bluuebunny/crossref_metadata_2025 huggingface dataset:
Plant Density‐Dependent Variations in Bioactive Markers and Root Yield in Australian‐Grown Salvia miltiorrhizaBunge
Authors: Guang Li Chun , Jun Sheng Shu , Pang Edwin C. K. , May Brian , Chang Li Xue Charlie
Published: April 2011

The plant density‐dependent variations in the root yield and content, and the yield of biomarkers in Australian grown Salvia miltiorrhiza Bunge, a commonly used Chinese medicinal herb for the treatment of cardiovascular diseases, were investigated in a field trial involving six different plant densities. The key biomarker compounds cryptotanshinone, tanshinone I, tanshinone IIA, and salvianolic acid B were quantified by a validated RP‐HPLC method, and the root yields were determined per plant pair or unit area. There were significant variations (p<0.05) in the root yields and contents and the yields of the biomarkers between the different plant densities. Positive linear correlations were observed between the contents of the three tanshinones, whereas negative linear correlations were revealed between the contents of the tanshinones and salvianolic acid B. The highest root yield per plant pair was achieved when the plants were grown at 45×30 cm or 45×40 cm, whereas the highest root production par unit area was obtained for a plant density of 30×30 cm. The highest contents of the three tanshinones and the most abundant production of these tanshinones per unit area were achieved when the plants were grown at 30×30 cm. However, the highest content of salvianolic acid B was found for a density of 45×40 cm, while its highest yield per unit area was obtained for densities of 30×40 cm or 45×30 cm. The findings suggest that the plant density distinctly affects the root yield and content and the yield of tanshinones and salvianolic acid B in Australian grown S. miltiorrhiza, which may be used as a guide for developing optimal agricultural procedures for cultivating this herb.
Composition, and Antimicrobial and Remarkable Antiprotozoal Activities of the Essential Oil of Rhizomes of Aframomum sceptrum K. Schum. (Zingiberaceae)
Authors: Cheikh‐Ali Zakaria , Adiko Marcelline , Bouttier Sylvie , Bories Christian , Okpekon Timothée , Poupon Erwan , Champy Pierre
Published: April 2011

The essential oil from the rhizomes of Aframomum sceptrum (Zingiberaceae) was analyzed by GC/MS, and its major constituents were found to be β‐pinene (12.7%), caryophyllene oxide (10.0%), and cyperene (6.0%). The oil was also evaluated for antimicrobial activities, in comparison with β‐pinene, caryophyllene oxide, and the leaf essential oil of Melaleuca alternifolia (Myrtaceae). The A. sceptrum essential oil exhibited bacteriostatic activity against the Gram‐positive bacteria Bacillus subtilis, Staphylococcus epidermidis, and S. aureus, but not against Gram‐negative bacteria. Moreover, it showed mild fungicidal activity against Candida albicans and Aspergillus fumigates, and remarkable antiprotozoal activity against Trypanosoma brucei brucei (MLC of 1.51 μl/ml) and Trichomonas vaginalis (IC50 of 0.12±0.02 and MLC of 1.72 μl/ml).
Chemical Constituents and Antimicrobial Activity of the Leaf and Rhizome Oils of Alpinia pahangensisRidl., an Endemic Wild Ginger from Peninsular Malaysia
Authors: Awang Khalijah , Ibrahim Halijah , Rosmy Syamsir Devi , Mohtar Mastura , Mat Ali Rasadah , Azah Mohamad Ali Nor
Published: April 2011

The essential oils from the leaves and rhizomes of Alpinia pahangensis Ridl., collected from Pahang, Peninsular Malaysia, were obtained by hydrodistillation, and their chemical compositions were determined by GC and GC/MS analyses. The major components of the rhizome oil were γ‐selinene (11.60%), β‐pinene (10.87%), (E,E)‐farnesyl acetate (8.65%), and α‐terpineol (6.38%), while those of the leaf oil were β‐pinene (39.61%), α‐pinene (7.55%), and limonene (4.89%). The investigation of the antimicrobial activity of the essential oils using the broth microdilution technique revealed that the rhizome oil of A. pahangensis inhibited five Staphylococcus aureus strains with minimum inhibitory concentration (MIC) values between 0.08 and 0.31 μg/μl, and four selected fungi with MIC values between 1.25 and 2.50 μg/μl.
Gold Catalysis: 1,3‐Oxazines by Cyclisation of Allene Amides
Authors: Hashmi A. Stephen K. , Schuster Andreas M. , Litters Sebastian , Rominger Frank , Pernpointner Markus
Published: April 2011

A series of allene amides was prepared and their gold‐catalysed cyclisation was investigated. The formation of six‐membered rings, 1,3‐oxazines, was observed. Dihydropyrroles originating from intramolecular hydroamination of the distal CC double bonds of the allenes were minor side products. Mechanistic studies by in situ 31P NMR spectroscopy showed only one additional species during the conversion in each case; a computational study of the different allyl gold(I) species involved allowed this to be assigned as the σ‐allyl gold species bearing the gold catalyst at the sterically less hindered methylene end. The regiospecific deuterodeauration of this intermediate confirmed a SE′‐type mechanism for this last step of the catalytic cycle.
Automation and Optimization of Startups, Load Changes and Batch Processes
Authors: Krämer Stefan , Dünnebier Guido , Kahrs Olaf , Luft Heiko
Published: April 2011

Bei Konti‐Anlagen treten oft dynamischen Übergangsvorgänge, wie Anfahr‐, Last‐ oder Produktwechsel, auf, wohingegen (Semi‐)Batch‐Prozesse eine inhärente Dynamik besitzen. Zielte die Automatisierung dieser Übergangsvorgänge bisher meist auf eine sichere und reproduzierbare Fahrweise ab, erlauben moderne Prozessführungsmethoden auch wirtschaftlich optimierte Fahrweisen. Herausforderungen bei der Umsetzung sind insbesondere die hohe Komplexität der Anlage, der oft geringe Instrumentierungs‐ und Automatisierungsgrad und die Notwendigkeit umfangreicher verfahrens‐ und automatisierungstechnischer Kenntnisse. Der Beitrag zeigt an Beispielen die Vorgehensweise in der industriellen Praxis auf und nennt innovative Lösungsansätze aus der akademischen Forschung.
Current trends and emerging future of indocyanine green usage in surgery and oncology
Authors: Polom Karol , Murawa Dawid , Rho Young‐soo , Nowaczyk Piotr , Hünerbein Michael , Murawa Pawel
Published: April 2011

Ever since Kitai first performed fluorescent navigation of sentinel lymph nodes (SLNs) using indocyanine green (ICG) dye with a charge‐couple device and light emitting diodes, the intraoperative use of near infrared fluorescence has served a critical role in increasing our understanding in various fields of surgical oncology. Here the authors review the emerging role of the ICG fluorophore in the development of our comprehension of the lymphatic system and its use in SLN mapping and biopsy in various cancers. In addition, they introduce the novel role of ICG‐guided video angiography as a new intraoperative method of assessing microvascular circulation. The authors attempt to discuss the promising potential in addition to assessing several challenges and limitations in the context of specific surgical procedures and ICG as a whole. PubMed and Medline literature databases were searched for ICG use in clinical surgical settings. Despite ICG's significant impact in various fields of surgical oncology, ICG is still in its nascent stages, and more in‐depth studies need to be carried out to fully evaluate its potential and limitations. Cancer 2011;. © 2011 American Cancer Society.
A method of reducing harmonic components in a large‐scale inverter
Authors: Harimoto Tsuyoshi , Hayashi Hidemi , Murata Katsuaki
Published: April 2011

The low harmonic component elimination method, a method of PWM control, is effective for miniaturizing filters, or for decreasing losses by lowering the switching frequency. However, this method is only applicable to specific uses such as static var generators, because it can only read a switching angle decided beforehand from memory and can only control the fundamental wave. In this paper a PWM method to control low harmonic components is proposed. The proposed method uses a curved triangular wave that was developed in this investigation as the carrier wave. The proposed method proves to decrease the total harmonic distortion better than the conventional low harmonic component elimination method and the subharmonic method, based on experimental results employing a single‐phase inverter. © 2011 Wiley Periodicals, Inc. Electr Eng Jpn, 175(4): 10–23, 2011; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/eej.21103
Nrf2 is essential for cholesterol crystal‐induced inflammasome activation and exacerbation of atherosclerosis
Authors: Freigang Stefan , Ampenberger Franziska , Spohn Gunther , Heer Sebastian , Shamshiev Abdijapar T. , Kisielow Jan , Hersberger Martin , Yamamoto Masayuki , Bachmann Martin F. , Kopf Manfred
Published: April 2011

Oxidative stress and inflammation — two components of the natural host response to injury — constitute important etiologic factors in atherogenesis. The pro‐inflammatory cytokine interleukin (IL)‐1 significantly enhances atherosclerosis, however, the molecular mechanisms of IL‐1 induction within the artery wall remain poorly understood. Here we have identified the oxidative stress‐responsive transcription factor NF‐E2‐related 2 (Nrf2) as an essential positive regulator of inflammasome activation and IL‐1‐mediated vascular inflammation. We show that cholesterol crystals, which accumulate in atherosclerotic plaques, represent an endogenous danger signal that activates Nrf2 and the NLRP3 inflammasome. The resulting vigorous IL‐1 response critically depended on expression of Nrf2, and Nrf2‐deficient apolipoprotein E (Apoe)−/− mice were highly protected against diet‐induced atherogenesis. Importantly, therapeutic neutralization of IL‐1α and IL‐1β reduced atherosclerosis in Nrf2+/−Apoe−/− but not in Nrf2−/−Apoe−/− mice, suggesting that the pro‐atherogenic effect of Nrf2‐signaling was primarily mediated by its permissive role in IL‐1 production. Our studies demonstrate a role for Nrf2 in inflammasome activation, and identify cholesterol crystals as disease‐relevant triggers of the NLRP3 inflammasome and potent pro‐atherogenic cytokine responses. These findings suggest a common pathway through which oxidative stress and metabolic danger signals converge and mutually perpetuate the chronic vascular inflammation that drives atherosclerosis.
Facile Three‐Component Synthesis of Macrocyclane‐Fused Pyrazolo[3,4‐b]pyridine Derivatives
Authors: Jiang Bo , Liu Yin‐Ping , Tu Shu‐Jiang
Published: April 2011

A series of new functionalized macrocyclane‐fused pyrazolo[3,4‐b]pyridine derivatives with an aryl group at the 2‐position of the pyridine nucleus have been synthesized by microwave‐assisted three‐component reactions of aldehydes, aminopyrazole and cycloketones in HOAc using 1.0 equiv. of TFA as a promoter. The procedure is facile, avoiding time‐consuming and costly syntheses, tedious work‐ups and purifications of precursors as well as protection/deprotection of functional groups. This method is very efficient due to short reaction times and easy work‐up and provides an efficient and promising synthetic strategy for the construction of the macrocyclane‐fused pyrazolo[3,4‐b]pyridine skeleton.
Electrochemical Polymerization and Investigation of Properties of Poly(5‐(4′‐aminophenylamino)‐10,20‐diphenylporphyrin)
Authors: Uygun Aysegul , Myjavcova Renata , Yavuz Ayse Gul , Ruppel Joshua V. , Fields Kimberly B. , Frankhauser Anita , Zhang X. Peter , Bhethanbotla Venkat R. , Bednar Petr
Published: April 2011

The preparation and electropolymerization of a new porphyrin monomer with an amino group connecting the porphyrin core and aniline unit were studied. Cyclic voltammetry, FTIR spectroscopy, and a tandem quadrupole/time of flight mass spectrometry with matrix‐assisted laser desorption/ionization source (MALDI‐QqTOF) were used for the characterization of poly(5‐(4′‐aminophenylamino)‐10,20‐diphenylporphyrin) (PAPADPP). The PAPADPP formed a smooth layer on the Indium tin oxide (ITO) electrode and grew perpendicular to the electrode surface. An oligonucleotide (ODN)‐probe was physisorbed onto the PAPADPP film and tested for hybridization with complementary and noncomplementary ODN segments. Biological recognition was monitored by comparison of the electrochemical signals (cyclic voltammogram) from single and double strand state oligonucleotides. The morphology of the physisorbed ODN‐probe and its hybridization were observed on ITO electrodes using AFM and SEM.
Electrochemical Impedance Spectroscopy for Assessing the Recognition of Cytochrome c by Immobilized Calixarenes
Authors: Mohsin Muhammad Ali , Banica Florinel‐Gabriel , Oshima Tatsuya , Hianik Tibor
Published: April 2011

We developed a biosensor based on supported lipid films (sBLM) with incorporated calixarenes for detection of cytochrome c (cyt c) using electrochemical impedance spectroscopy (EIS). Calix[6]arene (CALIX) was incorporated into soybean phosphatidylcholine (SBPC) liposomes in different molar ratios (SBPC:CALIX=10 : 1, 30 : 1 and 100 : 1). The lipid layer containing calixarenes has been formed on the surface of a gold electrode previously covered with an octadecanethiol monolayer. Both the sBLM capacitance and the electron transfer resistance showed noticeable modification at a cyt c concentration as low as 10 nM. However, a much higher concentration of free lysine (>30 µM) was necessary to induce a similar effect. Nonspecific interaction of cyt c with sBLM without CALIX was negligible.
Chemosensory processing in the taste‐reward pathway
Authors: Gutierrez Ranier , Simon Sidney A
Published: April 2011

Although the act of eating is voluntary, its initiation depends on several factors including its taste and the animal's internal state as related to hunger or satiety. These factors, together with the food's hedonic value, will determine whether food will be ingested. The taste of food will depend on the activation of receptors located on taste cells but also on the expectation of what it will taste like. For these reasons, it is important to investigate, in behaving animals, the neural correlates of feeding behaviour in the taste–reward pathway. Here we review particular coding strategies, present experiments using freely licking rodents with chronically implanted arrays of electrodes throughout the taste–reward pathway to investigate the changes that occur when animals learn to discriminate among tastants and after they are ingested. In summary, we found that gustatory processing does not only depend on the input from the oral cavity but on expectation, learning, and post‐ingestive effects. Copyright © 2011 John Wiley & Sons, Ltd.
WCSPH viscosity diffusion processes in vortex flows
Authors: Macià F. , Sánchez J. M. , Souto‐Iglesias A. , González L. M.
Published: April 2011

The aim of this paper is to clarify the role played by the most commonly used viscous terms in simulating viscous laminar flows using the weakly compressible approach in the context of smooth particle hydrodynamics (WCSPH). To achieve this, Takeda et al. (Prog. Theor. Phys. 1994; 92(5):939–960), Morris et al. (J. Comput. Phys. 1997; 136:214–226) and Monaghan–Cleary–Gingold's (Appl. Math. Model. 1998; 22(12):981–993; Monthly Notices of the Royal Astronomical Society 2005; 365:199–213) viscous terms will be analysed, discussing their origins, structures and conservation properties. Their performance will be monitored with canonical flows of which related viscosity phenomena are well understood, and in which boundary effects are not relevant. Following the validation process of three previously published examples, two vortex flows of engineering importance have been studied. First, an isolated Lamb–Oseen vortex evolution where viscous effects are dominant and second, a pair of co‐rotating vortices in which viscous effects are combined with transport phenomena. The corresponding SPH solutions have been compared to finite‐element numerical solutions. The SPH viscosity model's behaviour in modelling the viscosity related effects for these canonical flows is adequate. Copyright © 2011 John Wiley & Sons, Ltd.
Genomic alterations with impact on survival in esophageal squamous cell carcinoma identified by array comparative genomic hybridization
Authors: Shi Zhi‐Zhou , Liang Jian‐Wei , Zhan Ting , Wang Bo‐Shi , Lin De‐Chen , Liu Shu‐Guang , Hao Jia‐Jie , Yang Hai , Zhang Yu , Zhan Qi‐Min , Zhang Kai‐Tai , Wang Ming‐Rong
Published: April 2011

Risk assessment of esophageal squamous cell carcinoma (ESCC) is currently based on clinicopathological parameters. To identify genomic markers that can predict overall survival in ESCC, we performed array comparative genomic hybridization (array CGH) on a screening set of 35 tumor samples from ESCC patients. Prognosis association of the genes selected on the basis of the array CGH results was further validated by real‐time PCR in two independent sample sets (n = 151 and 84). Genomic analysis revealed seven high‐level amplifications and two homozygous deletions. Gain of 11q13.2 and loss of 7q34 and 18q21.1–q23 were associated with poor outcome. Gain of 11q13.2 was an independent prognostic factor and was selected for further validation. In both validation sets of samples, copy number increase of CPT1A in 11q13.2 was correlated with short overall survival (P = 0.015, n = 151 and P = 0.044, n = 84). Multivariate analysis confirmed that CPT1A gain provided prognostic information in ESCC (HR, 1.643; 95% CI: 1.076–2.509; P = 0.022; HR, 2.488; 95% CI: 1.235–5.013; P = 0.011). Immunohistochemistry showed significant correlation between strong expression of CPT1A protein and poor outcome of ESCC patients (P = 0.018, n = 73). Our data suggest that gain of CPT1A may be a candidate prognostic factor. © 2011 Wiley‐Liss, Inc.
DNMT3B gene amplification predicts resistance to DNA demethylating drugs
Authors: Simó‐Riudalbas Laia , Melo Sónia A. , Esteller Manel
Published: April 2011

Disruption of the DNA methylation landscape is one of the most common features of human tumors. However, genetic alterations of DNA methyltransferases (DNMTs) have not been described in carcinogenesis. Herein, we show that pancreatic and breast cancer cells undergo gene amplification of the DNA methyltransferase 3B (DNMT3B). The presence of extra copies of the DNMT3B gene is linked to higher levels of the corresponding mRNA and protein. Most importantly, the elevated gene dosage of DNMT3B is associated with increased resistance to the growth‐inhibitory effect mediated by DNA demethylating agents. In particular, cancer cells harboring DNMT3B gene amplification are less sensitive to the decrease in cell viability caused by 5‐azacytidine (Vidaza), 5‐aza‐2‐deoxycytidine (Decitabine), and SGI‐1027. Overall, the data confirm DNMT3B as a bona fide oncogene in human cancer and support the incorporation of the DNMT3B copy number assay into current clinical trials assessing the efficacy of DNA demethylating drugs in solid tumors. © 2011 Wiley‐Liss, Inc.
Association of germline or somatic TP53 missense mutation with oncogene amplification in tumors developed in patients with Li‐Fraumeni or Li‐Fraumeni‐like syndrome
Authors: Sugawara Waka , Arai Yasuhito , Kasai Fumio , Fujiwara Yuiko , Haruta Masayuki , Hosaka Rie , Nishida Kazunori , Kurosumi Masashi , Kobayashi Yasuhito , Akagi Kiwamu , Kaneko Yasuhiko
Published: April 2011

Germline TP53 mutations are found in Li‐Fraumeni syndrome (LFS) patients, predisposed to soft tissue sarcoma and other malignancies. The mutations and succeeding genetic events are thought to cause LFS‐associated cancer, whose genetic alterations have rarely been investigated. Here, we study two LFS or Li‐Fraumeni‐like syndrome (LFLS) patients whose cancers showed aggressive phenotypes. Patient 1 with LFS and TP53R273H developed a rhabdomyosarcoma twice at the ages of 18 months and 21 years. A single‐nucleotide polymorphism array‐based analysis revealed two amplicons in the second tumor; one at 5q11.2 containing MAP3K1 and the other at 11q22.2 containing BIRC2/3 and YAP1. Increase of kinase signaling of MAP3K1 along with anti‐apoptosis function of BIRC2/3 may have facilitated progression of this tumor. Patient 2 with LFLS and wild‐typeTP53 suffered from acute myeloid leukemia. The leukemic cells had TP53I195T and two amplicons; one at 8q24.1 containing DEPDC6 and the other at 8q24.2 containing TRIB1, MYC, and PVT1. Quantitative PCR confirmed amplification of the genes and FISH revealed co‐amplification of DEPDC6 and PVT1 in the same double minutes. Quantitative RT‐PCR revealed increased expression levels of TRIB1, but no or little expression of DEPDC6, MYC, and PVT1. The results indicate that TRIB1 may be the target gene in the amplicon in the leukemia cells. Mutant TP53 can be engaged in pathways triggering gene amplification through impairment of DNA double‐stranded break repair. The amplified candidate oncogenes identified in this study may have played a part in cancer development and lead to the poor outcome of LFS or LFLS‐associated tumors. © 2011 Wiley‐Liss, Inc.
EWSR1‐ATF1 fusion is a novel and consistent finding in hyalinizing clear‐cell carcinoma of salivary gland
Authors: Antonescu Cristina R. , Katabi Nora , Zhang Lei , Sung Yun Shao , Seethala Raja R. , Jordan Richard C. , Perez‐Ordoñez Bayardo , Have Cherry , Asa Sylvia L. , Leong Iona T. , Bradley Grace , Klieb Hagen , Weinreb Ilan
Published: April 2011

Hyalinizing clear‐cell carcinoma (HCCC) is a rare, low‐grade salivary gland tumor with distinctive clear‐cell morphology and pattern of hyalinization as well as focal mucinous differentiation. However, histological overlap exists with other salivary gland tumors, such as epithelial–myoepithelial carcinoma (EMCa), salivary myoepithelial carcinoma, and mucoepidermoid carcinoma (MEC). The potential relationship between HCCC and its morphological mimics has not been yet investigated at the genetic level. In this study, we conducted a molecular analysis for the presence of rearrangements in MAML2, commonly seen in MECs, and EWSR1, involved in “soft tissue myoepithelial tumors” (SMET) by fusion with POU5F1, PBX1, or ZNF444. Fluorescence in situ hybridization (FISH) was performed on 23 HCCC cases for abnormalities in MAML2, EWSR1, FUS, POU5F1, PBX1, and ZNF444. FISH for MAML2 was negative in all cases (0 of 14), including those with mucinous differentiation (0 of 7). An EWSR1 rearrangement was identified in 18 of 22 HCCCs (82%), while no break‐apart signals were seen in FUS, POU5F1, PBX1, or ZNF444. 3′RACE on an EWSR1 rearranged HCCC identified an EWSR1‐ATF1 fusion, which was confirmed by RT‐PCR. ATF1 involvement was further confirmed by FISH analysis in 13 of 14 EWSR1‐rearranged HCCC cases (93%). In contrast, all control cases tested, including among others 5 EMCa and 3 MEC with clear cells, were negative for EWSR1 and ATF1 rearrangements. The presence of EWSR1‐ATF1 fusion in most HCCCs reliably separates these tumors from its histological mimics. The distinction from MEC is particularly important, as conventional MEC grading schemes overgrade these indolent HCCCs, potentially impacting on treatment. © 2011 Wiley‐Liss,Inc.
Norse–Inuit interaction and landscape change in southern Greenland? A geochronological, Pedological, and Palynological investigation
Authors: Golding Kirsty A. , Simpson Ian A. , Schofield J. Edward , Edwards Kevin J.
Published: April 2011

Ruins representing both medieval Norse and Inuit (Thule culture) settlements can be found together on the coast at Sandhavn (59°59′ N, 44°46′ W), Greenland. The site presents a rare opportunity to investigate the character of past contact and interaction between these two peoples. Soils‐based, radiocarbon, and palynological analyses demonstrate the creation of hortic anthrosols within Norse home‐fields used between the mid‐11th and late 14th centuries A.D. Irrigation channels have been identified within the home‐fields, while rising grass pollen influx reveals intensification in hay production over the period ca. A.D. 1260–1350 despite climatic deterioration setting in around this time. Floor deposits and wall packing from an Inuit winter house returned dates of cal. A.D. 1220–1290 (2σ), yet no direct landscape‐based evidence for Inuit activity could be determined. Although the exact nature of the relationship between Norse and Thule at Sandhavn remains unclear, the role of this site as a harbor and possible trading area may have attracted Inuit settlers keen to participate in European trade networks. © 2011 Wiley Periodicals, Inc.
Thalamic‐insular dysconnectivity in schizophrenia: Evidence from structural equation modeling
Authors: Corradi‐Dell'Acqua Corrado , Tomelleri Luisa , Bellani Marcella , Rambaldelli Gianluca , Cerini Roberto , Pozzi‐Mucelli Roberto , Balestrieri Matteo , Tansella Michele , Brambilla Paolo
Published: April 2011

Structural and functional studies have shown that schizophrenia is often associated with frontolimbic abnormalities in the prefrontal and mediotemporal regions. It is still unclear, however, if such dysfunctional interaction extends as well to relay regions such as the thalamus and the anterior insula. Here, we measured gray matter volumes of five right‐hemisphere regions in 68 patients with schizophrenia and 77 matched healthy subjects. The regions were amygdala, thalamus, and entorhinal cortex (identified as anomalous by prior studies on the same population) and dorsolateral prefrontal cortex and anterior insula (isolated by voxel‐based morphometry analysis). We used structural equation modeling and found altered path coefficients connecting the thalamus to the anterior insula, the amygdala to the DLPFC, and the entorhinal cortex to the DLPFC. In particular, patients exhibited a stronger thalamus‐insular connection than healthy controls. Instead, controls showed positive entorhinal‐DLPFC and negative amygdalar‐DLPFC connections, both of which were absent in the clinical population. Our data provide evidence that schizophrenia is characterized by an impaired right‐hemisphere network, in which intrahemispheric communication involving relay structures may play a major role in sustaining the pathophysiology of the disease. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Reorganization of brain functional small‐world networks during finger movements
Authors: Jin Seung‐Hyun , Lin Peter , Hallett Mark
Published: April 2011

A functional measure of brain organization is the efficiency of functional connectivity. The degree of functional connectivity can differ during a task compared to the rest, and to study this issue, we investigated the functional connectivity networks in healthy subjects during a simple, right‐handed, sequential finger‐tapping task using graph theoretic measures. EEGs were recorded from 58 channels in 15 healthy subjects at rest and during a motor task. We estimated mutual information values of wavelet coefficients to create an association matrix between EEG electrodes and produced a series of adjacency matrices or graphs, A, by thresholding with network cost. These graphs are called small‐world networks, and we assessed their efficiency measures. We found economical small‐world properties in brain functional connectivity networks in the alpha and beta band networks. The efficiency of the brain networks was enhanced during the task in the beta band networks, but not in the alpha band networks. A regional efficiency analysis during the task showed that the bilateral primary motor and left sensory areas showed increased nodal efficiency, Enodal, whereas decreased Enodal was found over the posterior parietal areas. The present study provides evidence for the reorganization of brain functional connectivity networks in a motor task with the greatest increase in Enodal in motor executive areas. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Communication with emblematic gestures: Shared and distinct neural correlates of expression and reception
Authors: Lindenberg Robert , Uhlig Marie , Scherfeld Dag , Schlaug Gottfried , Seitz Ruediger J.
Published: April 2011

Emblematic (or symbolic) gestures allow individuals to convey a variety of thoughts and emotions ranging from approval to hostility. The use of such gestures involves the execution of a codified motor act by the addresser and its perception and decoding by the addressee. To examine underlying common and distinct neural correlates, we used fMRI tasks in which subjects viewed video clips of emblematic one‐hand gestures. They were asked to (1) take the perspective of the addresser and imagine executing the gestures (“expression” condition), and to (2) take the perspective of the addressee and imagine being confronted with the gestures (“reception” condition). Common areas of activation were found in inferior frontal, medial frontal, and posterior temporal cortices with left‐hemispheric predominance as well as in the cerebellum. The distinction between regions specifically involved in the expression or reception condition partly resembled the dorsal and ventral stream dichotomy of visual processing with junctions in inferior frontal and medial prefrontal cortices. Imagery of gesture expression involved the dorsal visual stream as well as higher‐order motor areas. In contrast, gesture reception encompassed regions related to semantic processing, and medial prefrontal areas known to be involved in the process of understanding the intentions of others. In conclusion, our results provide evidence for a dissociation in representations of emblematic gesture processing between addresser and addressee in addition to shared components in language‐related areas. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Patient complexity and GPS' income under mixed remuneration
Authors: Olsen K. R.
Published: April 2011

Because of problems with recruiting GPs to deprived areas in Denmark, it has been discussed whether the mixed remuneration scheme is flexible enough to compensate GPs serving patients with high need for services. The objective is to assess how patient heterogeneity affects list size, income and total utility of GPs operating under a mixed remuneration scheme. We adapt the model by Iversen (2004) as a theoretical framework for analysing the consequences of patient heterogeneity in a mixed remuneration system. We use a data set of Danish solo practitioners to analyse the effect of patient complexity on list size and income. From the theoretical model we find that higher levels of patient complexity lead GPs to choose a lower list size, whereas the effect on income is ambiguous. The effect on total utility (income and leisure) is, however, shown to be negative. Using empirical data from 1039 solo practices we find that patient complexity reduces both list size and income and conclude that a mixed per capita and fee for service remuneration system does not fully compensate practices with more complex patients. Differentiated per capita payment may represent a means of ensuring fair and equal income of GPs. Copyright © 2011 John Wiley & Sons, Ltd.
Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells
Authors: Csak Timea , Ganz Michal , Pespisa Justin , Kodys Karen , Dolganiuc Angela , Szabo Gyongyi
Published: April 2011

Abstract:

The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro–interleukin-1β (pro–IL-1β) into secreted IL-1β, is induced by endogenous and exogenous danger signals. Lipopolysaccharide (LPS), a toll-like receptor 4 ligand, plays a role in NASH and also activates the inflammasome. In this study, we hypothesized that the inflammasome is activated in NASH by multiple hits involving endogenous and exogenous danger signals. Using mouse models of methionine choline–deficient (MCD) diet–induced NASH and high-fat diet–induced NASH, we found up-regulation of the inflammasome [including NACHT, LRR, and PYD domains–containing protein 3 (NALP3; cryopyrin), apoptosis-associated speck-like CARD-domain containing protein, pannexin-1, and pro–caspase-1] at the messenger RNA (mRNA) level increased caspase-1 activity, and mature IL-1β protein levels in mice with steatohepatitis in comparison with control livers. There was no inflammasome activation in mice with only steatosis. The MCD diet sensitized mice to LPS-induced increases in NALP3, pannexin-1, IL-1β mRNA, and mature IL-1β protein levels in the liver. We demonstrate for the first time that inflammasome activation occurs in isolated hepatocytes in steatohepatitis. Our novel data show that the saturated fatty acid (FA) palmitic acid (PA) activates the inflammasome and induces sensitization to LPS-induced IL-1β release in hepatocytes. Furthermore, PA triggers the release of danger signals from hepatocytes in a caspase-dependent manner. These hepatocyte-derived danger signals, in turn, activate inflammasome, IL-1β, and tumor necrosis factor α release in liver mononuclear cells. Conclusion: Our novel findings indicate that saturated FAs represent an endogenous danger in the form of a first hit, up-regulate the inflammasome in NASH, and induce sensitization to a second hit with LPS for IL-β release in hepatocytes. Furthermore, hepatocytes exposed to saturated FAs release danger signals that trigger inflammasome activation in immune cells. Thus, hepatocytes play a key role in orchestrating tissue responses to danger signals in NASH. (HEPATOLOGY 2011;)
Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1–infected patients
Authors: Wagner Frank , Thompson Robert , Kantaridis Constantino , Simpson Paul , Troke Philip J. F. , Jagannatha Shyla , Neelakantan Srividya , Purohit Vivek S. , Hammond Jennifer L.
Published: April 2011

Abstract:

More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200–1400 mg daily, and the duration of dosing ranged from 3–10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from −0.97 log10 IU/mL with filibuvir given at 100 mg twice daily to −2.30 log10 IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log10 IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing. Conclusion: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients. (Hepatology 2011;)
Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt -deficient zebrafish
Authors: Thakur Prakash C. , Stuckenholz Carsten , Rivera Marcus R. , Davison Jon M. , Yao Jeffrey K. , Amsterdam Adam , Sadler Kirsten C. , Bahary Nathan
Published: April 2011

Hepatic steatosis is the initial stage of nonalcoholic fatty liver disease (NAFLD) and may predispose to more severe hepatic disease, including hepatocellular carcinoma. Endoplasmic reticulum (ER) stress has been recently implicated as a novel mechanism that may lead to NAFLD, although the genetic factors invoking ER stress are largely unknown. During a screen for liver defects from a zebrafish insertional mutant library, we isolated the mutant

cdipt

hi559Tg
/+ (
hi559

). CDIPT is known to play an indispensable role in phosphatidylinositol (PtdIns) synthesis. Here we show that

cdipt

is expressed in the developing liver, and its disruption in

hi559

mutants abrogates

de novo

PtdIns synthesis, resulting in hepatomegaly at 5 days postfertilization. The

hi559

hepatocytes display features of NAFLD, including macrovesicular steatosis, ballooning, and necroapoptosis. Gene set enrichment of microarray profiling revealed significant enrichment of endoplasmic reticulum stress response (ERSR) genes in

hi559

mutants. ER stress markers, including

atf6
,
hspa5
,
calr
, and

xbp1
, are selectively up-regulated in the mutant liver. The

hi559

expression profile showed significant overlap with that of mammalian hepatic ER stress and NAFLD. Ultrastructurally, the

hi559

hepatocytes display marked disruption of ER architecture with hallmarks of chronic unresolved ER stress. Induction of ER stress by tunicamycin in wild-type larvae results in a fatty liver similar to

hi559
, suggesting that ER stress could be a fundamental mechanism contributing to hepatic steatosis.

Conclusion: cdipt

-deficient zebrafish exhibit hepatic ER stress and NAFLD pathologies, implicating a novel link between PtdIns, ER stress, and steatosis. The tractability of

hi559

mutant provides a valuable tool to dissect ERSR components, their contribution to molecular pathogenesis, and evaluation of novel therapeutics of NAFLD. (Hepatology 2011;)
The metastasis-associated protein-1 gene encodes a host permissive factor for schistosomiasis, a leading global cause of inflammation and cancer
Authors: Nair Sujit S. , Bommana Anitha , Bethony Jeffrey M. , Lyon Amanda J. , Ohshiro Kazufumi , Pakala Suresh B. , Rinaldi Gabriel , Keegan Brian , Suttiprapa Sutas , Periago Maria V. , Hotez Peter J. , Brindley Paul J. , Kumar Rakesh
Published: April 2011

Abstract:

Schistosoma haematobium is responsible for two-thirds of the world's 200 million to 400 million cases of human schistosomiasis. It is a group 1 carcinogen and a leading cause of bladder cancer that occurs after years of chronic inflammation, fibrosis, and hyperproliferation in the host liver. The coevolution of blood flukes of the genus Schistosoma and their human hosts is paradigmatic of long-term parasite development, survival, and maintenance in mammals. However, the contribution of host genes, especially those discrete from the immune system, necessary for parasite establishment and development remains poorly understood. This study investigated the role of metastasis-associated protein-1 gene (Mta1) product in the survival of S. haematobium and productive infection in the host. Using a Mta−1 null mouse model, here we provide genetic evidence to suggest that MTA1 expression positively influences survival and/or maturation of schistosomes in the host to patency, as we reproducibly recovered significantly fewer S. haematobium worms and eggs from Mta1−/− mice than wild−type mice. In addition, we found a distinct loss of cytokine interdependence and aberrant Th1 and Th2 cytokine responses in the Mta1−/− mice compared to age-matched wild-type mice. Thus, utilizing this Mta1-null mouse model, we identified a distinct contribution of the mammalian MTA1 in establishing a productive host–parasite interaction and thus revealed a host factor critical for the optimal survival of schistosomes and successful parasitism. Moreover, MTA1 appears to play a significant role in driving inflammatory responses to schistosome egg–induced hepatic granulomata reactions, and thus offers a survival cue for parasitism as well as an obligatory contribution of liver in schistosomiasis. Conclusion: These findings raise the possibility to develop intervention strategies targeting MTA1 to reduce the global burden of schistosomiasis, inflammation, and neoplasia. (HEPATOLOGY 2011;)
Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis
Authors: Rong Guanghua , Zhong Renqian , Lleo Ana , Leung Patrick S.C. , Bowlus Christopher L. , Yang Guo-Xiang , Yang Chen-Yen , Coppel Ross L. , Ansari Aftab A. , Cuebas Dean A. , Worman Howard J. , Invernizzi Pietro , Gores Gregory J. , Norman Gary , He Xiao-Song , Gershwin Eric M.
Published: April 2011

Abstract:

A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Our laboratory has reported that after apoptosis, human intrahepatic biliary epithelial cells (HiBECs) translocate the E2 subunit of the pyruvate dehydrogenase complex immunologically intact into apoptotic bodies, forming an apotope. However, the cell type and specificity of this reaction has not been fully defined. To address this issue, we investigated whether the E2 subunit of the pyruvate dehydrogenase complex, the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex, the E2 subunit of the oxo-glutarate dehydrogenase complex, four additional inner mitochondrial enzymes, and four nuclear antigens remain immunologically intact with respect to postapoptotic translocation in HiBECs and three additional control epithelial cells. We report that all three 2-oxo acid dehydrogenase enzymes share the ability to remain intact within the apotope of HiBECs. Interestingly, the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex also remained intact in the other cell types tested. We extended the data, using sera from 95 AMA-positive and 19 AMA-negative patients with PBC and 76 controls, by testing for reactivity against the seven mitochondrial proteins studied herein and also the ability of AMA-negative sera to react with HiBEC apotopes. Sera from 3 of 95 AMA-positive sera, but none of the controls, reacted with 2,4-dienoyl coenzyme A reductase 1, an enzyme also present intact only in the HiBEC apotope, but which has not been previously associated with any autoimmune disease. Finally, the specificity of HiBEC apotope reactivity was confined to AMA-positive sera. Conclusion: We submit that the biliary specificity of PBC is secondary to the unique processes of biliary apoptosis. (HEPATOLOGY 2011)
Fatty liver index and mortality: The cremona study in the 15th year of follow-up
Authors: Calori Giliola , Lattuada Guido , Ragogna Francesca , Garancini Maria Paola , Crosignani Paolo , Villa Marco , Bosi Emanuele , Ruotolo Giacomo , Piemonti Lorenzo , Perseghin Gianluca
Published: April 2011

Abstract:

A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non–hepatic-related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02–1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's ρ = 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality. Conclusion: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state. (HEPATOLOGY 2011;)
Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice
Authors: Corradini Elena , Meynard Delphine , Wu Qifang , Chen Shan , Ventura Paolo , Pietrangelo Antonello , Babitt Jodie L.
Published: April 2011

Abstract:

The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo. (HEPATOLOGY 2011;)
Evidence for area CA1 as a match/mismatch detector: A high‐resolution fMRI study of the human hippocampus
Authors: Duncan Katherine , Ketz Nicholas , Inati Souheil J. , Davachi Lila
Published: April 2011

The hippocampus is proposed to switch between memory encoding and retrieval by continually computing the overlap between what is expected and what is encountered. Central to this hypothesis is that area CA1 performs this calculation. However, empirical evidence for this is lacking. To test the theoretical role of area CA1 in match/mismatch detection, we had subjects study complex stimuli and then, during high‐resolution fMRI scanning, make memory judgments about probes that either matched or mismatched expectations. More than any other hippocampal subfield, area CA1 displayed responses consistent with a match/mismatch detector. Specifically, the responses in area CA1 tracked the total number of changes present in the probe. Additionally, area CA1 was sensitive to both behaviorally relevant and irrelevant changes, a key feature of an automatic comparator. These results are consistent with, and provide the first evidence in humans for, the theoretically important role of area CA1 as a match/mismatch detector. © 2011 Wiley Periodicals, Inc.