An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has major advantages over other immunosuppressive drugs, but frequent gastrointestinal (GI) side-effects limit its use. The mechanism(s) underlying MMF-related GI toxicity have yet to be elucidated. METHODS: To investigate MMF-related GI toxicity, experimental mice were fed chow containing MMF (0.563%) and multiple indices of toxicity, including weight loss and colonic inflammation, were measured. Changes in intestinal microbial composition were detected using 16S rRNA Illumina sequencing, and downstream PICRUSt analysis was used to predict metagenomic pathways involved. Germ-free (GF) mice and mice treated with orally administered broad-spectrum antibiotics (ABX) were utilized to interrogate the importance of the microbiota in MMF-induced GI toxicity. RESULTS: Mice treated with MMF exhibited significant weight loss, related to loss of body fat and muscle, and marked colonic inflammation. MMF exposure was associated with changes in gut microbial composition, as demonstrated by a loss of overall diversity, expansion of Proteobacteria (specifically Escherichia/Shigella), and enrichment of genes involved in lipopolysaccharide (LPS) biosynthesis, which paralleled increased levels of LPS in the feces and serum. MMF-related GI toxicity was dependent on the intestinal microbiota, as MMF did not induce weight loss or colonic inflammation in GF mice. Furthermore, ABX prevented and reversed MMF-induced weight loss and colonic inflammation. CONCLUSIONS: An intact intestinal microbiota is required to initiate and sustain the GI toxicity of MMF. MMF treatment causes dynamic changes in the composition of the intestinal microbiota that may be a targetable driver of the GI side-effects of MMF.

THEORETICAL GAS CONCENTRATIONS ACHIEVING 100% FILL OF THE VITREOUS CAVITY IN THE POSTOPERATIVE PERIOD: A Gas Eye Model Study.

PURPOSE: To determine the concentrations of different gas tamponades in air to achieve 100% fill of the vitreous cavity postoperatively and to examine the influence of eye volume on these concentrations. METHODS: A mathematical model of the mass transfer dynamics of tamponade and blood gases (O2, N2, and CO2) when injected into the eye was used. Mass transfer surface areas were calculated from published anatomical data. The model has been calibrated from published volumetric decay and composition results for three gases sulphahexafluoride (SF6), hexafluoroethane (C2F6), or perfluoropropane (C3F8). The concentrations of these gases (in air) required to achieve 100% fill of the vitreous cavity postoperatively without an intraocular pressure rise were determined. The concentrations were calculated for three volumes of the vitreous cavity to test whether ocular size influenced the results. RESULTS: A table of gas concentrations was produced. In a simulation of pars plana vitrectomy operations in which an 80% to 85% fill of the vitreous cavity with gas was achieved at surgery, the concentrations of the 3 gases in air to achieve 100% fill postoperatively were 10% to 13% for C3F8, 12% to 15% for C2F6, and 19% to 25% for SF6. These were similar to the so-called "nonexpansive" concentrations used in the clinical setting. The calculations were repeated for three different sizes of eye. Aiming for an 80% fill at surgery and 100% postoperatively, an eye with a 4-mL vitreous cavity required 24% SF6, 15% C2F6, or 13% C3F8; 7.2 mL required 25% SF6, 15% C2F6, or 13% C3F8; and 10 mL required 25% SF6, 16% C2F6, or 13% C3F8. When using 100% gas (e.g., used in pneumatic retinopexy), to achieve 100% fill postoperatively, the minimum vitreous cavity fill at surgery was 43% for SF6, 29% for C2F6, and 25% for C3F8 and was only minimally changed by variation in the size of the eye. CONCLUSION: A table has been produced, which could be used for surgical innovation in gas usage in the vitreous cavity. It provides concentrations for different percentage fills, which will achieve a moment postoperatively with a full fill of the cavity without a pressure rise. Variation in axial length and size of the eye does not seem to alter the values in the table significantly. Those using pneumatic retinopexy need to increase the volume of gas injected with increased size of the eye to match the percentage fill of the vitreous cavity recommended for a given tamponade agent.

A thermoelastic deformation model of tissue contraction during thermal ablation.

PURPOSE: Thermal ablation is an energy-based ablation technique widely used during minimally invasive cancer treatment. Simulations are used to predict the dead tissue post therapy. However, one difficulty with the simulations is accurately predicting the ablation zone in post-procedural images due to the contraction of tissue as a result of exposure to elevated temperatures. MATERIALS AND METHODS: A mathematical model of the thermoelastic deformation for an elastic isotropic material was coupled with a three state thermal denaturation model to determine the contraction of tissue during thermal ablation. A finite difference method was considered to quantify the tissue contraction for a typical temperature distribution during thermal ablation. RESULTS: The simulations show that tissue displacement during thermal ablation was not bound to the tissue heated regions only. Both tissue expansion and contraction were observed at the different stages of the heating process. Tissue contraction of up to 42% was obtained with an applicator temperature of 90 °C. A recovery of around 2% was observed with heating removed as a result of unfolded state proteins returning back to its native state. Poisson's ratio and the applicator temperature have both been shown to affect the tissue displacement significantly. The maximum tissue contraction was found to increase with both increasing Poisson's ratio and temperature. CONCLUSIONS: The model presented here will allow predictions of thermal ablation to be corrected for tissue contraction, which is an important effect, during comparison with post-procedural images, thus improving the accuracy of mathematical simulations for treatment planning.

Mathematical model of the post-ablation enhancement zone as a tissue-level oedematic response.

PURPOSE: A hyperdense rim is commonly observed at the periphery of ablation zones during post-ablation imaging (e.g. ultrasound) in tumours. A mathematical model has been developed here to investigate the occurrence of this enhanced rim, caused by the ablated cells, giving an indication of the location of the final ablation region. MATERIALS AND METHODS: The enhanced rim has been assumed here to be due to a tissue-level oedematic response of viable cells, which necessitated coupling multiple modelling elements in a spatially distributed system: thermal cell death, tissue-state dependent ion concentration dynamics, ion transport in the extracellular space, and osmotic cell volume regulation. RESULTS: In response to the imposed temperature function, an ablation zone was predicted, distinguishing the tissue state between 'dead' and 'alive'. A disturbance in intracellular/extracellular ion concentrations was induced due to ion redistribution, which acted as an osmotic stress and contributed to significant cell swelling in a thin rim at the periphery of the ablation zone. It was also found that the rim size only changed slightly with varying lesion size, in response to different temperature profiles. CONCLUSIONS: The study presents a novel mathematical model to understand the enhanced rim surrounding the ablation zone by assuming tissue-level cell oedema as the primary potential cause. The model links the direct response to thermal injury to an observable secondary response, which could be of clinical value in that the location of this bright ring could potentially be used for more accurate determination of the extent of the ablation zone.

A model of tissue contraction during thermal ablation.

A model of a globular protein is used to describe the contraction of tissue exposed to elevated temperatures. This will be useful in predicting the contraction of tissue that is observed during thermal ablation of tumours, which is a problem when trying to determine the ablation zone in post-operative images. The transitions between the states of the protein can be related to a change in the length of the molecule, which can be directly observed as a change in the length of the tissue. A three state model of a globular protein is used to describe the contraction of tissue exposed to elevated temperatures. A nonlinear fitting algorithm is considered here to fit available experimental data and thus to obtain the values of the model parameters. A sensitivity analysis of the proposed mathematical model is performed to determine the most important parameters in the model. The model parameters were obtained from experimental data of isothermal free shrinkage experiments. The predictions of the complete model show similar agreement with the data, well within the experimental error of 10%. The overall activation energy and frequency factor were found to be 201 kJ mol(-1) and [Formula: see text] s(-1) respectively. The results show that the experimental data were well described by the three state model considered here. Furthermore, it was possible to determine the most sensitive parameters in the model. The model presented here will allow predictions of thermal ablation to be corrected for tissue shrinkage, thus improving mathematical simulations for treatment planning, although clinical translation will require adapting the model from experimentally obtained tendon data to soft tissue data.

Clinical utilization of genomics data produced by the international Pseudomonas aeruginosa consortium.

The International Pseudomonas aeruginosa Consortium is sequencing over 1000 genomes and building an analysis pipeline for the study of Pseudomonas genome evolution, antibiotic resistance and virulence genes. Metadata, including genomic and phenotypic data for each isolate of the collection, are available through the International Pseudomonas Consortium Database (http://ipcd.ibis.ulaval.ca/). Here, we present our strategy and the results that emerged from the analysis of the first 389 genomes. With as yet unmatched resolution, our results confirm that P. aeruginosa strains can be divided into three major groups that are further divided into subgroups, some not previously reported in the literature. We also provide the first snapshot of P. aeruginosa strain diversity with respect to antibiotic resistance. Our approach will allow us to draw potential links between environmental strains and those implicated in human and animal infections, understand how patients become infected and how the infection evolves over time as well as identify prognostic markers for better evidence-based decisions on patient care.

Cell death, perfusion and electrical parameters are critical in models of hepatic radiofrequency ablation.

PURPOSE: A sensitivity analysis has been performed on a mathematical model of radiofrequency ablation (RFA) in the liver. The purpose of this is to identify the most important parameters in the model, defined as those that produce the largest changes in the prediction. This is important in understanding the role of uncertainty and when comparing the model predictions to experimental data. MATERIALS AND METHODS: The Morris method was chosen to perform the sensitivity analysis because it is ideal for models with many parameters or that take a significant length of time to obtain solutions. A comprehensive literature review was performed to obtain ranges over which the model parameters are expected to vary, crucial input information. RESULTS: The most important parameters in predicting the ablation zone size in our model of RFA are those representing the blood perfusion, electrical conductivity and the cell death model. The size of the 50 °C isotherm is sensitive to the electrical properties of tissue while the heat source is active, and to the thermal parameters during cooling. CONCLUSIONS: The parameter ranges chosen for the sensitivity analysis are believed to represent all that is currently known about their values in combination. The Morris method is able to compute global parameter sensitivities taking into account the interaction of all parameters, something that has not been done before. Research is needed to better understand the uncertainties in the cell death, electrical conductivity and perfusion models, but the other parameters are only of second order, providing a significant simplification.

IslandViewer 3: more flexible, interactive genomic island discovery, visualization and analysis.

IslandViewer (http://pathogenomics.sfu.ca/islandviewer) is a widely used web-based resource for the prediction and analysis of genomic islands (GIs) in bacterial and archaeal genomes. GIs are clusters of genes of probable horizontal origin, and are of high interest since they disproportionately encode genes involved in medically and environmentally important adaptations, including antimicrobial resistance and virulence. We now report a major new release of IslandViewer, since the last release in 2013. IslandViewer 3 incorporates a completely new genome visualization tool, IslandPlot, enabling for the first time interactive genome analysis and gene search capabilities using synchronized circular, horizontal and vertical genome views. In addition, more curated virulence factors and antimicrobial resistance genes have been incorporated, and homologs of these genes identified in closely related genomes using strict filters. Pathogen-associated genes have been re-calculated for all pre-computed complete genomes. For user-uploaded genomes to be analysed, IslandViewer 3 can also now handle incomplete genomes, with an improved queuing system on compute nodes to handle user demand. Overall, IslandViewer 3 represents a significant new version of this GI analysis software, with features that may make it more broadly useful for general microbial genome analysis and visualization.

A mathematical framework for minimally invasive tumor ablation therapies.

Minimally invasive tumor ablations (MITAs) are an increasingly important tool in the treatment of solid tumors across multiple organs. The problems experienced in modeling different types of MITAs are very similar, but the development of mathematical models is mostly performed in isolation according to modality. Fundamental research into the modeling of specific types of MITAs is indeed required, but to choose the optimal treatment for an individual the primary clinical requirement is to have reliable predictions for a range of MITAs. In this review of the mathematical modeling of MITAs 4 modalities are considered: radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation. The similarities in the mathematical modeling of these treatments are highlighted, and the analysis of the models within a general framework is discussed. This will aid in developing a deeper understanding of the sensitivity of MITA models to physiological parameters and the impact of uncertainty on predictions of the ablation zone. Through robust validation and analysis of the models it will be possible to choose the best model for a given application. This is important because many different models exist with no objective comparison of their performance. The collection of relevant in vivo experimental data is also critical to parameterize such models accurately. This approach will be necessary to translate the field into clinical practice.

Immunogenic display of diverse peptides on virus-like particles of RNA phage MS2.

The high level of immunogenicity of peptides displayed in dense repetitive arrays on virus-like particles makes recombinant VLPs promising vaccine carriers. Here, we describe a platform for vaccine development based on the VLPs of RNA bacteriophage MS2. It serves for the engineered display of specific peptide sequences, but will also allow the construction of random peptide libraries from which specific binding activities can be recovered by affinity selection. Peptides representing the V3 loop of HIV gp120 and the ECL2 loop of the HIV coreceptor, CCR5, were inserted into a surface loop of MS2 coat protein. Both insertions disrupted coat VLP assembly, apparently by interfering with protein folding, but these defects were suppressed efficiently by genetically fusing coat protein's two identical polypeptides into a single-chain dimer. The resulting VLPs displayed the V3 and ECL2 peptides on their surfaces where they showed the potent immunogenicity that is the hallmark of VLP-displayed antigens. Experiments with random-sequence peptide libraries show the single-chain dimer to be highly tolerant of six, eight and ten amino acid insertions. MS2 VLPs support the display of a wide diversity of peptides in a highly immunogenic format, and they encapsidate the mRNAs that direct their synthesis, thus establishing the genotype/phenotype linkage necessary for recovery of affinity-selected sequences. The single-chain MS2 VLP therefore unites in a single structural platform the selective power of phage display with the high immunogenicity of VLPs.

Mechanical properties of nanoparticle chain aggregates by combined AFM and SEM: isolated aggregates and networks.

Mechanical properties of nanoparticle chain aggregates (NCA) including tensile strength and Young's modulus were measured using an instrument incorporating an AFM tip under SEM imaging. The NCA were studied individually and as network films. Carbon NCA were made by laser ablation of graphite, and SnO2 NCA were made by oxidation of a tin compound. The films were deformable and showed elastic behavior. NCA serve as reinforcing fillers in rubber and films of SnO2 NCA for trace gas detection.

Molecular dynamics simulations of the straining of nanoparticle chain aggregates: the case of copper.

Previous studies in our laboratory have shown that individual nanoparticle chain aggregates (NCAs) exhibit unusual mechanical behaviour when under strain inside the transmission electron microscope. NCAs made of various materials (e.g. carbon, metal oxides and metals) were strained by as much as 100% under tension. The nanoparticles that compose the chains were 5-10 nm in diameter and the chains of the order of 1 µm in length. Such aggregates are of technological importance in the manufacture of nanocomposite materials (e.g. rubber), aggregate break-up (e.g. sampling diesel emissions) and chemical-mechanical planarization. The goal of this study was to simulate the mechanical behaviour of chain aggregates with morphological properties similar to those of technological interest. Molecular dynamics (MD) and energy minimization computer simulations are employed to investigate, at the atomic scale, the behaviour of short nanoparticle aggregates under strain and to obtain quantitative information on the forces involved in aggregate straining and fracturing. The interaction potential used is that of copper obtained with the embedded atom method (EAM). Two seven-nanoparticle aggregates are studied, one linear and the other kinked. The seven nanoparticles in both aggregates are single crystals and about 2.5 nm in diameter each. The aggregates are strained along their longest dimension, to the breaking point, at strain rates spanning from 2.5 × 10(7) to 8.0 × 10(8) s(-1) (MD simulations). The linear aggregate yield strain is about 0.1. The kinked aggregate elastic limit is also about 0.1, but only one-third of the stress develops along the straining direction compared to the linear aggregate. The kinked aggregate breaks at a strain of about 0.5, five times higher than the breaking strain of the linear aggregate. The ability of the kinked aggregate to straighten through combined nanoparticle interface sliding and rotation accounts for the extra strain accommodation. Simulation strain rates are orders of magnitude higher than the experimental ones. However, aggregate behaviour is independent of strain rates over the range studied here. The MD and energy minimization straining gave very similar results. In the elastic regime, the 1/S(11) modulus for the seven-nanoparticle kinked aggregate is about one-fifth of the bulk value. This is due to a combined effect of the small primary particle diameter and the aggregate kinked structure. If this softening behaviour also occurs for nanoparticle aggregates of other materials (e.g. carbon, silica), nanoparticle aggregates, in some cases, may be strained along with the nanocomposite they reinforce.

Nanostructure manipulation device for transmission electron microscopy: application to titania nanoparticle chain aggregates.

Experimental difficulties in studying nanostructures stem from their small size, which limits the use of traditional techniques for measuring their physical properties. We have developed a nanostructure manipulation device to apply tension to chain aggregates mounted in a transmission electron microscope. A 1-mm-long slit was cut in the center of a lead-tin alloy disc, measuring 3 mm in diameter and 200 microm in thickness. The disc was heated to about 140 degrees C before it was pressed between two quartz slides. The disc was then thinned by mechanical dimpling and ion milling until holes developed around the slit. The edges of the slit were 0.2 to 3 microm in thickness while the gap between them was up to a few microns. This disc was bonded to the two plates of a cartridge. The slit could be widened or narrowed at controlled speeds of 0.5 to 300 nm/s. The system was tested using titania (TiO2) nanoparticle chain aggregates (NCA) deposited across the slit. The ends of the NCA remained attached to the edges of the slit, which was widened at about 0.7 nm/s. In this way, the NCA was stretched up to 176% of its initial length before breaking.

The self-preserving size distribution theory. I. Effects of the Knudsen number on aerosol agglomerate growth.

Gas-phase synthesis of fine solid particles leads to fractal-like structures whose transport and light scattering properties differ from those of their spherical counterparts. Self-preserving size distribution theory provides a useful methodology for analyzing the asymptotic behavior of such systems. Apparent inconsistencies in previous treatments of the self-preserving size distributions in the free molecule regime are resolved. Integro-differential equations for fractal-like particles in the continuum and near continuum regimes are derived and used to calculate the self-preserving and quasi-self-preserving size distributions for agglomerates formed by Brownian coagulation. The results for the limiting case (the continuum regime) were compared with the results of other authors. For these cases the finite difference method was in good in agreement with previous calculations in the continuum regime. A new analysis of aerosol agglomeration for the entire Knudsen number range was developed and compared with a monodisperse model; Higher agglomeration rates were found for lower fractal dimensions, as expected from previous studies. Effects of fractal dimension, pressure, volume loading and temperature on agglomerate growth were investigated. The agglomeration rate can be reduced by decreasing volumetric loading or by increasing the pressure. In laminar flow, an increase in pressure can be used to control particle growth and polydispersity. For D(f)=2, an increase in pressure from 1 to 4 bar reduces the collision radius by about 30%. Varying the temperature has a much smaller effect on agglomerate coagulation.

The self-preserving size distribution theory. II. Comparison with experimental results for Si and Si3N4 aerosols.

The gas to particle synthesis route is a relatively clean and efficient manner for the production of high-quality ceramic powders. These powders can be subsequently sintered in any wanted shape. The modeling of these production systems is difficult because several mechanisms occur in parallel. From theoretical considerations it can be determined, however, that coagulation and sintering are dominant mechanisms as far as shape and size of the particles are considered. In part I of this article an extensive theoretical analysis was given on the self-preserving size distribution theory for power law particles. In this second part, cumulative particle size distributions of silicon and silicon nitride agglomerates, produced in a laser reactor, were determined from TEM pictures and compared to the distributions calculated from this self-preserving theory for power law particles. The calculated distributions were in fair agreement with the measured results, especially at the high end of the distributions. Calculated and measured particle growth rates were also in fair agreement. Using the self-preserving theory an analysis was made on the distribution of annealed silicon agglomerates, of interest in applications to nanoparticle technology.

Getting older, getting better? Personal strivings and psychological maturity across the life span.

Measures of psychological maturity based on personal strivings (R. A. Emmons, 1989) were administered to 108 adults aged 17-82. On the basis of organismic-theoretical assumptions regarding maturity, age was hypothesized to be positively associated with K. M. Sheldon and T. Kasser's (1995, 1998) two goal-based measures of personality integration. E. Erikson's (1963) assumptions regarding maturity were the basis for the hypothesis that older people would tend to list more strivings concerning generativity and ego integrity and fewer strivings concerning identity and intimacy. Finally, on the basis of past research findings, maturity and age were hypothesized to be positively associated with subjective well-being. Results supported these hypotheses and also showed that measured maturity mediated the relationship between age and well-being. Thus, older individuals may indeed be more psychologically mature than younger people and may be happier as a result.

Why positive psychology is necessary.

The authors provide a definition of positive psychology and suggest that psychologists should try to cultivate a more appreciative perspective on human nature. Examples are given of a negative bias that seems to pervade much of theoretical psychology, which may limit psychologists' understanding of typical and successful human functioning. Finally, a preview of the articles in the special section is given.

Self-concordance, goal attainment, and the pursuit of happiness: can there be an upward spiral?

Two studies used the self-concordance model of healthy goal striving (K. M. Sheldon & A. J. Elliot, 1999) to examine the motivational processes by which people can increase their level of well-being during a period of time and then maintain the gain or perhaps increase it even further during the next period of time. In Study 1, entering freshmen with self-concordant motivation better attained their 1st-semester goals, which in turn predicted increased adjustment and greater self-concordance for the next semester's goals. Increased self-concordance in turn predicted even better goal attainment during the 2nd semester, which led to further increases in adjustment and to higher levels of ego development by the end of the year. Study 2 replicated the basic model in a 2-week study of short-term goals set in the laboratory. Limits of the model and implications for the question of how (and whether) happiness may be increased are discussed.

What is satisfying about satisfying events? Testing 10 candidate psychological needs.

Three studies compared 10 candidate psychological needs in an attempt to determine which are truly most fundamental for humans. Participants described "most satisfying events" within their lives and then rated the salience of each of the 10 candidate needs within these events. Supporting self-determination theory postulates (Ryan & Deci, 2000)--autonomy, competence, and relatedness, were consistently among the top 4 needs, in terms of both their salience and their association with event-related affect. Self-esteem was also important, whereas self-actualization or meaning, physical thriving, popularity or influence, and money-luxury were less important. This basic pattern emerged within three different time frames and within both U.S. and South Korean samples and also within a final study that asked, "What's unsatisfying about unsatisfying events?" Implications for hierarchical theories of needs are discussed.

Social roles as mechanisms for psychological need satisfaction within social groups.

The authors explored ways in which needs for autonomy and relatedness can be simultaneously met within the context of group life. Specifically, it was hypothesized that social role performances provide means of both expressing the self and connecting with group members. Consistent with the assumption that autonomy and relatedness are complementary rather than conflictual, these needs were positively correlated in all 5 studies. Consistent with the authors' assumption that these needs are both important, feelings of autonomy and relatedness in social roles independently predicted subjective well-being, as measured by concurrent (Studies I and 3), peer-report (Study 2). and longitudinal (Studies 4 and 5) methodologies. Study 5 showed that participants whose characteristics matched an assigned role experienced more autonomy and relatedness and thus more positive mood during a group task. Implications for optimal functioning in group contexts are discussed.