Free Energy Gap Dependence of the Electron-Transfer Rate from the Inverted to the Normal Region

numerical study of the free energy gap (FEG) dependence of the electron-transfer rate in polar solvents is presented. This study is based on the generalized multidimensional hybrid model, which not only includes the solvent polarization and the molecular vibration modes, but also the biphasic polar response of the solvent. The free energy gap dependence is found to be sensitive to several factors, including the solvent relaxation rate, the electronic coupling between the surfaces, the frequency of the high-frequency quantum vibrational mode, and the magnitude of the solvent reorganization energy. It is shown that in some cases solvent relaxation can play an important role even in the Marcus normal regime. The minimal hybrid model involves a large number of parameters, giving rise to a diverse non-Marcus FEG behavior which is often determined collectively by these parameters. The model gives the linear free energy gap dependence of the logarithmic rate over a substantial range of FEG, spanning from the normal to the inverted regime. However, even for favorable values of the relevant parameters, a linear free energy gap dependence of the rate could be obtained only over a range of 5000-6000 cm(-1) (compared to the experimentally observed range of 10000 cm(-1) reported by Benniston et al.). The present work suggests several extensions/generalizations of the hybrid model which might be necessary to fully understand the observed free energy gap dependence.

Optimal barrier subdivision for Kramers' escape rate

We examine the effect of subdividing the potential barrier along the reaction coordinate on Kramers' escape rate for a model potential. Using the known supersymmetric potential approach, we show the existence of an optimal number of subdivisions that maximizes the rate.

Oxygen transfer and energy dissipation rate in surface aerator

The dissipation rate of turbulent kinetic energy (epsilon) is a key parameter for mixing in surface aerators. In particular, determination epsilon across the impeller stream, where the most intensive mixing takes place, is essential to ascertain that an appropriate degree of mixing is achieved. Present work by using commercial software VisiMix (R) calculates the energy dissipation rate in geometrically similar unbaffled surface aeration systems in order to scale-up the oxygen transfer process. It is found that in geometrically similar system, oxygen transfer rate is uniquely correlated with dissipation rate of energy. Simulation or scale-up equation governing oxygen transfer rate and dissipation rate of energy has been developed in the present work.

Oxygen transfer and energy dissipation rate in surface aerator

The dissipation rate of turbulent kinetic energy(e)is a key parameter for mixing in surface aerators. In particular, determination e across the impeller stream, where the most intensive mixing takes place, is essential to ascertain that an appropriate degree of mixing is achieved. Present work by using commercial software VisiMix calculates the energy dissipation rate in geometrically similar unbaffled surface aeration systems in order to scale-up the oxygen transfer process. It is found that in geometrically similar system,oxygen transfer rate is uniquely correlated with dissipation rate of energy. Simulation or scale-up equation governing oxygen transfer rate and dissipation rate of energy has been developed in the present work.

MRI-based strain and strain rate analysis of left ventricle: A modified hierarchical transformation model

Background Different from other indicators of cardiac function, such as ejection fraction and transmitral early diastolic velocity, myocardial strain is promising to capture subtle alterations that result from early diseases of the myocardium. In order to extract the left ventricle (LV) myocardial strain and strain rate from cardiac cine-MRI, a modified hierarchical transformation model was proposed. Methods A hierarchical transformation model including the global and local LV deformations was employed to analyze the strain and strain rate of the left ventricle by cine-MRI image registration. The endocardial and epicardial contour information was introduced to enhance the registration accuracy by combining the original hierarchical algorithm with an Iterative Closest Points using Invariant Features algorithm. The hierarchical model was validated by a normal volunteer first and then applied to two clinical cases (i.e., the normal volunteer and a diabetic patient) to evaluate their respective function. Results Based on the two clinical cases, by comparing the displacement fields of two selected landmarks in the normal volunteer, the proposed method showed a better performance than the original or unmodified model. Meanwhile, the comparison of the radial strain between the volunteer and patient demonstrated their apparent functional difference. Conclusions The present method could be used to estimate the LV myocardial strain and strain rate during a cardiac cycle and thus to quantify the analysis of the LV motion function.

MRI-based fatigue analysis predicts plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

BACKGROUND: Rupture of atheromatous plaque in the carotid artery often leads to thrombosis and subsequent stroke. The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap and biomechanical stress as the trigger leading to plaque rupture. As the cardiovascular system is a classic fatigue environment, the weakening of plaque leading to rupture may be a fatigue process, which is a symptomatically quiescent but potentially progressive failure process. In this study, we used a fatigue analysis based on in vivo magnetic resonance imaging (MRI) to investigate the rupture initiation location, crack propagation path and fatigue life within plaques of asymptomatic and symptomatic individuals. METHODS: Forty non-consecutive subjects (20 symptomatic and 20 asymptomatic) underwent high-resolution multi-sequence in vivo MRI of the carotid bifurcation. Fatigue analysis was performed based on the plaque geometry derived from in vivo MRI of the carotid artery at the point of maximum stenosis. Paris’ Law in fracture mechanics is adopted to determine the fatigue crack growth rate. Incremental crack propagation was dynamically simulated based on stress distributions. Plaque initiation location, crack propagation path and fatigue cycle of symptomatic and asymptomatic individuals were compared. RESULTS: Cracks were often found to begin at the lumen wall at areas of stress concentration. The preferred rupture direction was radial from the lumen center. The crack initially advanced slowly but accelerated as it developed, depending on plaque morphology. The fatigue cycles of symptomatic plaques were significantly less than those in the asymptomatic group (2.3 ± 0.9 vs 3.1 ± 0.7 (x106); p = 0.003). CONCLUSIONS: The number of cycles to rupture in symptomatic patients was higher than those predicted in asymptomatic patients by fatigue analysis, suggesting the possibility that plaques with a less fatigue life may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, fatigue analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma.

In vivo velocity vector imaging and time-resolved strain rate measurements in the wall of blood vessels using MRI

In this paper, we present a new approach for velocity vector imaging and time-resolved measurements of strain rates in the wall of human arteries using MRI and we prove its feasibility on two examples: in vitro on a phantom and in vivo on the carotid artery of a human subject. Results point out the promising potential of this approach for investigating the mechanics of arterial tissues in vivo.

Synergy between tribo-oxidation and strain rate response on governing the dry sliding wear behavior of titanium.

The present work provides an insight into the dry sliding wear behavior of titanium based on synergy between tribo-oxidation and strain rate response. Pin-on-disc tribometer was used to characterize the friction and wear behavior of titanium pin in sliding contact with polycrystalline alumina disk under ambient and vacuum condition. The sliding speed was varied from 0.01 to 1.4 ms(-1), normal load was varied from 15.3 to 76 N and with a sliding distance of 1500 m. It was seen that dry sliding wear behavior of titanium was governed by combination of tribo-oxidation and strain rate response in near surface region of titanium. Strain rate response of titanium was recorded by conducting uni-axial compression tests at constant true strain rate of 100 s(-1) in the temperature range from 298 to 873 K. Coefficient of friction and wear rate were reduced with increased sliding speed from 0.01 to 1.0 ms(-1). This is attributed to the formation of in situ self lubricating oxide film (TiO) and reduction in the intensity of adiabatic shear band cracking in the near surface region. This trend was confirmed by performing series of dry sliding tests under vacuum condition of 2 x 10(-4) Torr. Characterization tools such as optical microscopy, scanning electron microscopy, and X-ray diffractometer provided evidence of such processes. These experimental findings can be applied to enhance the dry sliding wear behavior of titanium with proper choice of operating conditions such as sliding speed, normal load, and environment.

Rapid assessment of genotype-by-environment interactions and heritability for growth rate in aquaculture species using in vitro fertilisation and DNA tagging

Commercial environments may receive only a fraction of expected genetic gains for growth rate as predicted from the selection environment This fraction is the result of undesirable genotype-by-environment interactions (G x E) and measured by the genetic correlation (r(g)) of growth between environments. Rapid estimates of genetic correlation achieved in one generation are notoriously difficult to estimate with precision. A new design is proposed where genetic correlations can be estimated by utilising artificial mating from cryopreserved semen and unfertilised eggs stripped from a single female. We compare a traditional phenotype analysis of growth to a threshold model where only the largest fish are genotyped for sire identification. The threshold model was robust to differences in family mortality differing up to 30%. The design is unique as it negates potential re-ranking of families caused by an interaction between common maternal environmental effects and growing environment. The design is suitable for rapid assessment of G x E over one generation with a true 0.70 genetic correlation yielding standard errors as low as 0.07. Different design scenarios were tested for bias and accuracy with a range of heritability values, number of half-sib families created, number of progeny within each full-sib family, number of fish genotyped, number of fish stocked, differing family survival rates and at various simulated genetic correlation levels

Rank regression for accelerated failure time model with clustered and censored data

For clustered survival data, the traditional Gehan-type estimator is asymptotically equivalent to using only the between-cluster ranks, and the within-cluster ranks are ignored. The contribution of this paper is two fold: - (i) incorporating within-cluster ranks in censored data analysis, and; - (ii) applying the induced smoothing of Brown and Wang (2005, Biometrika) for computational convenience. Asymptotic properties of the resulting estimating functions are given. We also carry out numerical studies to assess the performance of the proposed approach and conclude that the proposed approach can lead to much improved estimators when strong clustering effects exist. A dataset from a litter-matched tumorigenesis experiment is used for illustration.

Process Analytical Technology Approach on Fluid Bed Granulation and Drying : Identifying Critical Relationships and Constructing the Design Space

Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

External signal-activated liposomal drug delivery systems

Modern drug discovery gives rise to a great number of potential new therapeutic agents, but in some cases the efficient treatment of patient may not be achieved because the delivery of active compounds to the target site is insufficient. Thus, drug delivery is one of the major challenges in current pharmaceutical research. Numerous nanoparticle-based drug carriers, e.g. liposomes, have been developed for enhanced drug delivery and targeting. Drug targeting may enhance the efficiency of the treatment and, importantly, reduce unwanted side effects by decreasing drug distribution to non-target tissues. Liposomes are biocompatible lipid-based carriers that have been studied for drug delivery during the last 40 years. They can be functionalized with targeting ligands and sensing materials for triggered activation. In this study, various external signal-assisted liposomal delivery systems were developed. Signals can be used to modulate drug permeation or release from the liposome formulation, and they provide accurate control of time, place and rate of activation. The study involved three types of signals that were used to trigger drug permeation and release: electricity, heat and light. Electrical stimulus was utilized to enhance the permeation of liposomal DNA across the skin. Liposome/DNA complex-mediated transfections were performed in tight rat epidermal cell model. Various transfection media and current intensities were tested, and transfection efficiency was evaluated non-invasively by monitoring the concentration of secreted reporter protein in cell culture medium. Liposome/DNA complexes produced gene expression, but electrical stimulus did not enhance the transfection efficiency significantly. Heat-sensitive liposomal drug delivery system was developed by coating liposomes with biodegradable and thermosensitive poly(N-(2-hydroxypropyl) methacrylamide-mono/dilactate polymer. Temperature-triggered liposome aggregation and contents release from liposomes were evaluated. The cloud point temperature (CP) of the polymer was set to 42 °C. Polymer-coated liposome aggregation and contents release were observed above CP of the polymer, while non-coated liposomes remained intact. Polymer precipitates above its CP and interacts with liposomal bilayers. It is likely that this induces permeabilization of the liposomal membrane and contents release. Light-sensitivity was introduced to liposomes by incorporation of small (< 5 nm) gold nanoparticles. Hydrophobic and hydrophilic gold nanoparticles were embedded in thermosensitive liposomes, and contents release was investigated upon UV light exposure. UV light-induced lipid phase transitions were examined with small angle X-ray scattering, and light-triggered contents release was shown also in human retinal pigment epithelial cell line. Gold nanoparticles absorb light energy and transfer it into heat, which induces phase transitions in liposomes and triggers the contents release. In conclusion, external signal-activated liposomes offer an advanced platform for numerous applications in drug delivery, particularly in the localized drug delivery. Drug release may be localized to the target site with triggering stimulus that results in better therapeutic response and less adverse effects. Triggering signal and mechanism of activation can be selected according to a specific application.

Influence of clofibrate administration on the rate of synthesis of macromolecules in regenerating rat liver

Administration of the antihypercholesterolaemic drug clofibrate stimulates the rates of synthesis of nucleic acids and proteins in rat liver. The biosynthesis of mitochondrial proteins also is enhanced by the drug. In drug-fed animals, the rates of incorporation in vivo of radioactive precursors into DNA, RNA and proteins are stimulated even when the liver undergoes regeneration following partial hepatectomy. The rate of synthesis of mitochondrial proteins in the regenerative phase is higher in clofibrate-fed animals. These effects are consistent with the hepatomegalic and mitochondria-proliferating property of the drug.

Bayesian designs with frequentist and Bayesian error rate considerations

So far, most Phase II trials have been designed and analysed under a frequentist framework. Under this framework, a trial is designed so that the overall Type I and Type II errors of the trial are controlled at some desired levels. Recently, a number of articles have advocated the use of Bavesian designs in practice. Under a Bayesian framework, a trial is designed so that the trial stops when the posterior probability of treatment is within certain prespecified thresholds. In this article, we argue that trials under a Bayesian framework can also be designed to control frequentist error rates. We introduce a Bayesian version of Simon's well-known two-stage design to achieve this goal. We also consider two other errors, which are called Bayesian errors in this article because of their similarities to posterior probabilities. We show that our method can also control these Bayesian-type errors. We compare our method with other recent Bayesian designs in a numerical study and discuss implications of different designs on error rates. An example of a clinical trial for patients with nasopharyngeal carcinoma is used to illustrate differences of the different designs.