bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a polarizable force field for proteins via ab initio quantum chemistry: First generation model and gas phase tests
Authors: Kaminski George A. , Stern Harry A. , Berne B. J. , Friesner Richard A. , Cao Yixiang X. , Murphy Robert B. , Zhou Ruhong , Halgren Thomas A.
Published: December 2002

We present results of developing a methodology suitable for producing molecular mechanics force fields with explicit treatment of electrostatic polarization for proteins and other molecular system of biological interest. The technique allows simulation of realistic‐size systems. Employing high‐level ab initio data as a target for fitting allows us to avoid the problem of the lack of detailed experimental data. Using the fast and reliable quantum mechanical methods supplies robust fitting data for the resulting parameter sets. As a result, gas‐phase many‐body effects for dipeptides are captured within the average RMSD of 0.22 kcal/mol from their ab initio values, and conformational energies for the di‐ and tetrapeptides are reproduced within the average RMSD of 0.43 kcal/mol from their quantum mechanical counterparts. The latter is achieved in part because of application of a novel torsional fitting technique recently developed in our group, which has already been used to greatly improve accuracy of the peptide conformational equilibrium prediction with the OPLS‐AA force field.1 Finally, we have employed the newly developed first‐generation model in computing gas‐phase conformations of real proteins, as well as in molecular dynamics studies of the systems. The results show that, although the overall accuracy is no better than what can be achieved with a fixed‐charges model, the methodology produces robust results, permits reasonably low computational cost, and avoids other computational problems typical for polarizable force fields. It can be considered as a solid basis for building a more accurate and complete second‐generation model. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1515–1531, 2002
Consistent treatment of inter‐ and intramolecular polarization in molecular mechanics calculations
Authors: Ren Pengyu , Ponder Jay W.
Published: December 2002

A protocol is described for the treatment of molecular polarization in force field calculations. The resulting model is consistent in that both inter‐ and intramolecular polarization are handled within a single scheme. An analytical formula for removing intramolecular polarization from a set of atomic multipoles for an arbitrary static structure or conformation is given. With the help of the intramolecular polarization, these permanent atomic multipoles can then be applied in modeling alternative conformations of a molecule. Equipped with this simple technique, one can derive transferable electrostatic parameters for peptides and proteins using flexible model compounds such as dipeptides. The proposed procedure is tested for its ability to describe the electrostatic potential around various configurations of theN‐methylacetamide dimer. The effect of different intramolecular polarization schemes on the accuracy of a force field model of the electrostatic potential of alanine dipeptide is investigated. A group‐based scheme for including direct intramolecular polarization is shown to be most successful in accounting for the conformational dependence of electrostatic potentials. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1497–1506, 2002
Parallel stored‐integral and semidirect Hartree–Fock and DFT methods with data compression
Authors: Mitin Alexander V. , Baker Jon , Wolinski Krzysztof , Pulay Peter
Published: December 2002

Recent developments in magnetic disk technology have made stored‐integral techniques competitive with the currently more widely used direct methods, which involve the recalculation of the basic two‐electron integrals. We present efficient conventional (all integrals stored) and semidirect Hartree–Fock and DFT algorithms with data compression for single‐processor and distributed memory parallel computers, and compare them with the corresponding direct algorithms. On inexpensive modern personal computer‐based hardware, the stored integral method is up to three times more efficient than the direct method in terms of total elapsed job time. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 154–160, 2003
Molecular dynamics simulations of the dinuclear zinc‐β‐lactamase from Bacteroides fragilis complexed with imipenem
Authors: Suárez Dimas , Díaz Natalia , Merz Kenneth M.
Published: December 2002

Herein, we present results from MD simulations of the Michaelis complex formed between the dizinc β‐lactamase from B. fragilis and imipenem. We considered two catalytically important configurations, which differ in the presence or absence of a hydroxide bridge connecting the two zinc ions in the active site. The structural and dynamical effects induced by substrate binding, the specific roles of the conserved residues and the zinc‐bound water molecules, the near attack conformers of the Michaelis complex, and so forth, are discussed in detail. The relative stability of the two configurations was estimated from QM linear scaling calculations on the enzyme‐substrate complex combined with Poisson‐Boltzmann electrostatic calculations and normal mode calculations. Importantly, we find that the two configurations have similar energies, indicating that these two structures could readily be interchanged, thereby facilitating catalysis. The configuration with the hydroxide bound to the two zinc ions is predicted to be the resting form of the enzyme, while the configuration without the bridge is the reactive form that was found to place the hydroxide in position to attack the carbonyl of the β‐lactam ring. Thus, we propose that the enzyme initiates catalysis by converting from the hydroxide bridge form into the configuration that lacks the hydroxide bridge. This interconversion increases the nucleophilicity of the hydroxide ion and exposes it to the β‐lactam carbonyl, which ultimately facilitates nucleophilic attack. The implications of the observed modes of binding, the possible influence of mutating the Lys184 and Asn193 residues on substrate binding, and the reaction mechanism are also discussed in detail. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1587–1600, 2002
An ab initio force field for the cofactors of bacterial photosynthesis
Authors: Ceccarelli Matteo , Procacci Piero , Marchi Massimo
Published: December 2002

This article presents a new ab initio force field for the cofactors of bacterial photosynthesis, namely quinones and bacteriochlorophylls. The parameters has been designed to be suitable for molecular dynamics simulations of photosynthetic proteins by being compatible with the AMBER force field. To our knowledge, this is the first force field for photosynthetic cofactors based on a reliable set of ab initio density functional reference data for methyl bacteriochlorophyll a, methyl bacteriopheophytin a, and of a derivative of ubiquinone. Indeed, the new molecular mechanics force field is able to reproduce very well not only the experimental and ab initio structural properties and the vibrational spectra of the molecules, but also the eigenvectors of the molecular normal modes. For this reason it might also be helpful to understand vibrational spectroscopy results obtained on reaction center proteins. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 129–142, 2003
Endothelial cell–Matrix interactions
Authors: Iivanainen Erika , Kähäri Veli‐Matti , Heino Jyrki , Elenius Klaus
Published: December 2002

Dynamic interactions between endothelial cells and components of their surrounding extracellular matrix are necessary for the invasion, migration, and survival of endothelial cells during angiogenesis. These interactions are mediated by matrix receptors that initiate intracellular signaling cascades in response to binding to specific extracellular matrix molecules. The interactions between endothelial cells and their environment are also modulated by enzymes that degrade different matrix components and thus enable endothelial invasion. Recent reports on gene targeting in mice have confirmed the role of two classes of matrix receptors, integrins and cell surface heparan sulfate proteoglycans, and a group of matrix degrading proteolytic enzymes, matrix metalloproteinases, in angiogenesis. The significance of endothelial cell–matrix interactions is further supported by several ongoing clinical trials that analyze the effects of drugs blocking this interaction on angiogenesis‐dependent growth of human tumors. Microsc. Res. Tech. 60:13–22, 2003. © 2002 Wiley‐Liss, Inc.
Genetic abnormalities of the endothelium
Authors: Butany Jagdish W. , Verma Subodh , Leask Richard L. , Mohsen Basal , Asa Sylvia L.
Published: December 2002

Endothelial cell dysfunction plays an important role in the development and progression of cardiovascular and other disease. The purpose of this review is to discuss some of the genetic diseases known to adversely affect endothelial function. Although the list is exhaustive, we focus our discussion on primary pulmonary hypertension, diabetes mellitus, Alzheimer's disease, Crohn's disease, Von‐Hippel‐Lindau disease, familial Mediterranean fever, thrombotic microangiopathy, and key vascular malformations. Endothelial dysfunction results from a complex interplay between genetic and environmental factors. This review highlights some of the growing body of evidence implicating endothelial dysfunction as an important mediator of diverse diseases. Microsc. Res. Tech. 60:30–37, 2003. © 2002 Wiley‐Liss, Inc.
Mast cells and angiogenesis
Authors: Hiromatsu Yuji , Toda Shuji
Published: December 2002

There is much evidence that angiogenesis is related to mast cells. Mast cells accumulate in many angiogenesis‐dependent situations, including tumor growth, rheumatoid arthritis, ovulation, would healing, and tissue repair. Several mast cell mediators are angiogenic and regulate endothelial cell proliferation and function. Stem cell factor, vascular endothelial growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet‐derived growth factor induce chemotactic migration of mast cells to sites of neovascularization. Mast cell products such as tryptase also degrade connective tissue matrix to provide space for neovascular sprouts. Angiogenesis has been proposed as a target for anticancer therapy and for treatment of inflammatory disorders such as rheumatoid arthritis. Future studies on the cascade of angiogenic events, including mast cell–target cell interaction, and various intracellular signaling pathways are indicated to provide a new approach for the treatment of cancer and inflammatory disorders and for tissue repair. Microsc. Res. Tech. 60:64–69, 2003. © 2002 Wiley‐Liss, Inc.
Role of growth factors and their receptors in proliferation of microvascular endothelial cells
Authors: Suhardja Agustinus , Hoffman Howard
Published: December 2002

Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis. The biological significance of VEGF, EGF, and bFGF is mediated by their receptors, which belong to the family of tyrosine kinase receptors: Flt‐1 (VEGFR‐1), KDR (VEGFR‐2), EGFR, FGFR‐1, FGFR‐2, FGFR‐3, and FGFR‐4. Deeper understanding of the mechanism of activation of these growth factor receptors has allowed the development of a new pharmacological strategy aimed at controlling cancer cell proliferation. The results of a large body of preclinical as well as early clinical studies conducted suggest that targeting the growth factor receptors could represent a significant contribution to cancer therapy. Microsc. Res. Tech. 60:70–75, 2003. © 2002 Wiley‐Liss, Inc.
Effects of steroid hormones on vascular functions
Authors: Suzuki Takashi , Nakamura Yasuhiro , Moriya Takuya , Sasano Hironobu
Published: December 2002

The purpose of this review is to present reported findings of effects of steroids on vascular function and to discuss the biological significance in vascular physiology and pathology. Steroid hormones play various roles in vascular functions through the specific receptor localized in the endothelium and underlying vascular smooth muscle cells (VSMCs). Estrogen replacement therapy in postmenopausal women is in general associated with a reduction in mortality from cardiovascular disease and the beneficial effects of estrogens are caused by modulation of lipid metabolism, expression of leukocyte adhesion molecules, and migration of VSMCs in the vascular wall. Estrogens also play a role as vasodilators through an increment in nitric oxide (NO) production in endothelium or modulation of calcium homeostasis in VSMCs. Some progestin molecules partially oppose the effects of estrogens on vascular functions, but striking differences exist among the types of molecules. Testosterone shows a vasorelaxant response, but detailed actions of androgens on vascular functions remain unknown. Glucocorticoids act on vasoconstriction through reduced prostacyclin production, increased α‐adrenoceptor numbers, and inhibition of NO synthase, while mineralocorticoids induce hypertrophy and hyperplasia of VSMCs and perivascular fibrosis and cause peripheral vascular resistance, in addition to changes in vascular electrocyte permeability. Some rapid actions of steroids are mediated by “nongenomic” responses in vascular tissues. Recent studies have also demonstrated that steroid‐producing or ‐metabolizing enzymes are expressed in the vascular wall, suggesting the local regulation of steroids in the vascular system. Thus, steroid hormones greatly influence vascular functions and an understanding of the mechanisms may provide new means to prevent vascular diseases. Microsc. Res. Tech. 60:76–84, 2003. © 2002 Wiley‐Liss, Inc.
Automated quantitative evaluation of diseased and nondiseased renal transplants with MR renography
Authors: de Priester Jacobus A. , den Boer Jacques A. , Christiaans Maarten H.L. , Kessels Alphons G.H. , Giele Eelco L.W. , Hasman Arie , van Hooff Hans P. , van Engelshoven Jos M.A.
Published: December 2002

Purpose

To present a method of automated parametric quantification of dynamic MR enhancement curves of renal transplants and evaluate the disease‐discriminating properties of the resulting MR renography (MRR) data.

Materials and Methods

This study included 27 patients with nondiseased renal transplants and eight patients with diseased renal transplants. The examination was repeated in 10 patients and the reproducibility of the enhancement parameters was estimated by analysis of variance (ANOVA). The disease‐discriminating properties of the transplant volumes and enhancement parameters were tested with t‐tests and logistic regression analysis.

Results

The enhancement parameters were reproducible. The mean medullary nephronal washout rate (λ1) and cortical arterial blood volume (μ0) were lower in diseased renal transplants. The combination of these parameters was a strong predictor of renal transplant disease (area under ROC curve 0.98; 95% confidence interval 0.96–1.0).

Conclusion

Automated parametric quantification of cortical and medullary enhancement is feasible and allows the accurate detection of nonsurgical disease in renal transplants by MRR. J. Magn. Reson. Imaging 2003;17:95–103. © 2002 Wiley‐Liss, Inc.
MRI/MRS evaluation of cariporide in a canine long‐term model of reperfused ischemic insults
Authors: Thompson Kerry , Wisenberg Gerald , Sykes RVT Jane , Thompson R. Terry
Published: December 2002

Purpose

To examine with magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) the long‐term effects of cariporide in a canine cardiac ischemia/reperfusion model.

Materials and Methods

Twenty‐two beagles underwent a 2‐hour occlusion followed by 10 days of reperfusion. Cine MRI and 31P MRS were performed to monitor function and metabolism of the heart in the control (N = 10) and cariporide (N = 12) groups. Radioactively labeled microspheres were injected to determine coronary blood flow, and contrast‐enhanced ex vivo MRI assessed infarct volumes.

Results

Cariporide produced a significant reduction vs. controls, in intracellular pH, during ischemia (P < 0.05) and at days 3 and 10 postreperfusion (P < 0.0005). Functional recovery of the myocardium was significantly improved immediately upon reperfusion (percent of baseline: 63.5% ± 3.5% for controls, 90.5% ± 7.2% for cariporide) and at day 3, but not by day 10. Normalized infarct ratios (IRs) were similar for controls and cariporide (0.58 ± 0.08, 0.58 ± 0.06, respectively).

Conclusion

Cariporide augments early functional recovery, while delaying normalization of intracellular pH following ischemia/reperfusion, but confers neither long‐term functional or metabolic protection nor, most importantly, myocardial salvage. J. Magn. Reson. Imaging 2003;17:136–141. © 2002 Wiley‐Liss, Inc.
Diffusion tensor MRI of myocardial fibers and sheets: Correspondence with visible cut‐face texture
Authors: Tseng Wen‐Yih I. , Wedeen Van J. , Reese Timothy G. , Smith R. Neal , Halpern Elkan F.
Published: December 2002

Purpose

To test the hypothesis that the primary, secondary, and tertiary eigenvectors of the diffusion tensor (DT) measured with DT‐MRI correspond to the fiber, sheet, and sheet normal directions, respectively, we compared DT‐MRI data with the texture visible in the cut face of fresh bovine myocardium.

Materials and Methods

DT‐MRI and optical images obtained under identical conditions were compared objectively. Ink prints were made of the cut tissue, and the local orientations within these images were defined by analysis of local autocorrelations for regions matching DT‐MRI pixels. Deviation angles between the cleavage orientations and the diffusion eigenvectors were analyzed in eight specimens sliced in three orthogonal planes.

Results

Root‐mean‐square (RMS) angular disparity was 11° between the first eigenvectors of the DT and the fiber direction, 14° between the second eigenvector and the sheet direction, 14° between the third eigenvector and the sheet normal direction, and 15° between the tensor orientation in the imaging plane and the cleavage orientation of the cut face.

Conclusion

The results support a parallel relationship between the eigenvectors of the DT and symmetry axes of the myocardial architecture. Specifically, the first, second and third eigenvectors correspond to the fiber, sheet, and sheet normal directions, respectively. J. Magn. Reson. Imaging 2003;17:31–42. © 2002 Wiley‐Liss, Inc.
Proton spin‐lock ratio imaging for quantitation of glycosaminoglycans in articular cartilage
Authors: Regatte Ravinder Reddy , Akella Sarma V.S. , Borthakur Arijitt , Reddy Ravinder
Published: December 2002

Purpose

To quantify glycosaminoglycans (GAG) in intact bovine patellar cartilage using the proton spin‐lock ratio imaging method. This approach exploits spin‐lattice relaxation time in the rotating frame (T1ρ) imaging and T1ρ relaxivity (R1ρ).

Materials and Methods

All the magnetic resonance imaging (MRI) experiments were performed on a 4‐T whole‐body GE Signa scanner (GEMS, Milwaukee, WI), and spectroscopy experiments of chondroitin sulfate (CS) phantoms were done on a 2‐T custom‐built spectrometer. A custom‐built 11‐cm‐diameter transmit‐receive birdcage coil, which was tuned to a proton frequency of 170 MHz, was employed for the imaging experiments. T1ρ measurements were made using a fast spin echo (FSE) sequence pre‐encoded with a three‐pulse cluster consisting of two 90° hard pulses separated by a low‐power rectangle pulse for spin‐locking.

Results

The methodology is first validated on CS phantoms and then used to quantify GAG content in intact bovine cartilage (N = 5). There is a good agreement between the GAG map calculated from the T1ρ ratio imaging method (71 ± 4%) and GAG measured from spectrophotometric assay (75 ± 5%) in intact bovine tissue.

Conclusion

We have demonstrated a proton spin‐lock ratio imaging method to quantify absolute GAG distribution in the cartilage in a noninvasive and nondestructive manner. J. Magn. Reson. Imaging 2003;17:114–121. © 2002 Wiley‐Liss, Inc.
Three‐pool model of white matter
Authors: Lancaster Jack L. , Andrews Trevor , Hardies L. Jean , Dodd Stephen , Fox Peter T.
Published: December 2002

Purpose

To investigate the use of a three‐pool relaxation model to measure myelin, myelinated‐axon, and mixed water‐pool fractions in white matter (WM) during myelination.

Materials and Methods

MRI at 1.9 Tesla, and conventional spin‐echo imaging were used to acquire T1 and T2 relaxation data in 15 normal children ranging in age from 3 months to 13 years 4 months. Three equations with three unknowns were solved to calculate three water‐pool fractions for each child in a frontal association‐fiber area and a frontal‐parietal projection‐fiber area. The temporal trend of the fractions was compared with a theoretical three‐pool myelination model.

Results

The myelin level in the projection‐fiber area rose earlier than in the association‐fiber area following the standard caudal‐to‐rostral trend. The temporal trend of the three‐pool fractions followed that predicted by the theoretical myelination model in both brain areas. The myelinated‐axon and mixed pool sizes were significantly different in the two WM areas following early myelination, although their myelin pools were similar. T1 values correlated more highly with the myelinated‐axon and mixed pool fractions than with the myelin pool fraction.

Conclusion

The three‐pool relaxation model provides measurements of water‐pool fractions in WM that follow values predicted during myelination. J. Magn. Reson. Imaging 2003;17:1–10. © 2002 Wiley‐Liss, Inc.
Is myo‐inositol a measure of glial swelling after stroke? a magnetic resonance study
Authors: Rumpel Helmut , Lim Winston Eng Hoe , Chang Hui Meng , Chan Ling Ling , Ho Gaik Lynn , Wong Meng Cheong , Tan Kim Ping
Published: December 2002

Purpose

To determine whether the hypothesis that the phenomenon of persistent cytotoxic edema in the subacute stage of ischemic stroke is in fact associated with the glial population. This is done by assessing the evolution of both the apparent diffusion coefficient (ADC) and the glial‐specific marker myo‐inositol (Ins) in a group of patients, and by comparing the results with the total cellular density by means of the creatine (Cre) level.

Material and Methods

Twenty‐two patients with stroke in the territory of the middle cerebral artery were each examined once only at a time ranging from eight hours to six days following the onset of symptoms. Lesion‐to‐contralateral values of ADC were obtained based on diffusion‐weighted echo‐planar imaging. Short TE single‐voxel proton magnetic resonance (1H MR) spectroscopy was used for quantification of cerebral metabolites in infarcted regions. Their levels were also compared with those in homotopic contralateral regions.

Results

In the stroke lesion, there was a significant correlation between ADC and the Ins level, albeit less pronounced than that for Cre. During different pathophysiological stages between 12 hours and three days, the Ins‐to‐Cre ratio increased by a factor of two and returned to apparently normal thereafter.

Conclusion

Our study provides the first demonstration of a relationship between persistent cytotoxic edema and the glial population in the context of cell swelling due to osmotic imbalance in stroke patients. J. Magn. Reson. Imaging 2003;17:11–19. © 2002 Wiley‐Liss, Inc.
Knees of ironman triathletes: Magnetic resonance imaging assessment of older (>35 years old) competitors
Authors: Shellock Frank G. , Hiller W. Douglas B. , Ainge George R. , Brown David W. , Dierenfield Laura
Published: December 2002

Purpose

To use magnetic resonance imaging (MRI) to evaluate the knees of older (>35 years old), competitive Ironman triathletes to determine the prevalence of abnormal findings.

Materials and Methods

The knees of 29 Ironman triathletes (20 men, 9 women; age range, 35–66 years old) were studied by MRI. The findings were analyzed collectively and categorized into group I (N = 13), subjects without prior knee injuries and symptoms, and group II (N = 16), subjects with prior knee injuries and/or current symptoms.

Results

Ten percent of the knees had ligamentous abnormalities, but the prevalence was not statistically different comparing group I to group II. Fifty‐five percent had abnormal menisci. The overall prevalence of abnormal menisci was significantly higher in group II (69%) than in group I (38%, P < 0.05). Cartilage abnormalities were found in 21% of the triathletes with a higher prevalence in group II (31%) than in group I (8%, P < 0.05). Twenty‐one percent (6/29) of the knees had bone contusions, with a higher prevalence in group II (31%) than in group I (8%, P < 0.05).

Conclusion

In general, the spectrum of abnormal MRI findings of the knee was no greater than age‐related changes previously reported for other athletic populations and nonathletes. These results have important implications for the diagnostic use of MRI of the knee in this high‐endurance, athletic population. J. Magn. Reson. Imaging 2003;17:122–130. © 2002 Wiley‐Liss, Inc.
Liquid‐phase oxidation of 1‐isopropyl‐ and 1‐ethyl‐4‐methoxybenzenes with oxygen to hydroperoxides
Authors: Zawadiak Jan , Stec Zbigniew , Jakubowski Bartłomiej , Orlińska Beata
Published: December 2002

A study was carried out on the kinetics of free‐radical chain oxidation of 1‐isopropyl‐4‐methoxybenzene (1a) and 1‐ethyl‐4‐methoxybenzene (1b) with oxygen in the liquid phase to yield 1‐methyl‐1‐(4‐methoxyphenyl)ethyl hydroperoxide (2a) and 1‐(4‐methoxyphenyl)ethyl hydroperoxide (2b). The oxidizability of 1a and 1b was studied over the temperature range 50–100°C. Long‐term oxidations of 1a and 1b to the corresponding hydroperoxides were carried out and the properties and thermal stability of 2a were established. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 35: 89–94, 2003
Abnormal angiogenesis in diabetes mellitus
Authors: Martin Alexandra , Komada Michael R. , Sane David C.
Published: December 2002

The adverse long‐term effects of diabetes mellitus have been well described and involve many organ systems. While diabetes management has largely focused on control of hyperglycemia, the presence of abnormalities of angiogenesis may cause or contribute to many of the clinical manifestations of diabetes. When compared with non‐diabetic subjects, diabetics demonstrate vascular abnormalities of the retina, kidneys, and fetus. Diabetics have impaired wound healing, increased risk of rejection of transplanted organs, and impaired formation of coronary collaterals. In each of these conditions, and possibly in diabetic neuropathy as well, abnormalities of angiogenesis can be implicated in the pathogenesis. A perplexing feature of the aberrant angiogenesis is that excessive and insufficient angiogenesis can occur in different organs in the same individual. In this review, the clinical features, molecular mechanisms, and potential therapeutic options of abnormal angiogenesis in diabetes will be reviewed. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 117–145, 2003
Carbonic anhydrase inhibitors
Authors: Supuran Claudiu T. , Scozzafava Andrea , Casini Angela
Published: December 2002

At least 14 different carbonic anhydrase (CA, EC 4.2.1.1) isoforms were isolated in higher vertebrates, where these zinc enzymes play crucial physiological roles. Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), others are membrane‐bound (CA IV, CA IX, CA XII, and CA XIV), CA V is mitochondrial and CA VI is secreted in saliva. Three acatalytic forms are also known, which are denominated CA related proteins (CARP), CARP VIII, CARP X, and CARP XI. Several important physiological and physio‐pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides as well as inorganic, metal complexing anions. The catalytic and inhibition mechanisms of these enzymes are understood in detail, and this helped the design of potent inhibitors, some of which possess important clinical applications. The use of such enzyme inhibitors as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme‐specific and organ‐selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: several potent sulfonamide inhibitors inhibited the growth of a multitude of tumor cells in vitro and in vivo, thus constituting interesting leads for developing novel antitumor therapies. Furthermore, some other classes of compounds that interact with CAs have recently been discovered, some of which possess modified sulfonamide or hydroxamate moieties. Some sulfonamides have also applications as diagnostic tools, in PET and MRI or as antiepileptics or for the treatment of other neurological disorders. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes are also discussed. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 146–189, 2003
Marine pyridoacridine alkaloids and synthetic analogues as antitumor agents
Authors: Delfourne Evelyne , Bastide Jean
Published: December 2002

Pyrido[4,3,2‐mn]acridines are of major interest as metabolites in sponges and ascidians. During the last few years, numerous additional compounds of this family were isolated, some of them being polycyclic structures already reported with different substituents (shermilamine or kuanoniamine‐derivatives), others, such as neoamphimedine, arnoamines and styelsamines having original structures. The synthesis of these compounds and analogues have been performed in order to allow their biological evaluation. In most of the cases, the cytotoxicity of analogues was improved compared to the natural product, specially in ascididemin or meridine series. The pyridoacridines have not a sole mode of action, but it seems that the reductive DNA cleavage mediated by reactive oxygen species is a potential general mode of action. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 234–252, 2003
Design of a new suture practice card for microsurgical training
Authors: Usón Jesús , Carmen Calles M.
Published: December 2002

Suturing technique is of paramount importance in microsurgery. Basic training in this technique can be done using the practice card, a purpose‐made polyurethane card. A practice card has been designed in the Minimally Invasive Surgery Centre to closely resemble microsurgical requirements in order to practice and learn correct microsuturing maneuvers. This practice card is a key part of microsurgical training. After many years of experience, and based on a survey we conducted, we can conclude that this practice card is essential for step‐by‐step microsurgical training. Using this card, the number of animals required to attain necessary microsurgical skills is reduced significantly. Furthermore, costs are also reduced, and the trainee can avoid mistakes during training with live animals, thus optimizing results. © 2002 Wiley‐Liss, Inc. MICROSURGERY 22:324–328 2002
Auxiliary partial liver grafting in rats: Effect of host hepatectomy on graft regeneration, and review of literature on surgical technique
Authors: Wang Jun , Tahara Kazunori , Hakamata Yoji , Mutoh Hiroyuki , Murakami Takashi , Takahashi Masafumi , Kusama Mikio , Kobayashi Eiji
Published: December 2002

Auxiliary partial liver transplantation (APLT) is beneficial for fulminant liver failure when there is potential for recovery of the diseased liver. However, the impact of host hepatectomy on regeneration of the grafted liver is unclear. In this study, we modified a previous rat model of auxiliary whole liver transplantation without portal vein reconstruction, and studied the effect of host hepatectomy on regeneration of the cut liver graft. Thirty percent of the liver was heterotopically transplanted, to connect the recipient's left renal artery and vein with the graft's aortic cuff of the hepatic artery and inferior vena cava, respectively, using a cuff technique; 30% of the recipient liver then was cut. The control group was left intact. The liver grafts were weighed preoperatively and 2 weeks postoperatively. This procedure prevented congestion of the graft liver and achieved a high success rate, even when performed by a surgeon who was relatively inexperienced with the technique. The weight of the grafted liver in the host hepatectomized group significantly increased (P < 0.05) compared with that of the control group. We developed an experimental model of APLT and reviewed the literature on rat heterotopic liver transplantation, and compared the surgical techniques. © 2002 Wiley‐Liss, Inc. MICROSURGERY 22:371–377 2002
Protective effects of immunosuppressants and steroids against ischemia‐reperfusion injury in cremaster muscle flap at microcirculatory level
Authors: Askar Ibrahi̇m , Bozkurt Mehmet
Published: December 2002

The sequential events between leukocytes and endothelium have significant implications in surgical procedures, trauma, vascular injury, and wound healing. These sequential events are mediated by free oxygen radicals, leukocytes, red blood cells, and endothelial cells. In this study, we investigated the protective effects of steroids and immunosuppressants against ischemia‐reperfusion injury in cremaster muscle flaps at the microcirculatory level. In this experimental study, 50 male Sprague‐Dawley rats, weighing about 120–130 g, were used. The rats were divided into five groups of 10 rats each: the control group (group 1, n = 10), methyl prednisolone group (group 2, n = 10), dexamethasone group (group 3, n = 10), cyclosporin A group (group 4, n = 10), and azathioprine (group 5, n = 10). Surgical procedures were divided into two stages. In the first stage, a cremaster muscle end‐organ tube flap was created by extracting the testes and spermatic cord. The flap was placed into a subcutaneous tunnel in the anteromedial aspect of the ipsilateral limb. In the experimental groups, ischemia was performed by clamping the femoral artery and vein above and below the cremaster pedicle for 4 h. Then the clamps were removed, and perfusion of the cremaster muscle was allowed for 24 h. In the second stage, a round flap was obtained from the cremaster muscle tube‐flap to evaluate microcirculation after 24 h of reperfusion, and dissected along its front wall using cauterization. Vessel diameter, red blood cell velocities, leukocyte activation, perfused capillaries, and endothelial edema index were measured and evaluated statistically. There was a significant decrease in the number of rolling, sticking, and transmigrating neutrophils of groups 2 (cyclosporin A), 4 (methylprednisolone), and 3 (azathioprine) (P < 0.05), whereas those of group 5 (dexamethasone) were not decreased (P > 0.05). There was a significant increase in the number of perfused capillaries of groups 2 (cyclosporin A), 4 (methylprednisolone), and 3 (azathioprine) (P < 0.05), nearly 0.75‐, 0.5‐, and 0.75‐fold, respectively. We conclude that cyclosporin and azathioprine showed a protective effect on muscle tissue against ischemia‐reperfusion injury by inhibiting leukocyte infiltration, and that methylprednisolone had a beneficial effect against ischemia‐reperfusion injury by reducing the synthesis of eicosanoids, edema formation, and leukocyte infiltration. However, we believe that dexamethasone might have a salutary effect due to reducing the synthesis of eicosanoids, edema formation, and release of free oxygen radicals, but not due to leukocyte infiltration. © 2002 Wiley‐Liss, Inc. MICROSURGERY 22:361–366 2002
Rapid neurorrhaphy with titanium clips
Authors: Park Jong Woong , Lee Kwang Suk , Kim Sung Kon , Park Jung Ho , Hong Jun Seok , Oh Kwang Jun
Published: December 2002

The purpose of this study was to evaluate the usefulness of titanium clips in the repair of transected peripheral nerves. The results of neurorrhaphy using titanium clips (VCS) were compared with the conventional technique of neurorrhaphy using nylon sutures. Transected sciatic nerves in 15 New Zealand white rabbits were repaired with VCS clips on one side and interrupted 9‐0 nylon sutures on the other. The average time required for neurorrhaphy using the clip closure was 8.7 ± 2.6 min, and this was shorter than the suture closure, which took 14.9 ± 3.6 min (P < 0.01). Electromyographic studies revealed no significant differences in amplitudes of compound motor action potentials in both groups. Also, the number and extent of myelinizations of regenerated axons were not significantly different in both methods of nerorrhaphies. These results demonstrate that microscopic neurorrhaphy using titanium clips is a potential alternative to conventional neurorrhaphy using sutures. © 2002 Wiley‐Liss, Inc. MICROSURGERY 22:386–390 2002
Effect of reduced impulse activity on the development of identified motor terminals in Drosophila larvae
Authors: Lnenicka Gregory A. , Spencer Gregory M. , Keshishian Haig
Published: December 2002

In Drosophila larvae, motoneurons show distinctive differences in the size of their synaptic boutons; that is, axon 1 has type Ib (“big” boutons) terminals and axon 2 has type Is (“small” boutons) terminals on muscle fibers 6 and 7. To determine whether axon 1 develops large boutons due to its high impulse activity, we reduced impulse activity and examined the motor terminals formed by axon 1. The number of functional Na+ channels was reduced either with the napts mutation or by adding tetrodotoxin (TTX) to the media (0.1 μg/g). In both cases, the rate of locomotion was decreased by approximately 40%, presumably reflecting a decrease in impulse activity. Locomotor activity was restored to above wild‐type (Canton‐S) levels when napts was combined with a duplication of para, the Na+‐channel gene. Lucifer yellow was injected into the axon 1 motor terminals, and we measured motor terminal area, length, the number of branches, and the number and width of synaptic boutons. Although all parameters were smaller in napts and TTX‐treated larvae compared to wild‐type, most of these differences were not significant when the differences in muscle fiber size were factored out. Only bouton width was significantly smaller in both different napts and TTX‐treated larvae: boutons were about 20% smaller in napts and TTX‐treated larvae, and 20% larger in napts; Dp para+ compared to wild‐type. In addition, terminal area was significantly smaller in napts compared to wild‐type. Bouton size at Ib terminals with reduced impulse activity was similar to that normally seen at Is terminals. Thus, differences in impulse activity play a major role in the differentiation of bouton size at Drosophila motor terminals. © 2002 Wiley Periodicals, Inc. J Neurobiol 54: 337–345, 2003
Lithium inhibits a late step in agrin‐induced AChR aggregation
Authors: Sharma S. K. , Wallace B. G.
Published: December 2002

Agrin activates an intracellular signaling pathway to induce the formation of postsynaptic specializations on muscle fibers. In myotubes in culture, this pathway has been shown to include autophosphorylation of the muscle‐specific kinase MuSK, activation of Src‐family kinases, tyrosine phosphorylation of the acetylcholine receptor (AChR) β subunit, a decrease in receptor detergent extractability, and the accumulation of AChRs into high‐density aggregates. Here we report that treating chick myotubes with lithium prevented any detectable agrin‐induced change in AChR distribution without affecting the number of AChRs or the agrin‐induced change in AChR tyrosine phosphorylation and detergent extractability. Lithium treatment also increased the rate at which AChR aggregates disappeared when agrin was removed. The effects of lithium developed slowly over the course of approximately 12 h. Thus, sensitivity to lithium identifies a late step in the agrin signaling pathway, after agrin‐induced MuSK and AChR phosphorylation, that is necessary for the recruitment of AChRs into visible aggregates. © 2002 Wiley Periodicals, Inc. J Neurobiol 54: 346–357, 2003
Serotonin in the developing stomatogastric system of the lobster, Homarus americanus
Authors: Richards Kathryn S. , Simon David J. , Pulver Stefan R. , Beltz Barbara S. , Marder Eve
Published: December 2002

We studied the development of the serotonergic modulation of the stomatogastric nervous system of the lobster, Homarus americanus. Although the stomatogastric ganglion (STG) is present early in embryonic development, serotonin immunoreactivity is not visible in the STG until the second larval stage. However, incubation of the STG with exogenous serotonin showed that a serotonin transporter is present in embryonic and early larval stages. Serotonin uptake was blocked by paroxetine and 0% Na+ saline. The presence of a serotonin transporter in the embryonic STG suggests that hormonally liberated serotonin could be taken up by the STG, and potentially released as a “borrowed transmitter”. Consistent with a potential hormonal role, serotonin is found in the pericardial organs, a major neurosecretory structure, by midembryonic development. The rhythmic motor patterns produced by embryonic and larval STGs were decreased in frequency by serotonin. Lateral Pyloric (LP) neuron‐evoked excitatory junctional potentials (EJPs) in the embryos and the first larval stage (LI) were larger, slower, and more variable than those in the adult. The amplitude of adult LP neuron‐evoked EJPs was increased more than twofold in serotonin, but in embryos and LI preparations this effect was negligible. In embryos and LI preparations, serotonin increased the occurrence of muscle fiber action potentials and altered the EJP wave‐form. These data demonstrate that serotonin receptors are present in the stomatogastric nervous system early in development, and suggest that the role of serotonin changes from modulation of muscle fiber excitability early in development to enhancement of neurally evoked EJPs in the adult. © 2002 Wiley Periodicals, Inc. J Neurobiol 54: 380–392, 2003
Biogenic amines in the antennal lobes and the initiation and maintenance of foraging behavior in honey bees
Authors: Schulz David J. , Elekonich Michelle M. , Robinson Gene E.
Published: December 2002

Previous findings showed that high levels of octopamine and serotonin in the antennal lobes of adult worker honey bees are associated with foraging behavior, and octopamine treatment induces precocious foraging. To better characterize the relationship between amines and foraging behavior in honey bees, we performed a detailed correlative analysis of amine levels in the antennal lobes as a function of various aspects of foraging behavior. Flight activity was measured under controlled conditions in a large outdoor flight cage. Levels of octopamine in the antennal lobes were found to be elevated immediately subsequent to the onset of foraging, but they did not change as a consequence of preforaging orientation flight activity, diurnal pauses in foraging, or different amounts of foraging experience, suggesting that octopamine helps to trigger and maintain the foraging behavioral state. In contrast, levels of serotonin and dopamine did not show changes that would implicate them as either causal agents of foraging, or as neurochemical systems affected by the act of foraging. Serotonin treatment had no effect on the likelihood of foraging. These results provide further support for the hypothesis that an increase in octopamine levels in the antennal lobes plays a causal role in the initiation and maintenance of the behavioral state of foraging, and thus is involved in the regulation of division of labor in honey bees. © 2002 Wiley Periodicals, Inc. J Neurobiol 54: 406–416, 2003
Aromatase inhibition affects testosterone‐induced masculinization of song and the neural song system in female canaries
Authors: Fusani Leonida , Metzdorf Reinhold , Hutchison John B. , Gahr Manfred
Published: December 2002

Songbirds have a specialized steroid‐sensitive network of brain nuclei, the song system, for controlling song. Most nuclei of the song system express androgen receptors, and the sensory‐motor integration nucleus High Vocal Center (HVC) alone also expresses estrogen receptors. Apart from expressing estrogen receptors in the vocal control system, songbirds are unique among birds because they have high concentrations of the estrogen‐synthesizing enzyme aromatase in the neostriatum surrounding HVC. However, the role of estrogen in controlling the development of the song structure has been scarcely investigated. In this work, we show that blocking the production of estrogen during testosterone‐induced song motor development in adult female canaries alters the song pattern compared to control females treated with testosterone only. These effects were correlated with inhibition of the expression of estrogen‐sensitive genes, such as brain‐derived nerve growth factor, in HVC. The expression of the ATP‐synthase gene, an indicator of cell activity, in HVC, and the size of HVC, were not affected by the treatment. Our results provide the first example of estrogen‐sensitive mechanisms controlling the structural features of adult birdsong. © 2002 Wiley Periodicals, Inc. J Neurobiol 54: 370–379, 2003
Domain decomposition for model heterogeneous anisotropic problem
Authors: Kwak D. Y. , Nepomnyaschikh S. V. , Pyo H. C.
Published: December 2002

The main focus of this paper is to suggest a domain decomposition method for finite element approximations of elliptic problems with anisotropic coefficients in domains consisting of anisotropic shape rectangles. The theorems on traces of functions from Sobolev spaces play an important role in studying boundary value problems of partial differential equations. These theorems are commonly used for a priori estimates of the stability with respect to boundary conditions, and also play very important role in constructing and investigating effective domain decomposition methods. The trace theorem for anisotropic rectangles with anisotropic grids is the main tool in this paper to construct domain decomposition preconditioners. Copyright © 2002 John Wiley & Sons, Ltd.
Study of slabstock flexible polyurethane foams based on varied toluene diisocyanate isomer ratios
Authors: Aneja Ashish , Wilkes Garth L. , Rightor Edward G.
Published: December 2002

The morphological features of three flexible slabstock polyurethane foams based on varied contents of 2,4 and 2,6 toluene diisocyanate (TDI) isomers are investigated. The three commercially available TDI mixtures, that is, 65:35 2,4/2,6 TDI, 80:20 2,4/2,6 TDI, and 100:0 2,4/2,6 TDI were used. The foams were characterized at different length scales with several techniques. Differences in the cellular structure of the foams were noted with scanning electron microscopy. Small‐angle X‐ray scattering was used to demonstrate that all three foams were microphase‐separated and possessed similar interdomain spacings. Transmission electron microscopy revealed that the aggregation of the urea phase into large urea‐rich regions decreased systematically on increasing the asymmetric TDI isomer content. Fourier transform infrared spectroscopy showed that the level of bidentate hydrogen bonding of the hard segments increased with the 2,6 TDI isomer content. Differential scanning calorimetry and dynamic mechanical analysis (DMA) were used to note changes in the soft‐segment glass‐transition temperature of the foams on varying the diisocyanate ratios and suggested that the perfection of microphase separation was enhanced on increasing the 2,6 TDI isomer content. The preceding observations were used to explain why the foam containing the highest content of the symmetric 2,6 TDI isomer exhibited the highest rubbery storage modulus, as measured by DMA. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 258–268, 2003