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PubMed2004

Digital three-dimensional models of Drosophila development.

Digital models of organs, cells and subcellular structures have become important tools in biological and medical research. Reaching far beyond their traditional widespread use as didactic tools, computer-generated models serve as electronic atlases to identify specific elements in complex patterns, and as analytical tools that reveal relationships between such pattern elements that would remain obscure in two-dimensional sections. Digital models also offer the unique opportunity to store and display gene-expression patterns, and pilot studies have been made in several genetic model organisms, including mouse, Drosophila and Caenorhabditis elegans, to construct digital graphic databases intended as repositories for gene-expression data.

Animals↗
PubMed2006

In vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

Tigecycline is a glycylcycline with promising broad-spectrum activity, including resistant Gram-positive organisms. This study characterizes in vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae (QRSP), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). An in vitro pharmacodynamic model generated specific bacterial kill profiles for tigecycline against clinical isolates of QRSP, MRSA and VRE. Tigecycline produced a 6.6 log total reduction and cleared QRSP from the pharmacodynamic model by 18 h. Tigecycline and vancomycin were unable to achieve 3-log reductions in the MRSA and VRE isolates; log reductions in MRSA and VRE were 1.5 and 1.2 logs for tigecycline and 2.8 and zero for vancomycin, respectively. Area under the concentration time curve to minimum inhibitory concentration (AUC/MIC) values for tigecycline ranged from 79 to 158 microg h/mL and tigecycline concentrations remained above the MIC (T>MIC) throughout the simulated dosing interval. Tigecycline showed in vitro activity against the QRSP, MRSA and VRE isolates studied. Low MIC values, prolonged elimination half-life and the associated post-antibiotic effect (PAE) observed with tigecycline are desirable attributes that make it a potentially attractive option for treating resistant Gram-positive organisms.

Anti-Bacterial Agents↗
PubMed2005

Respiratory flow in obstructed airways.

Chronic obstructive pulmonary disease (COPD) is one of the most common diseases in human community. The COPD always results in inflammation that leads to narrowing and obstruction of the airways. The obstructive airways have significant effect on respiratory flow. In order to understand the flow phenomenon in such obstructive airways, four three-dimensional four-generation lung models based on the 23-generation model of Weibel [1963. Morphometry of the Human Lung. Springer, Academic Press, Berlin, New York] are generated. The fully three-dimensional incompressible laminar Navier-Stokes equations are solved using computational fluid dynamics (CFD) solver on unstructured tetrahedral meshes. Therein, a symmetric four-generation airway model is served as the reference, the other three models are considered to be obstructed at each generation, respectively. The calculation results show that the obstructive airway has significant influence on the air flow in both up- and down-stream airways and it even results in flow separation in the conjunction region. The re-circulation cell blocks the air from entering the downstream branches. This may be the reason why COPD patients should breathe gently, and this also provides some valuable information for medicine powder deposition.

Airway Resistance↗
PubMed1995

[Geometrical modeling of the spine and the thorax for the biomechanical analysis of scoliotic deformities using the finite element method].

In order to study the biomechanical behavior of the whole human spine and thorax, as well as orthopaedic treatment effects, a new generation model is proposed, which includes a precise functional representation of the posterior part of the spine, while respecting computational capabilities. This paper presents the geometrical aspects of this model. The latter is built using an hybrid method which combines steroradiographic 3-D reconstructions of the spine and thorax [1] to serial CT scan 3-D reconstructions of typical human vertebrae and sternum [4] and published morphometric data of ribs [2, 3]. These anatomical structures were deformed in order to fit as well as possible the personalized data of scoliotic patients using geometrical transformations as well as interpolation or extrapolation techniques. In the posterior part, articular facets are modelled and parameterized as elementary surface shapes (plane, cylinder, sphere). For the articular facet geometry of a given normal subject, results revealed that the zygapophyseal facets are better represented by planes for T1 to T11 and by portions of cylinders for T12 to L5, which is in concordance with the literature [5, 6]. Evaluation of this modelling approach was done on 2 cadaveric vertebral segments. Parametric data obtained from the model were compared to precise measurements done on the vertebrae using a 3-D digitizer, and concordance was found. These personalized geometric informations were then used to build a finite element model [7], which will be useful to study scoliotic deformities as well as personalized orthopaedic treatments.

Humans↗
PubMed1993

Extending the multiple indicator dilution method to include slow intracellular diffusion.

The traditional multiple indicator dilution (MID) method is extended to incorporate cytoplasmic concentration gradients due to slow intracellular diffusion of the permeable molecule. The new model is governed by a system of partial differential equations that are solved using Laplace transformation. An analysis of the transformed solution shows that the traditional MID method is a special case of the extended model. We then use simulation analysis to show that the traditional MID model and the new diffusion model generate similar outflow curves. However, when the traditional MID equations were used to analyze outflow curves generated using a system in which intracellular diffusion is slow compared to other transport processes, the recovered rate constants for the transmembrane and excretion processes were incorrect. The diffusion model permits estimation of the rate of intracellular transport of amphipathic molecules from suitable indicator dilution data.

Animals↗
PubMedDate not supplied

Morphological analysis and modeling of neuronal dendrites.

Morphological data on two classes of neurons from mammalian midbrain have quantitatively been analyzed for dendritic shape parameters. Their frequency distributions were used to optimize the parameters of a dendritic growth model which describes dendritic morphology by a stochastic growth process of segment branching. The model assumes randomness with respect to both the selection of the branching segment out of the tree segments and the occurrence of the branching event in time. Model-generated trees have shape properties closely matching the observed ones. The dendritic trees of each of the two classes of neurons are represented by a specific set of growth model parameters, thus achieving morphological data compression.

Animals↗
PubMed2005

Approaches to determine clinical significance of genetic variants.

The clinical significance of genetic variants (single nucleotide polymorphisms, SNPs) has implications for risk assessment and also for predicting the outcome of a disease process, especially in response to intervention. Approaches to determine the clinical significance of genetic polymorphisms are now beginning to be developed. The technology tools and procedures currently available have significant potential in identifying and validating polymorphisms associated with environmentally sensitive phenotypes. Numerous concepts can now provide the methodology to selectively identify SNPs with the potential for impacting gene function. These include computational algorithms, biochemical assays, yeast mutagenicity assays, and epidemiological studies, either as a stand-alone screen, or in various combinations depending on the gene of interest. Proof of principle will ultimately depend on large-scale epidemiological and clinical studies, but will require intensive resources. Therefore, the use of the mouse as a preclinical biological model is paramount in helping screen valid SNPs or combinations of SNPs for human studies. But more importantly, mouse modeling will help answer the question of what role gene variants play in sensitivity or resistance to a wide variety of environmental insults ranging from toxic chemicals and carcinogens to more mundane and routine exposure items, such as dietary factors, air quality, over the counter and prescription medications, and ultraviolet light. Our focus on SNPs that result in an amino acid change is a matter of expediency because these variants are more amenable to the prescreening approaches currently available that are expected to help identify SNPs that affect protein function. The mouse models generated to evaluate the environmental relevance of selected SNPs will be extremely valuable biological tools to validate gene variant and environment interaction in a variety of settings. Informative mouse models will also provide the basis of pursuing relevant SNPs in epidemiological and clinical investigations.

Algorithms↗
PubMed2005

Convergence of auditory-nerve fiber projections onto globular bushy cells.

Globular bushy cells are a key element of brainstem circuits that mediate the early stages of sound localization. Many of their physiological properties have been attributed to convergence of inputs from the auditory nerve, many of which are large with complex geometry, but the number of these terminals contacting individual cells has not been measured directly. Herein we report, using cats as the experimental model, that this number ranged greatly (9-69) across a population of 12 cells, but over one-half of the cells (seven of 12) received between 15 and 23 inputs. In addition, we provide the first measurements of cell body surface area, which also varies considerably within this population and is uncorrelated with convergence. For one cell, we were able to document axonal structure over a distance greater than 100 microm, between the soma and the location where the axon expanded to its characteristic large diameter. These data were combined with accumulated physiological information on vesicle release, receptor kinetics and voltage-gated ionic conductances, and incorporated into computational models for four cells that are representative of the structural variation within our sample population. This predictive model reveals that basic physiological features, such as precise first spike latencies and peristimulus time histogram shapes, including primary-like with notch and onset-L, can be generated in these cells without including inhibitory inputs. However, phase-locking is not significantly enhanced over auditory-nerve fibers. These combined anatomical and computational approaches reveal additional parameters, such as active zone density, nerve terminal size, numbers and sources of inhibitory inputs and their activity patterns, that must be determined and incorporated into next-generation models to understand the physiology of globular bushy cells.

Action Potentials↗
PubMed2003

Non-peptide angiotensin II receptor antagonists: chemical feature based pharmacophore identification.

Chemical feature based pharmacophore models were elaborated for angiotensin II receptor subtype 1 (AT(1)) antagonists using both a quantitative and a qualitative approach (Catalyst HypoGen and HipHop algorithms, respectively). The training sets for quantitative model generation consisted of 25 selective AT(1) antagonists exhibiting IC(50) values ranging from 1.3 nM to 150 microM. Additionally, a qualitative pharmacophore hypothesis was derived from multiconformational structure models of the two highly active AT(1) antagonists 4u (IC(50) = 0.2 nM) and 3k (IC(50) = 0.7 nM). In the case of the quantitative model, the best pharmacophore hypothesis consisted of a five-features model (Hypo1: seven points, one hydrophobic aromatic, one hydrophobic aliphatic, a hydrogen bond acceptor, a negative ionizable function, and an aromatic plane function). The best qualitative model consisted of seven features (Hypo2: 11 points, two aromatic rings, two hydrogen bond acceptors, a negative ionizable function, and two hydrophobic functions). The obtained pharmacophore models were validated on a wide set of test molecules. They were shown to be able to identify a range of highly potent AT(1) antagonists, among those a number of recently launched drugs and some candidates presently undergoing clinical tests and/or development phases. The results of our study provide confidence for the utility of the selected chemical feature based pharmacophore models to retrieve structurally diverse compounds with desired biological activity by virtual screening.

Acrylates↗
PubMed1990

A dimension reduction framework for understanding cortical maps.

We argue that cortical maps, such as those for ocular dominance, orientation and retinotopic position in primary visual cortex, can be understood in terms of dimension-reducing mappings from many-dimensional parameter spaces to the surface of the cortex. The goal of these mappings is to preserve as far as possible neighbourhood relations in parameter space so that local computations in parameter space can be performed locally in the cortex. We have found that, in a simple case, certain self-organizing models generate maps that are near-optimally local, in the sense that they come close to minimizing the neuronal wiring required for local operations. When these self-organizing models are applied to the task of simultaneously mapping retinotopic position and orientation, they produce maps with orientation vortices resembling those produced in primary visual cortex. This approach also yields a new prediction, which is that the mapping of position in visual cortex will be distorted in the orientation fracture zones.

Animals↗
PubMed2000

Lateral arm fascial flap: microarterial anatomy and potential clinical applications.

Previously, muscle flaps and the omentum have been used to indirectly vascularize tissues. Induction of synangiogenesis, or indirect vascularization through the formation of collateral vessels, occurs through the development of vascular connections at the interface between the donor and recipient tissues. Unfortunately, muscle and omental flaps are bulky and, when used to salvage ischemic hands and digits, may limit digital range of motion. Additionally, disadvantages to using omentum include a requirement for an intraabdominal procedure and a lack of subsequent donor tissue if the contralateral limb becomes involved at a later time. The purpose of this anatomic study was to develop a customized lateral arm fascial flap (LAFF) which may be used for flap prefabrication or synangiogenesis of non-bypassable ischemia. Detailed anatomic dissections were performed to more thoroughly define the microvascular anatomy of the LAFF. Computer analysis of the data was performed to demonstrate the potential clinical application of using the LAFF. Dissections revealed a consistent pattern of vessels branching within the lateral arm fascia and to the neighboring musculature. In order to optimize the surgical use of available tissue, computer-aided design techniques were used to model a reliable fascial free flap for inducing synangiogenesis while imparting minimal donor-site morbidity. Anatomic studies of the LAFF revealed pitfalls in flap dissection, while computer-generated models illustrated the detailed microarterial anatomy of the LAFF and potential limitations in flap design. Potential clinical applications for use of this low-profile fasciovascular conduit are noted.

Arm↗
PubMed1996

Experimental verification of a mathematical model for pelleted growth of Streptomyces coelicolor A3(2) in submerged batch culture.

A published mathematical model for growth of pellets of filamentous microorganisms has been tested by comparison of model predictions with experimental data on growth of Streptomyces coelicolor in liquid batch culture. The original model considered the classification of pellets into a range of size classes. Growth resulted in movement of pellets to classes of increasing size, while shear forces produced mycelial fragments which entered the smallest size class, from which they grew to form further pellets. This model did not correctly describe changes in pellet size distributions during growth and was therefore modified in two ways. In the first, new pellets were assumed to be formed by the break-up, by shear forces, of existing pellets into two pellets of equal size, rather than removal of small hyphal fragments from the pellet surface. The second modification assumed that the outer shell of active mycelial biomass had a density less than 1 g cm-3 and that hyphal density within this shell decreased with distance from the pellet centre. The modified model generated predictions which agreed closely with experimental data on biomass concentration, pellet size distribution, pellet number and pellet radius during batch growth, thereby supporting the assumptions on which the model was based. The model did not accurately describe final biomass concentration, through lack of consideration of autolysis of mycelia at the centre of larger pellets in which growth was limited by diffusion of nutrients. Attempts to incorporate autolysis into the model improved prediction of biomass concentration but were not based on sound biological assumptions and increased the complexity of the model. Further experimental work is required for accurate description of the effects of autolysis on pellet growth.

Models, Theoretical↗
PubMed2006

Modeling opportunity costs of conservation in transitional landscapes.

Conservation scientists recognize the urgency of incorporating opportunity costs into conservation planning. Despite this, applications to date have been limited, perhaps partly because of the difficulty in determining costs in regions with limited data on land prices and ownership. We present methods for estimating opportunity costs of land preservation in landscapes or ecoregions that are a changing mix of agriculture and natural habitat. Our approach derives from the literature on estimating land values as opportunity costs of alternate land uses and takes advantage of general availability of necessary data, even in relatively data-poor regions. The methods integrate probabilities of habitat conversion with region-wide estimates of economic benefits from agricultural land uses and estimate land values with a discount rate to convert annual values into net present values. We applied our method in a landscape undergoing agricultural conversion in Paraguay. Our model of opportunity costs predicted an independent data set of land values and was consistent with implicit discount rates of 15-25%. Model-generated land values were strongly correlated with actual land values even after correcting for the effect of property size and proportion of property that was forested. We used the model to produce a map of opportunity costs and to estimate the costs of conserving forest within two proposed corridors in the landscape. This method can be applied to conservation planning in situations where natural habitat is currently being converted to market-oriented land uses. Incorporating not only biological attributes but also socioeconomic data can help in the design of efficient networks of protected areas that represent biodiversity at minimum costs.

Conservation of Natural Resources↗
PubMed2002

Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid.

Up-regulation of folate receptor (FR) type-beta in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-beta in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-beta lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent in FR-beta from AML cells from patient marrow, which bound folate. From flow cytometric analysis of 78 AML bone marrow specimens of different subtypes, 68% expressed FR-beta, most of which were also CD34+. In model cell lines that are FR - (KG-1a, L1210, and Chinese hamster ovary [CHO]) or FR + (KG-1, L1210 JF, and recombinant CHO-FR-beta), selective FR-mediated binding and cytotoxicity was obtained using folate-coated liposomes encapsulating fluorescent calcein (f-L-calcein) and doxorubicin (f-L-DOX), respectively, which could be blocked by 1 mM free folic acid. In the FR-beta-expressing KG-1 human AML cells, treatment with ATRA further increased this specificity. In mouse ascites leukemia models generated using L1210JF or KG-1 cells, increased median survival times were obtained with f-L-DOX treatment compared to nontargeted L-DOX. In the KG-1 model, ATRA treatment increased the cure rate with f-L-DOX from 10% to 60%. The above combined data from our 2 laboratories further support the feasibility and potential usefulness of selective ATRA-facilitated liposomal drug delivery in FR-beta + AMLs.

Animals↗
PubMed2003

Effect of two different videotaped instructional models on motor and verbal behaviors of adults' lifting: a pilot study.

This study examined two different videotaped instructional models on subsequent motor and verbal behaviors of adults (N=9) learning how to lift properly. The correct model group viewed a narrated videotape of a skilled individual demonstrating lifting; the learning model group viewed a videotape of an unskilled individual being taught lifting by an instructor, and the controls received no intervention. Adults lifted from floor to waist a plastic crate during 15 acquisition and 3 retention trials and lowered the crate from waist to floor during 3 transfer trials. Learning and correct model motor performances were similar yet higher than those of controls during acquisition and transfer trials. Verbal reports indicated learning, and correct models generated more extensive and associated mechanical concepts than controls yet rarely monitored such concepts during performance. A single presentation of videotapes of proper lifting using either correct or learning models is effective in enhancing motor performance and proper lifting knowledge.

Adolescent↗
PubMed1999

Three- and four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors.

The program Catalyst was used to build three-dimensional quantitative structure activity relationship (3D-QSAR) pharmacophore models of the structural features common to competitive-type inhibitors of cytochrome P-450 (CYP) 3A4. These were compared with 3D- and four-dimensional (4D)-QSAR partial least-squares (PLS) models built using molecular surface-weighted holistic invariant molecular (MS-WHIM) descriptors for size and shape of the inhibitor. The Catalyst pharmacophore model generated from multiple conformers of competitive inhibitors of CYP3A4-mediated midazolam 1'-hydroxylation (n = 14) yielded a high correlation of observed and predicted Ki values of r = 0.91. Similarly, PLS MS-WHIM was used to produce 3D- and 4D-QSARs for this data set and produced models that were statistically predictable after cross-validation. Two additional Catalyst pharmacophores were constructed from literature Ki values (n = 32) derived from the inhibition of CYP3A-mediated cyclosporin A metabolism and IC50 data (n = 22) from the inhibition of CYP3A4-mediated quinine 3-hydroxylation. These Catalyst pharmacophores illustrated correlations of observed and predicted inhibition for CYP3A4 of r = 0.77 and 0.92, respectively. The corresponding 4D-QSARs generated by PLS MS-WHIM for these data sets were of comparable quality as judged by cross-validation. Both Ki pharmacophores generated with Catalyst were also validated by predicting the Ki(apparent) values of a test set of eight CYP3A4 inhibitors not included in either model. In seven of eight cases, the residuals of the predicted Ki(apparent) values were within 1 log unit of the observed values. The 3D- and 4D-QSAR models produced in this study suggest the utility of future in silico prediction of CYP3A4-mediated drug-drug interactions.

Catalysis↗
PubMed2004

Models for the development of graduate entry medical courses: two case studies.

INTRODUCTION: The introduction of graduate entry medical courses requires attention to models of decision-making and change. Much of the educational literature describes change as either centralised or decentralised with the latter claimed to be more effective. Recently Fullan has argued for the importance of an ongoing culture of change. This paper examines the change culture of two medical schools adopting graduate entry courses; Flinders University in South Australia and St George's Hospital Medical School, London. METHOD: Comparative case study was used. Key informants were interviewed and documents and records analysed. Data were cross-checked and categorised to generate models of change. RESULTS: There were four components of the change culture at Flinders but they were not sufficient on their own to generate change. The process was triggered by a significant external event. The nature of the change was also important. The descriptive model developed suggested a complex interplay of factors rather than attributing the success of the change to the change mechanisms adopted alone. The model was tested for explanatory potential at St George's. The culture there was described as both 'macro-innovative' and 'micro-conservative'. External events were also important but they exerted a positive force. A more centralised approach was adopted. DISCUSSION: The models developed represent change as 'dynamic, complex and open' rather than a simple centralised or decentralised dichotomy. While some of the elements of a change culture were evident at both schools there were longer term questions of sustainability. This has implications for development of all programmes but particularly for graduate entry schools.

Australia↗
PubMed2006

Identification of active bacterial communities in a model drinking water biofilm system using 16S rRNA-based clone libraries.

Recent phylogenetic studies have used DNA as the target molecule for the development of environmental 16S rRNA gene clone libraries. As DNA may persist in the environment, DNA-based libraries cannot be used to identify metabolically active bacteria in water systems. In this study, an annular reactor was used to generate model drinking water biofilms grown on polycarbonate slides. High-quality RNA was extracted from 2-month-old biofilms and used to generate 16S rRNA-based clones. Sequencing analyses of 16S rRNA-based clones suggested that the active bacterial fraction consisted of a few dominant bacterial groups related to Nevskia ramosa and to uncultured bacteria. Several of these bacterial groups were closely related to clones characterized in a DNA-based clone library also generated in this study. Altogether, these results suggest that some of the predominant drinking water bacteria identified using DNA-based techniques are indeed active.

Bacteria↗