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The macro-ethics of genomics to health: the physiome project.

Advances in pharmacology and genomics, and their intervention in human biology are beyond our abilities to understand their consequences. Therapeutic intervention in highly complex, non-linear, adaptive biological systems results in some unforeseen and undesirable consequences. To do the most good with the least harm, the information on biological systems should be gathered into databases, and into comprehensive quantitative models that can help to predict the long-range effects of proposed interventions. This is a societal or professional macro-ethical imperative. The Physiome Project helps to meet this imperative via databasing and creating models and tools for large-scale integration.

Computational Biology↗

PubMed2005

Length control of the metaphase spindle.

BACKGROUND: The pole-to-pole distance of the metaphase spindle is reasonably constant in a given cell type; in the case of vertebrate female oocytes, this steady-state length can be maintained for substantial lengths of time, during which time microtubules remain highly dynamic. Although a number of molecular perturbations have been shown to influence spindle length, a global understanding of the factors that determine metaphase spindle length has not been achieved. RESULTS: Using the Drosophila S2 cell line, we depleted or overexpressed proteins that either generate sliding forces between spindle microtubules (Kinesin-5, Kinesin-14, dynein), promote microtubule polymerization (EB1, Mast/Orbit [CLASP], Minispindles [Dis1/XMAP215/TOG]) or depolymerization (Kinesin-8, Kinesin-13), or mediate sister-chromatid cohesion (Rad21) in order to explore how these forces influence spindle length. Using high-throughput automated microscopy and semiautomated image analyses of >4000 spindles, we found a reduction in spindle size after RNAi of microtubule-polymerizing factors or overexpression of Kinesin-8, whereas longer spindles resulted from the knockdown of Rad21, Kinesin-8, or Kinesin-13. In contrast, and differing from previous reports, bipolar spindle length is relatively insensitive to increases in motor-generated sliding forces. However, an ultrasensitive monopolar-to-bipolar transition in spindle architecture was observed at a critical concentration of the Kinesin-5 sliding motor. These observations could be explained by a quantitative model that proposes a coupling between microtubule depolymerization rates and microtubule sliding forces. CONCLUSIONS: By integrating extensive RNAi with high-throughput image-processing methodology and mathematical modeling, we reach to a conclusion that metaphase spindle length is sensitive to alterations in microtubule dynamics and sister-chromatid cohesion, but robust against alterations of microtubule sliding force.

Animals↗

PubMed2005

Pathway information for systems biology.

Pathway information is vital for successful quantitative modeling of biological systems. The almost 170 online pathway databases vary widely in coverage and representation of biological processes, making their use extremely difficult. Future pathway information systems for querying, visualization and analysis must support standard exchange formats to successfully integrate data on a large scale. Such integrated systems will greatly facilitate the constructive cycle of computational model building and experimental verification that lies at the heart of systems biology.

Animals↗

PubMed2005

A quantitative description of the activation and inhibition of CFTR by potentiators: Genistein.

The CFTR, encoded by the gene mutated in cystic fibrosis (CF) patients, is responsible for cAMP dependent chloride transport in epithelia. Substances that activate CFTR have been suggested as possible CF therapy. Most substances investigated so far exert a dual effect on the CFTR: low concentrations stimulate CFTR, whereas higher concentrations inhibit CFTR. Besides, the CFTR phosphorylation level determines the apparent affinity of the drug. We have studied the properties of genistein, the well known CFTR potentiator, by measuring apical membrane current on epithelia formed by cells stably transfected with CFTR and stimulated with different concentrations of CPTcAMP. We propose a quantitative model to describe the activatory and inhibitory effect of genistein, accounting also for the cAMP dependent activation.

Animals↗

PubMed2005

Transfollicular drug delivery--is it a reality?

Once regarded as merely evolutionary remnants, the hair follicles and sebaceous glands are increasingly recognised as potentially significant elements in the percutaneous drug delivery paradigm. Interest in pilosebaceous units has been directed towards their use as depots for localised therapy, particularly for the treatment of follicle-related disorders such as acne or the alopecias. Furthermore, considerable attention has also been focused on exploiting the follicles as transport shunts for systemic drug delivery. This paper reviews various key facets of this field including; relevant aspects of pilosebaceous anatomy and physiology, the design and efficacy of follicle-targeting formulations and the emergence of quantitative modeling systems. Several novel developments in this area promise to greatly expand our understanding of this field in the near future.

Administration, Cutaneous↗

PubMed2004

Interactions between two bubbles on a hot or cold wall.

A temperature gradient normal to a planar wall produces two-dimensional motion and aggregation or separation of bubbles on the hot or cold wall, respectively. The origin of the motion is fluid convection driven by the thermal Marangoni stress on the surface of the bubbles. Previous theories for the dynamics of two or more bubbles have been based on an analysis of flow about a single bubble and the resulting convection that entrains its neighbors. Here we extend the theory by solving the quasi-steady equations for the temperature and velocity fields for two bubbles. The result is a quantitative model for the relative velocity between two bubbles as a function of both the distance between them and the gap between each bubble and the surface. Interactions between the bubbles strongly increase the approach velocity, which is counter-intuitive because the hydrodynamic resistance increases as the bubbles approach each other. An asymptotic analysis indicates the thermocapillary force bringing them together or pushing them apart is singular in the separation when the bubbles are close to each other. The two-bubble theory agrees reasonably well with the experimentally measured velocities of pairs of bubbles on hot or cold surfaces, though it slightly overestimates the velocities.

Journal Article↗

PubMed2004

Designing of nanostructured hollow TiO2 spheres obtained by ultrasonic spray pyrolysis.

Theoretical model describing the mechanism of droplet formation and structure of hollow TiO2 spheres prepared by the process of ultrasonic spray pyrolysis, using colloidal solution consisting of the 2.5-nm TiO2 nanoparticles as a precursor, is developed. The proposed model quantitatively defines each line in the size distribution spectrum. The mechanism of droplet formation and/or particle genesis is fully determined by harmonization between the physical fields inherent to the system as the consequence of its physical characteristics: external, e.g., ultrasound, and internal. Agreement between theoretically obtained basic structural parameters (size distribution and geometry) and experimentally determined values was found.

Journal Article↗

PubMed2005

The role of polymer membrane formation in sustained release drug delivery systems.

A discussion of the role of polymer membrane-based drug delivery systems is presented. This is followed with a review of recent studies in our laboratories of the membrane formation and drug delivery characteristics of injectable polymer solution platforms. Attention is focused on the role of depot formulation in terms of solvent quality and water miscibility and polymer type (amorphous versus crystallizable), as well as the effects of bath-side additives on the in vitro release behavior. A quantitative model describing the protein release dynamics in fast phase inverting systems (FPI) is also discussed.

Crystallization↗

PubMed2004

Early events during folding of wild-type staphylococcal nuclease and a single-tryptophan variant studied by ultrarapid mixing.

A continuous-flow mixing device with a dead time of 100 micros coupled with intrinsic tryptophan and 1-anilinonaphthalene-8-sulfonate (ANS) fluorescence was used to monitor structure formation during early stages of the folding of staphylococcal nuclease (SNase). A variant with a unique tryptophan fluorophore in the N-terminal beta-barrel domain (Trp76 SNase) was obtained by replacing the single Trp140 in wild-type SNase with His in combination with Trp substitution of Phe76. A common background of P47G, P117G and H124L mutations was chosen in order to stabilize the protein and prevent accumulation of cis proline isomers under native conditions. In contrast to WT(*) SNase, which shows no changes in tryptophan fluorescence prior to the rate-limiting folding step ( approximately 100 ms), the F76W/W140H variant shows additional changes (enhancement) during an early folding phase with a time constant of 75 micros. Both proteins exhibit a major increase in ANS fluorescence and identical rates for this early folding event. These findings are consistent with the rapid accumulation of an ensemble of states containing a loosely packed hydrophobic core involving primarily the beta-barrel domain while the specific interactions in the alpha-helical domain involving Trp140 are formed only during the final stages of folding. The fact that both variants exhibit the same number of kinetic phases with very similar rates confirms that the folding mechanism is not perturbed by the F76W/W140H mutations. However, the Trp at position 76 reports on the rapid formation of a hydrophobic cluster in the N-terminal beta-sheet region while the wild-type Trp140 is silent during this early stage of folding. Quantitative modeling of the (un)folding kinetics and thermodynamics of these two proteins versus urea concentration revealed that the F76W/W140H mutation selectively destabilizes the native state relative to WT(*) SNase while the stability of transient intermediates remains unchanged, leading to accumulation of intermediates under equilibrium conditions at moderate denaturant concentrations.

Anilino Naphthalenesulfonates↗

PubMed2004

A phase cycle scheme that significantly suppresses offset-dependent artifacts in the R2-CPMG 15N relaxation experiment.

R2-CPMG 15N relaxation experiments form the basis of NMR dynamics measurements, both for analysis of nano-pico second dynamics and milli-micro second dynamics (kinetics). It has been known for some time that in the practical limit of finite pulse widths, which becomes acute when using cryogenic probes, systematic errors in the apparent R2 relaxation behavior occur for spins far off-resonance from the RF carrier. Inaccurate measurement of R2 rates propagates into quantitative models such as model-free relaxation analysis, rotational diffusion tensor analysis, and relaxation dispersion. The root of the problem stems from evolution of the magnetization vectors out of the XY-plane, both during the pulses as well as between the pulses. These deviations vary as a function of pulse length, number of applied CPMG pulses, and CPMG inter-pulse delay. Herein, we analyze these effects in detail with experimentation, numerical simulations, and analytical equations. Our work suggests a surprisingly simple change in the phase progression of the CPMG pulses, which leads to a remarkable improvement in performance. First, the applicability range of the CPMG experiment is increased by a factor of two in spectral width; second, the dynamical/kinetic processes that can be assessed are significantly extended towards the slower time scale; finally, the robustness of the relaxation dispersion experiments is greatly improved.

Artifacts↗

PubMed2005

Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy.

In an aqueous environment, polymorphic forms I-III of carbamazepine all convert to the dihydrate. This study investigated the conversion of each polymorphic form individually and of a mixture of forms III and I to the dihydrate. Two batches of form I with different crystal morphology were used. Samples were dispersed independently in water at 23+/-1 degrees C and recovered at various timepoints varying from 10 to 210 min. Scanning electron microscopy, X-ray powder diffraction and Raman spectroscopy were used to characterize the initial polymorphic forms and the recovered samples after 210 min. Raman spectroscopy combined with partial least squares analysis was used to generate quantitative models of binary and ternary mixtures of the different polymorphic forms with the dihydrate. On the basis of these models the conversion kinetics of the polymorphic forms I-III were characterized. First-order kinetics with an unconverted portion were used to model the data (R2> or =0.95). The unconverted portions ranged from 16 to 51% after dispersion for 210 min. The conversion kinetics were similar between polymorphic forms with comparable crystal morphology, but differed significantly between batches of the same polymorph (form I) with different crystal morphology. Furthermore, the conversion of forms III and I in the aqueous suspension was not influenced by the presence of the other polymorph when dispersed together.

Anticonvulsants↗

PubMed2006

Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening.

OBJECTIVES: To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. STUDY DESIGN: We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. RESULTS: Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. CONCLUSIONS: IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.

Biomarkers↗

PubMed2004

Bistability and switching in the lysis/lysogeny genetic regulatory network of bacteriophage lambda.

Bistability and switching are two important aspects of the genetic regulatory network of lambda phage. Positive and negative feedbacks are key regulatory mechanisms in this network. By the introduction of threshold values, the developmental pathway of lambda phage is divided into different stages. If the protein level reaches a threshold value, positive or negative feedback will be effective and regulate the process of development. Using this regulatory mechanism, we present a quantitative model to realize bistability and switching of lambda phage based on experimental data. This model gives descriptions of decisive mechanisms for different pathways in induction. A stochastic model is also introduced for describing statistical properties of switching in induction. A stochastic degradation rate is used to represent intrinsic noise in induction for switching the system from the lysogenic pathway to the lysis pathway. The approach in this paper represents an attempt to describe the regulatory mechanism in genetic regulatory network under the influence of intrinsic noise in the framework of continuous models.

Bacteriolysis↗

PubMed2005

Diagnosis of ventilator-associated pneumonia.

The diagnosis of ventilator pneumonia remains a controversial area. Use of standard clinical criteria has been found to be inadequate. Use of a clinical pulmonary infection score (CPIS) has improved the diagnostic utility of clinical criteria. For the intubated patient, there is ready access to the lower respiratory tract. Samples include endotracheal aspirates, bronchoalveolar lavage and protected brush specimen. The latter two can be obtained blindly or via a bronchoscope. The culture results are more meaningful if reported in a semi-quantitative model. There is increasing evidence that culture results predict mortality and can be used to direct duration and type of therapy.

Bacteria↗

PubMed2006

BOLD responses to stimuli: dependence on frequency, stimulus form, amplitude, and repetition rate.

A quantitative theory is developed for the relationship between stimulus and the resulting blood oxygen level-dependent (BOLD) functional MRI signal. The relationship of stimuli to neuronal activity during evoked responses is inferred from recent physiology-based quantitative modeling of evoked response potentials (ERPs). A hemodynamic model is then used to calculate the BOLD response to neuronal activity having the form of an impulse, a sinusoid, or an ERP-like damped sinusoid. Using the resulting equations, the BOLD response is analyzed for different forms, frequencies, and amplitudes of stimuli, in contrast with previous research, which has mostly concentrated on sustained stimuli. The BOLD frequency response is found to be closely linear in the parameter ranges of interest, with the form of a low-pass filter with a weak resonance at approximately 0.07 Hz. An improved BOLD impulse response is systematically obtained which includes initial dip and post-stimulus undershoot for some parameter ranges. It is found that the BOLD response depends strongly on the precise temporal course of the evoked neuronal activity, not just its peak value or typical amplitude. Indeed, for short stimuli, the linear BOLD response is closely proportional to the time-integrated activity change evoked by the stimulus, regardless of amplitude. It is concluded that there can be widely differing proportionalities between BOLD and peak activity, that this is the likely reason for the low level of correspondence seen experimentally between ERP sources and BOLD measurements and that non-BOLD measurements, such as ERPs, can be used to correct for this effect to obtain improved activity estimates. Finally, stimulus sequences that optimize the signal-to-noise ratio in event-related BOLD fMRI (efMRI) experiments are derived using the hemodynamic transfer function.

Brain↗

PubMed2006

Spatial and temporal patterns of serotonin release in the rat's lumbar spinal cord following electrical stimulation of the nucleus raphe magnus.

The monoamine neurotransmitter serotonin is released from spinal terminals of nucleus raphe magnus (NRM) neurons and important in sensory and motor control, but its pattern of release has remained unclear. Serotonin was measured by the high-resolution method of fast cyclic voltammetry (2 Hz) with carbon-fiber microelectrodes in lumbar segments (L3-L6) of halothane-anesthetized rats during electrical stimulation of the NRM. Because sites of serotonin release are often histologically remote from membrane transporters and receptors, rapid emergence into aggregate extracellular space was expected. Increased monoamine oxidation currents were found in 94% of trials of 50-Hz, 20-s NRM stimulation across all laminae. The estimated peak serotonin concentration averaged 37.8 nM (maximum 287 nM), and was greater in dorsal and ventral laminae (I-III and VIII-IX) than in intermediate laminae (IV-VI). When measured near NRM-evoked changes, basal monoamine levels (relative to dorsal white matter) were highest in intermediate laminae, while changes in norepinephrine level produced by locus ceruleus (LC) stimulation were lowest in laminae II/III and VII. The NRM-evoked monoamine peak was linearly proportional to stimulus frequency (10-100 Hz). The peak often occurred before the stimulus ended (mean 15.6 s at 50 Hz, range 4-35 s) regardless of frequency, suggesting that release per impulse was constant during the rise but fell later. The latency from stimulus onset to electrochemical signal detection (mean 4.2 s, range 1-23 s) was inversely correlated with peak amplitude and directly correlated with time-to-peak. Quantitative modeling suggested that shorter latencies mostly reflected the time below detection threshold (5-10 nM), so that extrasynaptic serotonin was significantly elevated well within 1 s. Longer latencies (>5 s), which were confined to intermediate laminae, appeared mainly to be due to diffusion from distant sources. In conclusion, except possibly in intermediate laminae, serotonergic volume transmission is a significant mode of spinal control by the NRM.

Afferent Pathways↗

PubMed2005

A recurring theme in protein engineering: the design, stability and folding of repeat proteins.

Repeat proteins are ubiquitous and are involved in a myriad of essential processes. They are typically non-globular structures that act as diverse scaffolds for the mediation of protein-protein interactions. These excitingly different structures, which arise from tandem arrays of a repeated structural motif, have generated significant interest with respect to protein engineering and design. Recent advances have been made in the design and characterisation of repeat proteins. The highlights include re-engineering of binding specificity, quantitative models of repeat protein stability and kinetic studies of repeat protein folding.

Humans↗

PubMed2005

Transport on fractal river networks: application to migration fronts.

A quantitative model of the US colonization in the 19th century is presented. We explore the idea that landscape heterogeneities should have strongly affected this process, as the need for water made the colonizers follow the routes of main rivers and set up their towns near them. So, we study transport processes on fractal networks modeling river basins, a case which may have a great ecological relevance for the study of hydrochory, and in general for species which spread along corridors. The analytical reaction-diffusion model presented here allows to predict the propagation rate of fronts spreading through Peano-like basins, and comparison with the Optimal Channels Network model is also reported. Finally, the propagation rates observed are compared with the results from our model, concluding that migration through fractal media, in spite of being a mathematical idealization of the problem, mimics the dynamics of real systems reasonably well.

Emigration and Immigration↗