bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical assessment of hepatocyte‐targeted MR contrast agents in stable human liver cell cultures
Authors: Reimer Peter , Bader Augustinus , Weissleder Ralph
Published: March 2007

Much effort has been expended in the search for hepatocyte‐specific MR contrast agents to improve the detection and characterization of liver tumors. The purpose of this study was to establish human hepatocyte cell cultures to preclinically assess hepatocytetargeted magnetopharmaceuticals. Cultured human hepatocytes were sandwiched between two layers of collagen preserving both hepatocyte function and morphology over prolonged period of time. Cultures (n = 37) were subsequently used to test different fluorescinated MR contrast agents. Plain and rhodaminated monocrystalline iron oxide particles (MION and MION‐rh) and asialoglycoprotein‐receptor‐specific rhodaminated asialofetuin coupled to MION (MION‐ASF‐rh) were prepared. Competition experiments of these agents were performed with D(+)‐galactose to study the specificity of galactose‐mediated cell uptake. To assess the impact of cell integrity on cell uptake, functional experiments with CCI4 were performed. Normal cell cultures showed significantly higher fluorescence light emission after incubation with hepatocyte‐di‐rected ASF‐MION‐rh than after incubation with MION‐rh. Competition experiments of ASF‐MION‐rh with galactose showed a dose‐dependent decrease of calibrated fluorescence light emission. Cell cultures treated with CCI4 demonstrated a dose‐dependent significant reduction of calibrated fluorescence light emission, indicating reduced uptake of ASF‐MION‐rh. Our data demonstrate that stable human hepatocyte cell cultures can be used to preclinically assess novel magnetopharmaceuticals. Different contrast agents may be directly compared to each other and may accelerate their preclinical design. Because the assay can be applied to cells from any species, it may represent an ideal test system before clinical trials of new cell‐directed MR contrast agents.
Small renal cell carcinoma: MRI with pathologic correlation
Authors: Shinmoto Hiroshi , Yuasa Yuji , Tanimoto Akihiro , Narimatsu Yoshiaki , Jinzaki Masahiro , Hiramatsu Kyoichi , Mukai Makio
Published: March 2007

The MRI features of small renal cell carcinomas (RCCs) were retrospectively reviewed and correlated with histology in 24 patients. MRI features on both T1‐ and T2‐weighted images were classified into hypointensity, isointensity, and hyperintensity. Each tumor was pathologically classified into four types: alveolar, papillary, tubular, and cystic. These findings were correlated with MR signal intensities. Alveolar tumors showed hypointensity to isointensity on T1‐weighted image and isointensity to hyperintensity on T2‐weighted image. In contrast, all papillary tumors showed hypointensity on T2‐weighted image. Four of six tumors with hypointensity on T2‐weighted image were caused by hemosiderin deposition, hemorrhage, and necrosis. However, there were two papillary RCCs that showed hypointensity on T2‐weighted image despite no hemosiderin deposition and no hemorrhage. We conclude that papillary RCC is associated with T2‐hypointense appearance as well as hemosiderin deposition, hemorrhage, and necrosis.
Structure‐activity relationship of macrocyclic and linear gadolinium chelates: Investigation of transmetallation effect on the zinc‐dependent metallopeptidase angiotensin‐converting enzyme
Authors: Corot Claire , Idee Jean‐Marc , Hentsch Anne‐Marie , Santus Robin , Mallet Catherine , Goulas Valérie , Bonnemain Bruno , Meyer Dominique
Published: March 2007

Transmetallation between commercially available solutions of gadolinium (Gd) chelates and the zinc (Zn)‐dependent angiotensin‐converting enzyme (ACE) was investigated. In vitro, the strongest inhibitions were observed for the linear Gd complexes, Gd diethylene‐triamine pentaacetic acid (DTPA) bis‐methylamide (BMA) (IC50 = .016 ± .006 mmol/1) and Gd‐DTPA (IC50 = .350 ± .034 mmol/1). The two macrocycles Gd tetraazacyclododecane tetraacetic acid (DOTA) and Gd‐HP‐DO3A were similar and 400 times less active than Gd‐DTPA‐BMA. These effects were mainly due to the presence of free ligand for DTPA and calcium (Ca) chelate in the case of DTPA‐BMA because the addition of Zn2+ in the same quantities suppresses their inhibitory effects. In vivo, these two solutions of linear Gd chelates significantly inhibited ACE activity (Gd‐DTPA: 67 ± 9% versus baseline; and Gd‐DTPA‐BMA: 73 ± 2% versus baseline at the clinical dose of .1 mmol/kg), whereas no significant effect was observed for the two macrocyclic chelates Gd‐DOTA and Gd‐HP‐DO3A. Formulating the Gd chelate solution with either an excess of free ligand or Ca chelate (to decrease Gd3+ release) in the case of linear Gd chelate may have deleterious biologic consequences.
MRI of the cartilaginous epiphysis of the femoral head in the piglet hip after ischemic damage
Authors: Babyn Paul S. , Kim Harry K. W. , Gahunia Harpal K. , Lemaire Claude , Salter Robert B. , Fornasier Victor , Pritzker Kenneth P. H.
Published: March 2007

MRI of the cartilaginous epiphysis (CE) of piglet femoral head was performed after ischemic damage to study the changes in the CE found on MRI and to correlate these changes with histologic findings. Avascular necrosis of the femoral head was induced with a suture ligature in nine piglets; one piglet was killed postoperatively on day 3 and on weeks 1, 2, 3, 4, 6, 7, and 8 (two piglets were killed on week 3). MRI of the ischemic and contralateral nonischemic hip joints were obtained with a 60‐mm field of view (low resolution MRI). Biopsy cores of the femoral heads were imaged with a 15‐mm field of view (high resolution MRI) and correlated with histologic sections. The CE for all operated hips, except for the 3‐day postoperative specimen, showed evidence of ischemic changes on histologic assessment; the severity of damage increased with time. The MRI appearance of ischemic and nonischemic CE was clearly different by 2 weeks after the operation. No trilaminar signal pattern was evident in the high resolution T2‐weighted (T2W) imaging of the ischemic CE from 2 weeks after the operation. In the 3‐ to 8‐week postoperative specimens, focal areas of low signal intensity on high resolution T1‐weighted (T1W) and T2W imaging corresponded to the areas of chondronecrosis found on histologic assessment. The regions of high signal intensity on T2W imaging corresponded to the areas of chondrocyte clusters with increased safranin‐O staining. High resolution MRI can demonstrate changes in the CE associated with ischemic injury and may have a role in the assessment of the CE and its development after ischemic injury.
Quantification of patellar tracking using kinematic MRI
Authors: Powers Christopher M. , Shellock Frank G. , Pfaff Martin
Published: March 2007

The purpose of this study was to describe a method to quantify dynamic patellar tracking using kinematic MRI (KMRI). Twelve normal females and three patients with patellofemoral pain participated. Imaging was performed with a 1.5‐T/64‐MHz MR system using a fast spoiled gradient‐recalled acquisition in the steady state (GRASS) pulse sequence. A nonferromagnetic positioning device permitted active, bilateral knee extension against resistance (15% bwt) from 45° knee flexion to full extension. Subjects were instructed to extend their knees at a rate of 9° per second, which allowed images to be obtained at 45°, 36°, 27°, 18°, 9°, and 0°. All images were assessed for medial/lateral patellar displacement, patellar tilt, and sulcus angle using a computer‐aided system. Normal patellar motion was characterized by medial movement from 45° to 18°, followed by a reversal toward lateral displacement from 18° to full extension. The results for patellar tilt revealed a tendency toward decreasing lateral tilt as the knee extended. Sulcus angle measurements indicated that the patella was moving to a more shallow portion of the trochlear groove (superiorly) during extension.
Invited. Japanese encephalitis
Authors: Abe Toshi , Kojima Kazuyuki , Shoji Hiroshi , Tanaka Norimitsu , Fujimoto Kiminori , Uchida Masafumi , Nishimura Hiroshi , Hayabuchi Naofumi , Norbash Alexander M.
Published: March 2007

Japanese encephalitis (JB) is an acute encephalomyelitis which is a primary viral encephalitis accompanying a viral infection. Clinically, the patient who either resides in an endemic region or who has been exposed to the viral vector (mosquito) may have symptoms including high fever, headache, and impaired consciousness. JE involves many portions of the supratentorial thalamus, basal ganglia, and white matter. Classically MR imaging demonstrates the lesions of JE as hyperintense on T2‐weighted images and hypointense on T1‐weighted images. Hemorrhagic transformations have also been described in JE lesions, with corresponding expected T1 and T2 changes. Differential considerations based on the MRI appearance are somewhat broad, including but not limited to primary viral encephalitis, acute encephalopathy, limbic encephalitis, and acute disseminated encephalomyelitis. The therapy for JE is primarily conservative and supportive since there is no specific treatment for JE, and the disease has a high fatality rate. The prognosis depends on the extent of involvement at primary presentation, and on the autoimmune mechanisms of this disease.
Differentiation of gray matter and white matter perfusion in patients with unilateral internal carotid artery occlusion
Authors: Kluytmans Manon , Grond Jeroen van der , Folkers Paul J. M. , Mali Willem P. Th. M. , Viergever Max A.
Published: March 2007

In this study, we investigated differences between gray matter and white matter perfusion in patients with a unilateral occlusion of the internal carotid artery (ICA) with dynamic susceptibility contrast. Seventeen patients and 17 control subjects were studied, using T2*‐weighted gradient echo acquisition. Gray and white matter regions were obtained by segmentation of inversion recovery MRI. Lesions were excluded by segmentation of T2‐weighted MRI. In the symptomatic hemisphere, cerebral blood volume was increased in white matter (P < .05) but not in gray matter. No cerebral blood flow changes were found. All timing parameters (mean transit time [MTT], time of appearance, and time to peak) showed a significant delay for both white and gray matter (P < .05), but the MTT increase of white matter was significantly larger than for gray matter (P < .05). These findings indicate that differentiation between gray and white matter is essential to determine the hemodynamic effects of an ICA occlusion.
Pharmacokinetic MRI for assessment of malignant glioma response to stereotactic radiotherapy: Initial results
Authors: Hawighorst Hans , Knopp Michael V. , Debus Jürgen , Hoffmann Ulf , Grandy Martin , Griebel Jürgen , Zuna Ivan , Essig Marco , Schoenberg Stefan O. , Devries Alexander , Brix G. , van Kaick Gerhard
Published: March 2007

The purpose of this study was to assess the value of dynamic, contrast‐enhanced MRI in patients with malignant glioma (a) to predict before stereotactic radiotherapy local tumor control, (b) to investigate temporal changes in tumor microcirculation after stereotactic radiotherapy, and (c) to analyze whether malignant glioma response may be predicted earlier by alterations in the tissue pharmacokinetics rather than in terms of tumor volume. Ninety MRI studies were performed of 18 patients with malignant glioma before and 6, 18, 26, 52, and 72 weeks after the end of stereotactic radiotherapy. The signal time courses of the contrast‐enhanced tumors were analyzed using a pharmacokinetic two‐compartment model that calculates for the parameter A, reflecting the degree of MRI signal enhancement [no units] and the exchange rate constant k21 [min−1]. Before radiotherapy, the amplitude A was significantly (P < .05) lower in patients with subsequent local tumor control (n = 8; mean A = .34 ± .15) compared to patients without subsequent local tumor control (n = 10; mean A = .94 ± .71). In the local tumor control group, early after stereotactic radiotherapy (at 6–18 weeks), there was a significant (P < .05) time‐dependent decrease in the parameter k21, whereas there was still no alteration in the tumor volume. A low amplitude A before radiotherapy, combined with an early drop of k21 after stereotactic radiotherapy, reliably characterized the group of patients with subsequent tumor volume decrease. Our preliminary results suggest that two contrast‐enhanced dynamic MR studies, one before and one early after stereotactic radiotherapy, offer important information on local tumor control within the first 6 to 18 weeks after stereotactic radiotherapy. Moreover, this response may be evidenced before tumor volume changes and provides a therapeutic window to broaden treatment options and to improve treatment outcome.
Comparison of gadopentetate dimeglumine and albumin‐(Gd‐DTPA)30 for microvessel characterization in an intracranial glioma model
Authors: Ostrowitzki Susanne , Fick James , Roberts Timothy P. L. , Wendland Michael F. , Aldape Kenneth D. , Mann Jeffry S. , Israel Mark A. , Brasch Robert C.
Published: March 2007

To compare the performance of macromolecular albumin gadolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA)30 and low molecular weight gadopentetate dimeglumine for microvessel characterization, we examined an intracranial 9L glioma model in which increased angiogenesis, hypervascularity, and hyperpermeability mimic characteristics of clinical malignant brain tumors. Dynamic MRI data were analyzed using a bidirectional, two‐compartment kinetic model to extract quantitative estimates for fractional blood volume (fBV) and permeability surface area product (PS). Three criteria were used for comparison of contrast agent performance: (a) tumor conspicuity, defined as the contrast‐to‐noise ratio (CNR); (b) dynamic range of differential permeability estimates between tumor and normal brain; (c) reasonableness of blood volume estimates. Gadopentetate was superior to macromolecular albumin‐(Gd‐DTPA)30 for detection of 9L brain gliomas and for measurements of hyperpermeability.
Biosynthesis and Biodegradability of Copolythioesters from 3,3′‐Thiodipropionic Acid and Plant Oils by Cupriviadus necator
Authors: Kamei Yasutaka , Nagai Atsushi , Nishida Haruo , Kimura Hiroshi , Endo Takeshi
Published: March 2007

To prepare sulfur‐containing natural polymers effectively, several plant oils and 3,3′‐thiodipropionic acid (TDP) have been used as carbon sources for the biosynthesis of copolymer poly[(3‐hydroxybutyrate)‐co‐(3‐mercaptopropionate)] [poly(3HB‐co‐3MP)] by a wild‐type bacterium Cupriviadus necator H16. By using the plant oils, copolymer accumulation and incorporation of 3MP units are greater than those of cases using sugars. The 3MP fraction is controllable over a range of 1–39 mol‐% by adjusting the cultivation conditions. Microbial degradability of the copolymers has been examined in an activated sludge supernatant. The biodegradation proceeded by two mechanisms: surface erosion and auto‐catalytic hydrolysis, depending on the 3MP unit fraction, and show preferential degradation of 3HB unit sequences.

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Levodopa “drug holiday” with amantadine infusions as a treatment of complications in Parkinson's disease
Authors: Koziorowski Dariusz , Friedman Andrzej
Published: March 2007

The loss of beneficial effect of levodopa due to progression of the disease and alteration of receptor sensitivity makes the treatment of the advanced stadium of Parkinson's disease (PD) very difficult. In the past “drug holidays” was used in attempt to resensitize dopamine receptors in the striatum to make the treatment easier. However possible serious complications like neuroleptical malignant‐like syndrome discouraged the use of this procedure. Intravenous administration of amantadine, another antiparkinsonian medication during “drug holidays,” procedure could be a solution for this problem. We studied 12 patients with PD suffering from complication of the therapy. Daily dose of Levodopa used as monotherapy before amantadine infusions ranged between 700 and 2,000 mg. Levodopa was discontinued for 3 days and during that time amantadine sulfate intravenous was administrated. After “drug holidays” levodopa in the same dose as before treatment was resumed. An assessment of the parkinsonian condition was performed with Unified Parkinson's Disease Rating Scale before “drug holidays” 2 days after and 1, 2, 3, 4, 5, 6 months later. The follow‐up study demonstrated a significant improvement both in the motor condition and complication of therapy. The improvement after therapy was maintained up to 4 month. The levodopa “drug holidays” with amantadine infusion is a valuable option in the therapy of advanced stages of PD. © 2007 Movement Disorder Society
Numerical analysis of Rayleigh–Plesset equation for cavitating water jets
Authors: Alehossein H. , Qin Z.
Published: March 2007

High‐pressure water jets are used to cut and drill into rocks by generating cavitating water bubbles in the jet which collapse on the surface of the rock target material. The dynamics of submerged bubbles depends strongly on the surrounding pressure, temperature and liquid surface tension. The Rayleigh–Plesset (RF) equation governs the dynamic growth and collapse of a bubble under various pressure and temperature conditions. A numerical finite difference model is established for simulating the process of growth, collapse and rebound of a cavitation bubble travelling along the flow through a nozzle producing a cavitating water jet. A variable time‐step technique is applied to solve the highly non‐linear second‐order differential equation. This technique, which emerged after testing four finite difference schemes (Euler, central, modified Euler and Runge–Kutta–Fehlberg (RKF)), successfully solves the Rayleigh–Plesset (RP) equation for wide ranges of pressure variation and bubble initial sizes and saves considerable computing time. Inputs for this model are the pressure and velocity data obtained from a CFD (computational fluid dynamics) analysis of the jet. Copyright © 2007 John Wiley & Sons, Ltd.
Class A scavenger receptor (CD204) attenuates hyperoxia‐induced lung injury by reducing oxidative stress
Authors: Kobayashi H , Sakashita N , Okuma T , Terasaki Y , Tsujita K , Suzuki H , Kodama T , Nomori H , Kawasuji M , Takeya M
Published: March 2007

To clarify the role of macrophage class A scavenger receptors (SR‐A, CD204) in oxidative lung injury, we examined lung tissue of SR‐A deficient (SR‐A−/−) and wild‐type (SR‐A+/+) mice in response to hyperoxic treatment. Protein levels of bronchoalveolar lavage fluid (BALF) and pulmonary oedema (wet : dry weight ratios) were higher in SR‐A−/− mice than those in SR‐A+/+ mice. Cumulative survival was significantly decreased in SR‐A−/− mice. However, there were no differences in BALF macrophage and neutrophil count between the two groups. Real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) revealed that messenger RNA (mRNA) levels of the inducible nitric oxide synthase (iNOS) were increased during hyperoxic injury, and this increase was more prominent in SR‐A−/− mice. Expression levels of iNOS in alveolar macrophages after hyperoxia in vivo and in vitro were higher in SR‐A−/− macrophages compared with SR‐A+/+ macrophages. Immunohistochemistry using anti‐nitrotyrosine antibodies revealed distinctive oxidative stress in the injured lung in both groups, but it was more remarkable in the SR‐A−/− mice. After hyperoxic treatment, pulmonary mRNA levels of tumour necrosis factor‐α(TNF‐α) were elevated more rapidly in SR‐A−/− mice than in SR‐A+/+ mice. Together these results suggest that SR‐A expression attenuates hyperoxia‐induced lung injury by reducing macrophage activation. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Changes in the chemical structure of natural rubber tyre vulcanisates in service
Authors: Russell R. M.
Published: March 2007

The chemical structure of tread vulcanisates in heavy duty tyres was examined when the tyres were new, after they had been rig‐tested under conditions designed to induce tread‐lift and after they had had service on the road. Considerable changes occurred near the breaker edge; these included a marked decrease in the concentration of polysulphide crosslinks, an increase in the concentration of monosulphide crosslinks, and an increase in the amount of sulphur bound to the rubber network in main‐chain modifications. Experiments with laboratory‐prepared vulcanisates indicated that the structural alterations in the tyres were due to thermal anaerobic reactions induced by heat build‐up and that they may lead to a deterioration in the durability of the tread vulcanisate. Tyre performance may be improved by reducing heat build‐up and/or increasing the thermal stability of the rubber network. The latter could be achieved by the use of modified forms of conventional vulcanisation recipes, or efficient vulcanisation systems that produce thermally stable monosulphide crosslinks.
Cure of polyester resins—determination by infra‐red spectroscopy
Authors: Learmonth G. S. , Pritchard G.
Published: March 2007

The measurement of the extent of the crosslinking process in unsaturated polyester resins by infra‐red spectroscopy is discussed. Quantitative use of such methods is considered. The concentration of free unreacted styrene is measured by the absorbence at 915 cm−1, and the fumarate unsaturation by the absorbence at 985 cm−1, after correcting for overlapping styrene. The carbonyl band is used as an internal standard.

Comparison of the results with refractive index measurements, solvent extraction and volatility data suggests that this method may be approximately quantitative.
Synthesis of α, α′, β‐trideuterovinyl acetate
Authors: Haken J. K. , Werner R. L.
Published: March 2007

Reaction conditions for the synthesis of α, α′, β‐trideuterovinyl acetate by the continuous vapour phase catalytic reaction of deuteroacetylene and acetic acid‐d (CH3COOD) are described.
Are social competence difficulties caused by performance or acquisition deficits? The importance of self‐regulatory mechanisms
Authors: Gumpel Thomas P.
Published: March 2007

We conducted three studies which examined the performance vs. skill acquisition model of social skills deficits. In Study 1, baseline social behaviors for a random sample of 12 boys with comorbid emotional and behavioral disorders (EBD), learning disabilities (LD), language delays, and Attention Deficit Hyperactivity Disorder (ADHD) revealed that prosocial behaviors as well as inappropriate behaviors exist comorbidly in behavioral repertoires, supporting a performance rather than acquisition model of social competence difficulties. In Study 2, an ABAC design was used to examine the efficacy of a self‐management intervention with noncontingent (B) and contingent (C) reinforcement for three elementary aged boys with EBD. Generalization was demonstrated in natural settings for the contingent reinforcement phase only, but was not observed over time. Study 3 replicated Study 2's procedures using an ABAC multiple baseline across participants design with a sample of adolescents with varying degrees of mental retardation. Two of the three participants responded favorably to the self‐monitoring training and showed marked improvements in prosocial play skills during recess; for the third participant, no behavioral changes were observed. Results from all three studies are discussed from a social learning theory perspective. The efficacy of the data collecting procedure and implications of the results are discussed. © 2007 Wiley Periodicals, Inc. Psychol Schs 44: 351–372, 2007.
The rational design of biological complexity: A deceptive metaphor
Authors: Van Regenmortel Marc H. V.
Published: March 2007

Biologists often claim that they follow a rational design strategy when their research is based on molecular knowledge of biological systems. This claim implies that their knowledge of the innumerable causal connections present in biological systems is sufficient to allow them to deduce and predict the outcome of their experimental interventions. The design metaphor is shown to originate in human intentionality and in the anthropomorphic fallacy of interpreting objects, events, and the behavior of all living organisms in terms of goals and purposes. Instead of presenting rational design as an effective research strategy, it would be preferable to acknowledge that advances in biomedicine are nearly always derived from empirical observations based on trial and error experimentation. The claim that rational design is an effective research strategy was tested in the case of current attempts to develop synthetic vaccines, in particular against human immunodeficiency virus. It was concluded that in this field of biomedicine, trial and error experimentation is more likely to succeed than a rational design approach. Current developments in systems biology may give us eventually a better understanding of the immune system and this may enable us in the future to develop improved vaccines.
Reconstructing biochemical pathways from time course data
Authors: Srividhya Jeyaraman , Crampin Edmund J. , McSharry Patrick E. , Schnell Santiago
Published: March 2007

Time series data on biochemical reactions reveal transient behavior, away from chemical equilibrium, and contain information on the dynamic interactions among reacting components. However, this information can be difficult to extract using conventional analysis techniques. We present a new method to infer biochemical pathway mechanisms from time course data using a global nonlinear modeling technique to identify the elementary reaction steps which constitute the pathway. The method involves the generation of a complete dictionary of polynomial basis functions based on the law of mass action. Using these basis functions, there are two approaches to model construction, namely the general to specific and the specific to general approach. We demonstrate that our new methodology reconstructs the chemical reaction steps and connectivity of the glycolytic pathway of Lactococcus lactis from time course experimental data.
The extant core bacterial proteome is an archive of the origin of life
Authors: Danchin Antoine , Fang Gang , Noria Stanislas
Published: March 2007

Genes consistently present in a clique of genomes, preferring the leading DNA strands are deemed persistent. The persistent bacterial proteome organises around intermediary and RNA metabolism, and RNA‐related information transfer, with a significant contribution to compartmentalisation. Despite inevitable losses during evolution, the extant persistent proteome displays functions present early on. Proteins coded by genes staying clustered in a majority of genomes constitute a network of mutual attraction made up of three concentric circles. The outer one, mostly devoted to metabolism, breaks into small pieces and fades away. The second, more continuous, one organises around class I tRNA synthetases. The well‐connected inner circle comprises the ribosome and information transfer. This reflects the progressive construction of cells, starting from the metabolism of coenzymes, nucleotides and fatty acids‐related molecules. Subsequently, a core set of aminoacyl‐tRNA synthetases scaffolded around RNA, connected to cell division machinery and organised metabolism around translation. This remarkable organisation reflects the evolution of life from small molecules metabolism to the RNA world, suggesting that extant microorganisms carry the marks of the ancient processes that created life. Further analysis suggests that RNA degradation, associated to the presence of iron, still plays a role in extant metabolism, including the evolution of genome structures.
Identifying functional modules in the physical interactome of Saccharomyces cerevisiae
Authors: Pu Shuye , Vlasblom Jim , Emili Andrew , Greenblatt Jack , Wodak Shoshana J.
Published: March 2007

Reliable information on the physical and functional interactions between the gene products is an important prerequisite for deriving meaningful system‐level descriptions of cellular processes. The available information about protein interactions in Saccharomyces cerevisiae has been vastly increased recently by two comprehensive tandem affinity purification/mass spectrometry (TAP/MS) studies. However, using somewhat different approaches, these studies produced diverging descriptions of the yeast interactome, clearly illustrating the fact that converting the purification data into accurate sets of protein–protein interactions and complexes remains a major challenge. Here, we review the major analytical steps involved in this process, with special focus on the task of deriving complexes from the network of binary interactions. Applying the Markov Cluster procedure to an alternative yeast interaction network, recently derived by combining the data from the two latest TAP/MS studies, we produce a new description of yeast protein complexes. Several objective criteria suggest that this new description is more accurate and meaningful than those previously published. The same criteria are also used to gauge the influence that different methods for deriving binary interactions and complexes may have on the results. Lastly, it is shown that employing identical procedures to process the latest purification datasets significantly improves the convergence between the resulting interactome descriptions.
Assignment of protein function and discovery of novel nucleolar proteins based on automatic analysis of MEDLINE
Authors: Schuemie Martijn , Chichester Christine , Lisacek Frederique , Coute Yohann , Roes Peter‐Jan , Sanchez Jean Charles , Kors Jan , Mons Barend
Published: March 2007

Attribution of the most probable functions to proteins identified by proteomics is a significant challenge that requires extensive literature analysis. We have developed a system for automated prediction of implicit and explicit biologically meaningful functions for a proteomics study of the nucleolus. This approach uses a set of vocabulary terms to map and integrate the information from the entire MEDLINE database. Based on a combination of cross‐species sequence homology searches and the corresponding literature, our approach facilitated the direct association between sequence data and information from biological texts describing function. Comparison of our automated functional assignment to manual annotation demonstrated our method to be highly effective. To establish the sensitivity, we defined the functional subtleties within a family containing a highly conserved sequence. Clustering of the DEAD‐box protein family of RNA helicases confirmed that these proteins shared similar morphology although functional subfamilies were accurately identified by our approach. We visualized the nucleolar proteome in terms of protein functions using multi‐dimensional scaling, showing functional associations between nucleolar proteins that were not previously realized. Finally, by clustering the functional properties of the established nucleolar proteins, we predicted novel nucleolar proteins. Subsequently, nonproteomics studies confirmed the predictions of previously unidentified nucleolar proteins.
Concentration‐dependent effects on the rapid and efficient activation of the MAP kinase signaling cascade
Authors: Schwacke John H. , Voit Eberhard O.
Published: March 2007

Modern proteomic techniques are making it possible to identify and quantitate increasingly complex mixtures of cellular proteins. Translating the relative expression measurements collected in these experiments into an understanding of the associated physiological phenomena continues to be a challenge for the field of systems biology. We demonstrate how methods of mathematical and computational systems biology permit us to proffer explanations for the observed concentration ranges of signaling components found in the highly conserved mitogen‐activated protein kinase (MAPK) cascade. The analysis demonstrates that alterations in the naturally occurring MAPK and MAPK kinase (MAPKK) concentrations would negatively affect the efficiency of short‐term responses of the cascade. Thus, while there seems to be no a priori rationale for particular features of the involved kinases, the observed ranges of their characteristic parameters appear to be far from coincidental. This result is deduced from the first principles of mass action kinetics and holds for wide variations in MAPKK kinase (MAPKKK) concentrations, differential preference for unphosphorylated and monophosphorylated forms of kinase substrates, and for cases where the monophosphorylated MAPKK exhibits kinase activity. The results demonstrate how theoretical systems biology complements molecular biology by providing specific rationale for observed natural designs in a fashion hardly achievable with experimentation alone.
Proteome informatics for cancer research: From molecules to clinic
Authors: Brusic Vladimir , Marina Ovidiu , Wu Catherine J. , Reinherz Ellis L.
Published: March 2007

Proteomics offers the most direct approach to understand disease and its molecular biomarkers. Biomarkers denote the biological states of tissues, cells, or body fluids that are useful for disease detection and classification. Clinical proteomics is used for early disease detection, molecular diagnosis of disease, identification and formulation of therapies, and disease monitoring and prognostics. Bioinformatics tools are essential for converting raw proteomics data into knowledge and subsequently into useful applications. These tools are used for the collection, processing, analysis, and interpretation of the vast amounts of proteomics data. Management, analysis, and interpretation of large quantities of raw and processed data require a combination of various informatics technologies such as databases, sequence comparison, predictive models, and statistical tools. We have demonstrated the utility of bioinformatics in clinical proteomics through the analysis of the cancer antigen survivin and its suitability as a target for cancer immunotherapy.
Surrogacy theory and models of convoluted organic systems
Authors: Konopka Andrzej K.
Published: March 2007

The theory of surrogacy is briefly outlined as one of the conceptual foundations of systems biology that has been developed for the last 30 years in the context of Hertz‐Rosen modeling relationship. Conceptual foundations of modeling convoluted (biologically complex) systems are briefly reviewed and discussed in terms of current and future research in systems biology. New as well as older results that pertain to the concepts of modeling relationship, sequence of surrogacies, cascade of representations, complementarity, analogy, metaphor, and epistemic time are presented together with a classification of models in a cascade. Examples of anticipated future applications of surrogacy theory in life sciences are briefly discussed.
Electrostatic potential–density relationships in molecules
Authors: Jalbout Abraham F.
Published: March 2007

In this work, we present Hartree–Fock and density functional theory nuclear electrostatic potential–density relationships for several homonuclear diatomic molecules. The results of our calculations are encouraging with relatively low errors in the energies. Implications for the application of this work to novel molecular energy equations as well as the need for further improvement of these newly proposed relationships in molecules have been addressed. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Theoretical evidence of d‐orbital aromaticity in anionic metal X (X = Sc, Y, La) clusters
Authors: Chi Xian X. , Liu Yong
Published: March 2007

The equilibrium geometries, total electronic energies, and vibrational frequencies for singlet, triplet, and quinted states of three all‐metal X (X = Sc, Y, and La) anions and nine relevant neutral singlet MX3 (M = Li, Na, K, X = Sc, Y, La) clusters are investigated with four density functional theory (DFT) and correlated ab initio methods B3LYP, B3PW91, MP2, and CCSD(T). To our knowledge, the theoretical study on these clusters composed of the transition metal Sc, Y, La is first reported here. The calculated results show that for the X clusters the singlet states with trigonal D3h structures are the lowest energetically, while the neutral singlet MX3 clusters each have two stable isomers: one trigonal pyramidal C3v and one bidentate C2v structures with the pyramidal C3v isomer being ground state. In addition, we calculate the resonance energies (RE) and nucleus‐independent chemical shift (NICS) for the singlet trigonal X rings and show that these singlet trigonal X rings exhibit higher degree of aromaticity. The detailed molecular orbital (MO) analyses reveal that the singlet trigonal X anions have one delocalized σ‐type and one delocalized π‐type MOs, which follow the 4n + 2 electron counting rule, respectively and play an important role in rendering these species two‐fold aromaticity. Here, an explicit theoretical evidence is given to prove that the contribution to the two‐fold aromaticity of the singlet trigonal X (X = Sc, Y, and La) rings originates primarily from the d‐orbital bonding interactions of these component transition metal X atoms. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Theoretical study on the Diels–Alder reaction of cyclopentadiene with methacrolein catalyzed by diethylimidazolium cation
Authors: Sun Hui , Zhang Dongju , Ma Chen , Liu Chengbu
Published: March 2007

The theoretical studies of how room temperature ionic liquids control desired reactions are very scarce in contrast with their increasing applications in many fields as recyclable solvents, catalysts, and reaction mediums. The present work considers the Diels–Alder (D‐A) reaction of cyclopentadiene with methacrolein in the presence of diethylimidazolium salts as the first prototype of our systemic studies about important organic synthesis reactions catalyzed by room temperature ionic liquids. We show the mechanism details of the D‐A reactions with and without the dialkylimidazolium cation and rationalize the experimental findings based on the results from the quantum chemistry calculations at the AM1, HF/6‐31G(d), and B3PW91/6‐31G(d,p) levels of theory, respectively. It is found that the diethylimidazolium cation acts as a Lewis acid center to catalyze the D‐A reaction, which decreases the barrier and increases the asynchronicity of the D‐A reaction, but does not change the potential energy surface profile of the reaction compared to the noncatalyzed process. The present results rationalize the early experimental findings well and provide the first prototype for theoretically understanding the D‐A reaction in the presence of dialkylimidazolium salts. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Net information measures for modified Yukawa and Hulthén potentials
Authors: Patil S. H. , Sen K. D.
Published: March 2007

The dimensional analyses of the position and momentum variances‐based quantum mechanical Heisenberg uncertainty measure, as well as the entropic information measures given by the Shannon information entropy sum and the product of Fisher information measures are carried out for two widely used nonrelativistic isotropic exponential‐cosine screened Coulomb potentials generated by multiplying the superpositions of (i) Yukawa‐like, −Z(e−μr/r), and (ii) Hulthén‐like, −Zμ(1/(eμr − 1)), potentials by cos(bμr) followed by addition of the term a/r2, where a and b ≥ 0, μ are the screening parameters and Z, in case of atoms, denotes the nuclear charge. Under the spherical symmetry, all the information measures considered are shown to be independent of the scaling of the set [μ, Z] at a fixed value of μ/Z, a, and b and the other parameters defining the superpositions of the potentials. Numerical results are presented, which support the validity of the scaling properties. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Computer aid molecular design based on meta‐heuristics techniques
Authors: Rusu T. , Bulacovschi V.
Published: March 2007

One of the challenges in modern chemistry is the problem of designing new molecules with desired properties. The traditional approach to this problem are usually expensive and time‐consuming iterative process with the scientist or engineer hypothesizing a compound, synthesizing the material, testing for desired properties, and redesigning the candidate if the desired properties are not met. In the last years, a lot of scientists have reached to the conclusion that the artificial intelligence methods can improve/facilitate the design of new macromolecules with desired properties. One of the challenges in computer aid macromolecular design is to avoid local minima. Our paper present the use of meta‐heuristics techniques that can solve this problem. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Electron ionization mass spectral study of selected N‐amide and N‐alkyl derivatives of cytisine
Authors: Przybył Anna K. , Prukała Wiesław , Kikut‐Ligaj Dariusz
Published: March 2007

(–)‐Cytisine and its derivatives are promising alkaloids in the development of new drugs for the treatment of disorders of the central nervous system (CNS). Electron ionization (EI) mass spectral fragmentations of cytisine (1), N‐methylcytisine (2), N‐ethylcytisine (3), N‐acetylcytisine (4), N‐propionylcytisine (5) and N‐benzoylcytisine (6) have been investigated. Detailed fragmentation pathways have been identified for all significant ions, including a few characteristic fragment ions. The principal fragmentation routes of compounds 1–6 have been determined on the basis of EI low‐resolution, high‐resolution and B2/E linked scans as well as linked scans at constant B/E. Copyright © 2007 John Wiley & Sons, Ltd.
Differentiation of three pairs of positional isomers of hybrid peptides with repeats of phenylalanine‐β3‐h‐valine/β3‐h‐valine‐phenylalanine by electrospray ionization tandem mass spectrometry
Authors: Ramesh V. , Reddy P. Nagi , Srinivas R. , Srinivasulu G. , Kunwar A. C.
Published: March 2007

Electrospray ionization ion trap mass spectrometry has been used to distinguish three pairs of positional isomers of a new series of N‐blocked hybrid peptides derived from repeats of phenylalanine(D)‐β3‐h‐valine/β3‐h‐valine‐phenylalanine(D) (FβV/βVF) non‐natural amino acids. MSn of protonated isomeric peptides produces characteristic fragmentation involving the peptide backbone, the Boc group and the side chain. FβV‐peptides can be distinguished from βVF‐peptides by the loss of R‐OH from [M+H−Boc+H]+, which is either of relatively low abundance or totally absent for the latter peptides. In contrast, βVF‐peptides show abundant Mannich base characteristic ions by the elimination of ammonia, and imine due to a retro‐Mannich cleavage. This fragmentation is absent for FβV‐peptides. When β‐valine is at the C‐terminus, abundant b ions are produced. This is ascribed to the probable formation of a stable diketopiperazine structure, and this has been supported by the loss of H2O and CO in the CID spectra of b ions. The hybrid dipeptide acids have also been distinguished in negative ion mass spectrometry. Copyright © 2007 John Wiley & Sons, Ltd.
The persistence of abnormal returns at industry and firm levels: Evidence from Spain
Authors: Bou Juan Carlos , Satorra Albert
Published: March 2007

We apply structural equation models to longitudinal data on profits of firms within industries to study the persistence of abnormal returns. We obtain a two‐way variance decomposition for abnormal returns: at firm vs. industry levels, and at permanent vs. transitory components. This decomposition enables us to assess the relative importance of the fundamental components of abnormal returns discussed in the literature. The method is applied to a panel of 5,000 Spanish firms observed over the period 1995–2000. We conclude that: (a) there are significant and permanent differences between profit rates at both industry and firm levels; (b) variation of abnormal returns at firm level is greater than at industry level; and (c) firm and industry levels do not differ significantly regarding rates of convergence of abnormal returns. Copyright © 2007 John Wiley & Sons, Ltd.
Performance consequences of new CEO ‘Outsiderness’: Moderating effects of pre‐ and post‐succession contexts
Authors: Karaevli Ayse
Published: March 2007

This study seeks to reconcile inconsistent findings on the performance consequences of new CEO origin. Drawing on five decades of empirical research on CEO succession outcomes, I develop a more refined theoretical conceptualization and a finer‐grained measurement of the underlying construct of the insider vs. outsider CEO, and build and test a more comprehensive and nuanced framework of the succession context. A longitudinal investigation of the U.S. airline and chemical industries (1972–2002) indicates that new CEO ‘Outsiderness’, conceptualized as a continuum raging from new CEOs who have a greater combination of firm and industry tenure to those who have no experience in the firm and the industry, has no main effect on post‐succession firm performance. However, significant moderating effects are found when environmental munificence, pre‐succession firm performance, and concomitant strategic and senior executive team changes are considered. Together, these findings highlight the need to consider both pre‐ and post‐succession contextual factors for evaluating the performance effects of new CEO outsiderness. Copyright © 2007 John Wiley & Sons, Ltd.
Does peripheral knowledge complement control? An empirical test in technology outsourcing alliances
Authors: Tiwana Amrit , Keil Mark
Published: March 2007

While the normative logic for forming technology outsourcing alliances is that such alliances allow outsourcing firms to specialize deeper in their domain of core competence without being distracted by noncore activities, recent empirical studies have reported the puzzling phenomenon of some firms continuing to invest in R&D in domains that are fully outsourced to specialized alliance partners. An underlying—and widely made—assertion that can potentially reconcile this contradiction is that ‘peripheral’ knowledge (specialized knowledge in the domain of outsourced activities) complements control in technology outsourcing alliances. However, this assertion is untested; and empirically testing it is the objective of this research study. Using data from 59 software services outsourcing alliances, we show that such peripheral knowledge and alliance control are imperfect complements: peripheral knowledge complements outcomes‐based formal control but not process‐based control. Thus, outsourcing firms might sometimes need knowledge outside their core domain because such knowledge facilitates effective alliance governance. Our theoretical elaboration and empirical testing of the assumed complementarities between peripheral knowledge and control in technology outsourcing alliances has significant implications for strategy theory and practice, which are also discussed. Copyright © 2007 John Wiley & Sons, Ltd.