Modeling the development of acquired clinical immunity to Plasmodium falciparum malaria

Individuals living in regions where malaria is endemic develop an acquired immunity to malaria which enables them to remain asymptomatic while still carrying parasites. Field studies indicate that cumulative exposure to a variety of diverse Plasmodium parasites is required for the transition from symptomatic to asymptomatic malaria. This study used a simulation model of the within-host dynamics of P. falciparum to investigate the development of acquired clinical immunity under different transmission conditions and levels of parasite diversity. Antibodies developed to P. falciparum erythrocyte membrane protein 1 (PfEMP1), a clonally variant molecule, were assumed to be a key human immunological response to P. falciparum infection, along with responses to clonally conserved but polymorphic antigens. The time to the development of clinical immunity was found to be proportional to parasite diversity and inversely proportional to transmission intensity. The effect of early termination of symptomatic infections by chemotherapy was investigated and found not to inhibit the host's ability to develop acquired immunity. However, the time required to achieve this state was approximately double that compared to when no treatment was administered. This study demonstrates that an immune response primarily targeted against PfEMP1 has the ability to reduce clinical symptoms of infections irrespective of whether treatment is administered, supporting its role in the development of acquired clinical immunity. The results also illustrate a novel use for simulation models of P. falciparum infections, investigation of the influence of intervention strategies on the development of naturally acquired clinical immunity.

Exploratory modelling of grinding pressure within a compressed particle bed

With increasing industry interest in high pressure roll grinding (HPGR) technology, there is a strong incentive for improved understanding of the nature of grinding pressure that exists in the interior of a compressed particle bed. This corresponds to the crushing region of the HPGR. The relationship between applied pressure (stress) to the particle bed and induced pressure (stress) within particles and at contact points between particles is of particular interest. A detailed parametric investigation is beyond the scope of this exploratory paper. However, this exploratory investigation does suggest some interesting behaviour. The compressed particle bed within an 80 turn diameter piston has been modelled using Particle Flow Code for three dimensions. PFC3D is a discrete element code. The total number of simulated particles was 1225 and 2450 for two beds of different thickness. Particle diameters were uniformly distributed between 4 and 4.5 mm. The results of the simulations show that stress intensity within the simulated particle beds and within the observed particles increased with increase of the applied stress. The intensity of the average vertical stress in the selected particles tended to be comparable with the intensity of the pressure applied to the surface of particle bed and was only occasionally higher. However, the stress at contact points between particles could be several times higher. In a real crusher, such high stress amplification at contacts will quickly decrease due to local crushing and a resultant increase the size of the contact area. Therefore, its significance is likely to be relatively small in an industrial context. The modelling results also suggest that failure within the particle bed will progress from the crushing surface towards the depth of the bed. (c) 2006 Elsevier Ltd. All rights reserved.

Modelling comminution patterns within a pilot scale AG/SAG mill

The patterns of rock comminution within tumbling mills, as well as the nature of forces, are of significant practical importance. Discrete element modelling (DEM) has been used to analyse the pattern of specific energy applied to rock, in terms of spatial distribution within a pilot AG/SAG mill. We also analysed in some detail the nature of the forces, which may result in rock comminution. In order to examine the distribution of energy applied within the mill, the DEM models were compared with measured particle mass losses, in small scale AG and SAG mill experiments. The intensity of contact stresses was estimated using the Hertz theory of elastic contacts. The results indicate that in the case of the AG mill, the highest intensity stresses and strains are likely to occur deep within the charge, and close to the base. This effect is probably more pronounced for large AG mills. In the SAG mill case, the impacts of the steel balls on the surface of the charge are likely to be the most potent. In both cases, the spatial pattern of medium-to-high energy collisions is affected by the rotational speed of the mill. Based on an assumed damage threshold for rock, in terms of specific energy introduced per single collision, the spatial pattern of productive collisions within each charge was estimated and compared with rates of mass loss. We also investigated the nature of the comminution process within AG vs. SAG mill, in order to explain the observed differences in energy utilisation efficiency, between two types of milling. All experiments were performed using a laboratory scale mill of 1.19 m diameter and 0.31 m length, equipped with 14 square section lifters of height 40 mm. (C) 2006 Elsevier Ltd. All rights reserved.

Modelling the effect of shear history on activated sludge flocculation

The aim of this paper is to investigate the effect of shear history on activated sludge flocculation dynamics and to model the observed relationships using population balances. Activated sludge flocs are exposed to dramatic changes in the shear rate within the treatment process, as they pass through localised high and low mixing intensities within the aeration basin and are cycled through the different unit operations of the treatment process. We will show that shear history is a key factor in determining floc size, and that the floc size varies irreversibly with changes in shear rate. A population balance model of the flocculation process is also introduced and evaluated.

Functional recycling of C2 domains throughout evolution: A comparative study of synaptotagmin, protein kinase C and phospholipase C by sequence, structural and modelling approaches

The C2 domain is one of the most frequent and widely distributed calcium-binding motifs. Its structure comprises an eight-stranded beta-sandwich with two structural types as if the result of a circular permutation. Combining sequence, structural and modelling information, we have explored, at different levels of granularity, the functional characteristics of several families of C2 domains. At the coarsest level,the similarity correlates with key structural determinants of the C2 domain fold and, at the finest level, with the domain architecture of the proteins containing them, highlighting the functional diversity between the various subfamilies. The functional diversity appears as different conserved surface patches throughout this common fold. In some cases, these patches are related to substrate-binding sites whereas in others they correspond to interfaces of presumably permanent interaction between other domains within the same polypeptide chain. For those related to substrate-binding sites, the predictions overlap with biochemical data in addition to providing some novel observations. For those acting as protein-protein interfaces' our modelling analysis suggests that slight variations between families are a result of not only complementary adaptations in the interfaces involved but also different domain architecture. In the light of the sequence and structural genomic projects, the work presented here shows that modelling approaches along with careful sub-typing of protein families will be a powerful combination for a broader coverage in proteomics. (C) 2003 Elsevier Ltd. All rights reserved.

Modelling inpatient length of stay by a hierarchical mixture regression via the EM algorithm

The modelling of inpatient length of stay (LOS) has important implications in health care studies. Finite mixture distributions are usually used to model the heterogeneous LOS distribution, due to a certain proportion of patients sustaining-a longer stay. However, the morbidity data are collected from hospitals, observations clustered within the same hospital are often correlated. The generalized linear mixed model approach is adopted to accommodate the inherent correlation via unobservable random effects. An EM algorithm is developed to obtain residual maximum quasi-likelihood estimation. The proposed hierarchical mixture regression approach enables the identification and assessment of factors influencing the long-stay proportion and the LOS for the long-stay patient subgroup. A neonatal LOS data set is used for illustration, (C) 2003 Elsevier Science Ltd. All rights reserved.

Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism

Molecular modelling of human CYP1B1 based on homology with the mammalian P450, CYP2C5, of known three-dimensional structure is reported. The enzyme model has been used to investigate the likely mode of binding for selected CYP1B1 substrates, particularly with regard to the possible effects of allelic variants of CYP1B1 on metabolism. In general, it appears that the CYP1B1 model is consistent with known substrate selectivity for the enzyme, and the sites of metabolism can be rationalized in terms of specific contacts with key amino acid residues within the CYP1B1 heme locus. Further-more, a mode of binding interaction for the inhibitor, a-naphthoflavone, is presented which accords with currently available information. The current paper shows that a combination of molecular modelling and experimental determinations on the substrate metabolism for CYP1B1 allelic variants can aid in the understanding of structure-function relationships within P450 enzymes. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

Hookworm aspartic protease, Na-APR-2, cleaves human hemoglobin and serum proteins in a host-specific fashion

Hookworms are voracious blood-feeders. The cloning and functional expression of an aspartic protease, Na-APR-2, from the human hookworm Necator americanus are described here. Na-APR-2 is more similar to a family of nematode-specific, aspartic proteases than it is to cathepsin D or pepsin, and the term nemepsins for members of this family of nematode-specific hydrolases is proposed. Na-apr-2 mRNA was detected in blood-feeding, developmental stages only of N. americanus, and the protease was expressed in the intestinal lumen, amphids, and excretory glands. Recombinant Na-APR-2 cleaved human hemoglobin (Hb) and serum proteins almost twice as efficiently as the orthologous substrates from the nonpermissive dog host. Moreover, only 25% of the Na-APR-2 cleavage sites within human Hb were shared with those generated by the related N. americanus cathepsin D, Na-APR-1. Antiserum against Na-APR-2 inhibited migration of 50% of third-stage N. americanus larvae through skin, which suggests that aspartic proteases might be effective vaccines against human hookworm disease.

Evidence for sympatric speciation by host shift in the sea

The genetic divergence and evolution of new species within the geographic range of a single population (sympatric speciation) contrasts with the well-established doctrine that speciation occurs when populations become geographically isolated (allopatric speciation). Although there is considerable theoretical support for sympatric speciation [1, 2], this mode of diversification remains controversial, at least in part because there are few well-supported examples [3]. We use a combination of molecular, ecological, and biogeographical data to build a case for sympatric speciation by host shift in a new species of coral-dwelling fish (genus Gobiodon). We propose that competition for preferred coral habitats drives host shifts in Gobiodon and that the high diversity of corals provides the source of novel, unoccupied habitats. Disruptive selection in conjunction with strong host fidelity could promote rapid reproductive isolation and ultimately lead to species divergence. Our hypothesis is analogous to sympatric speciation by host shift in phytophagous insects [4, 5] except that we propose a primary role for intraspecific competition in the process of speciation. The fundamental similarity between these fishes and insects is a specialized and intimate relationship with their hosts that makes them ideal candidates for speciation by host shift.

Using DEM to model ore breakage within a pilot scale SAG mill

The best accepted method for design of autogenous and semi-autogenous (AG/SAG) mills is to carry out pilot scale test work using a 1.8 m diameter by 0.6 m long pilot scale test mill. The load in such a mill typically contains 250,000-450,000 particles larger than 6 mm, allowing correct representation of more than 90% of the charge in Discrete Element Method (DEM) simulations. Most AG/SAG mills use discharge grate slots which are 15 mm or more in width. The mass in each size fraction usually decreases rapidly below grate size. This scale of DEM model is now within the possible range of standard workstations running an efficient DEM code. This paper describes various ways of extracting collision data front the DEM model and translating it into breakage estimates. Account is taken of the different breakage mechanisms (impact and abrasion) and of the specific impact histories of the particles in order to assess the breakage rates for various size fractions in the mills. At some future time, the integration of smoothed particle hydrodynamics with DEM will allow for the inclusion of slurry within the pilot mill simulation. (C) 2004 Elsevier Ltd. All rights reserved.

Morphological variation and host range of two Ganoderma species from Papua New Guinea

Two species of Ganoderma belonging to different subgenera which cause disease on oil palms in PNG are identified by basidiome morphology and the morphology of their basidiospores. The names G. boninense and G. tornatum have been applied. Significant pleiomorphy was observed in basidiome characters amongst the specimens examined. This variation in most instances did not correlate well with host or host status. Sporemorphology appeared uniform within a species and spore indices varied only slightly. G. tornatum was found to have a broad host range whereas G. boninense appears to be restricted to palms in Papua New Guinea.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immuno suppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

Effect of addition of maltodextrin on drying kinetics and stickiness of sugar and acid-rich foods during convective drying: experiments and modelling

The effect of addition of maltodextrin on drying kinetics of drops containing fructose, glucose, sucrose and citric acid individually and in mixtures was studied experimentally using single drop drying experiments and numerically by solving appropriate mass and heat transfer equations. The numerical predictions agreed with the experimental moisture and temperature histories within 5-6% average relative (absolute) errors and average differences of +/- 1degreesC, respectively. The stickiness of these drops was determined using the glass transition temperature (T-g) of the drops' surface layer as an indicator. The experimental stickiness histories followed the model predictions with reasonable accuracy. A safe drying (non-sticky) regime in a spray drying environment has been proposed, and used to estimate the optimum amount of addition of maltodextrin for successful spray drying of 120 micron diameter droplets of fruit juices. (C) 2003 Elsevier Ltd. All rights reserved.

Numerical modelling of radiating superorbital flows

Experimental aerodynamic studies of the flows around new aerocapture spacecraft configurations are presently being done in the superorbital expansion tubes at The University of Queensland. Short duration flows at speeds of 10--13 km/s are produced in the expansion tube facility and are then applied to the model spacecraft. Although high-temperature effects, such as molecular dissociation, have long been a part of the computational modelling of the expansion tube flows for speeds below 10 km/s, radiation may now be a significant mechanism of energy transfer within the shock layer on the model. This paper will study the coupling of radiation energy transport for an optically thin gas to the flow dynamics in order to obtain accurate predictions of thermal loads on the spacecraft. The results show that the effect of radiation on the flowfields of subscale models for expansion tube experiments can be assessed by measurements of total heat transfer and radiative heat transfer.