Numerical modeling of 11.1 T MRI of a human head using MoM/FDTD methods

In a recent study, severe distortions in the proton images of an excised, fixed, human brain in an 11.1 Tesla/40 cm MR instrument have been observed, and the effect modeled on phantom images using a finite difference time domain (FDTD) model. in the present study, we extend these simulations to that of a complete human head, employing a hybrid FDTD and method of moments (MoM) approach, which provides a validated method for simulating biological samples in coil structures. The effect of fixative on the image distortions is explored. importantly, temperature distributions within the head are also simulated using a bioheat method based on parameters derived from the electromagnetic simulations. The MoM/FDTD simulations confirm that the transverse magnetic field (B,) from a ReCav resonator exhibits good homogeneity in air but strong inhomogeneity when loaded with the head with or without fixative. The fixative serves to increase the distortions, but they are still significant for the in vivo simulations. The simulated signal intensity (SI) distribution within the sample confirm the distortions in the experimental images are caused by the complex interactions of the incident electromagnetic fields with tissue, which is heterogeneous in terms of conductivity and permittivity. The temperature distribution is likewise heterogeneous, raising concerns regarding hot spot generation in the sample that may exceed acceptable levels in future in vivo studies. As human imaging at 11.1 T is some time away, simulations are important in terms of predicting potential safety issues as well as evaluating practical concerns about the quality of images. Simulation on a whole human head at 11.1 T implies the wave behavior presents significant engineering challenges for ultra-high-field (UHF) MRI. Novel strategies will have to be employed in imaging technique and resonator design for UHF MRI to achieve the theoretical signal-to-noise ratio (SNR) improvements it offers over lower field systems. (C) 2005 Wiley Periodicals, Inc.

Identification and molecular modeling of a novel, plant-like, human purple acid phosphatase

Purple acid phosphatases are a family of binuclear metallohydrolases that have been identified in plants, animals and fungi. Only one isoform of similar to 35 kDa has been isolated from animals, where it is associated with bone resorption and microbial killing through its phosphatase activity, and hydroxyl radical production, respectively. Using the sensitive PSI-BLAST search method, sequences representing new purple acid phosphatase-like proteins have been identified in mammals, insects and nematodes. These new putative isoforms are closely related to the similar to 55 kDa purple acid phosphatase characterized from plants. Secondary structure prediction of the new human isoform further confirms its similarity to a purple acid phosphatase from the red kidney bean. A structural model for the human enzyme was constructed based on the red kidney bean purple acid phosphatase structure. This model shows that the catalytic centre observed in other purple acid phosphatases is also present in this new isoform. These observations suggest that the sequences identified in this study represent a novel subfamily of plant-like purple acid phosphatases in animals and humans. (c) 2006 Elsevier B.V. All rights reserved.

Effector dynamics of rhythmic wrist activity and its implications for (modeling) bimanual coordination

To examine the role of the effector dynamics of the wrist in the production of rhythmic motor activity, we estimated the phase shifts between the EMG and the task-related output for a rhythmic isometric torque production task and an oscillatory movement, and found a substantial difference (45-52degrees) between the two. For both tasks, the relation between EMG and task-related output (torque or displacement) was adequately reproduced with a physiologically motivated musculoskeletal model. The model simulations demonstrated the importance of the contribution of passive structures to the overall dynamics and provided an account for the observed phase shifts in the dynamic task. Additional simulations of the musculoskeletal model with added load suggested that particular changes in the phase relation between EMG and movement may follow largely from the intrinsic muscle dynamics, rather than being the result of adaptations in the neural control of joint stiffness. The implications of these results are discussed in relation to (models of) interlimb coordination in rhythmic tasks. (C) 2004 Elsevier B.V. All rights reserved.

Potent cyclic antagonists of the complement C5a receptor on human polymorphonulcear leukocytes. Relationships between structures and activity

Human C5a is a plasma protein with potent chemoattractant and pro-inflammatory properties, and its overexpression correlates with severity of inflammatory diseases. C5a binds to its G protein-coupled receptor (C5aR) on polymorphonuclear leukocytes (PMNLs) through a high-affinity helical bundle and a low-affinity C terminus, the latter being solely responsible for receptor activation. Potent and selective C5a antagonists are predicted to be effective anti-inflammatory drugs, but no pharmacophore for small molecule antagonists has yet been developed, and it would significantly aid drug design. We have hypothesized that a turn conformation is important for activity of the C terminus of C5a and herein report small cyclic peptides that are stable turn mimics with potent antagonism at C5aR on human PMNLs. A comparison of solution structures for the C terminus of C5a, small acyclic peptide ligands, and cyclic antagonists supports the importance of a turn for receptor binding. Competition between a cyclic antagonist and either C5a or an acyclic agonist for C5aR on PMNLs supports a common or overlapping binding site on the C5aR. Structure-activity relationships for 60 cyclic analogs were evaluated by competitive radioligand binding with C5a (affinity) and myeloperoxidase release (antagonist potency) from human PMNLs, with 20 compounds having high antagonist potencies (IC50, 20 nM(-1) muM). Computer modeling comparisons reveal that potent antagonists share a common cyclic backbone shape, with affinity-determining side chains of defined volume projecting from the cyclic scaffold. These results define a new pharmacophore for C5a antagonist development and advance our understanding of ligand recognition and receptor activation of this G protein-coupled receptor.

Active site mutations and substrate inhibition in human sulfotransferase 1A1 and 1A3

Human SULT1A1 is primarily responsible for sulfonation of xenobiotics, including the activation of promutagens, and it has been implicated in several forms of cancer. Human SULT1A3 has been shown to be the major sulfotransferase that sulfonates dopamine. These two enzymes shares 93% amino acid sequence identity and have distinct but overlapping substrate preferences. The resolution of the crystal structures of these two enzymes has enabled us to elucidate the mechanisms controlling their substrate preferences and inhibition. The presence of two p-nitrophenol (pNP) molecules in the crystal structure of SULT1A1 was postulated to explain cooperativity at low and inhibition at high substrate concentrations, respectively. In SULT1A1, substrate inhibition occurs with pNP as the substrate but not with dopamine. For SULT1A3, substrate inhibition is found for dopamine but not with pNP. We investigated how substrate inhibition occurs in these two enzymes using molecular modeling, site-directed mutagenesis, and kinetic analysis. The results show that residue Phe-247 of SULT1A1, which interacts with both p-nitrophenol molecules in the active site, is important for substrate inhibition. Mutation of phenylalanine to leucine at this position in SULT1A1 results in substrate inhibition by dopamine. We also propose, based on modeling and kinetic studies, that substrate inhibition by dopamine in SULT1A3 is caused by binding of two dopamine molecules in the active site. © 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

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.

Modeling the age of tropical moist forest fragments in heavily-cleared lowland landscapes of Colombia

Increasingly, large areas of native tropical forests are being transformed into a mosaic of human dominated land uses with scattered mature remnants and secondary forests. In general, at the end of the land clearing process, the landscape will have two forest components: a stable component of surviving mature forests, and a dynamic component of secondary forests of different ages. As the proportion of mature forests continues to decline, secondary forests play an increasing role in the conservation and restoration of biodiversity. This paper aims to predict and explain spatial and temporal patterns in the age of remnant mature and secondary forests in lowland Colombian landscapes. We analyse the age distributions of forest fragments, using detailed temporal land cover data derived from aerial photographs. Ordinal logistic regression analysis was applied to model the spatial dynamics of mature and secondary forest patches. In particular, the effect of soil fertility, accessibility and auto-correlated neighbourhood terms on forest age and time of isolation of remnant patches was assessed. In heavily transformed landscapes, forests account for approximately 8% of the total landscape area, of which three quarters are comprised of secondary forests. Secondary forest growth adjacent to mature forest patches increases mean patch size and core area, and therefore plays an important ecological role in maintaining landscape structure. The regression models show that forest age is positively associated with the amount of neighbouring forest, and negatively associated with the amount of neighbouring secondary vegetation, so the older the forest is the less secondary vegetation there is adjacent to it. Accessibility and soil fertility also have a negative but variable influence on the age of forest remnants. The probability of future clearing if current conditions hold is higher for regenerated than mature forests. The challenge of biodiversity conservation and restoration in dynamic and spatially heterogeneous landscape mosaics composed of mature and secondary forests is discussed. (c) 2004 Elsevier B.V. All rights reserved.

Human sulfotransferases and their role in chemical metabolism

Sulfonation is an important reaction in the metabolism of numerous xenobiotics, drugs, and endogenous compounds. A supergene family of enzymes called sulfotransferases (SULTs) catalyze this reaction. In most cases, the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. However, many of these enzymes are also capable of bioactivating procarcinogens to reactive electrophiles. In humans three SULT families, SULT1, SULT2, and SULT4, have been identified that contain at least thirteen distinct members. SULTs have a wide tissue distribution and act as a major detoxification enzyme system in adult and the developing human fetus. Nine crystal structures of human cytosolic SULTs have now been determined, and together with site-directed mutagenesis experiments and molecular modeling, we are now beginning to understand the factors that govern distinct but overlapping substrate specificities. These studies have also provided insight into the enzyme kinetics and inhibition characteristics of these enzymes. The regulation of human SULTs remains as one of the least explored areas of research in the field, though there have been some recent advances on the molecular transcription mechanism controlling the individual SULT promoters. Interindividual variation in sulfonation capacity may be important in determining an individual's response to xenobiotics, and recent studies have begun to suggest roles for SULT polymorphism in disease susceptibility. This review aims to provide a summary of our present understanding of the function of human cytosolic sulfotransferases.

A Drug-Based Intervention Study on the Importance of Buffaloes for Human Schistosoma Japonicum Infection around Poyang Lake, People’s Republic of China

Schistosomiasis japonica is a zoonosis of major public health importance in southern China. We undertook a drug intervention to test the hypothesis that buffalo are major reservoirs for human infection in the marshlands/lake areas, where one million people are infected. We compared human and buffalo infection rates and intensity in an intervention village (Jishan), where humans and buffalo were treated with praziquantel, and a control village (Hexi), where only humans were treated, in the Poyang Lake region. Over the four-year study, human incidence in Jishan decreased but increased in Hexi. Adjustment of incidence by age, sex, water exposure, year, and village further confirmed the decreased human infection in Jishan. Chemotherapy for buffaloes resulted in a decrease in buffalo infection rates in Jishan, which coincided with the reduction in human infection rates there in the last two years of the study. Mathematical modeling predicted that buffalo are responsible for 75% of human transmission in Jishan. Copyright © 2006 by The American Society of Tropical Medicine and Hygiene.

Multiple-acquisition parallel imaging combined with a transceive array for the amelioration of high-field RF distortion: a modeling study

A new method for ameliorating high-field image distortion caused by radio frequency/tissue interaction is presented and modeled, The proposed method uses, but is not restricted to, a shielded four-element transceive phased array coil and involves performing two separate scans of the same slice with each scan using different excitations during transmission. By optimizing the amplitudes and phases for each scan, antipodal signal profiles can be obtained, and by combining both images together, the image distortion can be reduced several-fold. A hybrid finite-difference time-domain/method-of-moments method is used to theoretically demonstrate the method and also to predict the radio frequency behavior inside the human head. in addition, the proposed method is used in conjunction with the GRAPPA reconstruction technique to enable rapid imaging. Simulation results reported herein for IIT (470 MHz) brain imaging applications demonstrate the feasibility of the concept where multiple acquisitions using parallel imaging elements with GRAPPA reconstruction results in improved image quality. (c) 2006 Wiley Periodicals, Inc.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

Simulation of Brugada syndrome using cellular and three-dimensional whole-heart modeling approaches

Brugada syndrome (BS) is a genetic disease identified by an abnormal electrocardiogram ( ECG) ( mainly abnormal ECGs associated with right bundle branch block and ST-elevation in right precordial leads). BS can lead to increased risk of sudden cardiac death. Experimental studies on human ventricular myocardium with BS have been limited due to difficulties in obtaining data. Thus, the use of computer simulation is an important alternative. Most previous BS simulations were based on animal heart cell models. However, due to species differences, the use of human heart cell models, especially a model with three-dimensional whole-heart anatomical structure, is needed. In this study, we developed a model of the human ventricular action potential (AP) based on refining the ten Tusscher et al (2004 Am. J. Physiol. Heart Circ. Physiol. 286 H1573 - 89) model to incorporate newly available experimental data of some major ionic currents of human ventricular myocytes. These modified channels include the L-type calcium current (ICaL), fast sodium current (I-Na), transient outward potassium current (I-to), rapidly and slowly delayed rectifier potassium currents (I-Kr and I-Ks) and inward rectifier potassium current (I-Ki). Transmural heterogeneity of APs for epicardial, endocardial and mid-myocardial (M) cells was simulated by varying the maximum conductance of IKs and Ito. The modified AP models were then used to simulate the effects of BS on cellular AP and body surface potentials using a three-dimensional dynamic heart - torso model. Our main findings are as follows. (1) BS has little effect on the AP of endocardial or mid-myocardial cells, but has a large impact on the AP of epicardial cells. (2) A likely region of BS with abnormal cell AP is near the right ventricular outflow track, and the resulting ST-segment elevation is located in the median precordium area. These simulation results are consistent with experimental findings reported in the literature. The model can reproduce a variety of electrophysiological behaviors and provides a good basis for understanding the genesis of abnormal ECG under the condition of BS disease.

High-field magnetic resonance imaging with reduced field/tissue RF artefacts - A modeling study using hybrid MoM/FEM and FDTD technique

Due to complex field/tissue interactions, high-field magnetic resonance (MR) images suffer significant image distortions that result in compromised diagnostic quality. A new method that attempts to remove these distortions is proposed in this paper and is based on the use of transceiver-phased arrays. The proposed system uses, in the examples presented herein, a shielded four-element transceive-phased array head coil and involves performing two separate scans of the same slice with each scan using different excitations during transmission. By optimizing the amplitudes and phases for each scan, antipodal signal profiles can be obtained, and by combining both the images together, the image distortion can be reduced several fold. A combined hybrid method of moments (MoM)/finite element method (FEM) and finite-difference time-domain (FDTD) technique is proposed and used to elucidate the concept of the new method and to accurately evaluate the electromagnetic field (EMF) in a human head model. In addition, the proposed method is used in conjunction with the generalized auto-calibrating partially parallel acquisitions (GRAPPA) reconstruction technique to enable rapid imaging of the two scans. Simulation results reported herein for 11-T (470-MHz) brain imaging applications show that the new method with GRAPPA reconstruction theoretically results in improved image quality and that the proposed combined hybrid MoM/FEM and FDTD technique is. suitable for high-field magnetic resonance imaging (MRI) numerical analysis.