bluuebunny/crossref_metadata_2025 huggingface dataset:
Operation of vehicles in AGV system and method for analyzing operation
Authors: Hoshino Takahiro , Tsuboi Kazuhiro , Yamanaka Kazuo , Hamamatsu Yoshio
Published: September 2011

It is important to discuss the behavior of traffic at merging sections for the design and realization of an automated guided vehicle system (AGVS). In this study, we deal with a merging section of the AGVS by considering the time limit for the merging of vehicles. Near the merging section, the traffic flow in one direction forms a queue to avoid collisions between vehicles. We present an improvement of the control strategy proposed in previous research. However, since it is difficult to analyze the mathematical model of the merging section, analysis can be performed only for the case in which the time limit is set to the least values. We also propose a method for analyzing the model for an arbitrary time limit by using a linear recurrence relation. We discuss quantitatively the influence of the time limit on the average queue length and the detour rate. © 2011 Wiley Periodicals, Inc. Electr Eng Jpn, 178(1): 56–68, 2012; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/eej.21190
CD6 attenuates early and late signaling events, setting thresholds for T‐cell activation
Authors: Oliveira Marta I. , Gonçalves Carine M. , Pinto Mafalda , Fabre Stéphanie , Santos Ana Mafalda , Lee Simon F. , Castro Mónica A. A. , Nunes Raquel J. , Barbosa Rita R. , Parnes Jane R. , Yu Chao , Davis Simon J. , Moreira Alexandra , Bismuth Georges , Carmo Alexandre M.
Published: September 2011

The T lineage glycoprotein CD6 is generally considered to be a costimulator of T‐cell activation. Here, we demonstrate that CD6 significantly reduces early and late T‐cell responses upon superantigen stimulation or TCR triggering by Abs. Measuring calcium mobilization in single cells responding to superantigen, we found that human T cells expressing rat CD6 react significantly less well compared with T cells not expressing the exogenous receptor. When the cytoplasmic domain of rat CD6 was removed, calcium responses were recovered, indicating that the inhibitory properties of CD6 are attributable to its cytoplasmic domain. Calcium responses, and also late indicators of T‐cell activation such as IL‐2 release, were also diminished in TCR‐activated Jurkat cells expressing human CD6, compared with CD6‐deficient cells or cells expressing a cytoplasmic deletion mutant of human CD6. Similarly, calcium signals triggered by anti‐CD3 were enhanced in human T lymphocytes following morpholino‐mediated suppression of CD6 expression. Finally, the proliferation of T lymphocytes was increased when the CD6–CD166 interaction was blocked with anti‐CD166 Abs, but inhibited when anti‐CD6 Abs were used. Our data suggest that CD6 is a signaling attenuator whose expression alone, i.e. in the absence of ligand engagement, is sufficient to restrain signaling in T cells.
Natural variations at position 93 of the invariant Vα24‐Jα18 α chain of human iNKT‐cell TCRs strongly impact on CD1d binding
Authors: Sanderson Joseph P. , Waldburger‐Hauri Kathrin , Garzón Diana , Matulis Gediminas , Mansour Salah , Pumphrey Nicholas J. , Lissin Nikolai , Villiger Peter M. , Jakobsen Bent , Faraldo‐Gómez José D. , Gadola Stephan D.
Published: September 2011

Human invariant natural killer T (NKT) cell TCRs bind to CD1d via an “invariant” Vα24‐Jα18 chain (iNKTα) paired to semi‐invariant Vβ11 chains (iNKTβ). Single‐amino acid variations at position 93 (p93) of iNKTα, immediately upstream of the “invariant” CDR3α region, have been reported in a substantial proportion of human iNKT‐cell clones (4–30%). Although p93, a serine in most human iNKT‐cell TCRs, makes no contact with CD1d, it could affect CD1d binding by altering the conformation of the crucial CDR3α loop. By generating recombinant refolded iNKT‐cell TCRs, we show that natural single‐nucleotide variations in iNKTα, translating to serine, threonine, asparagine or isoleucine at p93, exert a powerful effect on CD1d binding, with up to 28‐fold differences in affinity between these variants. This effect was observed with CD1d loaded with either the artificial α‐galactosylceramide antigens KRN7000 or OCH, or the endogenous glycolipid β‐galactosylceramide, and its importance for autoreactive recognition of endogenous lipids was demonstrated by the binding of variant iNKT‐cell TCR tetramers to cell surface expressed CD1d. The serine‐containing variant showed the strongest CD1d binding, offering an explanation for its predominance in vivo. Complementary molecular dynamics modeling studies were consistent with an impact of p93 on the conformation of the CDR3α loop.
Photophysical and Electrochemical Properties of Phenanthroline‐Based Bis‐cyclometallated Iridium Complexes in Aqueous and Organic Media
Authors: Kiran Reshmi V. , Hogan Conor F. , James Bruce D. , Wilson David J. D.
Published: September 2011

The electrochemical and photophysical properties of biscyclometallated iridium(III) complexes containing phenanthroline‐based ligands have been investigated and compared in organic and aqueous media. Complexes having general formula [Ir(ppy)2(N∩N)]+/– were synthesized, where ppy is the cyclometallating ligand, 2‐phenylpyridine, and N∩N represents one of the following phenanthroline based ligands: 1,10‐phenanthroline (phen), 4,7‐diphenyl‐1,10‐phenanthroline (dpp) and 4,7‐diphenyl‐1,10‐phenanthrolinedisulfonate (BPS). In the case of [Ir(ppy)2(BPS)]–, the SO3– group located on the phenyl ring of BPS dramatically increases the aqueous solubility of the complex compared to the dpp complex, which is only soluble in organic media. The chloride salt of the underivatized phen complex, though not as soluble as the BPS chelated complex, is sufficiently soluble (> 1 mM) for sensing and other applications in aqueous media. The electrochemical response depends markedly on the medium; all the complexes showed reversible behaviour in organic media, whereas the oxidative electrochemistry of [Ir(ppy)2BPS]– and [Ir(ppy)2phen]+ was irreversible. Results from spectroelectrochemical experiments indicate that electrolysis produces significant changes to the UV region of the spectrum associated with the ppy moieties. Significantly, this demonstrates that the highest occupied molecular orbital (HOMO) is not entirely metal based but is also associated with the cyclometallating ligand. The variation in emission maxima between the iridium complexes was small in organic and aqueous media, but the colour of the emission depends on solvent polarity and strongly on temperature. Most significantly, the quantum yields for these species are also strongly influenced by the solvent: high quantum yields, ranging from 14.0 to 28.6 %, are observed in CH2Cl2. However, in aqueous media the water‐soluble complexes, [Ir(ppy)2BPS]– and [Ir(ppy)2phen]+, exhibited significantly diminished quantum yields of 2.5 and 2.6 %, respectively. Theoretical calculations confirm the spectroscopic assignments and that the HOMO is significantly delocalized over the metal and cyclometallating ligands. The relationship between the electrochemical, spectroscopic and theoretical results is discussed.
Organochromium Complexes Bearing Noninnocent Diimine Ligands
Authors: Kreisel Kevin A. , Yap Glenn P. A. , Theopold Klaus H.
Published: September 2011

We have prepared several anionic and neutral organochromium complexes featuring noninnocent α‐diimine ligands. All neutral and anionic complexes refrain from insertion of the C=N bonds of the diimine ligand into the chromium–carbon bonds, presumably due to the reduced nature of the diimine ligand. However, insertion can be facilitated by one‐electron oxidation. Thus, oxidation of [(HLiPr)CrR(THF)] [HLiPr = Ar–N=C(H)–(H)C=N–Ar in which Ar = 2,6‐diisopropylphenyl and R = CH2SiMe3 or CH3] with [(C5H5)2Fe]+ presumably forms [(HLiPr)CrR(THF)]+, which contains a neutral diimine ligand coordinated to CrII. This cationic complex apparently undergoes immediate insertion of the C=N bond of the diimine ligand into the Cr–alkyl bond, followed by C–H activation of the isopropyl substituent of an N–aryl group on the diimine ligand. DFT calculations confirm that [(HLiPr)CrR(THF)]+ contains a neutral innocent diimine ligand that undergoes C=N bond insertion into the Cr–R bond.
Supramolecular Hydrogen‐Bonding Tautomeric Sulfonamido–Phosphinamides: A Perfect P‐Chirogenic Memory
Authors: Patureau Frederic W. , Siegler Maxime A. , Spek Anthony L. , Sandee Albertus J. , Jugé Sylvain , Aziz Sarwar , Berkessel Albrecht , Reek Joost N. H.
Published: September 2011

P‐chirogenic, supramolecular hydrogen‐bonding C1‐symmetrical sulfonamido–phosphinamides (METAMORPhos) have been successfully prepared. They were all found to possess a characteristic prototropic equilibrium between the PIII and the PV tautomers that is slow on the NMR spectroscopic timescale. Despite the dynamic and reversible protonation of the P centre, the P‐chirogenic information was found to be retained in the tautomerization process, even in a protic solvent environment. Several strategies to access the corresponding enantiopure compounds were investigated, such as diastereoselective crystallization, or enantioselective synthesis. It was possible to resolve such a class of chiral ligands with up to 99 % ee, and apply them in the Rh‐catalyzed asymmetric hydrogenation of alkenes. These ligands are interesting new building blocks in the area of acid/base‐type noninnocent ligand catalysis.
Dysfunctional anticipatory thoughts and the self‐handicapping strategy
Authors: McCrea Sean M. , Flamm Aneka
Published: September 2011

Self‐handicapping is an anticipatory self‐protective strategy in which individuals create or claim obstacles to success prior to an important performance to excuse potential failure. The present research sought in four studies to document the anticipatory nature of self‐handicapping, examining the role of prefactual (“what if …?”) thoughts in this strategy. Individuals prone to self‐handicap were more likely to generate prefactuals, identifying ways to undermine their performance. Moreover, inducing individuals to consider these thoughts increased self‐handicapping behavior, whereas focusing individuals on ways to improve their performance actually reduced self‐handicapping behavior. Implications of this work for understanding the cognitive processes underlying self‐handicapping behavior and for interventions that seek to minimize this self‐defeating behavior are discussed. Copyright © 2011 John Wiley & Sons, Ltd.
Fe3+‐immobilized nanoparticle‐modified capillary for capillary electrophoretic separation of phosphoproteins and non‐phosphoproteins
Authors: Hu Qin , Hu Shaoqiang , Zhang Zhenyang , Zhou Ximin , Yang Shanshan , Zhang Yuan , Chen Xinguo
Published: September 2011

A fused‐silica capillary modified with Fe3+‐immobilized magnetic nanoparticles (Fe3+‐IMAN) has been investigated for the capillary electrophoretic (CE) separation of phosphoproteins and non‐phosphoproteins. The Fe3+‐IMAN capillary was achieved by covalently immobilising epoxy‐based magnetic silica nanoparticles (160 nm) on the prederivatized 3‐aminopropyl‐trimethoxysilane (APTMS) fused‐silica capillary (75 μm id), followed by disodium iminodiacetate and Fe3+. The buildup process was examined by measuring the streaming potentials of the bare capillary, APTMS capillary, epoxy‐based nanoparticle capillary and Fe3+‐IMAN capillary by varying the buffer pH. An inverted fluorescence microscope was used to determine the surface features of the Fe3+‐IMAN capillary derivatized with morin. Further experimental results confirmed that Fe3+‐IMAN bonded on the inner wall of the APTMS capillary could provide sufficient solute‐bonded phase interactions to allow for the CE separation of phosphoproteins and non‐phosphoproteins at concentration levels down to 50 μg/mL. The highest number of theoretical plates obtained was about 233 000/m, and the relative standard deviation (RSD) for migration times was <2.57% for eight consecutive runs, respectively. Additionally, the Fe3+‐IMAN modifing method was also applied to the analyses of bovine milk proteins. With simplicity, high resolving power, and high repeatability, the proposed method has shown great potential for phosphoproteomics applications.
Regeneration of the heart
Authors: Steinhauser Matthew L. , Lee Richard T.
Published: September 2011

The death of cardiac myocytes diminishes the heart's pump function and is a major cause of heart failure, one of the dominant causes of death worldwide. Other than transplantation, there are no therapies that directly address the loss of cardiac myocytes, which explains the current excitement in cardiac regeneration. The field is evolving in two important directions. First, although endogenous mammalian cardiac regeneration clearly seems to decline rapidly after birth, it may still persist in adulthood. The careful elucidation of the cellular and molecular mechanisms of endogenous heart regeneration may therefore provide an opportunity for developing therapeutic interventions that amplify this process. Second, recent breakthroughs have enabled reprogramming of cells that were apparently terminally differentiated, either by dedifferentiation into pluripotent stem cells or by transdifferentiation into cardiac myocytes. These achievements challenge our conceptions of what is possible in terms of heart regeneration. In this review, we discuss the current status of research on cardiac regeneration, with a focus on the challenges that hold back therapeutic development.
Land subsidence along the Ionian coast of SE Sicily (Italy), detection and analysis via Small Baseline Subset (SBAS) multitemporal differential SAR interferometry
Authors: Canova Fabio , Tolomei Cristiano , Salvi Stefano , Toscani Giovanni , Seno Silvio
Published: September 2011

The paper presents the results of a multi‐temporal, differential interferometric synthetic aperture radar (DInSAR) analysis aiming to identify active surface deformation phenomena in south‐eastern Sicily. The study area has been chosen because of its strong seismicity, high concentration of industrial and agricultural activities, and high density of people living in the coastal area. Furthermore, the morphology, lithology and climatic features of this sector of the Hyblean foreland are suitable for an interferometric analysis, providing a high coherence over the area. The Small BAseline Subset (SBAS) multitemporal DInSAR technique was used to calculate mean ground velocity maps and displacement time series from a large data set of European Remote Sensing Satellites (ERS 1–2) images spanning the time period 1992–2000. The reliability of the DInSAR results was tested calculating the EastSAR and UpSAR values over two permanent global positioning system (GPS) stations in the area, and comparing them with the EastGPS and UpGPS values. The residuals between GPS and DInSAR velocities were 1 and 0.6 mm/yr for the Up and East components, respectively. Four main subsiding areas, previously undetected, have been identified, corresponding with the towns of Augusta, Siracusa, Priolo, and Villasmundo. The observed deformation phenomena are located within coastal structural basins, filled with Pleistocene and Holocence deposits, except the Villasmundo land subsidence, which is located on the Hyblean plateau. The measured deformation rates reach values up to −18 mm/yr in Augusta, –6 mm/yr in Siracusa, –5 mm/yr in Villasmundo and −4.5 mm/yr in Priolo. The examination of velocity profiles, time series, and geological data allows us to relate all the detected deformation patterns primarily to groundwater over‐exploitation. A multi‐dimensional interpolation with kriging was performed to obtain a field subsidence map. A first‐order elastic deformation model was used to simulate the peculiar features of the Villasmundo subsidence. Copyright © 2011 John Wiley & Sons, Ltd.
Ecosystem functions and densities of contributing functional groups respond in a different way to chemical stress
Authors: De Laender Frederik , Taub Frieda B , Janssen Colin R
Published: September 2011

Understanding whether and to what extent ecosystem functions respond to chemicals is a major challenge in environmental toxicology. The available data gathered by ecosystem-level experiments (micro- and mesocosms) often describe the responses of taxa densities to stress. However, whether these responses are proportional to the responses of associated ecosystem functions to stress is unclear. By combining a carbon budget modeling technique with data from a standardized microcosm experiment with a known community composition, we quantified three ecosystem functions (net primary production [NPP], net mesozooplankton production [NZP], and net bacterial production [NBP]) at three Cu concentrations, with a control. Changes of these ecosystem functions with increasing chemical concentrations were not always proportional to the Cu effects on the densities of the contributing functional groups. For example, Cu treatments decreased mesozooplankton density by 100-fold and increased phytoplankton density 10- to 100-fold while increasing NZP and leaving NPP unaltered. However, in contrast, Cu affected microzooplankton and the associated function (NBP) in a comparable way. We illustrate that differences in the response of phytoplankton/mesozooplankton densities and the associated ecosystem functions to stress occur because functional rates (e.g., photosynthesis rates/ingestion rates) vary among Cu treatments and in time. These variations could be explained by food web ecology but not by direct Cu effects, indicating that ecology may be a useful basis for understanding environmental effects of stressors. Environ. Toxicol. Chem. 2011;30:2892–2898. © 2011 SETAC
Comparison of the parameter estimation methods of surge arresters using modified particle swarm optimization algorithm
Authors: Nafar M. , Gharehpetian G. B. , Niknam T.
Published: September 2011

The measurements show that the residual voltage of the metal oxide surge arrester (MOSA) has a dynamic characteristic. The accurate modeling and simulation of this dynamic characteristic is very important for arrester allocation, systems reliability, and insulation coordination studies. Several models with acceptable accuracy have been suggested to describe this behavior. It should be noted that the determination of nonlinear elements of MOSAs is very important for all models. In this article, a comparison among the different methods of the determination of the surge arrester voltage–current characteristics is represented. A new method, which is the combination of particle swarm optimization (PSO) and ant colony optimization methods, is proposed to estimate the parameters of MOSA models. In the proposed algorithm, to overcome the drawback of the PSO algorithm (convergence to local optima), to improve the global search capability, and to prevent the convergence to local minima, ant colony optimization algorithm is combined to PSO algorithm. The proposed method is called modified PSO. The transient models of MOSA have been simulated by using ATP‐EMTP. The results of simulations have been applied to the program, which is based on the modified PSO method and can determine the fitness and parameters of different models. The validity and the accuracy of the estimated parameters are assessed by comparing the predicted residual voltage with the experimental results. Copyright © 2011 John Wiley & Sons, Ltd.
Late effects of high‐dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging
Authors: de Ruiter Michiel B. , Reneman Liesbeth , Boogerd Willem , Veltman Dick J. , Caan Matthan , Douaud Gwenaëlle , Lavini Cristina , Linn Sabine C. , Boven Epie , van Dam Frits S.A.M. , Schagen Sanne B.
Published: September 2011

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high‐dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract‐based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H‐MRS) in the left centrum semiovale (white matter) showed a reduction of N‐acetylasparate/creatine indicative of axonal injury. Voxel‐based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H‐MRS only in the chemotherapy group. These results converge to suggest that high‐dose adjuvant chemotherapy for breast cancer is associated with long‐term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Functional connectivity changes in multiple sclerosis patients: A graph analytical study of MEG resting state data
Authors: Schoonheim Menno M. , Geurts Jeroen J.G. , Landi Doriana , Douw Linda , van der Meer Marieke L. , Vrenken Hugo , Polman Chris H. , Barkhof Frederik , Stam Cornelis J.
Published: September 2011

Multiple sclerosis (MS) is characterized by extensive damage in the central nervous system. Within this field, there is a strong need for more advanced, functional imaging measures, as abnormalities measured with structural imaging insufficiently explain clinicocognitive decline in MS. In this study we investigated functional connectivity changes in MS using resting‐state magnetoencephalography (MEG). Data from 34 MS patients and 28 age and gender‐matched controls was assessed using synchronization likelihood (SL) as a measure of functional interaction strength between brain regions, and graph analysis to characterize topological patterns of connectivity changes. Cognition was assessed using extensive neuropsychological evaluation. Structural measures included brain and lesion volumes, using MRI. Results show SL increases in MS patients in theta, lower alpha and beta bands, with decreases in the upper alpha band. Graph analysis revealed a more regular topology in the lower alpha band in patients, indicated by an increased path length (λ) and clustering coefficient (γ). Attention and working memory domains were impaired, with decreased brain volumes. A stepwise linear regression model using clinical, MRI and MEG parameters as predictors revealed that only increases in lower alpha band γ predicted impaired cognition. Cognitive impairments and related altered connectivity patterns were found to be especially predominant in male patients. These results show specific functional changes in MS as measured with MEG. Only changes in network topology were related to poorer cognitive outcome. This indicates the value of graph analysis beyond traditional structural and functional measures, with possible implications for diagnostic and/or prognostic purposes in MS. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.
Anti‐EGFR–targeting agents in recurrent or metastatic head and neck carcinoma: A meta‐analysis
Authors: Petrelli Fausto , Barni Sandro
Published: September 2011

Background

Anti–epidermal growth factor receptor (EGFR) therapies are effective in head and neck carcinoma. A meta‐analysis was performed to assess their efficacy and safety in advanced head and neck carcinoma.

Methods

Six trials randomizing 2257 patients with recurrent/metastatic head and neck carcinoma for chemotherapy or best supportive care with or without anti‐EGFR therapies were identified. The efficacy data included progression‐free survival (PFS), overall survival (OS), response rate, and toxicity.

Results

The response rate was higher in the experimental arm (p < .0001; relative risk = 1.62). A significant PFS benefit (p < .0001; hazard ratio [HR] = 0.70) favored the anti‐EGFR treatment. Survival was significantly increased if trials of monoclonal antibodies were included (p = .004; HR = 0.83). A higher incidence of diarrhea, skin rash, anorexia, and hypomagnesemia was observed.

Conclusions

This meta‐analysis suggests that in recurrent/metastatic head and neck cancer the addition of anti‐EGFR monoclonal antibodies to standard therapy confers a statistically significant improvement in OS, PFS, and overall response rate. © 2011 Wiley Periodicals, Inc. Head Neck, 2011
Serum Ferritin Is An Independent Predictor of Histologic Severity and Advanced Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
Authors: Kowdley Kris V. , Belt Patricia , Wilson Laura A. , Yeh Matthew M. , Neuschwander–Tetri Brent A. , Chalasani Naga , Sanyal Arun J. , Nelson James E.
Published: September 2011

Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥18 years) with biopsy–proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin–iron saturation, iron stain grade, and decreased platelets (

P

< 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (

P

< 0.026). On multiple regression analysis, SF >1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05–2.62;

P

= 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06–3.75;

P

= 0.033).

Conclusions:

A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis. (Hepatology 2012)
Hepatocyte Polarization Is Essential for the Productive Entry of the Hepatitis B Virus
Authors: Schulze Andreas , Mills Kerry , Weiss Thomas S. , Urban Stephan
Published: September 2011

Human hepatitis B virus (HBV) is characterized by a high species specificity and a distinct liver tropism. Within the liver, HBV replication occurs in differentiated and polarized hepatocytes. Accordingly, the

in vitro

HBV infection of primary human hepatocytes (PHHs) and the human hepatoma cell line, HepaRG, is restricted to differentiated, hepatocyte-like cells. Though preparations of PHH contain up to 100% hepatic cells, cultures of differentiated HepaRG cells are a mixture of hepatocyte-like and biliary-like epithelial cells. We used PHH and HepaRG cells and compared the influence of virus inoculation dose, cell differentiation, and polarization on productive HBV infection. At multiplicities of genome equivalents (mge) >8,000, almost 100% of PHHs could be infected. In contrast, only a subset of HepaRG cells stained positive for HBcAg at comparable or even higher mge. Infection predominantly occurred at the edges of islands of hepatocyte-like HepaRG cells. This indicates a limited accessibility of the HBV receptor, possibly as a result of its polar sorting. Multidrug resistance protein 2 (MRP2), a marker selectively transported to the apical (i.e., canalicular) cell membrane, revealed two polarization phenotypes of HepaRG cells. HBV infection within the islands of hepatocyte-like HepaRG cells preferentially occurred in cells that resemble PHH, exhibiting canalicular structures. However, disruption of cell-cell junctions allowed the additional infection of cells that do not display a PHH-like polarization.

Conclusion:

HBV enters hepatocytes via the basolateral membrane. This model, at least partially, explains the difference of PHH and HepaRG cells in infection efficacy, provides insights into natural HBV infection, and establishes a basis for optimization of the HepaRG infection system. (Hepatology 2012)
Induction of Heme Oxygenase 1 Prevents Progression of Liver Fibrosis in Mdr2 Knockout Mice
Authors: Barikbin Roja , Neureiter Daniel , Wirth Jan , Erhardt Annette , Schwinge Dorothee , Kluwe Johannes , Schramm Christoph , Tiegs Gisa , Sass Gabriele
Published: September 2011

Induction or overexpression of the heme-degrading enzyme, heme oxygenase 1 (HO-1), has been shown to protect mice from liver damage induced by acute inflammation. We have investigated the effects of HO-1 induction in a mouse model of chronic liver inflammation and fibrogenesis with progression to hepatocellular carcinoma (HCC) (Mdr2ko; FVB.129P2-Abcb4tm1Bor). HO-1 was induced in vivo by treatment with cobalt protoporphyrin IX, starting at week 5 or 12 of mice lifespan, and continued for 7 weeks. Our results showed that HO-1 induction reduced liver damage and chronic inflammation by regulating immune cell infiltration or proliferation as well as tumor necrosis factor receptor signaling. Fibrosis progression was significantly reduced by HO-1 induction in mice with mild, as well as established, portal and lobular fibrosis. HO-1 induction significantly suppressed hepatic stellate cell activation. During established fibrosis, HO-1 induction was able to revert portal inflammation and fibrosis below levels observed at the start of treatment. Moreover, hepatocellular proliferation and signs of dysplasia were decreased after HO-1 induction.

Conclusion:

Induction of HO-1 interferes with chronic inflammation and fibrogenesis and, in consequence, might delay progression to HCC. (Hepatology 2012;)
Extrinsic and local glutamatergic inputs of the rat hippocampal CA1 area differentially innervate pyramidal cells and interneurons
Authors: Takács Virág T. , Klausberger Thomas , Somogyi Peter , Freund Tamás F. , Gulyás Attila I.
Published: September 2011

The two main glutamatergic pathways to the CA1 area, the Schaffer collateral/commissural input and the entorhinal fibers, as well as the local axons of CA1 pyramidal cells innervate both pyramidal cells and interneurons. To determine whether these inputs differ in their weights of activating GABAergic circuits, we have studied the relative proportion of pyramidal cells and interneurons among their postsynaptic targets in serial electron microscopic sections. Local axons of CA1 pyramidal cells, intracellularly labeled in vitro or in vivo, innervated a relatively high proportion of interneuronal postsynaptic targets (65.9 and 53.8%, in vitro and in vivo, respectively) in stratum (str.) oriens and alveus. In contrast, axons of in vitro labeled CA3 pyramidal cells in str. oriens and str. radiatum of the CA1 area made synaptic junctions predominantly with pyramidal cell spines (92.9%). The postsynaptic targets of anterogradely labeled medial entorhinal cortical boutons in CA1 str. lacunosum‐moleculare were primarily pyramidal neuron dendritic spines and shafts (90.8%). The alvear group of the entorhinal afferents, traversing str. oriens, str. pyramidale, and str. radiatum showed a higher preference for innervating GABAergic cells (21.3%), particularly in str. oriens/alveus. These data demonstrate that different glutamatergic pathways innervate CA1 GABAergic cells to different extents. The results suggest that the numerically smaller CA1 local axonal inputs together with the alvear part of the entorhinal input preferentially act on GABAergic interneurons in contrast to the CA3, or the entorhinal input in str. lacunosum‐moleculare. The results highlight differences in the postsynaptic target selection of the feed‐forward versus recurrent glutamatergic inputs to the CA1 and CA3 areas. © 2011 Wiley Periodicals, Inc.
Sex differences in sleep after a single oral morning dose of olanzapine in healthy volunteers
Authors: Giménez Sandra , Romero Sergio , Gich Ignasi , Clos Susana , Grasa Eva , Rosa‐María Antonijoan , Barbanoj Manuel‐José
Published: September 2011

Objective

Polysomnography abnormalities are frequent in schizophrenia and have been correlated with clinical variables. Because women with schizophrenia present a general better clinical outcome than men, we aimed to determine whether sex differences in antipsychotic‐induced effects on sleep could contribute to this difference.

Methods

Single oral morning doses of olanzapine (5 mg) were administered to 10 men and 10 women. Sleep variables were evaluated using traditional polysomnography Rechstschaffen and Kales criteria and all‐night sleep electroencephalogram spectral analysis. Drug plasma concentrations were also measured.

Results

Significant sex‐by‐drug interactions were obtained in slow‐wave sleep. After olanzapine, women showed an increase in slow‐wave sleep, whereas men showed a decrease. We did not observe sex differences in olanzapine‐induced hypnotic effects. Neither did we find any significant differences in pharmacokinetic parameters between sexes. Significant sex effects were observed in deep sleep, with women showing longer periods than men.

Conclusion

Our results showed significant pharmacodynamic differences in olanzapine sleep effects between men and women. Further studies in clinical populations are needed to assess if these sex‐based differences suggest that optimal treatment and doses should differ between men and women. Copyright © 2011 John Wiley & Sons, Ltd.
Rapid nutrient load reduction during infiltration of managed aquifer recharge in an agricultural groundwater basin: Pajaro Valley, California
Authors: Schmidt C. M. , Fisher A. T. , Racz A. , Wheat C. G. , Los Huertos M. , Lockwood B.
Published: September 2011

Artificial recharge of groundwater is an increasingly important method for augmenting groundwater supply and can have a positive or negative influence on the quality of water resources. We instrumented a managed aquifer recharge (MAR) pond in central coastal California to assess how patterns of infiltration and recharge affect the load of nitrate delivered to the underlying aquifer. The concentration of nitrate in infiltrating water consistently decreased during passage through the first metre of subsurface soils. Enrichment of 18O and 15 N in the residual nitrate in infiltrating water proceeded in a ratio of 1:2, indicating that denitrification plays a significant role in the quantitative reduction of nutrients exported during infiltration through shallow soils. The extent and rate of nitrate removal was spatially and temporally variable across the bottom of the recharge pond, with 30% to 60% of the nitrate load being removed over the first 6 weeks of managed aquifer recharge operation. During the period of highest N loading to the system, when the average infiltration rate was > 1 m/day, the recharge pond achieved a load reduction efficiency of 7 kg NO3−‐N/day/ha, which compares favourably to nitrate load reductions achieved by treatment wetlands. Groundwater mounding and water composition below the recharge pond suggest that recharge and subsequent lateral transport occur heterogeneously in the underlying aquifer. Nitrate concentrations in the aquifer following infiltration were lowered primarily by dilution, with little evidence for additional denitrification occurring in the aquifer in comparison to high rates documented during shallow infiltration. Copyright © 2011 John Wiley & Sons, Ltd.
A novel treatment strategy for EGFR mutant NSCLC with T790M‐mediated acquired resistance
Authors: Taube Erika , Jokinen Elina , Koivunen Peppi , Koivunen Jussi P.
Published: September 2011

The purpose of our study was to identify novel kinase inhibitors for the treatment of genetic subsets of non‐small cell lung cancer (NSCLC). NSCLC cell lines (n = 8) with known oncogenic backgrounds (K‐Ras, EGFR and EML4‐ALK) were exposed to several kinase inhibitors and analyzed for cell growth/cytotoxicity and signaling. Gö6976, a classical protein kinase C inhibitor, showed high potency against mutated EGFR and was further validated in vitro using additional NSCLC lines (n = 4) and Ba/F3 models and in vivo using a xenograft model. Gö6976 was identified to be a potent inhibitor of mutated EGFR with IC50 values from 0.033 nM to 3.3 μM and down regulating phosphorylation of EGFR, AKT and ERK1/2 at concentrations in the range of the IC50 values. Gö6976 has only a minor effect on wild‐type EGFR and cell lines independent of signaling from the mutant EGFR. Most importantly, the activity of Gö6976 remains unchanged despite the presence of the T790M‐mediated resistance, and it prevents the occurrence of this resistance in vitro. Gö6976 was also shown to significantly reduce tumor growth in an in vivo xenograft model with a EGFR‐mutated NSCLC cell line containing T790M. These findings demonstrate that Gö6976 acts as a potent inhibitor of mutant EGFR despite the presence of T790M, the most important mechanism of acquired resistance for EGFR tyrosine kinase inhibitors, in both in vitro and in vivo models.
Global microRNA expression profiling of microdissected tissues identifies miR‐135b as a novel biomarker for pancreatic ductal adenocarcinoma
Authors: Munding Johanna B. , Adai Alex T. , Maghnouj Abdelouahid , Urbanik Aleksandra , Zöllner Hannah , Liffers Sven T. , Chromik Ansgar M. , Uhl Waldemar , Szafranska‐Schwarzbach Anna E. , Tannapfel Andrea , Hahn Stephan A.
Published: September 2011

Pancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis resulting from being diagnosed at an advanced stage. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. MicroRNAs (miRNAs), considered a new class of biomarkers and therapeutic targets, may be able to fulfill those needs. Combining tissue microdissection with global miRNA array analyses, cell type‐specific miRNA expression profiles were generated for normal pancreatic ductal cells, acinar cells, PDAC cells derived from xenografts and also from macrodissected chronic pancreatitis (CP) tissues. We identified 78 miRNAs differentially expressed between ND and PDAC cells providing new insights into the miRNA‐driven pathophysiological mechanisms involved in PDAC development. Having filtered miRNAs which are upregulated in the three pairwise comparisons of PDAC vs. ND, PDAC vs. AZ and PDAC vs. CP, we identified 15 miRNA biomarker candidates including miR‐135b. Using relative qRT‐PCR to measure miR‐135b normalized to miR‐24 in 75 FFPE specimens (42 PDAC and 33 CP) covering a broad range of tumor content, we discriminated CP from PDAC with a sensitivity and specificity of 92.9% [95% CI=(80.5, 98.5)] and 93.4% [95% CI=(79.8, 99.3)], respectively. Furthermore, the area under the curve (AUC) value reached of 0.97 was accompanied by positive and negative predictive values of 95% and 91%, respectively. In conclusion, we report pancreatic cell‐specific global miRNA profiles, which offer new candidate miRNAs to be exploited for functional studies in PDAC. Furthermore, we provide evidence that miRNAs are well‐suited analytes for development of sensitive and specific aid‐in‐diagnosis tests for PDAC.
The effect of storage medium on the elution of monomers from composite materials
Authors: Polydorou Olga , Huberty Catherine , Wolkewitz Martin , Bolek Richard , Hellwig Elmar , Kümmerer Klaus
Published: September 2011

The aim of this study was to evaluate the effect of four different storage media on the elution of monomers from two composite materials. Samples (n = 10, diameter: 4.5 mm, thickness: 2 mm) of two different composite materials (Ceram X™ & Filtek™ Supreme XT) were stored after polymerization in four different media (NaCl, saliva, ethanol 75% & acetone) for 24 h, 7 days, and 28 days. From the storage medium of each tested time period, samples were prepared and analyzed by LC‐MS/MS, for the elution of BisGMA, TEGDMA, HEMA, Bisphenol A, and two types of UDMA. No monomers were detected in the samples of Ceram X™, independently of the storage medium used. In the samples of Filtek™ Supreme XT, no Bisphenol A, HEMA, and UDMA 1 were found. BisGMA was detected only in the ethanol and acetone samples. The amount of BisGMA eluted in acetone was significant higher compared with ethanol 75% (p < 0.0001). TEGDMA was the only monomer that could be detected in all tested storage media. Storage in acetone resulted in higher release of TEGDMA when compared with other media. The amount of TEGDMA released in saliva was similar to the one released in ethanol 75%. It can be concluded that acetone is not a suitable medium for elution experiments and although ethanol 75% can simulate saliva concerning the elution of TEGDMA, it does not represent a laboratory substitute of saliva with respect to the elution of monomers like BisGMA. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.
Higher premenarcheal bone mass in elite gymnasts is maintained into young adulthood after long-term retirement from sport: A 14-year follow-up
Authors: Erlandson Marta C , Kontulainen Saija A , Chilibeck Phil D , Arnold Cathy M , Faulkner Robert A , Baxter-Jones Adam DG
Published: September 2011

Sports that impact-load the skeleton during childhood and adolescence increase determinants of bone strength such as bone mineral content and density; however, it is unclear if this benefit is maintained after retirement from the sport. The purpose of this study was to assess whether the previously reported higher bone mass in a group of premenarcheal gymnasts was still apparent 10 years after the cessation of participation and withdrawal of the gymnastics loading stimulus. In 1995, 30 gymnasts 8 to 15 years of age were measured and compared with 30 age-matched nongymnasts. Twenty-five former gymnasts and 22 nongymnasts were measured again 14 years later (2009 to 2010). Gymnasts had been retired from gymnastics training and competition for an average of 10 years. Total body (TB), lumbar spine (LS), and femoral neck (FN) bone mineral content (BMC) was assessed at both measurement occasions by dual-energy X-ray absorptiometry (DXA). Multivariate analysis of covariance (MANCOVA) was used to compare former gymnasts' and nongymnasts' BMC while controlling for differences in body size and maturation (covariates: age, height, weight, and years from menarche [1995] or age at menarche [2009 to 2010]). Premenarcheal gymnasts (measured in 1995) had significantly greater size-adjusted TB, LS, and FN BMC (p < 0.05) (15%, 17%, and 12%, respectively) than nongymnasts. Ten years after retirement, gymnasts had maintained similar size-adjusted TB, LS, and FN BMC differences (p < 0.05) (13%, 19%, and 13%, respectively) when compared with nongymnasts. Bone mass benefits in premenarcheal gymnasts were still apparent even after long-term (10 years) removal of the gymnastics loading stimulus. © 2012 American Society for Bone and Mineral Research
Subtrochanteric/femoral shaft Versus hip fractures: Incidences and identification of risk factors
Authors: Maravic Milka , Ostertag Agnès , Cohen-Solal Martine
Published: September 2011

Subtrochanteric and femoral shaft (ST/FS) fractures are now considered to be fragility fractures in osteoporotic patients. Although rare, there is growing evidence of the burden that they constitute. Little is known about the change over time in incidence of ST/FS fractures. We assessed the incidence of ST/FS fractures and the associated risk factors from 2002 to 2009 compared with those of hip fractures. Data were obtained from the French National Database, which includes all hospital discharge codes from acute care facilities. Hospitalizations for primary surgical management of neck/trochanteric (hip) and ST/FS fractures in patients aged above 50 years were selected and described for different age groups. Incidences per million populations were calculated using the estimated French population adjusted for each year, age, and gender. We studied the change for each fracture site. The comorbidity factors related to these fractures were assessed in 2009 using multivariate logistic regression. From 2002 to 2009, the adjusted incidence of hip fractures decreased continuously from 4368 to 3662 in women (p < 0.0001), and a mild increase from 1476 to 1384 in men (p < 0.0001) after an initial decrease. In contrast, the incidence of ST/FS increased significantly in both genders (from 353 to 395 in women, from 146 to 159 in men). In 2009, the incidence of ST/FS in the general population remained low, reaching the levels of 412 in women and 168 in men, but were 2966 and 1461 in women and men aged >89 years. The adjusted risk of having a ST/FS fracture was significantly higher in a context of obesity (odds ratio [OR]: 2.26; 1.95–2.61) and dementia (OR: 1.23; 1.16–1.30), but decreased with age (OR: 0.83; 0.79–0.88) and hypertension (OR: 0.90; 0.86–0.95). In conclusion, ST/FS fractures mainly affect elderly people and incidence increased significantly from 2002 to 2009. Obesity and dementia are the risk factors associated with these rare fractures, compared with regular hip fractures. © 2012 American Society for Bone and Mineral Research
Atorvastatin suppresses inflammatory response induced by oxLDL through inhibition of ERK phosphorylation, IκBα degradation, and COX‐2 expression in murine macrophages
Authors: Shao Qin , Shen Ling‐Hong , Hu Liu‐Hua , Pu Jun , Jing Qing , He Ben
Published: September 2011

Macrophages crosstalk with oxidized low‐density lipoprotein (oxLDL), play a critical role in the initiation, progression, and subsequently stability of atherosclerotic plaques. Statins, inhibitors of HMG CoA (3‐hydroxy‐3‐methylglutaryl coenzyme A) reductase, reduce the expression of inflammatory proteins in addition to their lipid‐lowering action. However, the effect and detailed anti‐inflammation mechanisms of statins in macrophages induced by oxLDL remain unclearly. In the present study, we investigated the effect of atorvastatin on inflammatory response upon oxLDL stimulation in murine macrophages and analyzed the underlying mechanisms. Tumor necrosis factor (TNF)α and monocyte chemoattractant protein‐1 (MCP‐1) mRNA levels were assayed by real‐time PCR. The expression of cyclooxygenases‐2 (COX‐2) was detected by real‐time PCR and Western blotting. While mitogen‐activated protein kinase (MAPK) phosphorylation and IκBα degradation were determined by Western blotting. Our results showed that exposure of RAW264.7 cells to oxLDL, substantially changed the morphology of the cells and increased TNFα and MCP‐1 secretion. While pretreatment with atorvastatin resulted in a significant inhibition of oxLDL‐induced morphological alteration and inflammatory cytokines expression in a dose‐dependent fashion. Further investigation of the molecular mechanism revealed that oxLDL upregulated the transcription and protein expression of COX‐2 in a time‐dependent manner. Whereas, pretreatment with atorvastatin suppressed COX‐2 expression, MAPK activation and IκBα degradation. Thus, we conclude that the anti‐inflammatory effect of atorvastatin is mediated through the inhibition of proinflammatory COX‐2. Furthermore, suppression of ERK phosphorylation and IκBα degradation is involved in this regulation. Our findings provide a novel evidence that statins suppress inflammatory response, exert its anti‐atherogenic actions via against inflammation beyond cholesterol‐lowing effect. J. Cell. Biochem. 113: 611–618, 2012. © 2011 Wiley Periodicals, Inc.