bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic identifiability testing for unambiguous mechanistic modeling – application to JAK-STAT, MAP kinase, and NF-κ B signaling pathway models
Authors: Quaiser Tom , Mönnigmann Martin 
Published: May 2009

Abstract

Background
When creating mechanistic mathematical models for biological signaling processes it is tempting to include as many known biochemical interactions into one large model as possible. For the JAK-STAT, MAP kinase, and NF-κ B pathways a lot of biological insight is available, and as a consequence, large mathematical models have emerged. For large models the question arises whether unknown model parameters can uniquely be determined by parameter estimation from measured data. Systematic approaches to answering this question are indispensable since the uniqueness of model parameter values is essential for predictive mechanistic modeling.

Results
We propose an eigenvalue based method for efficiently testing identifiability of large ordinary differential models and compare this approach to three existing ones. The methods are benchmarked by applying them to models of the signaling pathways mentioned above. In all cases the eigenvalue method proposed here and the orthogonal method find the largest set of identifiable parameters, thus clearly outperforming the other approaches. The identifiability analysis shows that the pathway models are not identifiable, even under the strong assumption that all system state variables are measurable. We demonstrate how the results of the identifiability analysis can be used for model simplification.

Conclusion
While it has undoubtedly contributed to recent advances in systems biology, mechanistic modeling by itself does not guarantee unambiguous descriptions of biological processes. We show that some recent signal transduction pathway models have reached a level of detail that is not warranted. Rigorous identifiability tests reveal that even if highly idealized experiments could be carried out to measure all state variables of these signaling pathways, some unknown parameters could still not be estimated. The identifiability tests therefore show that the level of detail of the investigated models is too high in principle, not just because too little experimental information is available. We demonstrate how the proposed method can be combined with biological insight, however, to simplify these models.
Microarray analysis of RNA extracted from formalin-fixed, paraffin-embedded and matched fresh-frozen ovarian adenocarcinomas
Authors: Fedorowicz Grazyna , Guerrero Steve , Wu Thomas D , Modrusan Zora 
Published: May 2009

Abstract

Background
Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) samples represents a valuable approach for advancing oncology diagnostics and enhancing retrospective clinical studies; however, at present, this methodology still requires optimization and thus has not been extensively used. Here, we utilized thorough quality control methods to assess RNA extracted from FFPE samples and then compared it to RNA extracted from matched fresh-frozen (FF) counterparts. We preformed genome-wide expression profiling of FF and FFPE ovarian serous adenocarcinoma sample pairs and compared their gene signatures to normal ovary samples.

Methods
RNA from FFPE samples was extracted using two different methods, Ambion and Agencourt, and its quality was determined by profiling starting total RNA on Bioanalyzer and by amplifying increasing size fragments of beta actin (ACTB) and claudin 3 (CLDN3) by reverse-transcriptase polymerase chain reaction. Five matched FF and FFPE ovarian serous adenocarcinoma samples, as well as a set of normal ovary samples, were profiled using whole genome Agilent microarrays. Reproducibility of the FF and FFPE replicates was measured using Pearson correlation, whereas comparison between the FF and FFPE samples was done using a Z-score analysis.

Results
Data analysis showed high reproducibility of expression within each FF and FFPE method, whereas matched FF and FFPE pairs demonstrated lower similarity, emphasizing an inherent difference between the two sample types. Z-score analysis of matched FF and FFPE samples revealed good concordance of top 100 differentially expressed genes with the highest correlation of 0.84. Genes characteristic of ovarian serous adenocarcinoma, including a well known marker CLDN3, as well as potentially some novel markers, were identified by comparing gene expression profiles of ovarian adenocarcinoma to those of normal ovary.

Conclusion
Conclusively, we showed that systematic assessment of FFPE samples at the RNA level is essential for obtaining good quality gene expression microarray data. We also demonstrated that profiling of not only FF but also of FFPE samples can be successfully used to identify differentially expressed genes characteristic of ovarian carcinoma.
Computational pregnant occupant model, ‘Expecting’, for crash simulations
Authors: Serpil Acar B , van Lopik D 
Published: May 2009

A computational model of the pregnant occupant, which is capable of simulating the dynamic response to acceleration impacts, is introduced. The occupant model represents a 5th percentile female at around the 38th week of pregnancy. A finite element uterus and multi-body fetus is integrated into an existing female model to incorporate pregnant female anthropometry. The complete model, ‘Expecting’, is used to simulate a range of frontal impacts of increasing severity from 15km/h to 45km/h. Three levels of occupant restraint, completely unrestrained, three-point seat belt, and three-point seat belt with an airbag, are investigated. The strains developed in the uterus because of loading from the seat belt and steering-wheel unit are presented, together with an analysis of stress distribution due to inertial loading of the fetus on the uterus. The unrestrained cases are shown to be the most dangerous to the fetus, owing to the large interaction with the vehicle steering wheel at the level of the placenta. The use of a three-point seat belt together with a driver airbag appears to offer the greatest protection to the fetus.
Predicted performance of integrated power plants based on diesel engines and steam cycles fuelled with a rapeseed oil chain
Authors: Cocco D 
Published: May 2009

This work focuses attention on the evaluation of global energy balances of an agro-energy system based on a diesel engine fuelled with rapeseed oil integrated with a steam plant fuelled with the residues of rape cultivation. The agro-energy system has been separated into the stages of in-the-field cultivation, transport of products to the industrial plant, and conversion into electric power. For each stage, inputs (fuels, electric power, fertilizers, and so on) and energy outputs (oil, electricity, residues, and by-products) are evaluated. Integration between the engine and the steam plant is implemented through thermal recovery of the engine exhaust gases and cooling fluids (supercharging air, lubricating oil, engine jacket cooling water) to preheat the boiler feed water. The results of the study show that the recovery of thermal energy made available by the diesel engine leads to an increase in steam plant conversion efficiency of more than three per cent (from 25.1 per cent to 28.4 per cent). In other words, energy recovery leads to an equivalent efficiency of the engine over 56 per cent, which is more than nine points above the efficiency of the diesel engine alone. In addition to the sole use of vegetable oil for energy production, the use of straw makes it possible to double net energy production per unit of cultivated area. Implementation of this agro-energy chain provides a net energy production of 55–60 GJ/ha, an energy output—input ratio around 3.0–3.3, and a primary energy saving of about 65–70 per cent compared to the use of fossil fuels.
Influence of Surface Energy and Roughness of Substrate on Thin Pentacene and C60 Films Prepared by Vacuum Deposition
Authors: Yan Hu , Uchida Takuya , Kagata Tsubasa , Iriyama Yu , Okuzaki Hidenori 
Published: May 2009

Abstract
Substrate surface roughness predominantly influenced grain size of pentacene in vacuum-deposited thin films while surface energy of the substrate did not, i.e., larger pentacene grain was obtained on a substrate with lower roughness instead of lower surface energy. On the other hand, grain size of C60 deposited in the same manner was influenced by both surface energy and roughness, i.e., large C60 grain was obtained on substrates with lower surface roughness and energy.
The US media, Camp David and the Oslo peace process
Authors: Piner Andrew 
Published: May 2009

This article examines US mainstream press coverage given to the aftermath of the Camp David negotiations in July 2000, offering a critical perspective on the events and reactions to the failed summit. In doing so the article is able to identify and highlight the detrimental effects of inaccurate reporting of the IsraeliPalestinian conflict in the US press. It demonstrates how this misrepresentation of failure at Camp David has contributed to the ever-decreasing prospects for a just and viable solution to the conflict. This important snapshot of the long-standing IsraeliPalestinian conflict, it argues, accurately encapsulates the flawed nature of many dominant truths of the debate over the conflict. Consequently it can provide a critical lens through which to draw broader conclusions about the issues that continue to impede and undermine the prospects for balanced negotiations and peace in the region.The conclusions reached through the analysis of mainstream US press reactions to the Camp David summit are subsequently contextualized through an exploration of the largely neglected issue of water sharing in the Palestinian Territories. The celebrated water-sharing agreements in the Oslo period are shown to have failed to bring about any meaningful change from the discriminatory water-distribution policies pursued by Israel in the occupied territories between 1967 and 1993.The article thus demonstrates how US mainstream press reactions to the failed Camp David summit simply reinforced the misleading impression of Israeli cooperation and compromise which masks a historically grounded policy of domination over the Palestinians. It concludes that only an approach grounded in critical theory, emphasizing different conceptions of security in the region, can offer its people a brighter and more peaceful future.
Regulative interactions of the osmosensing C-terminal domain in the trimeric glycine betaine transporter BetP from Corynebacterium
glutamicum
Authors: Krämer Reinhard , Ziegler Christine 
Published: May 2009

Abstract
Activation of the osmoregulated trimeric betaine transporter BetP from Corynebacterium glutamicum was shown to depend mainly on the correct folding and integrity of its 55 amino acid long, partly α-helical C-terminal domain. Reorientation of the three C-terminal domains in the BetP trimer indicates different lipid-protein and protein-protein interactions of the C-terminal domain during osmoregulation. A regulation mechanism is suggested where this domain switches the transporter from the inactive to the active state. Interpretation of recently obtained electron and X-ray crystallography data of BetP led to a structure-function based model of C-terminal molecular switching involved in osmoregulation.
The peptide-loading complex – antigen translocation and MHC class I loading
Authors: Schölz Christian , Tampé Robert 
Published: May 2009

AbstractA large and dynamic membrane-associated machinery orchestrates the translocation of antigenic peptides into the endoplasmic reticulum (ER) lumen for subsequent loading onto major histocompatibility complex (MHC) class I molecules. The peptide-loading complex ensures that only high-affinity peptides, which guarantee long-term stability of MHC I complexes, are presented to T-lymphocytes. Adaptive immunity is dependent on surface display of the cellular proteome in the form of protein fragments, thus allowing efficient recognition of infected or malignant transformed cells. In this review, we summarize recent findings of antigen translocation by the transporter associated with antigen processing and loading of MHC class I molecules in the ER, focusing on the mechanisms involved in this process.
Tumor-associated MUC1 glycopeptide epitopes are not subject to self-tolerance and improve responses to MUC1 peptide epitopes in MUC1 transgenic mice
Authors: Ryan Sean O. , Vlad Anda M. , Islam Kazi , Gariépy Jean , Finn Olivera J. 
Published: May 2009

AbstractHuman adenocarcinomas overexpress a hypoglycosylated, tumor-associated form of the mucin-like glycoprotein MUC1 containing abnormal mono- and disaccharide antigens, such as Tn, sialyl-Tn, and TF, as well as stretches of unglycosylated protein backbone in the variable number of tandem repeats (VNTR) region. Both peptide and glycopeptide epitopes generated from the VNTR are candidates for cancer vaccines and we performed experiments to evaluate their relative potential to elicit tumor-MUC1-specific immunity. We show here that immunization with the 100 amino acid-long VNTR peptide (MUC1p) elicits weaker responses in MUC1 transgenic mice compared to wild type mice suggesting self-tolerance. In contrast, when glycosylated with tumor-associated Tn antigen (GalNAc-O-S/T), TnMUC1 induces glycopeptide-specific T cell and antibody responses in both strains of mice and helps enhance responses to MUC1p in MUC1 transgenic mice. Using newly derived MUC1-specific mouse T cell hybridomas we show that the only antigen-presenting cells able to cross-present TnMUC1 glycopeptide are dendritic cells (DCs). This is likely due to their exclusive expression of receptors capable of binding TnMUC1. We conclude that MUC1 glycopeptides induce stronger immunity in MUC1-Tg mice because they are recognized as `foreign' rather than `self' and because they are cross-presented preferentially by DCs.
Carbohydrate microarrays: key developments in glycobiology
Authors: Liu Yan , Palma Angelina S. , Feizi Ten 
Published: May 2009

Abstract
Carbohydrate chains of glycoproteins, glycolipids, proteoglycans, and polysaccharides mediate processes of biological and medical importance through their interactions with complementary proteins. The unraveling of these interactions is therefore a priority in biomedical sciences. Carbohydrate microarray technology is a new development at the frontier of glycomics that is revolutionizing the study of carbohydrate-protein interactions and the elucidation of their specificities in endogenous biological processes, microbe-host interactions, and immune defense mechanisms. In this review, we briefly refer to the principles of numerous platforms since the introduction of carbohydrate microarrays in 2002, and we highlight platforms that are beyond proof-of-concept and have provided new biological information.
From structural to functional glycomics: core substitutions as molecular switches for shape and lectin affinity of N-glycans
Authors: André Sabine , Kožár Tibor , Kojima Shuji , Unverzagt Carlo , Gabius Hans-Joachim 
Published: May 2009

Abstract
Glycan epitopes of cellular glycoconjugates act as versatile biochemical signals (sugar coding). Here, we test the hypothesis that the common N-glycan modifications by core fucosylation and introduction of the bisecting N-acetylglucosamine moiety have long-range effects with functional consequences. Molecular dynamics simulations indicate a shift in conformational equilibria between linear extension or backfolding of the glycan antennae upon substitution. We also present a new fingerprint-like mode of presentation for this multi-parameter system. In order to delineate definite structure-function relationships, we strategically combined chemoenzymatic synthesis with bioassaying cell binding and the distribution of radioiodinated neoglycoproteins in vivo. Of clinical relevance, tailoring the core region affects serum clearance markedly, e.g., prolonging circulation time for the neoglycoprotein presenting the N-glycan with both substitutions. α2,3-Sialylation is another means toward this end, similarly seen for type II branching in triantennary N-glycans. This discovery signifies that rational glycoengineering along the given lines is an attractive perspective to optimize pharmacokinetic behavior of glycosylated pharmaproteins. Of general importance for the concept of the sugar code, the presented results teach the fundamental lesson that N-glycan core substitutions convey distinct characteristics to the concerned oligosaccharide relevant for cis and trans biorecognition processes. These modifications are thus molecular switches.
Regulation and pathophysiological implications of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) as the key enzyme of sialic acid biosynthesis
Authors: Reinke Stefan O. , Lehmer Gerhard , Hinderlich Stephan , Reutter Werner 
Published: May 2009

Abstract
The key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed, is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). GNE is a highly conserved protein found throughout the animal kingdom. Its highest expression is seen in the liver and placenta. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. GNE knock-out in mice leads to embryonic lethality, emphasizing the crucial role of this key enzyme for sialic acid biosynthesis. The metabolic capacity to synthesize sialic acid and CMP-sialic acid upon ManNAc loads is amazingly high. An additional characteristic of GNE is its interaction with proteins involved in the regulation of development, which might play a crucial role in the hereditary inclusion body myopathy. Due to the importance of increased concentrations of tumor-surface sialic acid, first attempts to find inhibitors of GNE have been successful.
Protein-lipid interactions: paparazzi hunting for snap-shots
Authors: Haberkant Per , van Meer Gerrit 
Published: May 2009

Abstract
Photoactivatable groups meeting the criterion of minimal perturbance allow the investigation of interactions in biological samples. Here, we review the application of photoactivatable groups in lipids enabling the study of protein-lipid interactions in (biological) membranes. The chemistry of various photoactivatable groups is summarized and the specificity of the interactions detected is discussed. The recent introduction of ‘click chemistry’ in photocrosslinking of membrane proteins by photo-activatable lipids opens new possibilities for the analysis of crosslinked products and will help to close the gap between proteomics and lipidomics.
Glycosylation pattern of brush border-associated glycoproteins in enterocyte-like cells: involvement of complex-type N-glycans in apical trafficking
Authors: Morelle Willy , Stechly Laurence , André Sabine , Seuningen Isabelle Van , Porchet Nicole , Gabius Hans-Joachim , Michalski Jean-Claude , Huet Guillemette 
Published: May 2009

Abstract
We have previously reported that galectin-4, a tandem repeat-type galectin, regulates the raft-dependent delivery of glycoproteins to the apical brush border membrane of enterocyte-like HT-29 cells. N-Acetyllactos-amine-containing glycans, known as galectin ligands, were found enriched in detergent-resistant membranes. Here, we analyzed the potential contribution of N- and/or O-glycans in this mechanism. Structural studies were carried out on the brush border membrane-enriched fraction using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and nano-ESI-QTOF-MS/MS. The pattern of N-glycans was very heterogeneous, with the presence of high mannose- and hybrid-type glycans as well as a multitude of complex-type glycans. In contrast, the pattern of O-glycans was very simple with the presence of two major core type 1 O-glycans, sialylated and bisialylated T-antigen structures [Neu5Acα2–3Galβ1–3GalNAc-ol and Neu5Acα2– 3Galβ1–3(Neu5Acα2–6)GalNAc-ol]. Thus, N-glycans rather than O-glycans contain the N-acetyllactosamine recognition signals for the lipid raft-based galectin-4-dependent apical delivery. In the presence of 1-deoxymannojirimycin, a drug which inhibits the generation of hybrid-type or complex type N-glycans, the extensively O-glycosylated mucin-like MUC1 glycoprotein was not delivered to the apical brush border but accumulated inside the cells. Altogether, our data demonstrate the crucial role of complex N-glycans in the galectin-4-dependent delivery of glycoproteins to the apical brush border membrane of enterocytic HT-29 cells.
Impact of glycosylation and detergent-resistant membranes on the function of intestinal sucrase-isomaltase
Authors: Wetzel Gabi , Heine Martin , Rohwedder Arndt , Naim Hassan Y. 
Published: May 2009

Abstract
Sucrase-isomaltase (SI) is a highly N- and O-glycosylated intestinal brush border membrane protein. SI is sorted with high fidelity to the apical membrane via O-linked glycans that mediate its association with lipid rafts or detergent-resistant membranes (DRMs). Here, we show that N- and O-glycosylation and DRMs are implicated in the regulation of the function of SI in intestinal Caco-2 cells. The activities of sucrase (SUC) and isomaltase (IM) increase substantially in DRMs when N- and O-glycosylation patterns are intact. Disruption of DRMs by solubilization with Triton X-100 at 37°C substantially reduces the activities of SUC and IM. Furthermore, modulation of O-glycosylation by benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside and N-glycosylation by deoxymannojirimycin is linked to a decreased capacity of SI to associate with DRMs, with a subsequent reduction of the enzymatic activities of SUC and IM. This is the first report that reveals a direct role of N- and O-glycans in association with DRMs in regulating the function of a membrane glycoprotein.
Solubility of plutonium in MgCl2 and CaCl2 solutions in contact with metallic iron
Authors: Altmaier Marcus , Neck Volker , Lützenkirchen J. , Fanghänel Thomas 
Published: May 2009

Abstract
The solubility of Pu(IV) hydrous oxide is studied at 22±2 °C under Ar atmosphere in 0.25 and 3.5 M MgCl2 (pHc≈9) and 3.5 M CaCl2 (pHc=11–12) solutions in contact with iron powder. In alkaline 3.5–4.0 M CaCl2 ternary Ca-Pu-OH complexes are formed and the solubility of PuO2·xH2O(s) increases from about 10-10 M at pHc=11 to 10-8–10-7 M at pHc=12, both in the presence and absence of Fe powder. In the presence of iron the aqueous speciation is dominated by Pu(III) at pHc<10 and by Pu(IV) complexes at pHc>10. In the absence of reducing agents the aqueous speciation is dominated by Pu(V), with significant contributions of Pu(IV) complexes at pHc>10. The effect of ternary Ca-Pu(III,IV,V)-OH complexes in alkaline CaCl2 solutions can be described by assuming complex stoichiometries and experimental data from the oxidation state analogs Cm(III)/Nd(III), Th(IV) and Np(V). The ion interaction Pitzer approach is used for model calculations.
Redox equilibria of Pu4+/Pu3+ and PuO2
2+/Pu4+ couples in molten NaCl-CsCl eutectic as measured by absorption spectrophotometry
Authors: Nagai Takayuki , Uehara Akihiro , Fujii Toshiyuki , Shirai Osamu , Myochin Munetaka , Yamana Hajimu 
Published: May 2009

Abstract
In order to enhance the understanding of redox reactions of plutonium ions in molten NaCl-CsCl eutectic, absorption spectrophotometry was performed for Pu3+, Pu4+, and PuO2
2+ in molten NaCl-CsCl at 923 K by controlling the flow-rate ratio of Cl2 and Ar or O2 in the ventilating mixture gas. Based upon the relations of the measured rest potentials to the concentration ratios of [Pu4+]/[Pu3+] and [PuO2
2+]/[Pu4+], the redox potentials of Pu4+/Pu3+ and PuO2
2+/Pu4+ couples in molten NaCl-CsCl eutectic at 923 K were estimated.