; in the same year, Alan Turing published his work on pattern formation in activator-inhibitor systems. These classic studies illustrate two ends of the spectrum in mathematical biology: the detailed model approach and the minimal model approach. When combined, they are highly synergistic in analyzing the mechanisms underlying the behavior of complex biological systems. Their effective integration will be essential for unraveling the physical basis of the mysteries of life.
Wilson, A. G., A. C. White, et al. (2003). "Role of predictive metabolism and toxicity modeling in drug discovery--a summary of some recent advancements." Curr Opin Drug Discov Devel 6(1): 123-8.
In this article, we discuss recent advances and selected publications in the area of computer-based (in silico) metabolism and toxicity prediction, and comment on the opportunities for prediction of metabolism-based toxicity. The article also discusses the growing interest and importance of in silico prediction of metabolism and toxicity as tools to assist in library design and lead optimization. In addition, we consider the status of commercial metabolism and toxicity databases, and the need for future improvement, since data is often from older studies and from structures not typically considered as 'drug-like'. The article highlights the current status and potential of in silico models for property prediction, and the potential for linkage with vivo models to improve the integration of metabolism and toxicity into the drug discovery process and extrapolation to clinical studies. The article underscores that the future development, integration and application of in silico models will require a balance of local and global model approaches. The article also indicates that implementation and integration of models into drug discovery processes needs to be carried out in a rational and systematic manner, if we are to fully capitalize on the opportunity presented by in silico predictive modeling.