bluuebunny/crossref_metadata_2025 huggingface dataset:
An early but intense cytokine production within the islets may be predictive for type 1 diabetes occurrence in the Bio Breeding (BB) rat
Authors: Papaccio Gianpaolo , Graziano Antonio , d'Aquino Riccardo , De Francesco Francesco , Puca Andrew , Pedullà Marcella
Published: September 2006

The Bio Breeding (BB) rat is a useful animal model of type 1 autoimmune diabetes. The aim of this study was to observe and follow the cytokine and antigenic expressions within the islets of Langerhans in young non‐diabetic, in pre‐diabetic hyperglycemic, and in overtly diabetic animals. BB rats were therefore checked at day 21 up to day 90 of life for blood glucose, insulin levels, degree of islet infiltration, expression of proinflammatory and protective cytokines and antibodies including CD4, CD8, CD25, LFA‐1, and ICAM‐1. Animals were treated with insulin as they became diabetic. We found that islets of non‐diabetic BB rats became positive to both IL‐1β and IL‐4 very early on, confirming a local but intense production of both cytokines within the islets during the initial non‐diabetic period. In addition, we observed that the production of these interleukins together with the expression levels of CD4 and CD25 are events predictive for type 1 diabetes onset in non‐diabetic BB rats, as for non‐obese diabetic (NOD) mice. In particular, the production of IL‐1β and IL‐4 during the non‐diabetic period together with the lack of enhancement of CD4 and CD25, indicating selective recruitment of activated T cells, may explain the failure of anti‐diabetic treatments in this animal model of type 1 diabetes. J. Cell. Physiol. 209: 1016–1020, 2006. © 2006 Wiley‐Liss, Inc.
High dose glucocorticoid hampers bone formation and resorption after bone marrow ablation in rat
Authors: Kondo Naoki , Tokunaga Kunihiko , Ito Tomoyuki , Arai Katsumitsu , Amizuka Norio , Minqi Li , Kitahara Hiroshi , Ito Masayuki , Naito Makoto , Shu‐Ying Jiang , Oda Kimimitsu , Murai Takehiro , Takano Reiko , Ogose Akira , Endo Naoto
Published: September 2006

We analyzed the effect of glucocorticoid on bone regeneration after bone marrow ablation in tibiae of 8‐week‐old rats. Methylprednisolone sodium succinate (MPSS) was injected intramuscularly at a dose of 100 mg/kg/day for 3 days. Tibiae on days 1, 3, 5, 7, 10, 12, and 14 after ablation were subjected to tartrate‐resistant acid phosphatase staining, immunohistochemistry, in situ hybridization, and transmission electron microscopy (TEM), and measurement of the volume of newly‐formed bone and the osteoclast number. MPSS significantly decreased the newly‐formed bone volume on day 7, and immature bone still remained on day 10 in the MPSS‐treated group. The volume of this bone was significantly higher than that in the control group. However, there were no differences between the groups in the osteoclast number, the expression of mRNAs for osteoblast differentiation markers, and alkaline phosphatase and cathepsin K judged by immunohistochemistry. TEM findings showed no difference in the form of osteoblasts, whereas osteoclasts in the MPSS‐treated group had less developed ruffled borders, compared to those in the control group. These results suggest that MPSS treatment affects neither the differentiation nor the shape of osteoblasts, and does not change the osteoclast number or the cathepsin K level. However, high dose MPSS inhibits both bone formation and resorption during bone regeneration after rat tibial bone marrow ablation, and inhibits ruffled border formation in osteoclasts. These data will be useful to develop bone regenerative therapies for bone diseases due to high dose steroid administration. Microsc. Res. Tech., 2006. © 2006 Wiley‐Liss, Inc.
Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging
Authors: Lo Wen , Teng Shu‐Wen , Tan Hsin‐Yuan , Kim Ki Hean , Chen Hsiao‐Ching , Lee Hsuan‐Shu , Chen Yang‐Fan , So Peter T.C. , Dong Chen‐Yuan
Published: September 2006

The aim of this work is to demonstrate that multiphoton microscopy is a preferred technique to investigate intact cornea structure without slicing and staining. At the micron resolution, multiphoton imaging can provide both large morphological features and detailed structure of epithelium, corneal collagen fibril bundles and keratocytes. A large area multiphoton cross‐section across an intact eye excised from a GFP mouse was obtained by a homebuilt multiphoton microscope. The broadband multiphoton fluorescence (435–700 nm) and second harmonic generation (SHG, 360–400 nm) signals were generated by the 760 nm output of a femtosecond titanium‐sapphire laser. A water immersion objective (Fluor ™, 40X, NA 0.8; Nikon) was used to facilitate imaging the curve ocular surface. The multiphoton image over entire cornea provides morphological information of epithelial cells, keratocytes, and global collagen orientation. Specifically, our planar, large area multiphoton image reveals a concentric pattern of the stroma collagen, indicative of the laminar collagen organization throughout the stroma. In addition, the green fluorescence protein (GFP) labeling contributed to fluorescence contrast of cellular area and facilitated visualizing of inactive keratocytes. Our results show that multiphoton imaging of GFP labeled mouse cornea manifests both morphological significance and structural details. The second harmonic generation imaging reveals the collagen orientation, while the multiphoton fluorescence imaging indicates morphology and distribution of cells in cornea. Our results support that multiphoton microscopy is an appropriate technology for further in vivo investigation and diagnosis of cornea. Microsc. Res. Tech., 2006. © 2006 Wiley‐Liss, Inc.
Product distributions from the OH radical‐induced oxidation of n‐pentane and isopentane (2‐methylbutane) in air
Authors: Heimann Gerald , Warneck Peter
Published: September 2006

Hydroxyl radicals, generated by photolysis of H2O2, were reacted with n‐pentane and isopentane in air in the absence of nitrogen oxides. The observed product distributions were compared with similar data derived by computer simulations, based on the known reaction mechanisms, to determine relative probabilities for hydrogen abstraction at different sites of the parent compounds and to estimate branching ratios and relative rate coefficients for cross‐combination reactions between different peroxy radicals. For n‐pentane, the distribution of the pentanols indicates probabilities for hydrogen abstraction, in percent, of q1 = 9.1 ± 0.7, q2 = 56.1 ± 1.8, and q3 = 34.8 ± 1.3, which agree with predictions based on the algorithm proposed by Atkinson. Branching ratios needed to harmonize calculated and observed product distributions are somewhat larger than, although still within the error ranges of, the values found by us previously. Comparison between experimental and calculated data confirms the isomerization and decomposition constants recently established for the three pentoxyl radical isomers. The product distribution for isopentane, which is dominated by acetone, acetaldehyde, 2‐methyl‐butan‐2‐ol, and 2‐methyl‐butan‐2‐hydroperoxide, is in harmony with the predicted oxidation mechanism. Probabilities for hydrogen abstraction from isopentane were estimated to occur to 12% at the primary, 28% at the secondary, and 60% at the tertiary sites, again in agreement with predictions based on the algorithm of Atkinson. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 677–688, 2006
The classical kinetic model for radical chain oxidation of hydrocarbon substrates initiated by bimolecular hydroperoxide decomposition
Authors: Colin X. , Fayolle B. , Audouin L. , Verdu J.
Published: September 2006

Kinetic modeling of the low‐temperature (typically T ⩽ 200°C) thermal aging of polymers is a problem of great technological importance, owing to the continuously increasing needs of industry in terms of reliable methods for lifetime prediction. In the temperature domain under consideration, for most hydrocarbon substrates, oxidation proceeds by a radical chain reaction initiated by bimolecular hydroperoxide decomposition. In other words, the reaction generates its own initiator, which explains its strong autoaccelerated character. The most pertinent model is, to our opinion, the model elaborated by Tobolsky et al. (J Am Chem Soc 1950, 72, 1942) in the early 1950s. This model is, however, based on three questionable assumptions: the existence of a stationary state for radical concentrations (hypothesis S), the presence of oxygen in excess (hypothesis E), and the fact that the onset of steady state can be observed in the domain of low conversions, where the substrate consumption can be neglected (hypothesis L). One hypothesis (S) lacks consistency. A sounder alternative, which does not modify significantly the mathematical expressions of the model, will be proposed. The other hypotheses (E and L) can be justified in certain cases, but the limits of their domain of validity were never established to our knowledge. It is tried, here, to express these limits in function of fundamental parameters: rate constants and concentrations of reactants. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38:666–676, 2006
Increase in body weight after pramipexole treatment in Parkinson's disease
Authors: Kumru Hatice , Santamaria Joan , Valldeoriola Francesc , Marti Maria J. , Tolosa Eduardo
Published: September 2006

Body weight changes occur during the clinical course of Parkinson's disease (PD) and with surgical treatment, but the effect of dopaminergic treatment on weight is unknown. Body mass index (BMI), Hamilton depression scale score (HDS), and Unified Parkinson's Disease Rating Scale III (UPRS‐III) were measured before and 3 months after starting pramipexole in 28 PD patients. Pramipexole produced a significant weight increase, as well as motor and mood improvement (P <0.001). HDS and BMI changes were mildly related (P = 0.05). A direct effect of pramipexole on limbic D3 receptors involved in the control of feeding may be responsible for weight gain in PD.
© 2006 Movement Disorder Society
Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor
Authors: Kuncel Alexis M. , Cooper Scott E. , Wolgamuth Barbara R. , Clyde Merlise A. , Snyder Scott A. , Montgomery Erwin B. , Rezai Ali R. , Grill Warren M.
Published: September 2006

Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus for essential tremor is sometimes limited by side effects. The mechanisms by which DBS alleviates tremor or causes side effects are unclear; thus, it is difficult to select stimulus parameters that maximize the width of the therapeutic window. The goal of this study was to quantify the impact on side effect intensity (SE), tremor amplitude, and the therapeutic window of varying stimulus parameters. Tremor amplitude and SE were recorded at 40 to 90 combinations of pulse width, frequency, and voltage across 14 thalami. Posterior variable inclusion probabilities indicated that frequency and voltage were the most important predictors of both SE and tremor amplitude. The amount of tremor suppression achieved at frequencies of 90 to 100 Hz was not different from that at 160 to 170 Hz. However, the width of the therapeutic window decreased significantly and power consumption increased as frequency was increased above 90 to 100 Hz. Improved understanding of the relationships between stimulus parameters and clinical responses may lead to improved techniques of stimulus parameter adjustment. © 2006 Movement Disorder Society
Involuntary painful muscle contractions in Satoyoshi syndrome: A surface electromyographic study
Authors: Drost Gea , Verrips Aad , van Engelen Baziel G.M. , Stegeman Dick F. , Zwarts Machiel J.
Published: September 2006

We report a child with Satoyoshi syndrome manifested by involuntary painful muscle contractions and alopecia. Although an autoimmune origin of Satoyoshi syndrome seems likely, its exact etiology remains as yet unknown, as is the origin of the involuntary contractions. To gain a better understanding of the electrophysiological characteristics of the involuntary contractions, we performed a surface electromyographic (EMG) study. We investigated muscle contractions in the legs using two noninvasive techniques: high‐density surface EMG (HD‐sEMG) recordings on one muscle, and polymyographic surface EMG (sEMG) recordings on various muscles. During the involuntary contractions, HD‐sEMG showed a fourfold increase in amplitude compared to maximal voluntary contractions. These high potentials were widely distributed across the whole muscle and showed a pronounced oscillatory behavior with a frequency around 45 Hz. Polymyographic sEMG revealed that the involuntary contractions often occur simultaneously in various muscles or showed a switch of activity from one muscle to another. These findings point to hyperactivity or a disinhibition at the alpha motor neuron level, originating probably at that level, although a central origin cannot be excluded. © 2006 Movement Disorder Society
Spectral properties and regularity of solutions to transport equations in slab geometry
Authors: Latrach Khalid , Megdiche Hatem
Published: September 2006

This paper deals with regularity properties of solutions to Cauchy problems governed by one‐dimensional transport equations for a wide class of anisotropic scattering operators and a variety of boundary conditions which cover, in particular, the classical known ones. Under adequate assumptions, various descriptions of the large time behaviour of solutions are derived. Copyright © 2006 John Wiley & Sons, Ltd.
Asymptotic analysis of elastic curved rods
Authors: Vodák Rostislav
Published: September 2006

We consider a sequence of curved rods which consist of isotropic material and which are clamped on the lower base or on both bases. We study the asymptotic behaviour of the stress tensor and displacement under the assumptions of linearized elasticity when the cross‐sectional diameter of the rods tends to zero and the body force is given in the particular form. The analysis covers the case of a non‐smooth limit line of centroids. We show how the body force and the choice of the approximating curved rods can affect the strong convergence and the limit form of the stress tensor for the curved rods clamped on both bases. Copyright © 2006 John Wiley & Sons, Ltd.
Instantaneous control for traffic flow
Authors: Herty M. , Kirchner C. , Klar A.
Published: September 2006

The solution methods for optimal control problems with coupled partial differential equations as constraints are computationally costly and memory intensive; in particular for problems stated on networks, this prevents the methods from being relevant. We present instantaneous control problems for the optimization of traffic flow problems on road networks. We derive the optimality conditions, investigate the relation to the full optimal control problem and prove that certain properties of the optimal control problem carry over to the instantaneous one. We propose a solution algorithm and compare quality of the computed controls and run‐times. Copyright © 2006 John Wiley & Sons, Ltd.
A least‐squares method for axisymmetric div–curl systems
Authors: Copeland Dylan M. , Pasciak Joseph E.
Published: September 2006

We present a negative‐norm least‐squares method for axisymmetric div–curl systems arising from Maxwell's equations for electrostatics and magnetostatics in three dimensions. The method approximates the solution in a two‐dimensional meridian plane. To achieve this dimension reduction, we must work with weighted spaces in cylindrical co‐ordinates. In this setting, a stable pair of approximation spaces is developed and analysed. We also report the results of some numerical experiments, which demonstrate a quasi‐optimal convergence rate and a robustness with respect to the domain and coefficients. Copyright © 2006 John Wiley & Sons, Ltd.
Survival, mortality, and complications in patients with β‐Thalassemia major in northern Taiwan
Authors: Chern Jimmy P. S. , Su Syi , Lin Kai‐Hsin , Chang Shu‐Hui , Lu Meng‐Yao , Jou Shiann‐Tarng , Lin Dong‐Tsamn , Ho Wan‐Ling , Lin Kuo‐Sin
Published: September 2006

Background

Advances in treatment have improved the prognosis in β‐thalassemia major. We present the survival and complications pattern of those patients in northern Taiwan born after 1970.

Procedure

One‐hundred and sixty patients with β‐thalassemia major born after 1970 were collected. The Kaplan–Meier method and log‐rank test were used to estimate and compare survival. Cox regression models were used to examine the associations of bone marrow transplantation (BMT), time of BMT procedure, and time of complications with survival.

Results

Better survival was observed for patients born after 1980 (P = 0.0121). Heart disease, BMT‐related deaths, and infections were the main causes of death. Among the living patients over age 15, hypogonadotropic hypogonadism, HCV infection, diabetes, heart failure, and arrhythmia were the common complications. No patients under age 15 had complications.

Conclusions

Survival for patients with β‐thalassemia major has improved significantly in Taiwan. More time is required to demonstrate whether these modalities added to the treatment of these patients will impact favorably on their outcome. Our success with BMT is improving and we are now in a position to offer this curative alternative. Pediatr Blood Cancer 2007;48:550–554. © 2006 Wiley‐Liss, Inc.
Symptoms in the palliative phase of children with cancer
Authors: Theunissen J.M.J. , Hoogerbrugge P.M. , van Achterberg T. , Prins J.B. , Vernooij‐Dassen M.J.F.J. , van den Ende C.H.M.
Published: September 2006

Background

The aim of the study was to make a comprehensive inventory of the physical, psychological, and social symptoms of children with cancer and their parents during the palliative phase and the extent to which health professionals address those symptoms.

Procedure

Forty parents of children who died 1–3 years prior to data collection (structured questionnaire) were invited to participate in the study.

Results

The response rate was 32 out of 40 parents (80%). Most frequently mentioned physical symptoms were pain, poor appetite, and fatigue. The children's most mentioned psychological symptoms were sadness, difficulty in talking to their parents about their feelings regarding illness and death and fear of being alone. The symptoms of fear of death of the child and fear of physical symptoms were most frequently mentioned parents' psychological symptoms. Health professionals addressed 82% of the children's physical symptoms, 43% of the children's psychological symptoms, and 56% of the parents' psychological symptoms. Parents indicated that after professional attention the proportion of children's physical symptoms that were completely or partially resolved was 18 and 26%, respectively. For children's psychological symptoms the figures were 9 and 25%, respectively, and for parents' psychological symptoms 2 and 23%, respectively.

Conclusions

The burden of symptoms of the child with cancer during the palliative phase and their parents is high. Health professionals focus mainly on the physical symptoms of the child. Relief of symptoms could not be achieved for a large proportion of symptoms. Further prospective research is necessary to investigate the kind, frequency and intensity of symptoms in order to tailor optimal palliative care to the needs of both child and parent. Pediatr Blood Cancer 2007;49:160–165. © 2006 Wiley‐Liss, Inc.
A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies
Authors: Gilheeney Stephen W. , Lyden David C. , Sgouros Shirley , Antunes Nuno , Gerald William , Kramer Kim , Lis Eric , Meyers Paul , Rosen Nancy , Thaler Howard T. , Trippett Tanya , Wexler Leonard , Dunkel Ira J.
Published: September 2006

Background

Previous clinical and pre‐clinical research has demonstrated synergy between anti‐angiogenic agents and cytotoxic chemotherapy. This trial was undertaken to investigate whether the combination of cyclophosphamide and thalidomide would be active against pediatric tumors.

Procedure

Patients with pediatric malignancies who had no remaining conventional therapeutic options were recruited from January 1999 to May 2001. They received thalidomide (6–12 mg/kg po every day; maximum daily dose 800 mg) and cyclophosphamide (1,200 mg/m2 IV every 28 days).

Results

Twenty‐seven patients were enrolled on the study. Seventeen were male and 10 were female. Median age at the time of registration was 15 years (range 1–54 years). The median number of prior treatment regimens was four. Twenty‐one patients were evaluable for response; 1 had a partial response (Hodgkin disease), 1 demonstrated stable disease (neuroendocrine tumor), and 19 had progressive disease. The most common toxicities were hematological (leukocytopenia and neutropenia) and gastrointestinal. One patient experienced a grade 3 rash. Fatigue and daytime somnolence were variable. No peripheral neuropathy was observed.

Conclusion

The combination of thalidomide and cyclophosphamide as described herein has a modest and tolerable toxicity profile but little evidence of efficacy. Pediatr Blood Cancer 2007;49:261–265. © 2006 Wiley‐Liss, Inc.
Synthesis, characterization, and molecular modeling studies of novel polyurethanes based on 2,2′‐[ethane‐1,2‐diylbis(nitrilomethylylidene)]diphenol and 2,2′‐[hexane‐1,6‐diylbis(nitrilomethylylidene)] diphenol hard segments
Authors: Raghu A. V. , Gadaginamath G. S. , Jawalkar S. S. , Halligudi S. B. , Aminabhavi T. M.
Published: September 2006

Novel polyurethanes (PUs) based on 2,2′‐[ethane‐1,2‐diylbis(nitrilomethylylidene)]diphenol and 2,2′‐[hexane‐1,6‐diylbis(nitrilomethylylidene)]diphenol as hard segments containing four aromatic diisocyanates (4,4′‐diphenylmethane diisocyanate, toluene 2,4‐diisocyanate, isophorone diisocyanate, and hexamethylene diisocyanate) have been prepared. Fourier transform infrared, UV spectrophotometry, fluorescence spectroscopy, 1H NMR and 13C NMR spectroscopy, thermogravimetric analysis, and differential thermal analysis have been used to determine the structural characterization and thermal properties of the segmented PUs. All the PUs contain domains of both semicrystalline and amorphous structures, as indicated by X‐ray diffraction. The acoustic properties have been calculated with the group contribution method. Molecular dynamics simulations have been performed on all the PUs to estimate the cohesive energy density and solubility parameter values, which compare well with the values calculated with the group contribution method. Furthermore, the simulation protocols have been applied to the PUs to produce X‐ray diffraction plots to determine the phase morphology of the PUs. The surface properties of the PUs have been estimated from the simulation protocols. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6032–6046, 2006
Characterization and tissue‐specific expression of two lepidopteran farnesyl diphosphate synthase homologs: Implications for the biosynthesis of ethyl‐substituted juvenile hormones
Authors: Cusson Michel , Béliveau Catherine , Sen Stephanie E. , Vandermoten Sophie , Rutledge Robert G. , Stewart Don , Francis Frédéric , Haubruge Éric , Rehse Peter , Huggins David J. , Dowling Ashley P.G. , Grant Guy H.
Published: September 2006

The sesquiterpenoid juvenile hormone (JH) regulates insect development and reproduction. Most insects produce only one chemical form of JH, but the Lepidoptera produce four derivatives featuring ethyl branches. The biogenesis of these JHs requires the synthesis of ethyl‐substituted farnesyl diphosphate (FPP) by FPP synthase (FPPS). To determine if there exist more than one lepidopteran FPPS, and whether one FPPS homolog is better adapted for binding the bulkier ethyl‐branched substrates/products, we cloned three lepidopteran FPPS cDNAs, two from Choristoneura fumiferana and one from Pseudaletia unipuncta. Amino acid sequence comparisons among these and other eukaryotic FPPSs led to the recognition of two lepidopteran FPPS types. Type‐I FPPSs display unique active site substitutions, including several in and near the first aspartate‐rich motif, whereas type‐II proteins have a more “conventional” catalytic cavity. In a yeast assay, a Drosophila FPPS clone provided full complementation of an FPPS mutation, but lepidopteran FPPS clones of either type yielded only partial complementation, suggesting unusual catalytic features and/or requirements of these enzymes. Although a structural analysis of lepidopteran FPPS active sites suggested that type‐I enzymes are better suited than type‐II for generating ethyl‐substituted products, a quantitative real‐time PCR assessment of their relative abundance in insect tissues indicated that type‐I expression is ubiquitous whereas that of type‐II is essentially confined to the JH‐producing glands, where its transcripts are ∼20 times more abundant than those of type‐I. These results suggest that type‐II FPPS plays a leading role in lepidopteran JH biosynthesis in spite of its apparently more conventional catalytic cavity. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Structure modeling, ligand binding, and binding affinity calculation (LR‐MM‐PBSA) of human heparanase for inhibition and drug design
Authors: Zhou Zhigang , Bates Maria , Madura Jeffry D.
Published: September 2006

Human heparanase is an endo‐β‐D‐glycosidase that cleaves heparan sulphate (HS) chains in the extracellular matrix and basement membrane. It is known that the cleavage of HS by heparanase results in cell invasion and metastasis of cancer. Therefore, heparanase is considered an important target for cancer drug development. The three‐dimensional structure of heparanase would be useful in the rational design of inhibitors targeted to the enzyme; however, the three‐dimensional structure has not yet been determined. In our effort to design inhibitors, we developed a three‐dimensional structure of heparanase using a homology‐modeling approach. The homology‐built structure is consistent to previous bioinformatics and site‐mutation experimental results. The heparanase features a (α/β)8 TIM‐barrel fold with two glutamate residues (Glu225 and Glu343) located in the active‐site cleft. This feature supports the putative mechanism of proton donor and nucleophilic sites. Docking simulations yielded 41 complex structures, which indicate that the bound inhibitor could block ligand binding into the catalytic site. A free energy of binding model was established for 25 heparanase inhibitors with a training set of 25 heparanase inhibitors using the linear response MM‐PBSA approach (LR‐MM‐PBSA). The correlation between calculated and experimental activity was 0.79 and the reliability of the model was validated with leave‐one‐out cross‐validation method. Its predictive capability was further validated using a test set of 16 inhibitors similar to the training set of inhibitors. The correlation between the predicted and observed activities is significantly improved by the protein “induced‐fit” that accounts for the flexibility of the receptor. These interaction and pharmacophore elements provide a unique insight to the rational design of new ligands targeted to the enzyme. Proteins 2006. © 2006 Wiley‐Liss, Inc.
ROSETTALIGAND: Protein–small molecule docking with full side‐chain flexibility
Authors: Meiler Jens , Baker David
Published: September 2006

Protein–small molecule docking algorithms provide a means to model the structure of protein–small molecule complexes in structural detail and play an important role in drug development. In recent years the necessity of simulating protein side‐chain flexibility for an accurate prediction of the protein–small molecule interfaces has become apparent, and an increasing number of docking algorithms probe different approaches to include protein flexibility. Here we describe a new method for docking small molecules into protein binding sites employing a Monte Carlo minimization procedure in which the rigid body position and orientation of the small molecule and the protein side‐chain conformations are optimized simultaneously. The energy function comprises van der Waals (VDW) interactions, an implicit solvation model, an explicit orientation hydrogen bonding potential, and an electrostatics model. In an evaluation of the scoring function the computed energy correlated with experimental small molecule binding energy with a correlation coefficient of 0.63 across a diverse set of 229 protein– small molecule complexes. The docking method produced lowest energy models with a root mean square deviation (RMSD) smaller than 2 Å in 71 out of 100 protein–small molecule crystal structure complexes (self‐docking). In cross‐docking calculations in which both protein side‐chain and small molecule internal degrees of freedom were varied the lowest energy predictions had RMSDs less than 2 Å in 14 of 20 test cases. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Homology modeling and molecular dynamics study of West Nile virus NS3 protease: A molecular basis for the catalytic activity increased by the NS2B cofactor
Authors: Zhou Hong , Singh N. Jiten , Kim Kwang S.
Published: September 2006

The West Nile virus (WNV) NS3 serine protease, which plays an important role in assembly of infective virion, is an attractive target for anti‐WNV drug development. Cofactors NS2B and NS4A increase the catalytic activity of NS3 in dengue virus and Hepatitis C virus, respectively. Recent studies on the WNV‐NS3 characterize the catalytically active form of NS3 by tethering the 40‐residue cofactor NS2B. It is suggested that NS2B is essential for the NS3 activity in WNV, while there is no information of the WNV‐NS3‐related crystal structure. To understand the role of NS2B/substrate in the NS3 catalytic activity, we built a series of models: WNV‐NS3 and WNV‐NS3‐NS2B and WNV‐NS3‐NS2B‐substrate using homology modeling and molecular modeling techniques. Molecular dynamics (MD) simulations were performed for 2.75 ns on each model, to investigate the structural stabilization and catalytic triad motion of the WNV NS3 protease with and without NS2B/substrate. The simulations show that the NS3 rearrangement occurs upon the NS2B binding, resulting in the stable D75‐OD1…H51‐NH hydrogen bonding. After the substrate binds to the NS3–NS2B active site, the NS3 protease becomes more stable, and the catalytic triad is formed. These results provide a structural basis for the activation and stabilization of the enzyme by its cofactor and substrate. by its cofactor and substrate. Proteins 2006. © 2006 Wiley‐Liss, Inc.
Quantum chemical study of cyclic dipeptides
Authors: Zhu Yanyan , Tang Mingsheng , Shi Xiaoyu , Zhao Yufen
Published: September 2006

The preferred conformations of cyclic dipeptides were first studied systemically using the density functional theory (DFT) B3LYP method at the 6‐31G(d) level. The structural characteristics of cyclic dipeptides were revealed, most of which have not been confirmed until now. Our studies showed that the six‐member main circles of cyclic dipeptides composed of natural L‐amino acid residues appeared as boat conformations. The important factors that influence conformations of cyclic dipeptides, such as molecular total energy, nuclear repulsion energy, molecular orbit, spatial effects, and reactive mechanism, are discussed in detail. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Comparison of large basis set DFT and MP2 calculations in the study of the barrier for internal rotation of 2,3,5,6‐tetrafluoroanisole
Authors: Kieninger Martina , Cachau Raúl E. , Oberhammer Heinz , Ventura Oscar N.
Published: September 2006

The barrier for internal rotation around the OCH3 bond in 2,3,5,6‐tetrafluoroanisole was calculated using the density functional theory (DFT) and second‐order Møller–Plesset (MP2) methods with Pople's basis sets up to 6‐311++G(3df,2p) and Jensen basis sets up to pc‐3. The results are converged only if fairly large basis sets are used (at least 6‐311++G(3df,2pd) or pc‐2). Both the DFT and MP2 potential energy curves show internal structure. Two minima and three maxima are observed on the curves, arising from the interplay between lone‐pair delocalization and changes in the hybridization around the oxygen atom, together with the attraction between the positively polarized hydrogens in the methyl group and the negatively polarized fluorine atom at the ortho position. These critical points are somehow ironed out by the addition of zero‐point and thermal corrections to the energy curves. At this level, the MP2 method can describe reasonably well the previously determined single‐well experimental rotational barrier, 2.7 ± 2.0 kcal/mol at 298 K, while all DFT methods yield a much smaller result. As observed experimentally, the OCH3 group is perpendicular to the aryl ring in the equilibrium structure, although two very close minima with an intermediate hump at 90° are still observable. The theoretical free energy barrier of rotation at the MP2(full)/pc‐2 level is 2.0 ± 1.0 kcal/mol, in reasonable agreement with the experimental determination. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Density functional and ab initio studies on structures and energies of the ground state of CrCO
Authors: Kim Joonghan , Lee Yoon Sup , Ihee Hyotcherl
Published: September 2006

CrCO was studied using density functional theory (DFT) and ab initio methods. We obtained the two‐dimensional potential energy surface (PES), geometry, and vibrational frequencies for CrCO in a septet state. Two minimum structures were found in the CCSD(T) calculation, including a local minimum that is a weak van der Waals (vdW) complex. All DFT methods yield only one minimum structure. We demonstrate that the bond dissociation energy (0.50 kcal/mol) and vibrational frequency (1981.1 cm−1) of CrCO calculated using CCSD(T) are in better agreement with experimental values (<1.5 kcal/mol and 1977 cm−1) than any of the reported theoretical studies. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Comparison of transition probabilities calculated using different parameters on WBEPM theory for some p‐d and d‐p transitions in excited atomic nitrogen
Authors: Çelik Gültekin , Akin Erhan , Kiliç Hamdi Şükür
Published: September 2006

The transition probabilities between individual and multiplet lines for some quartet terms of excited p‐d and d‐p transition arrays of nitrogen atom have been calculated using the weakest bound electron potential model (WBEPM) theory. For determination relevant parameters, we employed both numerical Coulomb approximation (NCA) method and numerical nonrelativistic Hartree–Fock (NRHF) wave functions for expectation values of radii. The necessary energy values have been taken from experimental energy data in the literature. The expectation values of radii obtained using the two different methods have been employed in the calculation of transition probabilities of all transition arrays. The results obtained have been compared with either each other or NIST data. Good agreement with accepted values taken from NIST has been observed for related excited transitions. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Random changepoint modelling of HIV immunologic responses
Authors: Ghosh Pulak , Vaida Florin
Published: September 2006

We propose a changepoint model for the analysis of longitudinal CD4 T‐cell counts for HIV infected subjects following highly active antiretroviral treatment. The profile of CD4 counts for each subject follows a simple, ‘broken stick’ changepoint model, with random subject‐specific parameters, including the changepoint. The model accounts for baseline covariates. The longitudinal CD4 records are censored at the time of the subject going off‐study‐treatment. This is a potentially informative drop‐out mechanism, which we address by modelling it jointly with the CD4 count outcome. The drop‐out model incorporates terms from the CD4 model, including the changepoint. The estimation is done in a Bayesian framework, with implementation via Markov chain Monte Carlo methods in the WinBUGS software. Model selection using DIC indicates that the data support the complex random changepoint and informative censoring model. Copyright © 2006 John Wiley & Sons, Ltd.
Optimal designs for estimating the most successful dose
Authors: Zohar Sarah , O'Quigley John
Published: September 2006

There has been much recent interest in phase I/II dose finding designs in which information on both toxicity and efficacy is used. Unlike the classic phase I dose finding design in which the aim is to identify the MTD (maximum tolerated dose corresponding to some percentile of acceptable toxicity), a phase I/II dose finding study aims to locate the most successful dose (MSD), i.e. the dose which maximizes the product of the probability of seeing no toxicity together with the probability of seeing a therapeutic response). In this work we present an abstract theoretical design for this purpose. We call this design a ‘virtual’ design. The virtual design, conceptually similar to that developed for phase I designs alone, is based on a bivariate response. The design has optimal properties in that the current estimates of both probability of toxicity and those for response achieve the Cramer–Rao bound for every dose level. Unhappily, the virtual design is not available for practical use but its use can be exploited in theoretical investigations in much the same way as one uses the Cramer–Rao bound for unbiased estimators, i.e. a tool which enables us to see how much room for improvement may exist for any given real design. Via examples taken from the literature on phase I/II dose finding we illustrate how this technique can provide us with further insight on the relative performance of competing designs. Copyright © 2006 John Wiley & Sons, Ltd.
Correction for regression dilution bias using replicates from subjects with extreme first measurements
Authors: Berglund Lars , Garmo Hans , Lindbäck Johan , Zethelius Björn
Published: September 2006

The least squares estimator of the slope in a simple linear regression model will be biased towards zero when the predictor is measured with random error, i.e. intra‐individual variation or technical measurement error. A correction factor can be estimated from a reliability study where one replicate is available on a subset of subjects from the main study. Previous work in this field has assumed that the reliability study constitutes a random subsample from the main study.

We propose that a more efficient design is to collect replicates for subjects with extreme values on their first measurement. A variance formula for this estimator of the correction factor is presented. The variance for the corrected estimated regression coefficient for the extreme selection technique is also derived and compared with random subsampling. Results show that variances for corrected regression coefficients can be markedly reduced with extreme selection. The variance gain can be estimated from the main study data. The results are illustrated using Monte Carlo simulations and an application on the relation between insulin sensitivity and fasting insulin using data from the population‐based ULSAM study.

In conclusion, an investigator faced with the planning of a reliability study may wish to consider an extreme selection design in order to improve precision at a given number of subjects or alternatively decrease the number of subjects at a given precision. Copyright © 2006 John Wiley & Sons, Ltd.
Balancing vertical integration and strategic outsourcing: effects on product portfolio, product success, and firm performance
Authors: Rothaermel Frank T. , Hitt Michael A. , Jobe Lloyd A.
Published: September 2006

Most prior research has focused on vertical integration or strategic outsourcing in isolation to examine their effects on important performance outcomes. In contrast, we focus on the simultaneous pursuit of vertical integration and strategic outsourcing. Our baseline proposition is that balancing vertical integration and strategic outsourcing in the pursuit of taper integration enriches a firm's product portfolio and product success, and in turn contributes to competitive advantage and thus to overall firm performance. We derive a set of detailed hypotheses, and test them on a unique and fine‐grained panel of longitudinal data documenting over 3,500 product introductions in the global microcomputer industry. The results provide strong support for the notion that carefully balancing vertical integration and strategic outsourcing when organizing for innovation helps firms to achieve superior performance. Copyright © 2006 John Wiley & Sons, Ltd.
CEO incentives, innovation, and performance in technology‐intensive firms: a reconciliation of outcome and behavior‐based incentive schemes
Authors: Makri Marianna , Lane Peter J. , Gomez‐Mejia Luis R.
Published: September 2006

Building on the agency view of corporate governance, we propose that technology‐intensive firms use both outcome and behavior‐based performance criteria for rewarding CEOs. Using a sample of 206 firms from 12 U.S. manufacturing industries, we find that as technological intensity increases CEO bonuses are more closely linked to financial results and that total CEO incentives are associated with two indicators of desirable innovation behaviors: invention resonance and science harvesting. Invention resonance refers to the impact a firm's inventions have on other firms' inventions, while science harvesting reflects a firm's commitment to scientific research. As technological intensity increases, aligning bonus with financial results, total incentives with invention resonance, and total incentives with science harvesting predict firm market performance. Copyright © 2006 John Wiley & Sons, Ltd.
The licensing dilemma: understanding the determinants of the rate of technology licensing
Authors: Fosfuri Andrea
Published: September 2006

The licensing of technology entails a trade‐off: licensing payments net of transaction costs (revenue effect) must be balanced against the lower price–cost margin and/or reduced market share implied by increased competition (profit dissipation effect) from the licensee. We argue that the presence of multiple technology holders, which compete in the market for technology, changes such a trade‐off and triggers more aggressive licensing behavior. To test our theory, we analyze technology licensing by large chemical firms during the period 1986–96 for 107 chemical products. We find that the rate of technology licensing displays an inverted U‐shaped relationship with the number of potential technology suppliers and is negatively related to the licensor's market share and to the degree of technology‐specific product differentiation. Copyright © 2006 John Wiley & Sons, Ltd.
Spreadsheets, Service Providers, and the Statehouse: Using Data and the Wraparound Process to Reform Systems for Children and Families
Authors: Bruns Eric J. , Rast Jim , Peterson Christa , Walker Janet , Bosworth Jone
Published: September 2006

Evaluation descriptions in the research literature tend to ignore the full context of the community change efforts from which they emerged. In this paper, we describe a range of evaluation studies and data collection activities conducted over the course of one state's effort to reform its child welfare system on behalf of families with children experiencing serious mental health problems. Initial activities included studies of the prevalence of unmet mental health need in children and youth in the state. As these needs were addressed, evaluation activities examined the impact of a pilot wraparound program that became a major part of systems reform. Later efforts included implementation analysis of wraparound programs and assessment of priorities for continued systems reform. As we describe this set of evaluation activities, we discuss how data collection evolved to meet the needs of stakeholders over time and consider lessons learned about the roles of research and information sharing in shaping community change efforts.
Necessary Conditions for Mean Square Convergence of the Best Linear Factor Predictor
Authors: Krijnen Wim P.
Published: September 2006

Several sufficient conditions are available for mean square convergence of factor predictors. A necessary and sufficient condition is given in the Heywood case with respect to (confirmatory) factor analysis. This condition generalizes that of Krijnen (2006) and performs better than a signal-to-noise type of condition (Schneeweiss & Mathes, 1995).
Expression of tryptophan hydroxylase in developing mouse taste papillae
Authors: Ortíz-Alvarado Rafael , Guzmán-Quevedo Omar , Mercado-Camargo Rosalio , Haertle Thomas , Vignes Caroline , Bolaños-Jiménez Francisco
Published: September 2006

Gustatory papillae and associated taste buds receive and process chemical information from the environment. In mammals, their development takes place during the late phase of embryogenesis. However, the cellular factors that regulate the differentiation of taste papillae remain largely unknown. Here, we show by quantitative real time RT‐PCR that both isoforms of tryptophan hydroxylase (TPH1 and TPH2), the first and rate limiting enzyme of serotonin (5‐HT) synthesis, are expressed in developing circumvallate papillae. Immuno‐staining experiments further indicated that TPH is localized both in gustatory fibers and in differentiated taste receptor cells. These results point to the synthesis of 5‐HT in gustatory papillae, and allow one to hypothesize that the development of taste buds might be modulated by serotonin.
The intracellular domain of the human protocadherin hFat1 interacts with Homer signalling scaffolding proteins
Authors: Schreiner Dietmar , Müller Kathrin , Hofer H. Werner
Published: September 2006

The cadherin superfamily protein Fat1 is known to interact with the EVH1 domain of mammalian Ena/VASP. Here we demonstrate that: (i) the scaffolding proteins Homer‐3 and Homer‐1 also interact with the EVH1 binding site of hFat1 in vitro, and (ii) binding of Homer‐3 and Mena to hFat1 is mutually competitive. Endogenous Fat1 binds to immobilised Homer‐3 and endogenous Homer‐3 binds to immobilised Fat1. Both, endogenous and over‐expressed Fat1 exhibit co‐localisation with Homer‐3 in cellular protrusions and at the plasma membrane of HeLa cells. As Homer proteins and Fat1 have been both linked to psychic disorders, their interaction may be of patho‐physiological importance.
Compact archaeal variant of heme A synthase
Authors: Lewin Anna , Hederstedt Lars
Published: September 2006

The N‐ and C‐terminal halves of the heme A synthase polypeptide of Bacillus subtilis, and many other organisms, are homologous. This indicates that these enzyme proteins originate from a tandem duplication and fusion event of a gene encoding a protein half as large. The ape1694 gene of the hyperthermophilic archaeon Aeropyrum pernix encodes a protein that is similar to the hypothetical small primordial protein. We demonstrate that this A. pernix protein is a heat‐stable membrane bound heme A synthase designated cCtaA. The case of cCtaA is unusual in evolution in that the primordial‐like protein has not become extinct and apparently carries out the same function as the twice as large more diversified heme A synthase protein variant found in most cytochrome a‐containing organisms.