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Biological Complexity Reviews: 2003

(58 References)

Alberghina, L., R. L. Rossi, et al. (2003). "Checking cell size in budding yeast: a systems biology approach." Ital J Biochem 52(1): 55-7.

            The regulation of cell cycle progression via the attainment of a critical cell size is a conserved feature from simpler unicellular organisms to mammalian cells that is obtaining much attention recently. Genome wide analysis of Saccharomyces cerevisiae deletion strains, genetic epistasis, DNA microarray analysis have recently revealed an increasingly complex network of cell size modulation mechanisms. A systems biology-based approach, that is needed to structure the underlying complexity of cell cycle regulatory mechanisms, is described.

Ares, J. (2003). "Time and space issues in ecotoxicology: population models, landscape pattern analysis, and long-range environmental chemistry." Environ Toxicol Chem 22(5): 945-57.

            Advances in ecotoxicology addressing problems of time and spatial scales are presented and interpreted in the frame of concepts on population/community dynamics and landscape pattern analysis. Example deterministic/probabilistic modeling experiments are used to illustrate key concepts. Space and time scales analyzed are single and multigenerations of local populations, metapopulations, community, and ecosystem/landscape. Most population models used in recent ecotoxicology studies are deterministic and do not include a formal treatment of spatial processes, like migration or local random extinction. Some metapopulation models have been applied with success. Upscaling of ecotoxicological results at the community level is less developed, probably because of the inherent complexity of indirect and direct coactions among organisms. Community and ecosystem toxicity end points that could find a broad use in regulatory applications have not yet been identified. Some practical issues like the estimation of the potential for the natural attenuation of toxicity and the transport of contaminants along food chains must be addressed at these scales/levels of biological complexity. The estimation of ecotoxicological effects has been increasingly evolving to integrate modeling and monitoring contaminant transport and fate, landscape pattern analysis, and spatially explicit population dynamics (including direct and indirect communal interactions).

Banerjee, S. K., P. K. Mukherjee, et al. (2003). "Garlic as an antioxidant: the good, the bad and the ugly." Phytother Res 17(2): 97-106.

            Garlic has played an important dietary and medicinal role throughout the history of mankind. In some Western countries, the sale of garlic preparations ranks with those of leading prescription drugs. The therapeutic efficacy of garlic encompasses a wide variety of ailments, including cardiovascular, cancer, hepatic and microbial infections to name but a few. However, the elucidation of its mechanism for therapeutic action has proved to be more elusive and a unifying theory, which could account for its reported multifarious activities, is yet to emerge. Reactive oxygen species (ROS) seem to be at the core of many disease processes and it is an attractive and convenient hypothesis that garlic might exert its activities through modulatory effects on ROS. A literature search on garlic and its antioxidant potential churned up a surprisingly large amount of data, some of it good, some bad and some of its definitely ugly.Various preparations of garlic, mainly aged garlic extract (AGE), have been shown to have promising antioxidant potential. However, the presence of more than one compounds in garlic, with apparently opposite biological effects, has added to the complexity of the subject. Raw garlic homogenate has been reported to exert antioxidant potential but higher doses have been shown to be toxic to the heart, liver and kidney.So where do we stand today on this issue of garlic? Is garlic always good for health? How safe is it? Is it necessary to isolate the antioxidant compounds for its medicinal use in a more effective way? These issues are addressed in this review.

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.

Boyle, P., G. Severi, et al. (2003). "The epidemiology of prostate cancer." Urol Clin North Am 30(2): 209-17.

            The etiology of prostate cancer remains virtually unknown. Although there are a number of new leads with regard to risk factors for prostate cancer, more research is required to confirm them. There is little purpose in conducting further case-control studies of prostate cancer-particularly since the use of PSA testing has become wide-spread. Instead, future epidemiologic studies should focus on prostate tumor subclassification, in terms of method of detection, markers of biological "aggressiveness," and genetic changes. Many of these new leads involve the possible influence of polymorphisms in key genes involved in important physiologic processes in the prostate. To fully explore the complexity of interrelationships between the several elements in these pathways will require large cohort studies in which blood is sampled prior to diagnosis. Such studies will be important for identifying which modifiable aspects of lifestyle (such as diet, alcohol, tobacco, physical activity) might be targeted for intervention, to reduce risk. The detection of early prostate cancers by PSA testing relatives of men with prostate cancer has affected the prevalence of phenocopies and, hence, the meaningfulness of risk estimation in prostate cancer families. Because multiple-case families form the substrate for gene hunting via linkage analysis, this phenocopy phenomenon is going to cause considerable confusion and wasted effort. Presently, men with a family history of prostate cancer can be provided with little advice in terms of preventive action. It is likely that one or more genetic mutations associated with a high risk for prostate cancer will be identified in the near future. Even so, the risks probably will be similar to those for mutations in the first two breast cancer genes--informative for very few families. It is difficult to foresee, as and when high-risk mutation carriers are identified, what advice should be offered to them: prophylactic prostatectomies seem to have less attraction than do prophylactic mastectomies for women at high risk of breast cancer. This issue becomes more complex when considering counseling on the basis of a genetic profile involving many low-risk polymorphisms. Hopefully, such genetic screening should occur only after its efficacy has been established; when there is a better understanding of prostate biology, tumor heterogeneity, and prognosis; and when there are proven treatment or prevention options available. Prevention is held to be better than cure, and there are some potentially interesting chemopreventive agents that require careful trial before public health initiatives can be promoted. Potential candidates include vitamin E, selenium, zinc, and lycopene as dietary supplements. There are other agents that may be appropriate for pharmaceutical development, including inhibitors of COX-2 and IGF-1 activity. It is important that chemoprevention trials are followed-up for a sufficient period of time and that other endpoints also are captured, because the supplementation of diets with superphysiologic doses of individual micronutrients sometimes has caused unexpected and unwanted results--for example, an 18% increase in lung cancers observed in the beta-carotene arm of the ATBC trial.

Buscaglia, C. A. and J. M. Di Noia (2003). "Trypanosoma cruzi clonal diversity and the epidemiology of Chagas' disease." Microbes Infect 5(5): 419-27.

            Chagas' disease is caused by the protozoan Trypanosoma cruzi and it has a variable clinical outcome. The basis for this variability relies in part on the complexity of the parasite population consisting of multiple clones displaying distinct biological properties. A major current challenge is to correlate parasite genetic variability with pathogenesis.

Chenivesse, X., V. Ridoux, et al. (2003). "[Quality control of gene therapy products: approach of the French Agency for the Safety of Health Products]." Med Sci (Paris) 19(4): 481-8.

            Gene therapy is a new therapeutic strategy which can constitute in some diseases a true alternative or a complement to the "classical treatments". Regarding the innovative features, the complexity and the extreme diversity of the gene therapy products (naked DNA, synthetic vectors, viral vectors, genetically modified cells), these new products presently in clinical trials have to be precisely evaluated and controlled for their medicine quality as well as their biological origin and/or their specific characteristics of genetically modified organisms. The French Agency for the Safety of Health Products engaged an in-depth scientific review concerning the control of this very heterogeneous class of potential therapeutics through the creation of a working group. The objectives of this group were to determine the testings to be performed by a national authority for each type of gene therapy products and to select the appropriate techniques or methods to be developed. Controls considered as essential are listed and include the verification of the identity, the purity, the transfer and expression efficiency as well as the microbiological and viral safety of the products. This implies the development of diverse techniques of molecular biology, cellular biology, physico-chemistry, animal testing, histology and microbiology. Finally, in order to define the basis of testings of these emerging products, the marketing of which should be effective for some of them in the next years, it appears extremely important to harmonize the quality, efficiency and safety criteria, to develop specific references and standards and to create specific guidelines for the control of gene therapy products.

Conner, S. D. and S. L. Schmid (2003). "Regulated portals of entry into the cell." Nature 422(6927): 37-44.

            The plasma membrane is the interface between cells and their harsh environment. Uptake of nutrients and all communication among cells and between cells and their environment occurs through this interface. 'Endocytosis' encompasses several diverse mechanisms by which cells internalize macromolecules and particles into transport vesicles derived from the plasma membrane. It controls entry into the cell and has a crucial role in development, the immune response, neurotransmission, intercellular communication, signal transduction, and cellular and organismal homeostasis. As the complexity of molecular interactions governing endocytosis are revealed, it has become increasingly clear that it is tightly coordinated and coupled with overall cell physiology and thus, must be viewed in a broader context than simple vesicular trafficking.

Davis, D. W., D. J. McConkey, et al. (2003). "Surrogate markers in antiangiogenesis clinical trials." Br J Cancer 89(1): 8-14.

            Novel antiangiogenic agents currently being developed may ultimately be more effective against solid tumours and less toxic than cytotoxic chemotherapy. As a result of the early clinical trials of angiogenesis inhibitors, investigators are beginning to appreciate the complexity of targeting angiogenesis and the realisation that developing clinically useful antiangiogenic therapy will be more challenging than originally thought. It is now apparent that new methods and surrogate markers to assess these agents' biological activity are crucial for their successful development. This review summarises the currently available clinical data on the development of surrogate markers of angiogenesis inhibitors.

Denslow, N., M. E. Michel, et al. (2003). "Application of proteomics technology to the field of neurotrauma." J Neurotrauma 20(5): 401-7.

            Near-completion of the Human Genome Project has stimulated scientists to begin looking for the next step in unraveling normal and abnormal functions within biological systems. Consequently, there is new focus on the role of proteins in these processes. Proteomics is a burgeoning field that may provide a valuable approach to evaluate the post-traumatic central nervous system (CNS). Although we cannot provide a comprehensive assessment of all methods for protein analysis, this report summarizes some of the newer proteomic technologies that have propelled this field into the limelight and that are available to most researchers in neurotrauma. Three technical approaches (two-dimensional gel electrophoresis, direct analysis by mass spectrometry, including two-dimensional chromatography coupled to mass spectrometry and isotope coded affinity tags, and antibody technologies) are reviewed, and their advantages and disadvantages presented. A discussion of proteomic technology in the context of brain and spinal cord trauma follows, addressing current and future challenges. Proteomics will likely be very useful for developing diagnostic predictors after CNS injury and for mapping changes in proteins after injury in order to identify new therapeutic targets. Neurotrauma results in complex alterations to the biological systems within the nervous system, and these changes evolve over time. Exploration of the "new nervous system" that follows injury will require methods that can both fully assess and simplify this complexity.

Deslys, J. P. (2003). "[Prions and risks for blood transfusion: the situation in 2003]." Transfus Clin Biol 10(3): 113-25.

            In 2003, Prions still constitute a biological enigma and a public health concern. The risks of transmission of the so called "mad cow disease" are now under control but concerns still persist about potential secondary transmissions, notably via blood transfusion. Information obtained from diseases previously observed in animals (scrapie of sheep and goat) and in man (Kuru, Creutzfeldt-Jakob disease) demonstrate the complexity of the relations between these transmissible agents and their host. The difficulty in decontamination, the very long silent incubation period during which diagnosis is not possible and the lack of treatment are alarming elements which explain the increased perception of risk for these diseases. The development of rapid screening tests used on bovine at slaughterhouse has represented an important improvement in the development of a targeted protection against these agents. Today, technical evolutions in diagnosis let us imagine the possibility of blood detection for prions: on one hand new garanties for security may arise but on the other hand it points out the potential infectivity of blood with these agents responsible for constant fatal diseases. Precautionary security measures have to ensure an optimal ratio benefit/risk for the patient and thus, in this field, to balance the risk linked to prions with those clearly identified elsewhere.

Eriksen, H. M. and V. Dimitrov (2003). "Ecology of oral health: a complexity perspective." Eur J Oral Sci 111(4): 285-90.

            Health and disease are determined by many interwoven factors. Complexity theory may facilitate an understanding of oral health and disease by studying their complex interplay, and not focusing only on the importance of each individual factor involved. This introduces a theoretical basis for a dynamic, holistic approach to oral health with possible far-reaching consequences for dental education and diagnosis, prevention and treatment of oral diseases.

Foukas, L. C. and K. Okkenhaug (2003). "Gene-targeting reveals physiological roles and complex regulation of the phosphoinositide 3-kinases." Arch Biochem Biophys 414(1): 13-8.

            Phosphoinositide 3-kinases (PI3Ks) are represented by a family of eight distinct enzymes that can be divided into three classes based on their structure and function. The class I PI3Ks are heterodimeric enzymes that are regulated by recruitment to plasma membrane following receptor activation and which control numerous cellular functions, including growth, differentiation, migration, survival, and metabolism. New light has been shed on the biological role of individual members of the class I PI3Ks and their regulatory subunits through gene-targeting experiments. In addition, these experiments have brought the complexity of how PI3K activation is regulated into focus.

Giese, M. A. and T. Poggio (2003). "Neural mechanisms for the recognition of biological movements." Nat Rev Neurosci 4(3): 179-92.

            The visual recognition of complex movements and actions is crucial for the survival of many species. It is important not only for communication and recognition at a distance, but also for the learning of complex motor actions by imitation. Movement recognition has been studied in psychophysical, neurophysiological and imaging experiments, and several cortical areas involved in it have been identified. We use a neurophysiologically plausible and quantitative model as a tool for organizing and making sense of the experimental data, despite their growing size and complexity. We review the main experimental findings and discuss possible neural mechanisms, and show that a learning-based, feedforward model provides a neurophysiologically plausible and consistent summary of many key experimental results.

Grant, P. J. (2003). "The genetics of atherothrombotic disorders: a clinician's view." J Thromb Haemost 1(7): 1381-90.

            The development of coronary artery disease is dependent on the interaction of multiple biochemical pathways that lead to the development of plaque in the arterial wall and ultimately plaque instability, plaque rupture and thrombosis. The latter stages lead to vascular obstruction, tissue death and the final phenotype of myocardial infarction. Hemostasis gene association studies of atherothrombotic disorders have been unrewarding, with largely underpowered studies reporting inconsistent results. Clinical studies such as the Multiple Risk Factor Intervention Trial clearly indicate that clustering of classical risk increases the likelihood of myocardial infarction, and the addition of diabetes mellitus to the risk profile exponentially increases the risk of a vascular event. The development of insulin resistance is considered to be a pivotal event in vascular risk with associated clustering of dysglycemia, hyperinsulinemia, systolic hypertension, raised triglyceride and low high-density lipoprotein cholesterol. Additionally, elevated levels of plasminogen activator inhibitor-1, factor (F)VII, FXII, fibrinogen and tissue plasminogen activator occur with insulin resistance to create an atherothrombotic risk cluster. Heritability studies of insulin resistance and the vascular risk profile demonstrate genetic pleitropy between diabetes and vascular risk, which indicate that common genes have an important role. Increasingly, it is felt that inflammation underpins both diabetes and cardiovascular disease and that the expression of the final phenotype(s) may depend on complex gene-environment interactions with regulatory genes, including those for nuclear transcription factors and RNA-binding proteins. The complexity of coronary artery disease and the risk factor interactions make it unlikely that genetic epidemiology will identify genes involved in these processes without a better understanding of environmental influences.

Hobert, O. (2003). "Behavioral plasticity in C. elegans: paradigms, circuits, genes." J Neurobiol 54(1): 203-23.

            Life in the soil is an intellectual and practical challenge that the nematode Caenorhabditis elegans masters by utilizing 302 neurons. The nervous system assembled by these 302 neurons is capable of executing a variety of behaviors, some of respectable complexity. The simplicity of the nervous system, its thoroughly characterized structure, several sets of well-defined behaviors, and its genetic amenability combined with its isogenic background make C. elegans an attractive model organism to study the genetics of behavior. This review describes several behavioral plasticity paradigms in C. elegans and their underlying neuronal circuits and then goes on to review the forward genetic analysis that has been undertaken to identify genes involved in the execution of these behaviors. Lastly, the review outlines how reverse genetics and genomic approaches can guide the analysis of the role of genes in behavior and why and how they will complement the forward genetic analysis of behavior.

Hofmann, H. A. (2003). "Functional genomics of neural and behavioral plasticity." J Neurobiol 54(1): 272-82.

            How does the environment, particularly the social environment, influence brain and behavior and what are the underlying physiologic, molecular, and genetic mechanisms? Adaptations of brain and behavior to changes in the social or physical environment are common in the animal world, either as short-term (i.e., modulatory) or as long-term modifications (e.g., via gene expression changes) in behavioral or physiologic properties. The study of the mechanisms and constraints underlying these dynamic changes requires model systems that offer plastic phenotypes as well as a sufficient level of quantifiable behavioral complexity while being accessible at the physiological and molecular level. In this article, I explore how the new field of functional genomics can contribute to an understanding of the complex relationship between genome and environment that results in highly plastic phenotypes. This approach will lead to the discovery of genes under environmental control and provide the basis for the study of the interrelationship between an individual's gene expression profile and its social phenotype in a given environmental context.

Holtzman, M. J. (2003). "Drug development for asthma." Am J Respir Cell Mol Biol 29(2): 163-71.

            Asthma is characterized by abnormal immune cell accumulation and activation in the airways as well as dysfunction of specialized parenchymal cells. Research strategies to define asthma pathogenesis have focused on the hypothesis that this altered state is a consequence of an excessive allergen-driven response. Drug development for asthma has been directed at improving existing agents and expanding new modalities that target the Th2 allergic cascade. Significant opportunities are being pursued in each of these areas. However, this strategy may not account for some critical aspects of asthma pathogenesis. Alternative considerations include the need for a multidisciplinary approach to dissect the complexity of the asthma phenotype as well as a better understanding of nonallergic factors (especially viral reprogramming of airway behavior) in the development of the phenotype. Each of these considerations may provide an alternative strategy for further drug development for asthma and other complex diseases.

Iborra, F., P. R. Cook, et al. (2003). "Applying microscopy to the analysis of nuclear structure and function." Methods 29(2): 131-41.

            One of the ultimate goals of biological research is to understand mechanisms of cell function within living organisms. With this in mind, many sophisticated technologies that allow us to inspect macromolecular structure in exquisite detail have been developed. Although knowledge of structure derived from techniques such as X-ray crystallography and nuclear magnetic resonance is of vital importance, these approaches cannot reveal the remarkable complexity of molecular interactions that exists in vivo. With this in mind, this review focuses on the use of microscopy techniques to analyze cell structure and function. We describe the different basic microscopic methodologies and how the routine techniques are best applied to particular biological problems. We also emphasize the specific capabilities and uses of light and electron microscopy and highlight their individual advantages and disadvantages. For completion, we also comment on the alternative possibilities provided by a variety of advanced imaging technologies. We hope that this brief analysis of the undoubted power of microscopy techniques will be enough to stimulate a wider participation in this rapidly developing area of biological discovery.

Jacobs, M. N., M. Dickins, et al. (2003). "Homology modelling of the nuclear receptors: human oestrogen receptorbeta (hERbeta), the human pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor alpha (hERalpha) crystal structure, and the human peroxisome proliferator activated receptor alpha (PPARalpha) ligand binding domain from the human PPARgamma crystal structure." J Steroid Biochem Mol Biol 84(2-3): 117-32.

            We have generated by homology the three-dimensional structures of the ligand binding domain (LBD) of several interrelated human steroid hormone receptors (SHRs).These are the oestrogen receptor beta (hERbeta), the pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR). They were produced by homology modelling from the human oestrogen receptor alpha (hERalpha) crystallographic coordinates [Nature 389 (1997) 753] as a template together with the amino acid sequences for hERbeta [FEBS Lett. 392 (1996) 49], PXR [J. Clin. Invest. 102 (1998) 1016], AhR [Proc. Natl. Acad. Sci. U.S.A. 89 (1992) 815] and CAR [Nature 395 (1998) 612; Mol. Cell. Biol. 14 (1994) 1544], respectively. The selective endogenous ligand, in each case, was docked interactively within the putative ligand binding site using the position of oestradiol in hERalpha as a guide, and the total energy was calculated. In each receptor model a number of different ligands known to fit closely within the ligand binding site were interactively docked and binding interactions noted. Specific binding interactions included combinations of hydrogen bonding and hydrophobic contacts with key amino acid sidechains, which varied depending on the nature of the ligand and receptor concerned. We also produced the human peroxisome proliferator activated receptor alpha (PPARalpha) by homology modelling using the human PPARgamma (hPPARgamma) LBD crystallographic coordinates summarised in [Toxicol. In Vitro 12 (1998) 619] as a template together with the amino acid sequence for hPPARalpha [Toxicol. In Vitro 12 (1998) 619; Nature 395 (1998) 137].The models will provide a useful tool in unravelling the complexity in the physiologic response to xenobiotics by examining the ligand binding interactions and differences between the steroid hormone receptors activation or inactivation by their ligands.

Janssen, C. R. and D. G. Heijerick (2003). "Algal toxicity tests for environmental risk assessments of metals." Rev Environ Contam Toxicol 178: 23-52.

            Current regulatory methods for assessing the effects of contaminants, and metals in particular, rely mainly on a limited number of standardized test methods and test species (OECD, ISO, ASTM, USEPA). However, these test protocols allow a certain degree of freedom in relation to physicochemical parameters or biological aspects, which may lead to large variability in test results. The current review, based on effects data and theoretical considerations reported in the literature, tried to determine and quantify the effect of variation of these factors on the outcome of metal toxicity tests with algae. Major physicochemical parameters that affect metal toxicity to algae are hardness, pH, preculture conditions, type of test medium, and presence of chelating agents: Literature data also clearly demonstrate the importance of test species or strain selection (inter- and intraspecies sensitivity variability) on the outcome of algal toxicity tests. For Zn, a factor of 8.3 is observed between the NOEC for Selenastrum capricornutum (currently renamed Pseudokirchneriella subcapitata) and Croococcus paris. An intraspecies difference for S. capricornutum of a factor of 60 is observed between various reported EC50S for Cd. Next to differences in physicochemical test conditions, possible adaptation or acclimation to deficient/elevated metal concentrations add to the reported differences: S. capricornutum became three times less sensitive to Zn when acclimated to 65 microg Zn/L compared to cultures in ISO medium. This review has revealed that currently accepted standard protocols used in regulatory frameworks contain a number of major shortcomings on the physicochemical and biological aspects of algal toxicity testing with metals. These shortcomings are summarized in Table 5, together with a number of suggestions that could help to modify and improve standard test protocols for evaluating metal toxicity to algae. Until now, important factors such as pH control during test performance, selection of test medium, test species, and the effects of possible adaptation/acclimation to natural metal concentrations have not been considered, which could have serious implications when the resulting unsuitable or irrelevant toxicity data are subsequently used for setting environmental management policies. These findings also have their consequences when extrapolating laboratory data to the field as the complexity of natural waters currently is not reflected in laboratory standard media. These media contain no dissolved organic matter, have a relatively high pH, and contain large amounts of essential nutrients. In addition, the limited number of laboratory test species do not reflect natural phytoplankton communities. Test procedures for assessing the environmental impact of metal contamination in a specified ecoregion should therefore be based on performing a battery of algal tests with species adapted to and tested under the specific natural conditions of the region.

Kates, R., M. Schmitt, et al. (2003). "Advanced statistical methods for the definition of new staging models." Recent Results Cancer Res 162: 101-13.

            Adequate staging procedures are the prerequisite for individualized therapy concepts in cancer, particularly in the adjuvant setting. Molecular staging markers tend to characterize specific, fundamental disease processes to a greater extent than conventional staging markers. At the biological level, the course of the disease will almost certainly involve interactions between multiple underlying processes. Since new therapeutic strategies tend to target specific processes as well, their impact will also involve interactions. Hence, assessment of the prognostic impact of new markers and their utilization for prediction of response to therapy will require increasingly sophisticated statistical tools that are capable of detecting and modeling complicated interactions. Because they are designed to model arbitrary interactions, neural networks offer a promising approach to improved staging. However, the typical clinical data environment poses severe challenges to high-performance survival modeling using neural nets, particularly the key problem of maintaining good generalization. Nonetheless, it turns out that by using newly developed methods to minimize unnecessary complexity in the neural network representation of disease course, it is possible to obtain models with high predictive performance. This performance has been validated on both simulated and real patient data sets. There are important applications for design of studies involving targeted therapy concepts and for identification of the improvement in decision support resulting from new staging markers. In this article, advantages of advanced statistical methods such as neural networks for definition of new staging models will be illustrated using breast cancer as an example.

Kyriazis, M. (2003). "Practical applications of chaos theory to the modulation of human ageing: nature prefers chaos to regularity." Biogerontology 4(2): 75-90.

            From time to time, novel ways of interpreting and modifying ageing mechanisms are proposed. Occasionally, these lead to a conceptual dead end, whereas at other times new and vital insights into basic ageing mechanisms are gained. This review concentrates on one such way of interpreting and manipulating ageing processes, based on chaos (dynamical systems) theory. One prediction of this theory is that a wide-ranging loss of physiological complexity from molecular to cellular, and from tissue to organismic levels accompanies ageing and age-related diseases. Although this view has been criticised, and arguments have been put forward to claim that there is also an increase of complexity during ageing and dysfunction, this review holds that the interpretation of ageing as a simplification of physiological dynamical complexity offers clear advantages. Ageing changes can be quantified and the results of treatment monitored. Clinical benefits can be predicted and intervention strategies improved. Two main practical suggestions for achieving successful ageing at the clinical level are examined. First, chaos theory challenges the traditional pharmacological regimes and implies that, for maximum benefit, medication aimed at modifying some of the signs of ageing should be given at irregular, pulsed or multiple intervals, and at constantly changing dosage strengths. Second, for preventing age-related disability, it is necessary to introduce and maintain a multiplicity of external and internal physiological stimuli, such as variable physical and mental exercise regimes.

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.

Lamont, S. J. (2003). "Unique population designs used to address molecular genetics questions in poultry." Poult Sci 82(6): 882-4.

            The ability to answer some of the questions of fundamental interest in functional genetics depends upon the utilization of appropriate and sometimes quite novel population designs. We will explore examples of how unique population designs of varied complexity can be used to explore questions, such as the following. What is the number of genes controlling different biological traits? Can streamlined genetics at the whole-animal level help to dissect complex genetic traits? Are there beneficial alleles "hiding" in undeveloped lines? To what extent is the expression of a specific gene modified by interactions with other genes in the population? Unique genetic resources, combined with novel experimental designs and contemporary analytical techniques, provide exceptional opportunities to explore both fundamental and practical questions in biological sciences.

Lewis, W. (2003). "Use of the transgenic mouse in models of AIDS cardiomyopathy." Aids 17 Suppl 1: S36-45.

            Heart disease in AIDS, particularly cardiomyopathy (CM), is an increasingly recognized clinical problem with as yet undefined pathogenetic mechanisms. Among the potential etiologies of AIDS CM are HIV-1 infection of cardiac myocytes and subsequent cardiac dysfunction, opportunistic infection, inflammatory reactions, cytokine effects, and cardiotoxicity of prescribed or illicit drugs. It seems probable that multiple factors may impact on the development of CM in AIDS. Transgenic mice (TG) are useful biological tools to explore mechanisms of cardiac function and disease. In AIDS models, TG offer novel ways to elucidate mechanisms of AIDS CM through combined in vivo and in vitro studies. With targeted and non-targeted TG, structural and functional effects of specific HIV-1 gene products on heart tissue may be addressed. The impact of environmental agents including therapeutics or cardiotoxins may also be defined. To address the complexity of AIDS CM using TG, an experimental approach has been employed in our laboratories to model the clinical condition. We utilize AIDS TG with generalized expression of HIV-1 gene products in CM models with combined antiretroviral regimens to define the cardiovascular effects of AIDS and its therapy on the structure and function of the murine heart. We are developing a series of cardiac specific TG bearing selected HIV-1 genes. These TG target the selected HIV-1 genes expressed in cardiac ventricular myocytes. Tissue-specific targeting of this type enables us to define structural and functional effects of specific HIV-1 gene products on the cardiac myocyte.

Luisi, P. L. (2003). "Autopoiesis: a review and a reappraisal." Naturwissenschaften 90(2): 49-59.

            The aim of the paper is to review critically the notion of autopoiesis as presented by Maturana and Varela. In particular, recognizing that there are difficulties in obtaining a complete and clear picture from the primary literature, an effort is made to present a coherent view-also based on many years of personal contact with Francisco Varela. The paper begins with a few historical notes to highlight the cultural background from which the notion of autopoiesis arose. The basic principles of autopoiesis as a theory of cellular life are then described, emphasizing also what autopoiesis is not: not an abstract theory, not a concept of artificial life, not a theory about the origin of life-but rather a pragmatic blueprint of life based on cellular life. It shown how this view leads to a conceptually clear definition of minimal life and to a logical link with related notions, such as self-organization, emergence, biological autonomy, auto-referentiality, and interactions with the environment. The perturbations brought about by the environment are seen as changes selected and triggered by the inner organization of the living. These selective coupling interactions impart meaning to the minimal life and are thus defined by Maturana and Varela with the arguable term of "cognition". This particular view on the mutual interactions between living organism and environment leads these authors to the notion of "enaction", and to the surprising view that autopoiesis and cognition are two complementary, and in a way equivalent, aspects of life. It is then shown how cognition, so defined, permits us to build a bridge between biology and cognitive science. Autopoiesis also allows one to conceive chemical models of minimal cellular life that can be implemented experimentally. The corresponding work on "chemical autopoiesis" is then reviewed. The surprising impact of autopoiesis in the social sciences ("social autopoiesis") is also briefly discussed. This review also comments on why the theory of autopoiesis had, and still has, a difficult time being accepted into the mainstream of life-science research. Finally, it is pointed out that the new interest in system biology and complexity theories may lead to a reappraisal of autopoiesis and related notions, as outlined also by other authors, such as Tibor Ganti and Stuart Kauffmann.

Mahler, M., M. Bluthner, et al. (2003). "Advances in B-cell epitope analysis of autoantigens in connective tissue diseases." Clin Immunol 107(2): 65-79.

            The characterization of autoantibody specificities in rheumatic diseases is important in both diagnostic and basic research areas. Identification of the epitopes recognized by autoantibodies and their clinical and biological significance is not a trivial task. Epitopes may range in complexity from simple linear sequences of amino acids to complex quaternary structures. In addition to this structural complexity the frequency with which an autoantigen and its epitopes are recognized in a patient population may be useful in diagnosis, defining disease subgroups, and may offer information on disease prognosis. In this review recent advances in the epitope mapping of autoantigens in connective tissue diseases are discussed, with particular emphasis placed on the methodologies used to identify epitopes and the classification of the structural features of epitopes. To illustrate the identification of epitope structure, clinically relevant autoantigens, including CENP-A, PM/Scl-100, fibrillarin, filaggrin, Ro-52, and dsDNA, are discussed as examples of each type of epitope.

Marriott, P. J., P. Haglund, et al. (2003). "A review of environmental toxicant analysis by using multidimensional gas chromatography and comprehensive GC." Clin Chim Acta 328(1-2): 1-19.

            The purpose of this review is to highlight the developments in coupled-column gas chromatography methods for qualitative analysis of selected environmental toxicants such as dioxin, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), etc. In particular, the new technique of GC x GC will be introduced, and its role, and the promise it offers to this field is discussed. The benefits of enhanced separation to quantitative analysis will be considered. In order to perform an accurate risk assessment, both the dose and biological effects of environmental toxicants have to be determined with a high degree of certainty. This is most often achieved by using chromatographic methods. Given the complexity of most environmental sample extracts, single-column gas chromatography is unable to fully resolve all the components of interest frequently leading to a positive bias in the reported concentrations. Advanced separation tools, such as multidimensional gas chromatography (MDGC), were investigated quite early and demonstrated improvements in separation. However, limitations in the number of target analytes that could be analyzed in a single run as well as insufficient robustness lead to a continued interest in alternative solutions. The parallel development of mass spectrometric identification and quantification strategies proved useful in many cases, although it frequently failed to provide positive identification of chromatographically unresolved isomeric compounds. More recently, comprehensive two-dimensional gas chromatography (GC x GC) may offer a solution to that problem, especially because it offers enhanced resolution for complex mixtures containing trace level environmental toxicants.

Mazumder, B., V. Seshadri, et al. (2003). "Translational control by the 3'-UTR: the ends specify the means." Trends Biochem Sci 28(2): 91-8.

            In most cases, translational control mechanisms result from the interaction of RNA-binding proteins with 5'- or 3'-untranslated regions (UTRs) of mRNA. In organisms ranging from viruses to humans, protein-mediated interactions between transcript termini result in the formation of an RNA loop. Such RNA 'circularization' is thought to increase translational efficiency and, in addition, permits regulation by novel mechanisms, particularly 3'-UTR-mediated translational control. Two general mechanisms of translational inhibition by 3'-UTR-binding proteins have been proposed, one in which mRNA closure is disrupted and another in which mRNA closure is required. Experimental evidence for the latter is provided by studies of interferon-gamma-mediated translational silencing of ceruloplasmin expression in monocytic cells. A multi-species analysis has shown that, in most vertebrates, 3'-UTRs are substantially longer than their 5' counterparts, indicating a significant potential for regulation. In addition, the average length of 3'-UTR sequences has increased during evolution, suggesting that their utilization might contribute to organism complexity.

Naldini, A., A. Pucci, et al. (2003). "Regulation of angiogenesis by Th1- and Th2-type cytokines." Curr Pharm Des 9(7): 511-9.

            Angiogenesis is a complex process, where several cell types and mediators interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels. Such biological processes occur in several physiological conditions, such as embryo development and wound healing, as well as in pathological conditions, including tumours and diabetic retinopathy. T lymphocytes, neutrophils and monocytes fully participate in the angiogenic process by secreting cytokines that may control endothelial cell (EC) proliferation, their survival and apoptosis, as well as their migration and activation. Angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. This balance is conceptually very similar to that of the Th1/Th2 cells that modulate an appropriate and specific immune response. Th1 or Th2 cytokines may control angiogenesis directly, by acting on cell growth and differentiation, indirectly by inducing the release of other cytokines in the microenvironment, and by modulating the expression of specific receptors, involved in the control of angiogenic processes, such as EC proliferation and migration. In this review we will mainly discuss the role of Th1- and Th2-type cytokines in the angiogenic process, emphasizing the complexity of the cytokine and leukocyte/EC network, and highlighting the care that needs to be taken when designing new therapeutic interventions involving Th1 and Th2 cytokines.

Newmeyer, D. D. and S. Ferguson-Miller (2003). "Mitochondria: releasing power for life and unleashing the machineries of death." Cell 112(4): 481-90.

            The mitochondrion has long been known both as a chemical powerplant and as a cellular compartment housing various biosynthetic pathways. However, studies on the function of mitochondria in apoptotic cell death have revealed a versatility and complexity of these organelles previously unsuspected. The mechanisms proposed for mitochondrial involvement in cell death are diverse and highly controversial. In one model, mitochondria are seen as passive containers that can be made to leak out cytotoxic proteins. In other scenarios, however, certain more or less familiar aspects of mitochondrial physiology, such as oxidative phosphorylation, generation of oxygen radicals, dynamic morphological rearrangements, calcium overload, and permeability transition, are proposed to play crucial roles. In this review, we examine a few promising mechanisms that have been gaining attention recently.

Pallone, T. L., M. R. Turner, et al. (2003). "Countercurrent exchange in the renal medulla." Am J Physiol Regul Integr Comp Physiol 284(5): R1153-75.

            The microcirculation of the renal medulla traps NaCl and urea deposited to the interstitium by the loops of Henle and collecting ducts. Theories have predicted that countercurrent exchanger efficiency is favored by high permeability to solute. In contrast to the conceptualization of vasa recta as simple "U-tube" diffusive exchangers, many findings have revealed surprising complexity. Tubular-vascular relationships in the outer and inner medulla differ markedly. The wall structure and transport properties of descending vasa recta (DVR) and ascending vasa recta (AVR) are very different. The recent discoveries of aquaporin-1 (AQP1) water channels and the facilitated urea carrier UTB in DVR endothelia show that transcellular as well as paracellular pathways are involved in equilibration of DVR plasma with the interstitium. Efflux of water across AQP1 excludes NaCl and urea, leading to the conclusion that both water abstraction and diffusion contribute to transmural equilibration. Recent theory predicts that loss of water from DVR to the interstitium favors optimization of urinary concentration by shunting water to AVR, secondarily lowering blood flow to the inner medulla. Finally, DVR are vasoactive, arteriolar microvessels that are anatomically positioned to regulate total and regional blood flow to the outer and inner medulla. In this review, we provide historical perspective, describe the current state of knowledge, and suggest areas that are in need of further exploration.

Parente, L. and M. Perretti (2003). "Advances in the pathophysiology of constitutive and inducible cyclooxygenases: two enzymes in the spotlight." Biochem Pharmacol 65(2): 153-9.

            The aim of this commentary is to discuss recent data on the role of prostaglandins generated by both constitutive and inducible cyclooxygenases (COXs). According to a popular hypothesis, COX-1 generates 'good' prostaglandins for physiological 'housekeeping' functions like gastrointestinal (GI) mucosal integrity and regulation of renal blood flow, while COX-2 forms the 'bad' prostaglandins responsible for inflammatory symptoms. However, recent data show that the biological functions of prostanoids formed by the two enzymes are much more complex and interrelated than previously appreciated. Experimental evidence indicates that a full inflammatory response is likely sustained by prostanoids generated by both enzymes, and an effective anti-inflammatory effect requires the inhibition of the two enzymes. Similarly, the selective inhibition of either COX-1 or COX-2 does not elicit GI damage, but inhibition of both enzymes is necessary for GI mucosal damage to develop. Prostaglandins generated by both enzymes contribute to normal renal function by regulating the vascular tone and the normal blood flow. The synthesis of endothelial prostacyclin is mainly driven by COX-2, so that the selective COX-2 inhibition may bias vascular prostaglandin synthesis in favour of COX-1-derived thromboxane A(2) in platelets, leading to a prothrombotic outcome. Moreover, prostaglandins formed by COX-2 appear to have a major role in myocardial protection. We propose that the complexity of the situation in the field of COX-derived mediators should be borne in mind when anti-inflammatory therapy is required.

Pettinati, H. M., H. R. Kranzler, et al. (2003). "The status of serotonin-selective pharmacotherapy in the treatment of alcohol dependence." Recent Dev Alcohol 16: 247-62.

            Research performed during the past 20 years has shown that serotonin (5-hydroxytryptamine; 5-HT) neurotransmission is related to alcohol dependence. Both theoretical and empirical research have supported the idea that alcohol dependence is a chronic disease and that, in addition, biological vulnerabilities contribute to the pathogenesis of alcohol dependence. Preclinical studies have consistently demonstrated that there is a relationship between 5-HT function and alcohol consumption. Furthermore, there is evidence building that lends support for the existence of distinct alcoholic subtypes that may be differentiated by the type or complexity of their 5-HT dysfunction. Beyond excessive drinking, behaviors that are indicators of 5-HT dysregulation are depression, anxiety, impulsiveness, and early-onset problem drinking. This chapter will discuss the usefulness of 5-HT-selective pharmacotherapy in treating alcohol dependence and will provide both historical and current perspectives on its use.

Pozzan, T., M. Mongillo, et al. (2003). "The Theodore Bucher lecture. Investigating signal transduction with genetically encoded fluorescent probes." Eur J Biochem 270(11): 2343-52.

            Ca2+ and cAMP are ubiquitous second messengers in eukaryotes and control numerous physiological responses ranging from fertilization to cell death induction. To distinguish between these different responses, their subtle regulation in time, space and amplitude is needed. Therefore, the characterization of the signalling process requires measurement of second messengers with tools of precise localization, high dynamic range and as little disturbance of cell physiology as possible. Recently, fluorescent proteins of marine jellyfish have given rise to a set of genetically encoded biosensors which fulfil these criteria and which have already led to important new insights into the subcellular handling of Ca2+ and cAMP. The use of these probes in combination with new microscopical methods such as two-photon microscopy now enables researchers to study second messenger signalling in intact tissues. In this review, the genetically encoded measurement probes and their origin are briefly introduced and some recent insights into the spatio-temporal complexity of both Ca2+ and cAMP signalling obtained with these tools are discussed.

Ralhan, R. and J. Kaur (2003). "Retinoids as chemopreventive agents." J Biol Regul Homeost Agents 17(1): 66-91.

            Retinoids are promising agents for cancer chemoprevention. The myriad effects of retinoids on biological processes including development, differentiation, homeostasis, carcinogenesis and apoptosis are mediated through their molecular targets, the retinoid and rexinoid receptors. Tissue specific expression patterns, ligand specificities, receptor numbers, their distinct functions and functional redundancy make retinoid signaling highly complex. The cross-talks of these receptors with cell surface receptors signaling pathways, as well as their interactions with multiple co-activators and co-repressors further add to the complexity of the pleiotropic effects of retinoids. Elucidation of retinoid signaling pathways and indepth understanding of the mechanisms that underlie the anti-proliferative and apoptotic action of retinoids has paved the way for designing synthetic retinoids for effective chemoprevention and therapy of cancer. Development of receptor selective synthetic retinoids is a major focus of molecular retinoid development. Other new avenues encompass identification of novel retinoid regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving receptor-independent apoptosis inducing activity and synergistic combinations with other agents for cancer prevention and therapy. This review focuses on recent advances in the understanding of molecular mechanisms underlying the action of retinoids and retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in context of chemoprevention. The clinical efficacy of retinoid based chemoprevention trials is discussed.

Ricard, J. (2003). "What do we mean by biological complexity?" C R Biol 326(2): 133-40.

            The purpose of the present paper is to offer a precise definition of the concepts of integration, emergence and complexity in biological networks through the use of the information theory. If two distinct properties of a network are expressed by two discrete variables, the classical subadditivity principle of Shannon's information theory applies when all the nodes of the network are associated with these properties. If not, the subadditivity principle may not apply. This situation is often to be encountered with enzyme and metabolic networks, for some nodes may well not be associated with these two properties. This is precisely what is occurring with an enzyme that binds randomly its two substrates. This situation implies that an enzyme, or a metabolic network, may display a joint entropy equal, smaller, or larger than the corresponding sum of individual entropies of component sub-systems. In the first case, the collective properties of the network can be reduced to the individual properties of its components. Moreover, the network is devoid of any information. In the second case, the system displays integration effects, behaves as a coherent whole, and has positive information. But if the joint entropy of the network is smaller than the sum of the individual entropies of its components, then the system has emergent collective properties and can be considered complex. Moreover, under these conditions, its information is negative. The extent of negative information is enhanced if the enzyme, or the metabolic network, is far away from equilibrium.

Rosenberg, E. (2003). "The potential of organic (electrospray- and atmospheric pressure chemical ionisation) mass spectrometric techniques coupled to liquid-phase separation for speciation analysis." J Chromatogr A 1000(1-2): 841-89.

            The use of mass spectrometry based on atmospheric pressure ionisation techniques (atmospheric pressure chemical ionisation, APCI, and electrospray ionisation, ESI) for speciation analysis is reviewed with emphasis on the literature published in and after 1999. This report accounts for the increasing interest that atmospheric pressure ionisation techniques, and in particular ESI, have found in the past years for qualitative and quantitative speciation analysis. In contrast to element-selective detectors, organic mass spectrometric techniques provide information on the intact metal species which can be used for the identification of unknown species (particularly with MS-MS detection) or the confirmation of the actual presence of species in a given sample. Due to the complexity of real samples, it is inevitable in all but the simplest cases to couple atmospheric pressure MS detection to a separation technique. Separation in the liquid phase (capillary electrophoresis or liquid chromatography in reversed phase, ion chromatographic or size-exclusion mode) is particularly suitable since the available techniques cover a very wide range of analyte polarities and molecular mass. Moreover, derivatisation can normally be avoided in liquid-phase separation. Particularly in complex environmental or biological samples, separation in one dimension is not sufficient for obtaining adequate resolution for all relevant species. In this case, multi-dimensional separation, based on orthogonal separation techniques, has proven successful. ESI-MS is also often used in parallel with inductively coupled plasma MS detection. This review is structured in two parts. In the first, the fundamentals of atmospheric pressure ionisation techniques are briefly reviewed. The second part of the review discusses recent applications including redox species, use of ESI-MS for structural elucidation of metal complexes, characterisation and quantification of small organometallic species with relevance to environment, health and food. Particular attention is given to the characterisation of biomolecules and metalloproteins (metallothioneins and phytochelatins) and to the investigation of the interaction of metals and biomolecules. Particularly in the latter field, ESI-MS is the ideal technique due to the softness of the ionisation process which allows to assume that the detected gas-phase ions are a true representation of the ions or ion-biomolecule complexes prevalent in solution. It is particularly this field, important to biochemistry, physiology and medical chemistry, where we can expect significant developments also in the future.

Saeglitz, C. and D. Bartsch (2003). "Regulatory and associated political issues with respect to Bt transgenic maize in the European union." J Invertebr Pathol 83(2): 107-9.

            Legislation at the national level in Europe as well as that developed by the European Union (EU) generally permits release and commercialization of genetically modified organisms (GMOs). However, only 10 plant/event combinations were registered as of 2002: three maize events (Bt176, Mon810, and Bt11), with the other seven divided among carnation (3), oil-seed rape (2), tobacco (1), and raddiccio (1). Of these, only one maize event (Bt176) has been registered as a legal variety, and this was in Spain, where 22,000ha have been planted annually since 1998. In this paper, we first provide an overview on the complexity of EU GMO legislation. Then we discuss the minor role that results of EU-funded biosafety research have had on governmental policy. Finally, we provide information about initiatives for post-commercialization monitoring plans of Bt maize in Europe. As a result of the slow progress to date, we conclude that commercialization of GMOs will be seriously delayed in the EU for the next several years.

Schreiber, G. and S. Avissar (2003). "Application of G-proteins in the molecular diagnosis of psychiatric disorders." Expert Rev Mol Diagn 3(1): 69-80.

            Mental disorders are highly prevalent and often difficult to diagnose. Although significant advances have been achieved in medication for mental disorders, the diagnosis and treatment monitoring of these disorders remain in a static situation. The absence of objective diagnostic 'gold standards', derives from the special complexity of diagnosis in psychiatry. Heterotrimeric G-proteins are crucial elements in post-receptor information transduction. These proteins have been implicated in the biochemical mechanism of action of drugs used to treat psychiatric disorders. G-protein measurements have unravelled a differential pattern characteristic of each of the major mental disorders. The accumulated data supports the potential use of G-protein measures as state-dependent markers for the biochemical diagnosis of mental disorders and as aid in the biochemical monitoring of the response to a specific treatment.

Shtiegman, K. and Y. Yarden (2003). "The role of ubiquitylation in signaling by growth factors: implications to cancer." Semin Cancer Biol 13(1): 29-40.

            Cancer cells depend on multiple, locally produced growth factors. Signaling by growth factors entails phosphorylation events, and its termination is determined primarily by endocytosis of growth factor receptor complexes. One group of growth factor receptors frequently implicated in human cancer is the ErbB family of receptor tyrosine kinases. By using ErbB as a prototype, here we review the role of protein ubiquitylation in the process that terminates signaling. Specifically, we concentrate on several adaptor proteins, including c-Cbl and Hgs, to elucidate the complexity of receptor sorting for degradation. Detailed understanding of ubiquitylation control on receptor desensitization may lead to better ways to diagnose and eradicate cancer.

Stanley, K. O. and R. Miikkulainen (2003). "A taxonomy for artificial embryogeny." Artif Life 9(2): 93-130.

            A major challenge for evolutionary computation is to evolve phenotypes such as neural networks, sensory systems, or motor controllers at the same level of complexity as found in biological organisms. In order to meet this challenge, many researchers are proposing indirect encodings, that is, evolutionary mechanisms where the same genes are used multiple times in the process of building a phenotype. Such gene reuse allows compact representations of very complex phenotypes. Development is a natural choice for implementing indirect encodings, if only because nature itself uses this very process. Motivated by the development of embryos in nature, we define artificial embryogeny (AE) as the subdiscipline of evolutionary computation (EC) in which phenotypes undergo a developmental phase. An increasing number of AE systems are currently being developed, and a need has arisen for a principled approach to comparing and contrasting, and ultimately building, such systems. Thus, in this paper, we develop a principled taxonomy for AE. This taxonomy provides a unified context for long-term research in AE, so that implementation decisions can be compared and contrasted along known dimensions in the design space of embryogenic systems. It also allows predicting how the settings of various AE parameters affect the capacity to efficiently evolve complex phenotypes.

Steiner, H., W. Kwan, et al. (2003). "Risk and protective factors for juvenile eating disorders." Eur Child Adolesc Psychiatry 12 Suppl 1: I38-6.

            Eating disorders are prevalent and complicated disorders which are difficult to treat. Unicausal and main effects models are not likely to do justice to the complexity of psychopathology encountered, as one considers etiology and pathogenesis. Risk and protection can arise out of several domains: biological, psychological and social. Risk and protective factors aggregate in specific developmental phases and interact to produce adverse outcomes. Temperamental factors, eating dysregulation, attachment, deficient self regulation and sociocultural ideals of health and beauty all contribute to pathogenesis. Applying the insights of developmental psychopathology to these disorders has considerable potential to lead to early and preventive interventions. Reviewing the current literature from this perspective and updating a similar discussion from 8 years ago, we witness a continued accumulation of quality empirical data. Compared to previous reviews, the field's attention has shifted to psychosocial/cultural domains relevant to eating, away from biological risk. In the aggregate, these data make possible the increasing differentiation of eating disorders from other psychopathology, and the specific pathways in which anorexia and bulimia may develop. Understanding of risk and vulnerability still outweighs our knowledge of protective factors and resilience. While an ideal study would be longitudinal, such studies are still extremely difficult to conduct and costly, thus, forcing us to further our understanding from lagged designs, cross-sectional data and case control studies. While these have many limitations, they do seem to produce an increasingly coherent account of the development of these disorders and prepare us for more targeted and longitudinal study of high risk populations.

Tang, G., H. K. Yip, et al. (2003). "Artificial mouth model systems and their contribution to caries research: a review." J Dent 31(3): 161-71.

            The complexity of the oral environment, and ethical problems associated with studies of oral diseases in humans inevitably directed the attention to development of laboratory models, that simulate the human oral microcosm. These developments and in particular the in vitro 'artificial mouth' systems have progressed from simple and basic apparatus devised by Magitot and Miller at the end of 19th century to the currently available, highly sophisticated, computer-controlled, multi-station artificial mouth systems. These advances have metamorphosed from the early studies devised primarily to investigate factors affecting the carious process to the present designs that evaluate growth, pathogenicity, metabolism and mineralization of dental plaque under highly controlled conditions. The modern 'artificial mouth systems' can evaluate microbial interactions in simulated dental plaque and similar biofilms and monitor their physical, chemical, biological and molecular features to a very high degree of accuracy. We review and trace here the historical aspects and developments leading to the currently available artificial mouth systems and discuss their contribution to the study of oral flora, especially related to many variants of dental caries.

Taylor, S. W., E. Fahy, et al. (2003). "Global organellar proteomics." Trends Biotechnol 21(2): 82-8.

            Cataloging the proteomes of single-celled microorganisms, cells, biological fluids, tissue and whole organisms is being undertaken at a rapid pace as advances are made in protein and peptide separation, detection and identification. For metazoans, subcellular organelles represent attractive targets for global proteome analysis because they represent discrete functional units, their complexity in protein composition is reduced relative to whole cells and, when abundant cytoskeletal proteins are removed, lower abundance proteins specific to the organelle are revealed. Here, we review recent literature on the global analysis of subcellular organelles and briefly discuss how that information is being used to elucidate basic biological processes that range from cellular signaling pathways through protein-protein interactions to differential expression of proteins in response to external stimuli. We assess the relative merits of the different methods used and discuss issues and future directions in the field.

Thellier, M., J. C. Vincent, et al. (2003). "Biological processes in organised media." C R Biol 326(2): 149-59.

            Embedding a simple Michaelis-Menten enzyme in a gel slice may allow the catalysis of not only scalar processes but also vectorial ones, including uphill transport of a substrate between two compartments, and may make it seem as if two enzymes or transporters are present or as if an allosterically controlled enzyme/transporter is operating. The values of kinetic parameters of an enzyme in a partially hydrophobic environment are usually different from those actually measured in a homogeneous aqueous solution. This implies that fitting kinetic data (expressed in reciprocal co-ordinates) from in vivo studies of enzymes or transporters to two straight lines or a sigmoidal curve does not prove the existence of two different membrane mechanisms or allosteric control. In the artificial transport systems described here, a functional asymmetry was sufficient to induce uphill transport, therefore, although the active transport systems characterised so far correspond to proteins asymmetrically anchored in a membrane, the past or present existence of structurally symmetrical systems of transport in vivo cannot be excluded. The fact that oscillations can be induced in studies of the maintenance of the electrical potential of frog skin by addition of lithium allowed evaluation of several parameters fundamental to the functioning of the system in vivo (e.g., relative volumes of internal compartments, characteristic times of ionic exchanges between compartments). Hence, under conditions that approach real biological complexity, increasing the complexity of the behaviour of the system may provide information that cannot be obtained by a conventional, reductionist approach.

Tian, B. and A. R. Brasier (2003). "Identification of a nuclear factor kappa B-dependent gene network." Recent Prog Horm Res 58: 95-130.

            Nuclear factor-kappa B (NF-kappaB) is a highly inducible transcription factor that plays an important role in the hepatic acute-phase response, innate/adaptive immunity, and cellular survival through the induction of genetic networks. The major transcriptional-activating species Rel A-NF-kappaB is a cytoplasmic complex whose nuclear translocation is controlled by its association with a family of inhibitory proteins, termed IkappaBs. Activation of NF-kappaB results in the targeted proteolysis of IkappaB, releasing NF-kappaB to enter the nucleus and bind to specific sequences in target promoters. Because the genomic actions of NF-kappaB are influenced by the stimulus applied and the promoter context/chromatin structure in which it binds, the spectrum of NF-kappaB-regulated genes has not been elucidated. We have begun to address this question, exploiting a tightly regulated cellular system expressing a nondegradable IkappaBalpha mutant that completely inhibits NF-kappaB action. High-density oligonucleotide microarrays were used to identify genetic responses in response to complex biological stimuli (viral replication) in the presence and absence of NF-kappaB. Using statistical and informatics tools, we identified two groups of NF-kappaB-dependent genes with distinct expression profiles: 1) a group with high constitutive expression whose expression levels fall in response to viral exposure and constitutive mRNA expression increases from NF-kappaB blockade, and 2) a group where constitutive expression was very low (or undetectable) and, after stimulation, expression levels strongly increased. In this group, NF-kappaB blockade inhibited the viral induction of genes. This latter cluster includes chemokines, transcriptional regulators, intracellular proteins regulating translation and proteolysis, and secreted proteins (e.g., complement components, growth factor regulators). These data reveal complexity in the genetic response to NF-kappaB and serve as a foundation for further informatics analysis to identify genetic features common to up- and downregulated NF-kappaB-dependent promoters.

Tompa, P. (2003). "Intrinsically unstructured proteins evolve by repeat expansion." Bioessays 25(9): 847-55.

            The proportion of the genome encoding intrinsically unstructured proteins increases with the complexity of organisms, which demands specific mechanism(s) for generating novel genetic material of this sort. Here it is suggested that one such mechanism is the expansion of internal repeat regions, i.e., coding micro- and minisatellites. An analysis of 126 known unstructured sequences shows the preponderance of repeats: the percentage of proteins with tandemly repeated short segments is much higher in this class (39%) than earlier reported for all Swiss-Prot (14%), yeast (18%) or human (28%) proteins. Furthermore, prime examples, such as salivary proline-rich proteins, titin, eukaryotic RNA polymerase II, the prion protein and several others, demonstrate that the repetitive segments carry fundamental function in these proteins. In addition, their repeat numbers show functionally significant interspecies variation and polymorphism, which underlines that these regions have been shaped by intense evolutionary activity. In all, the major point of this paper is that the genetic instability of repetitive regions combined with the structurally and functionally permissive nature of unstructured proteins has powered the extension and possible functional expansion of this newly recognized protein class.

Urena, P. (2003). "[The PTH/PTHrP receptor: biological implications]." Nefrologia 23 Suppl 2: 12-7.

            Since its discovery in 1923, the parathyroid hormone (PTH), was thought to be the sole hormone capable of stimulating bone resorption, renal tubular calcium reabsorption, calcitriol synthesis, and urinary excretion of phosphate. However, in 1987, the PTHrP (PTH-related peptide), was demonstrated to share most of the biological actions of PTH through the activation of the same receptor. This receptor was cloned in 1992 and named PTH/PTHrP receptor or PTH-R1. Both, PTH and PTHrP bind with great affinity to PTH-R1 and stimulate a signal transduction system involving different G-proteins, phospholipase C, and adenylate cyclase. A third member of the PTH family, the TIP-39 (tuberoinfundibular peptide), binds and activates another PTH receptor (PTH-R2). There is evidence for other PTH receptors, a PTH-R3, probably specific for PTHrP in keratinocytes, kidney, placenta and a PTH-R4 specific for C-terminal PTH fragments. Activating mutations in the PTH-R1 gene cause Jansen type metaphyseal chondrodysplasia, whereas inactivating mutations are responsible for Blomstrand type rare chondrodysplasia and enchondromatosis. The renal and bone PTH-R1 expression is upregulated in vitamin D deficient rats and by endotoxin, interleukin-2, dexamethasone, T3, and TGF beta. On the contrary, PTH, PTHrP, angiotensin-II, IGF-1, PGE2, vitamin D, and chronic renal failure decrease its expression. In conclusions, the biological implications of the identification and cloning of different PTH receptors are at their beginning. The almost ubiquitous distribution of PTHrP and PTH-R1, the numerous PTHrP and PTH fragments, let us suppose the existence of other PTH-related receptors, and a great complexity of the bone and mineral metabolism.

Vale, R. D. (2003). "The molecular motor toolbox for intracellular transport." Cell 112(4): 467-80.

            Eukaryotic cells create internal order by using protein motors to transport molecules and organelles along cytoskeletal tracks. Recent genomic and functional studies suggest that five cargo-carrying motors emerged in primitive eukaryotes and have been widely used throughout evolution. The complexity of these "Toolbox" motors expanded in higher eukaryotes through gene duplication, alternative splicing, and the addition of associated subunits, which enabled new cargoes to be transported. Remarkably, fungi, parasites, plants, and animals have distinct subsets of Toolbox motors in their genomes, suggesting an underlying diversity of strategies for intracellular transport.

Vereb, G., J. Szollosi, et al. (2003). "Dynamic, yet structured: The cell membrane three decades after the Singer-Nicolson model." Proc Natl Acad Sci U S A 100(14): 8053-8.

            The fluid mosaic membrane model proved to be a very useful hypothesis in explaining many, but certainly not all, phenomena taking place in biological membranes. New experimental data show that the compartmentalization of membrane components can be as important for effective signal transduction as is the fluidity of the membrane. In this work, we pay tribute to the Singer-Nicolson model, which is near its 30th anniversary, honoring its basic features, "mosaicism" and "diffusion," which predict the interspersion of proteins and lipids and their ability to undergo dynamic rearrangement via Brownian motion. At the same time, modifications based on quantitative data are proposed, highlighting the often genetically predestined, yet flexible, multilevel structure implementing a vast complexity of cellular functions. This new "dynamically structured mosaic model" bears the following characteristics: emphasis is shifted from fluidity to mosaicism, which, in our interpretation, means nonrandom codistribution patterns of specific kinds of membrane proteins forming small-scale clusters at the molecular level and large-scale clusters (groups of clusters, islands) at the submicrometer level. The cohesive forces, which maintain these assemblies as principal elements of the membranes, originate from within a microdomain structure, where lipid-lipid, protein-protein, and protein-lipid interactions, as well as sub- and supramembrane (cytoskeletal, extracellular matrix, other cell) effectors, many of them genetically predestined, play equally important roles. The concept of fluidity in the original model now is interpreted as permissiveness of the architecture to continuous, dynamic restructuring of the molecular- and higher-level clusters according to the needs of the cell and as evoked by the environment.

Vermeulen, K., D. R. Van Bockstaele, et al. (2003). "The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer." Cell Prolif 36(3): 131-49.

            The cell cycle is controlled by numerous mechanisms ensuring correct cell division. This review will focus on these mechanisms, i.e. regulation of cyclin-dependent kinases (CDK) by cyclins, CDK inhibitors and phosphorylating events. The quality checkpoints activated after DNA damage are also discussed. The complexity of the regulation of the cell cycle is also reflected in the different alterations leading to aberrant cell proliferation and development of cancer. Consequently, targeting the cell cycle in general and CDK in particular presents unique opportunities for drug discovery. This review provides an overview of deregulation of the cell cycle in cancer. Different families of known CDK inhibitors acting by ATP competition are also discussed. Currently, at least three compounds with CDK inhibitory activity (flavopiridol, UCN-01, roscovitine) have entered clinical trials.

Vettori, M. V., R. Alinovi, et al. (2003). "[In vitro models for the evaluation of the neurotoxicity of methylmercury. Current state of knowledge]." Med Lav 94(2): 183-91.

            BACKGROUND: In adults, MeHg poisoning is characterized by damage to discrete anatomical areas of the brain (visual cortex, loss of neurons from the granule layer of the cerebellum). However, the immature central nervous system (CNS), which is extremely sensitive to MeHg neurotoxicity, shows a diffuse and widespread damage disorganization of cerebral cortex cytoarchitecture, disappearance of granule cells with narrowing of the molecular layer. While adverse effects have been unequivocally demonstrated in poisoning incidents in humans (visual abnormalities, sensory impairment of the extremities, cerebellar ataxia, hearing loss, muscle weakness, tremor and mental deterioration), the implications of lower level exposures, such as those occurring in fish-eating populations, are still controversial. The high affinity of MeHg for thiol groups makes proteins and peptides bearing cysteines the predominant targets for structural and functional modification by MeHg in all subcellular compartments. METHODS: The identification of MeHg cellular and sub-cellular targets in the CNS is complicated by the fact that it is difficult to observe the outcomes directly in vivo. In neurobiology, in vitro cell culture techniques have been successfully developed and employed to address specific questions of cell biology and nervous system functioning and provide a means to systematically study the complexity of cellular functions of the CNS elements. Moreover, they provide a convenient experimental tool for testing possible functions or postulates in vivo that otherwise might not be conducted. RESULTS: Several mechanisms have been proposed as being implicated in the neurotoxic effects of MeHg. Examples of MeHg molecular effects which may be relevant to risk assessment are presented, including cell death mode, effects on microtubules, calcium signalling, oxidative stress, effects on neurotransmitter systems. CONCLUSIONS: Molecular and cellular approaches permit exploration of early biological responses to chemical or physical agents and definition of the role of these early effects in altered cellular structure and function.

Volff, J. N. and M. Schartl (2003). "Evolution of signal transduction by gene and genome duplication in fish." J Struct Funct Genomics 3(1-4): 139-50.

            Fishes possess more genes encoding receptor tyrosine kinases from the epidermal growth factor receptor (EGFR) family than other organisms. Three of the four genes present in higher vertebrates have been duplicated early during the evolution of the ray-finned fish lineage possibly as a consequence of an event of whole genome duplication. In the fish Xiphophorus, a much more recent local event of gene duplication of the egfr co-orthologue egfr-b generated a eighth gene, the Xmrk oncogene. This duplicate acquired within a short time a constitutive activity and a pigment cell-specific overexpression responsible for the induction of melanoma in certain interspecific hybrids. Despite its frequent loss during evolution of the genus Xiphophorus, the maintenance of Xmrk in numerous species and its evolution under purifying selection suggest a so far unknown function under certain natural conditions. One of the known functions of Xmrk in tumor cells is the suppression of differentiation of melanocytes induced by the microphthalmia-associated transcription factor MITF. While only one gene with alternative 5' exons and promoters is present in higher vertebrates, two mitf genes were identified in fish. Subfunctionalization of mitf paralogues by differential degeneration of alternative exons and regulatory sequences led particularly to the formation of a mitf gene specifically expressed in the melanocyte lineage. These observations validate fish as an outstanding model to study the mechanisms and biological consequences of gene and genome duplication but underline the complexity of the fish model and the caution necessary in transferring knowledge from fish to higher vertebrates and vice versa.

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.

Wood, I. S. and P. Trayhurn (2003). "Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins." Br J Nutr 89(1): 3-9.

            The number of known glucose transporters has expanded considerably over the past 2 years. At least three, and up to six, Na+-dependent glucose transporters (SGLT1-SGLT6; gene name SLC5A) have been identified. Similarly, thirteen members of the family of facilitative sugar transporters (GLUT1-GLUT12 and HMIT; gene name SLC2A) are now recognised. These various transporters exhibit different substrate specificities, kinetic properties and tissue expression profiles. The number of distinct gene products, together with the presence of several different transporters in certain tissues and cells (for example, GLUT1, GLUT4, GLUT5, GLUT8, GLUT12 and HMIT in white adipose tissue), indicates that glucose delivery into cells is a process of considerable complexity.

Zhou, H. (2003). "Pharmacokinetic strategies in deciphering atypical drug absorption profiles." J Clin Pharmacol 43(3): 211-27.

            Drug absorption is a very complex process that manifests itself through potential interaction with a host of physicochemical and physiological variables. Some factors that may affect the absorption processes include presystemic metabolism/efflux, the "absorption window" along the gastrointestinal tract, disease states, demographics (gender, age, ethnicity), and biopharmaceutical classification of solid dosage forms. Despite the complexity of the absorption processes, the analysis of the absorption kinetic data is mostly empirical, and the assumption of first-order absorption is axiomatic. Nevertheless, we often encounter irregular drug absorption profiles (such as double-peak, absorption window-type absorption profiles, etc.) that cannot be satisfactorily described by a simple first-order absorption process. The selection of an inappropriate absorption model would result in the misspecification of the pharmacokinetic model and subsequent erroneous prediction of the dosing regimen. This article presents several pharmacokinetic strategies in analyzing typical and atypical absorption profiles. The atypical absorption profiles discussed in this article include parallel first-order absorption, mixed zero-order and first-order absorption, Weibull-type absorption, absorption window with or without Michaelis-Menton absorption, time-dependent absorption, and inverse Gaussian density absorption. In any event, intravenous drug concentration-time data are generally needed to avoid the ambiguousness in the absorption analyses.

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