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PubMed2006

Genetic instability and the quasispecies model.

Genetic instability is a defining characteristic of cancers. Microsatellite instability (MIN) leads to by elevated point mutation rates, whereas chromosomal instability (CIN) refers to increased rates of losing or gaining whole chromosomes or parts of chromosomes during cell division. CIN and MIN are, in general, mutually exclusive. The quasispecies model is a very successful theoretical framework for the study of evolution at high mutation rates. It predicts the existence of an experimentally verified error catastrophe. This catastrophe occurs when the mutation rates exceed a threshold value, the error threshold, above which replicative infidelity is incompatible with cell survival. We analyse the semiconservative quasispecies model of both MIN and CIN tumors. We consider the role of post-methylation DNA repair in tumor cells and demonstrate that DNA repair is fundamental to the nature of the error catastrophe in both types of tumors. We find that CIN introduces a plateau in the maximum viable mutation rate for a repair-free model, which does not exist in the case of MIN. This provides a plausible explanation for the mutual exclusivity of CIN and MIN.

Chromosomal Instability↗

PubMed2006

Visualisation of tibiofemoral contact in total knee replacement using optical device.

An in situ optical visualization technique (OVT) has been developed to identify the tibiofemoral contact (TFC) area during prosthesis indentation. An artificial total knee replacement (TKR) with borosilicate glass femoral component has been reproduced similarly to the original one. The medial and lateral contact areas have been observed, located and measured by means of in situ OVT. Therefore, it was experimentally possible to ensure a good axial alignment of the femoral component and tibial polyethylene insert. In addition, experimental measurement for load-displacement curves became reproducible. Furthermore, the evolution of the medial and lateral TFC areas as a function of the normal load was established. Finally, this study has shown that the in situ OVT is a simple in vitro method that provides comparable results with well-known methods such as Fuji film technique.

Arthroplasty, Replacement, Knee↗

PubMed2005

Evolution of solid state systems containing mutually coupled dipolar and quadrupole spins: perturbation treatment.

Perturbation approach to time evolution of multi-spin systems containing quadrupole and dipolar spins has been presented and discussed. The treatment comprises polarization transfer effects, field-dependent relaxation processes of dipolar as well as quadrupole spins and combined results of both of them. Complete theories dealing with various aspects of the spin dynamic processes have been proposed. Because of an educational character of this paper, relevant assumptions, limitations and even particular steps of the proposed treatments have been discussed in detail. Special emphasis is put on understanding of validity regimes of the perturbation treatment, depending on relative strengths of spin interactions and timescales of relevant motional processes affecting them. Motional regimes required for spins to be involved in essentially different evolution pathways like polarization transfers or relaxation have been illustrated by experimental examples.

Journal Article↗

PubMed1997

Spatially resolved in vitro molecular ecology.

Sensitive CCD-based fluorescence detection has made spatially resolved studies of evolving cell-free molecular systems possible. In recent years our attention has focussed on making the transition to open and interacting spatially-resolved amplification systems using silicon microreactor technology and on providing a hardware platform for individual based simulation of such systems. Significant progress has been achieved in this direction. Open microflow reactors have been realized in zero (well-mixed), one and two dimensions with volumes small enough to allow long-time studies with limited biochemical materials. The primer directed 3SR reaction (amplifying DNA and RNA) has been used as a basis for constructing interacting model systems with both predator-prey and cooperative amplification character. Theoretical work has demonstrated the need for individual based modeling of such systems: a significant fraction of the population consists of distinct sequence polymers in any case. A massively parallel processor-configurable computer NGEN has been designed and constructed which allows the high speed simulation in hardware of relatively large populations of locally interacting individual strings of chosen length (e.g. up to 2000*2000 for 64 bases), in addition to its application as an evolvable hardware machine. Simulations show self-replicating spots to stabilize the cooperative amplification in evolving systems (a mechanism proposed by the author in 1994). Both oscillatory kinetics and pattern formation are expected in the experimental model systems under investigation which profoundly affect the course of evolution. Such in vitro model systems serve both to test current theories of cooperative evolution and provide clues for optimisation strategies in molecular biotechnology.

Biotechnology↗

PubMed1998

Current therapy for Langerhans cell histiocytosis.

The changing concept of the pathogenesis of Langerhans cell histiocytosis over the past 50 years has been mirrored by evolving treatment regimens. The publications by the Histiocyte Society in the 1980s of diagnostic, clinical, and laboratory criteria allowed international collaboration in treatment trials. These, in turn, have allowed stratification of risk groups and the evolution of a salvage therapy protocol for the poorest risk patients. Experimental therapies now being evaluated may be the treatment strategies for the next decade.

Histiocytosis, Langerhans-Cell↗

PubMed2000

Trophic-dynamic considerations in relating species diversity to ecosystem resilience.

Complexity in the networks of interactions among and between the living and abiotic components forming ecosystems confounds the ability of ecologists to predict the economic consequences of perturbations such as species deletions in nature. Such uncertainty hampers prudent decision making about where and when to invest most intensively in species conservation programmes. Demystifying ecosystem responses to biodiversity alterations may be best achieved through the study of the interactions allowing biotic communities to compensate internally for population changes in terms of contributing to ecosystem function, or their intrinsic functional redundancy. Because individual organisms are the biologically discrete working components of ecosystems and because environmental changes are perceived at the scale of the individual, a mechanistic understanding of functional redundancy will hinge upon understanding how individuals' behaviours influence population dynamics in the complex community setting. Here, I use analytical and graphical modelling to construct a conceptual framework for predicting the conditions under which varying degrees of interspecific functional redundancy can be found in dynamic ecosystems. The framework is founded on principles related to food web successional theory, which provides some evolutionary insights for mechanistically linking functional roles of discrete, interacting organisms with the dynamics of ecosystems because energy is the currency both for ecological fitness and for food web commerce. Net productivity is considered the most contextually relevant ecosystem process variable because of its socioeconomic significance and because it ultimately subsumes all biological processes and interactions. Redundancy relative to productivity is suggested to manifest most directly as compensatory niche shifts among adaptive foragers in exploitation ecosystems, facilitating coexistence and enhancing ecosystem recovery after disturbances which alter species' relative abundances, such as extinctions. The framework further explicates how resource scarcity and environmental stochasticity may constitute 'ecosystem legacies' influencing the emergence of redundancy by shaping the background conditions for foraging behaviour evolution and, consequently, the prevalence of compensatory interactions. Because it generates experimentally testable predictions for a priori hypothesis testing about when and where varying degrees of functional redundancy are likely to be found in food webs, the framework may be useful for advancing toward the reliable knowledge of biodiversity and ecosystem function relations necessary for prudent prioritization of conservation programmes. The theory presented here introduces explanation of how increasing diversity can have a negative influence on ecosystem sustainability by altering the environment for biotic interactions and thereby changing functional compensability among biota--under particular conditions.

Animals↗

PubMed2005

Design principles of a bacterial signalling network.

Cellular biochemical networks have to function in a noisy environment using imperfect components. In particular, networks involved in gene regulation or signal transduction allow only for small output tolerances, and the underlying network structures can be expected to have undergone evolution for inherent robustness against perturbations. Here we combine theoretical and experimental analyses to investigate an optimal design for the signalling network of bacterial chemotaxis, one of the most thoroughly studied signalling networks in biology. We experimentally determine the extent of intercellular variations in the expression levels of chemotaxis proteins and use computer simulations to quantify the robustness of several hypothetical chemotaxis pathway topologies to such gene expression noise. We demonstrate that among these topologies the experimentally established chemotaxis network of Escherichia coli has the smallest sufficiently robust network structure, allowing accurate chemotactic response for almost all individuals within a population. Our results suggest that this pathway has evolved to show an optimal chemotactic performance while minimizing the cost of resources associated with high levels of protein expression. Moreover, the underlying topological design principles compensating for intercellular variations seem to be highly conserved among bacterial chemosensory systems.

Adaptation, Physiological↗

PubMed2005

Theoretical interpretation of the line shape of the gaseous acetic acid cyclic dimer.

A general quantum theoretical approach of the nu(X-H) IR line shape of cyclic dimers of weakly H-bonded species in the gas phase is proposed. In this model, the adiabatic approximation (allowing to separate the high frequency motion from the slow one of the H-bond bridge), is performed for each separate H-bond bridge of the dimer and a strong nonadiabatic correction is introduced into the model via the resonant exchange between the fast mode excited states of the two moieties. The present model reduces satisfactorily to many models in the literature dealing with more special situations. It has been applied to the cyclic dimers (CD(3)CO(2)H)(2) and (CD(3)CO(2)D)(2) in the gas phase. It correctly fits the experimental line shape of the hydrogenated compound and predict satisfactorily the evolution in the line shapes, to the deuterated one by reducing simply the angular frequency of the H-bond bridge and the anharmonic coupling parameter by the factor 1/ square root of 2.

Journal Article↗

PubMed2006

Theoretical interpretation of the line shape of crystalline adipic acid.

A general quantum theoretical approach of the upsilon(X-H) IR line shape of cyclic dimers of weakly H-bonded species in the crystal state is proposed. In this model, the adiabatic approximation (allowing to separate the high-frequency motion from the slow one of the H-bond bridge) is performed for each separate H-bond bridge of the dimer and a strong nonadiabatic correction is introduced into the model via the resonant exchange between the fast-mode excited states of the two moieties. Quantum indirect damping and Fermi resonances are taken into account. The present model reduces satisfactorily to many models in the literature dealing with more special situations. It has been applied to the cyclic dimers of adipic acid in the crystal phase. It correctly fits the experimental line shape of the hydrogenated compound and predicts satisfactorily the evolution in the line shapes with temperature and the change in the line shape with isotopic substitution.

Journal Article↗

PubMed2002

Population genomics of drug resistance in Candida albicans.

We followed adaptation in experimental microbial populations to inhibitory concentrations of an antimicrobial drug. The evolution of drug resistance was accompanied in all cases by changes in gene expression that persisted in the absence of the drug; the new patterns of gene expression were constitutive. The changes in gene expression occurred in four replicate populations of the pathogenic fungus Candida albicans during 330 generations of evolution in the presence of the antifungal drug fluconazole. Genome-wide expression profiling of over 5,000 ORFs identified 301 whose expression was significantly modulated. Cluster analysis identified three distinct patterns of gene expression underlying adaptation to the drug. One pattern was unique to one population and included up-regulation of the multidrug ATP-binding cassette transporter gene, CDR2. A second pattern occurred at a late stage of adaptation in three populations; for two of these populations profiled earlier in their evolution, a different pattern was observed at an early stage of adaptation. The succession of early- and late-stage patterns of gene expression, both of which include up-regulation of the multidrug major facilitator transporter gene, MDR1, must represent a common program of adaptation to this antifungal drug. The three patterns of gene expression were also identified in fluconazole-resistant clinical isolates, providing further evidence that these patterns represent common programs of adaptation to fluconazole.

ATP-Binding Cassette Transporters↗

PubMed1975

Molecular model of postsynaptic potential.

A molecular model of the excitatory postsynaptic membrane is given in terms of two biochemical cycles intimately associated: an acetylcholine cycle and a calcium cycle. The acetylcholine controls the Na ionophores while calcium ions control the tk ionophore. The two ionophores are spatially separated but interact in such a way that the variation in K conductance precedes that in Na conductance. Digital simulation shows that our model accounts quantitatively for both the evolution of excitatory postsynaptic potential and current in a variety of experimental conditions.

Acetylcholine↗

PubMed2004

Glycoprotein hormone assembly in the endoplasmic reticulum: III. The seatbelt and its latch site determine the assembly pathway.

Vertebrate glycoprotein hormone heterodimers are stabilized by a strand of their beta-subunits known as the "seatbelt" that is wrapped around loop 2 of their alpha-subunits (alpha2). The cysteine that terminates the seatbelt is "latched" by a disulfide to a cysteine in beta-subunit loop 1 (beta1) of all vertebrate hormones except some teleost follitropins (teFSH), wherein it is latched to a cysteine in the beta-subunit NH(2) terminus. As reported here, teFSH analogs of human choriogonadotropin (hCG) are assembled by a pathway in which the subunits dock before the seatbelt is latched; assembly is completed by wrapping the seatbelt around loop alpha2 and latching it to the NH(2) terminus. This differs from hCG assembly, which occurs by threading the glycosylated end of loop alpha2 beneath the latched seatbelt through a hole in the beta-subunit. The seatbelt is the part of the beta-subunit that has the greatest influence on biological function. Changes in its sequence during the divergence of lutropins, follitropins, and thyrotropins and the speciation of teleost fish may have impeded heterodimer assembly by a threading mechanism, as observed when the hCG seatbelt was replaced with its salmon FSH counterpart. Whereas wrapping is less efficient than threading, it may have facilitated natural experimentation with the composition of the seatbelt during the co-evolution of glycoprotein hormones and their receptors. Migration of the seatbelt latch site to the NH(2)-terminal end of the beta-subunit would have facilitated teFSH assembly by a wraparound mechanism and may have contributed also to its ability to distinguish lutropin and follitropin receptors.

Amino Acid Sequence↗

PubMed2005

Influence of the vehicle on the properties and efficacy of microparticles containing amphotericin B.

New microparticles containing amphotericin B (AMB) have been developed and manufactured by spray drying. To this end albumin, polylactic-co-glycolic acids (PLGA) and poly(sebacic anhydride) have been employed as drug carriers. The selection of the solvent used to disperse the drug and the vehicle before spray drying was critical on production yields and physical properties of the microparticles. Once particle size, morphology and dispersability in some aqueous media were shown to be acceptable for an intravenous administration, in vivo efficacy was evaluated and compared with the reference medicine Fungizone. Microparticles prepared with albumin, albumin heated at a high temperature, some kinds of PLGA or polyanhydride, as well as Fungizone, were tested in an experimental hamster model of infection with Leishmania infantum, by evaluating the evolution of parasitic burdens in spleen, liver and antibody responses. After the injection of three doses corresponding to 2 mg of AMB per kilogram each, diverse reactions were reported depending on the vehicle. The best dispersability, reduction of parasites and antibody response were achieved when the treatment was performed with AMB in albumin microspheres.

Albumins↗

PubMed1958

Metachromasy: an experimental and theoretical reevaluation.

Non-chromotropic substances such as fibrin and gelatin and most tissue and cellular structures stain orthochromatically with internal dye concentrations of such metachromatic dyes as methylene blue and toluidine blue which, if in solution, would be metachromatic. Therefore, at ordinary levels of staining these substances depress the natural tendency of these dyes to change color. However, at elevated levels of dye-binding metachromasy eventually occurs. This phenomenon is explained on the basis of the distribution of dye-binding sites. In these substrates, by contrast with chromotropic substances, many binding sites are too far removed for dye interaction, consequently the interaction frequency can become high enough to produce a color change only as saturation of the available sites is approached. It is also shown that the destruction of color is a characteristic of metachromasy and that water molecules intercalated between approximated dye ions are responsible for the loss and change of color. A concept of metachromasy is proposed in which the interaction between water molecules and suitably approximated dye ions plays an essential role. The experimental studies are described against a background of the history and evolution of ideas on metachromasy. The literature is reviewed and reassessed particularly from the physicochemical viewpoint.

Coloring Agents↗

PubMed1987

T cell subsets in multiple sclerosis. Gradients at plaque borders and differences in nonplaque regions.

This report provides a quantitative analysis of the distribution of helper-inducer T cells (H-I, LEU3A+) and cytotoxic-suppressor T cells (C-S, OKT8+) performed in a standardized fashion on material from 10 cases of multiple sclerosis. Particular attention was paid to cells at the plaque edge and to normal appearing white matter adjacent to plaques. Numbers of both the C-S and the H-I subset peaked directly at the edges of plaques, whether histopathologically active or inactive (P less than 0.01). Normal appearing areas outside active plaques had fewer C-S cells than equivalent areas outside inactive plaques (P less than 0.05). A study of three whole plaques showed that the sum of the two T cell subsets was significantly greater than the number of cells bearing the pan-T cell marker in two plaques and in two border regions. The present results support a crucial role for the balance of T cell subsets in the evolution of plaque margins. When taken together with similar findings in experimental allergic encephalomyelitis, they suggest that helper-inducer cell dominance at the border is necessary for plaque expansion while C-S dominance in non plaque areas is associated with controlled disease. In addition, they suggest either modulation of the OKT3 surface antigen or the presence of a non-T cell bearing OKT8 in association with the site of histopathological change.

Cell Count↗

PubMed1995

Increased intrapancreatic trypsinogen activation in ischemia-induced experimental pancreatitis.

OBJECTIVE: The potential of pancreatic ischemia to cause acute pancreatitis as indicated by morphologic changes and ectopic trypsinogen activation was investigated. BACKGROUND: Experimental evidence has shown that pancreatic ischemia is important in the evolution of severe pancreatitis, but whether ischemia can initiate pancreatitis has been disputed. METHODS: Pancreatic ischemia was induced in rats by hemorrhagic hypotension (30 mm Hg for 30 min; n = 64). Changes of pancreatic microcirculatory perfusion were studied using diffuse reflectance spectroscopy. Serum amylase, trypsinogen activation peptide (TAP) in serum and pancreatic tissue, wet/dry weight ratio, and histology were determined over 24 hours and compared with sham-operated control subjects (n = 35). RESULTS: In control animals, serum amylase (47.9 +/- 2.1 units/L), serum (7.9 +/- 0.7 nmol/L) and tissue TAP (63.0 +/- 5.4 nmol/L x g), wet/dry weight ratio (2.8 +/- 0.1), and histology remained unchanged. Temporary hypotension markedly decreased pancreatic perfusion with incomplete recovery after reperfusion. Pancreatic isoamylase activity increased within 1 hour (110 +/- 5 units/L, p < 0.05) and further to 151 +/- 18 units/L at 24 hours. Tissue TAP was elevated at 1 hour (134 +/- 16 nmol/L x g, p < 0.05) and increased to 341 +/- 43 nmol/L x g (p < 0.001) after 24 hours, whereas serum TAP remained unchanged (8.3 +/- 0.5 nmol/L). Morphologic alterations included elevated wet/dry weight ratio (4.1 +/- 0.3, p < 0.01) and increased histologic scores for edema (p < 0.05) and acinar necrosis (p < 0.05) at 24 hours. Trypsinogen activation preceded the development of pancreatic necrosis. CONCLUSIONS: In addition to its potentiating role, severe pancreatic ischemia can play a pathogenetic role in the initiation of acute pancreatitis.

Amylases↗

PubMed2001

Different classifications of UPOs in the parametrically different chaotic ISI series of a neural pacemaker.

Various interspike intervals (ISIs) in a series of spontaneous discharges of experimental neural pacemakers were identified as chaotic and as lying between stable period 2 and stable period 3. The method of So et al. for detection of unstable periodic orbits (UPOs) was applied to analyze two chaotic ISI series generated under the action of [Ca2+]o in different concentrations. In the chaotic ISI series near the stable period 2, an unstable period 2 orbit was detected. In the chaotic ISI series near the stable period 3, both an unstable period 2 orbit and an unstable period 3 orbit were detected. The location of the unstable period 2 orbit was close to that of the stable period 2 in the return map, while the location of the unstable period 3 orbit was close to that of the stable period 3. The results not only revealed the structures of various chaotic ISI series, but also indicated that the classification of UPOs could reflect the experimental control parameters at which the chaotic ISI series were generated. The previously discovered period adding bifurcation in the ISI series generated by experimental neural pacemakers [12] was further described in terms of the evolution of the period orbits.

Action Potentials↗

PubMed2002

Speckle statistics in a chaotic multimode fiber.

Wave chaos is devoted to the study of wave motion when the geometrical limit of rays is chaotic. Imprints of ray chaos may be found either in spectral and spatial properties of modes or in spatio-temporal evolution of wave packets. In this paper, we present a thorough experimental and theoretical analysis of field statistics for light propagating in a multimode fiber with a noncircular cross section. This optical fiber serves as a powerful tool to image waves in a system where light rays exhibit a chaotic dynamics. We show that, in the speckle regime, the experimentally measured statistical properties of intensity patterns are well accounted for by a "random Gaussian" hypothesis. A comparison is also made in the case of regular ray motion by using a circular optical fiber. Possible extensions and applications of the tools and concepts of wave chaos are mentioned in modern communication technology.

Journal Article↗