bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolution of 1‐n‐Butyl‐3‐Methyl‐3‐Phospholene 1‐Oxide With TADDOL Derivatives and Calcium Salts of O,O'‐Dibenzoyl‐(2R,3R)‐ or O,O'‐di‐p‐Toluoyl‐(2R,3R)‐tartaric Acid
Authors: Bagi Péter , Fekete András , Kállay Mihály , Hessz Dóra , Kubinyi Miklós , Holczbauer Tamás , Czugler Mátyás , Fogassy Elemér , Keglevich György
Published: February 2014

The resolution methods applying (−)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane (“TADDOL”), (−)‐(2R,3R)‐α,α,α',α'‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol (“spiro‐TADDOL”), as well as the acidic and neutral Ca2+ salts of (−)‐O,O'‐dibenzoyl‐ and (−)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid were extended for the preparation of 1‐n‐butyl‐3‐methyl‐3‐phospholene 1‐oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single‐crystal X‐ray analysis. The absolute P‐configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra. Chirality 26:174–182, 2014. © 2014 Wiley Periodicals, Inc.
Analysis and evaluation of incentive mechanisms in P2P networks: a spatial evolutionary game theory perspective
Authors: Cui Guanghai , Li Mingchu , Wang Zhen , Ren Jiankang , Jiao Dong , Ma Jianhua
Published: February 2014

In peer‐to‐peer (P2P) networks, contributions are made by peers voluntarily for the autonomous character of peers. However, selfish peers may refuse to be cooperative when considering their limited transmission resources. Incentive mechanisms are always used to guarantee successful cooperations among peers. Although the inventive mechanisms have been widely investigated on the basis of game theory, most researches assume that peers are well mixed in the network, regardless of the influence of peers' transaction relationships. In this paper, a novel analysis framework based on spatial evolutionary game theory is proposed to verify the effectiveness of incentive mechanisms. In the framework, a transaction overlay network is used to model the transaction relationships of peers. The transactions between clients and servers are modeled as the donor‐recipient game to satisfy their asymmetric characters. Influences of the learning noise and some common behaviors of peers on incentive mechanisms are also considered. Moreover, in order to demonstrate the utility of the framework, a reciprocation‐based incentive mechanism, which considers the requestors' behaviors of providing and consuming services, is thoroughly investigated under the framework in scenarios with homogeneous and heterogeneous benefits of services. By using the framework, besides the effectiveness of incentive mechanisms, the detailed spatiotemporal evolutions of peers' strategies driven by incentive mechanisms can also be obtained. Copyright © 2014 John Wiley & Sons, Ltd.
Combining geo‐referencing and network coding for distributed large‐scale information management
Authors: Picone Marco , Amoretti Michele , Martalò Marco , Zanichelli Francesco , Ferrari Gianluigi
Published: February 2014

The widespread and ubiquitous availability of Internet access enables the collective sharing of huge amount of data generated by heterogeneous sources. For example, the information, which will be exchanged among entities (sensors, people, and services) of future smart cities to enhance the security and lifestyle of their citizens, poses the challenging question of how this information can be efficiently and effectively maintained across the city. In this article, we propose a decentralized approach, based on the distributed geographic table (DGT) overlay scheme, which exploits geo‐referenced information about nodes to achieve efficient data management. After recalling DGT main concepts, we illustrate the possible node types and how information can be published and retrieved within the network. To cope with the unavoidable node failures and disconnections, our approach leverages upon randomized network coding to increase the robustness of publish/retrieval operations. Evaluation is carried out through an extensive simulation analysis for a realistic urban scenario using the metrics of efficiency in data publication/search, resource availability, and storage occupancy requirements. Results show the approach effectiveness for large‐scale sharing of geo‐referenced information and tradeoffs between redundancy overhead and resource availability. A few results obtained with a preliminary DGT implementation are also presented in the paper. Copyright © 2014 John Wiley & Sons, Ltd.
Angular Velocity Distribution of the Electric Microfield in Plasma
Authors: Adaika H. , Meftah M. T.
Published: February 2014

In theory of the spectral line shapes, the conventional scheme use two approximations for the local electric field (microfield) due to all charged particles of the plasma. The quasi‐static approximations for the ions and the impact approximation for the electrons. The first approximation consists to say that the electric field is constant during the characteristic time. In this work we shall transpose the idea of the first approximation, to the angular velocity of the microfield whereas its strength is kept constant and equal to its mean value. We shall use the Holtsmark approach and the independent particles model (due to Margeneau and Lewis) to compute the static distribution function of the angular velocity of the microfield. In the first approach (Holtsmark), the distribution shows a Lorentzian behavior, whereas the second approach (Margenau and Lewis) shows a gaussian behavior. Subsequently, we have applied the obtained static distribution to show the effect on the broadening of Lyman‐alpha line for a plasma composed of He+ ions. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Aiming for better glucose control: is HbA1c of 7% the ‘holy grail’? The clinical approach or seven clinical questions about 7
Authors: Koren Shlomit , Rapoport Micha J.
Published: February 2014

The diabetes epidemic imposes a substantial burden on health systems and economy all over the world. Over the last two decades, many health systems adopted health care quality and performance measures for diabetes mellitus, most notably haemoglobin A1c. This article raises concerns regarding the significance of HbA1c as a performance measure and emphasizes the need for individualized therapy. Copyright © 2014 John Wiley & Sons, Ltd.
Progressive change of intra‐islet GLP‐1 production during diabetes development
Authors: O'Malley Thomas J. , Fava Genevieve E. , Zhang Yanqing , Fonseca Vivian A. , Wu Hongju
Published: February 2014

Background

Glucagon‐like peptide 1 (GLP‐1) and glucagon share the same precursor molecule proglucagon, but each arises from a distinct posttranslational process in a tissue‐specific manner. Recently, it has been shown that GLP‐1 is co‐expressed with glucagon in pancreatic islet cells. This study was aimed to investigate the progressive changes of GLP‐1 versus glucagon production in pancreatic islets during the course of diabetes development.

Methods

Both type 1 (non‐obese diabetes mice) and type 2 (db/db mice) diabetes models were employed in this study. The mice were monitored closely for their diabetes progression and were sacrificed at different stages according to their blood glucose levels. GLP‐1 and glucagon expression in the pancreatic islets was examined using immunohistochemistry assays. Quantitative analysis was performed to evaluate the significance of the changes.

Results

The ratio of GLP‐1‐expressing cells to glucagon‐expressing cells in the islets showed significant, progressive increase with the development of diabetes in db/db mice. The increase of GLP‐1 expression was in agreement with the upregulation of PC1/3 expression in these cells. Interestingly, intra‐islet GLP‐1 expression was not significantly changed during the development of type 1 diabetes in non‐obese diabetes mice.

Conclusions

The study demonstrated that GLP‐1 was progressively upregulated in pancreatic islets during type 2 diabetes development. In addition, the data suggest clear differences in intra‐islet GLP‐1 production between type 1 and type 2 diabetes developments. These differences may have an effect on the clinical and pathophysiological processes of these diseases and may be a target for therapeutic approaches. Copyright © 2014 John Wiley & Sons, Ltd.
Bulky Titanium Amides: C–H Bond Activation under Mild Conditions
Authors: Adler Christian , Bekurdts Alexander , Haase Detlev , Saak Wolfgang , Schmidtmann Marc , Beckhaus Rüdiger
Published: February 2014

The bulky titanium monoamido complex Cl3TiNCy2 (1) was synthesized from TiCl4 and dicyclohexylamine (Cy2NH). The solid‐state structure of 1 demonstrates a close intramolecular contact between the metal centre and one ipso carbon atom of the amido ligand. This contact may indicate an agostic interaction analogous to those of transition metal alkyl compounds. The alteration of the coordination sphere of 1 with neutral ligands [pyridine (2), 2,2′‐bipyridyl (3), N,N,N′,N′‐tetramethylethane‐1,2‐diamine (tmeda, 4), and 1,2‐bis(dimethylphosphanyl)ethane (dmpe, 5)] results in octahedral compounds with a meridional arrangement of the ligands. The solid‐state structure of 5 reveals a significantly closer contact between the titanium atom and one ipso carbon atom of the ligand. The magnesium reduction of 1 in the presence of adamantylidenepentafulvene yields the dark green complex (η5,η1‐adamantylidenepentafulvene)Ti(NCy2)Cl (8). The exchange of the last chlorine atom with other bulky amido ligands [NCy2, N(SiMe3)2] by salt metathesis reactions initiates a spontaneous C–H activation at room temperature. The titanaaziridine (η5‐CpAd)(η2‐NCy2)TiNCy2 (9) formed after a β‐C–H activation with LiNCy2. The use of NaN(SiMe3)2 results in a γ‐C–H activation and the formation of the azatitanacyclobutane (10). The alkylation of ClTi(NCy2)3 (7) with methyllithium produces the reactive complex MeTi(NCy2)3 (11). The spontaneous reaction of 11 at room temperature by β‐C–H activation to release methane and cyclohexene yields the dinuclear imido‐bridged complex [(Cy2N)2Ti(NCy)]2 (12). The formation of 12 can also be observed by 1H NMR spectroscopic measurements.
Does remembering past ingroup harmdoing promote postwar cross‐group contact? Insights from a field‐experiment in Liberia
Authors: Mazziotta Agostino , Feuchte Friederike , Gausel Nicolay , Nadler Arie
Published: February 2014

In the aftermath of the Liberian civil wars, we investigated whether it is possible to systematically influence how people construe their group's role during the conflict and how this affects intergroup emotions and behavioral intentions. In a field experiment, 146 participants were randomly assigned to think about incidents of violence during the war that were either committed by fellow ingroup members (perpetrator‐focus) or against fellow ingroup members (victim‐focus). Adopting a perpetrator‐focus led to greater willingness to engage in cross‐group contact, greater need for acceptance, and greater intergroup empathy. The focus manipulation did not affect participants' need for empowerment.

Key message: Appraising the ingroup as “victim” or “perpetrator” after conflicts with reciprocal harmdoing is largely a matter of psychological construction. A promising avenue for promoting positive cross‐group contact consists in widening the ingroup's victim role by also remembering the harm that the ingroup inflicted upon others. This amplifies the need of acceptance, which leads to greater intergroup empathy and greater willingness to engage in cross‐group contact. Copyright © 2013 John Wiley & Sons, Ltd.
Regeneration of hexamminecobalt(II) under the catalysis of activated carbon treated with K2S2O8 solution
Authors: Long Xiang‐Li , Zhang Ruo‐Chuan , Chou Xue‐Wei , Li Bei‐Bei , Yuan Wei‐Kang
Published: February 2014

The combined elimination of NO and SO2 can be realized by hexamminecobalt(II) solution. Activated carbon is utilized to catalyze the reduction of hexamminecobalt(III) (Co(NH3)63+) to hexamminecobalt(II) (Co(NH3)62+), so as to maintain a high NO removal efficiency for a long time. K2S2O8 solution has been tried to modify coconut activated carbon to enhance its catalytic capability in the reduction of hexamminecobalt(III). The experiments have been performed in a stirred cell to investigate the effects of K2S2O8 concentration, impregnation temperature, and impregnation time on the catalytic ability of activated carbon. The results showed that the best K2S2O8 concentration for the improvement of activated carbon is 0.3 mol L−1. The optimal impregnation temperature was 40°C. The optimum impregnation duration was 9 h. After treated with K2S2O8 solution, the surface area of activated carbon decreased. But the acidity on its surface was enhanced, which played a crucial role in improving the catalytic capacity of activated carbon in the reduction of Co(NH3)63+. The experimental results showed that the modified carbon could obtain a higher NO removal efficiency than the original carbon. © 2014 American Institute of Chemical Engineers Environ Prog, 34: 65–73, 2015
Assessment of 80 years of ancient‐badlands restoration in Saldaña, Spain
Authors: Hevia Joaquín Navarro , de Araújo José Carlos , Manso Jorge Mongil
Published: February 2014

This paper presents the history of badland generated in the Saldaña region, Spain; as well as the main responses eight decades after the start of restoration – in terms of vegetation, soil and erosive processes. The restoration consisted of intense reforestation and construction of more than 100 check dams and numerous wattle fences. Presently, the dense vegetation (87% cover) contrasts markedly with the degraded landscape from the early 20th century (5% cover). The thickness of litter and the natural presence of some species (Quercus pyrenaica, Paeonia broteroi and Lactarius deliciosus) clearly indicate the recovery of the site. The development of the forest cover shows that the intervention has the potential to recover almost 90% of the area. There is also evidence of soil regeneration, although some properties (erodibility, resistance to penetration and shear‐strength resistance) are not that different between the forested and degraded areas. In the restored zones, runoff is negligible, since a thick layer of moss covers the spillways of all the check dams. Erosion has almost been stopped by the effects of vegetation cover, litter and higher infiltration rates (infiltration rate in forested slopes is 43.4 times greater than in bare slopes). Sediment detachment, such as landslides, mudflows and piping, still occur, but are restricted to the degraded zones. Furthermore, even when sediments are mobilized from the upper degraded hillslopes during the larger storms events (2000–2010), check dams and the lower elevation restored forest‐buffers effectively work to reduce the sediment yield into the Carrión River by almost three orders of magnitude (<102 mg L‐1), compared with data from the 1930s and 1940s (>105 mg L‐1). Copyright © 2014 John Wiley & Sons, Ltd.
Paleoflood events recorded by speleothems in caves
Authors: Gázquez Fernando , Calaforra José María , Forti Paolo , Stoll Heather , Ghaleb Bassam , Delgado‐Huertas Antonio
Published: February 2014

Speleothems are usually composed of thin layers of calcite (or aragonite). However, cemented detrital materials interlayered between laminae of speleothemic carbonate have been also observed in many caves. Flowstones comprising discontinuous carbonate layers form due to flowing water films, while flood events introduce fluviokarstic sediments in caves that, on occasion, are recorded as clayey layers inside flowstones and stalagmites. This record provides a potential means of understanding the frequency of palaeofloods using cave records. In this work, we investigate the origin of this type of detrital deposit in El Soplao Cave (Northern Spain). The age of the lowest aragonite layer of a flowstone reveals that the earliest flood period occurred before 500 ka, though most of the flowstone formed between 422 +69/‐43 ka and 400 +66/‐42 ka. This suggests that the cave was periodically affected by palaeoflood events that introduced detrital sediments from the surface as a result of occasional extreme rainfall events, especially at around 400 ka. The mineralogical data enable an evolutionary model for this flowstone to be generated based on the alternation of flood events with laminar flows and carbonate layers precipitation that can be extrapolated to other caves in which detrital sediments inside speleothems have been found. Copyright © 2014 John Wiley & Sons, Ltd.
Channel pattern of proglacial rivers: topographic forcing due to glacier retreat
Authors: Marren Philip M. , Toomath Shamus C.
Published: February 2014

Glacier retreat leads to changes in channel pattern during deglaciation, in response to changing water, sediment and base level controls. Recent ongoing retreat at Skaftafellsjökull, Iceland (c. 50 m per year since 1998) has resulted in the formation of a sequence of river terraces, and several changes in river channel pattern. This paper compares widely used models of river channel pattern against the changes observed at Skaftafellsjökull. Doing this reveals the role of topographic forcing in determining proglacial channel pattern, whilst examining the predictive power and limitations of the various approaches to classifying river channels. Topography was found to play a large role in determining channel pattern in proglacial environments for two reasons: firstly, glacier retreat forces rivers to flow through confined moraine reaches. In these reaches, channels which theory predicts should be braided are forced to adopt a single channel. Secondly, proximal incision of proglacial rivers, accompanied by downstream aggradation, leads to changes in slope which force the river to cross channel pattern thresholds. The findings of this work indicate that in the short term, the majority of channel pattern change in proglacial rivers is due to topographic forcing, and that changes due to changing hydrology and sediment supply are initially relatively minor, although likely to increase in significance as deglaciation progresses. These findings have implications for palaeohydraulic studies, where changes in proglacial channel pattern are frequently interpreted as being due to changes in water or sediment supply. This paper shows that channel pattern can change at timescales faster than hydrological or sediment budget changes usually occur, in association with relatively minor changes in glacier mass balance. Copyright © 2014 John Wiley & Sons, Ltd.
The significance of landforms – the contribution of geomorphology to the World Heritage Programme of UNESCO
Authors: Migoń Piotr
Published: February 2014

This discussion paper addresses the role of geomorphology in designating UNESCO World Heritage properties. Two of the defined criteria employed in the process are explicitly relevant to geomorphology. Criterion (vii) emphasizes the occurrence of superlative natural phenomena, while criterion (viii) directly refers to landforms and on‐going surface processes, along with historical geological values. Superlative natural phenomena may be singular features, but in recent nominations the focus has tended to be on geomorphic diversity over limited areas. Overall, this is a criterion significantly influenced by subjective judgement. The significance of landforms, as included in the wording of criterion (viii), may be considered in three ways. Landforms may be significant for the science of geomorphology itself, and/or for other natural science disciplines, particularly biology and ecology, and/or be of wider cultural significance, including for history, architecture, general landscape aesthetics, art, or religion, underpinning cultural developments. To better determine the conditions to be fulfilled by a property to be considered as geomorphologically significant at the highest global level required for World Heritage listing seems a timely and useful exercise. Copyright © 2014 John Wiley & Sons, Ltd.
Landscape Evolution Modelling of naturally dammed rivers
Authors: van Gorp Wouter , Temme Arnaud J.A.M. , Baartman Jantiene E.M. , Schoorl Jeroen M.
Published: February 2014

Natural damming of upland river systems, such as landslide or lava damming, occurs worldwide. Many dams fail shortly after their creation, while other dams are long‐lived and therefore have a long‐term impact on fluvial and landscape evolution. This long‐term impact is still poorly understood and landscape evolution modelling (LEM) can increase our understanding of different aspects of this response. Our objective was to simulate fluvial response to damming, by monitoring sediment redistribution and river profile evolution for a range of geomorphic settings. We used LEM LAPSUS, which calculates runoff erosion and deposition and can deal with non‐spurious sinks, such as dam‐impounded areas. Because fluvial dynamics under detachment‐limited and transport‐limited conditions are different, we mimicked these conditions using low and high erodibility settings, respectively. To compare the relative impact of different dam types, we evaluated five scenarios for each landscape condition: one scenario without a dam and four scenarios with dams of increasing erodibility. Results showed that dam‐related sediment storage persisted at least until 15 000 years for all dam scenarios. Incision and knickpoint retreat occurred faster in the detachment‐limited landscape than in the transport‐limited landscape. Furthermore, in the transport‐limited landscape, knickpoint persistence decreased with increasing dam erodibility. Stream capture occurred only in the transport‐limited landscape due to a persisting floodplain behind the dam and headward erosion of adjacent channels. Changes in sediment yield variation due to stream captures did occur but cannot be distinguished from other changes in variation of sediment yield. Comparison of the model results with field examples indicates that the model reproduces several key phenomena of damming response in both transport‐limited and detachment‐limited landscapes. We conclude that a damming event which occurred 15 000 years ago can influence present‐day sediment yield, profile evolution and stream patterns. Copyright © 2014 John Wiley & Sons, Ltd.
Bicarbonate toxicity to Ceriodaphnia dubia and the freshwater shrimp Paratya australiensis and its influence on zinc toxicity
Authors: Vera Carolina Lopez , Hyne Ross V. , Patra Ron , Ramasamy Sunderam , Pablo Fleur , Julli Moreno , Kefford Ben J.
Published: February 2014

Bicarbonate is often a major ionic constituent associated with produced waters from methane gas extraction and coal mining, yet few studies have determined its specific toxicity. Currently, the environmental risk of bicarbonate anion in water discharges is assessed based on the toxicity of sodium chloride or artificial seawater and is regulated via electrical conductivity. Increased NaHCO3 added to Ceriodaphnia dubia in synthetic or natural water gave similar 48-h 10% effective concentration (EC10) values of 1750 ± 125 mg NaHCO3/L (mean ± standard error) and 1670 ± 180 mg NaHCO3/L, respectively. Bicarbonate was toxic to C. dubia in both waters with conductivities above 1900 µS/cm. In contrast, when conductivity was elevated with NaCl, toxicity to C. dubia was observed only above 2800 µS/cm. Bicarbonate also impaired C. dubia reproduction with an EC10 of 340 mg NaHCO3/L. Major ion composition also influenced Zn bioavailability, a common co-occurring metal contaminant in coal mine waters, with sublethal concentrations of NaHCO3 and elevated pH increasing Zn toxicity. Higher pH was the dominant parameter determining a 10-fold increase in the 48-h 50% effective concentration (EC50) for Zn toxicity to C. dubia at pH 8.6 of 34 µg Zn/L (95% confidence limit = 32–37 µg Zn/L) compared with the Zn toxicity at approximately circumneutral pH. Exposure of the freshwater shrimp Paratya australiensis (Atyidae) in natural water to increasing bicarbonate gave a mean 10-d 10% lethal concentration (LC10) of 850 ± 115 mg NaHCO3/L, associated with a mean conductivity EC10 of 1145 µS/cm, which is considerably lower than toxicity of NaCl and artificial seawater to this species reported elsewhere. Because toxicity was influenced by salt composition, specific ions should be regulated rather than conductivity alone in mine wastewater discharges. Environ Toxicol Chem 2014;33:1179–1186. © 2014 SETAC
Quantification of furocoumarins in hydroalcoholic fragrances by a liquid chromatography–high resolution/accurate mass method
Authors: Corbi Elise , Pérès Christophe , David Nathalie
Published: February 2014

Furocoumarins are secondary metabolites that occur in various plant species used as ingredients in fragrances and cosmetics. Those compounds have received an increased interest in those matrices since they are known to induce photosensitization and to have potential carcinogenic, mutagenic and reprotoxic effects. To date, there are no restricted limits regarding these compounds; however, some committees proposed following seven targeted compounds at low level concentration in finished cosmetic products (≤1 mg/l). This implies the need for a robust and specific analytical method to control and determine their concentrations in essential oils or more complex matrices such as fragrances. An innovative RP‐HPLC high‐resolution/accurate‐mass MS method based on Orbitrap technology was developed to quantify seven furocoumarins in fragrances in the range 0.01–1 mg/l. This method was developed and validated according to accuracy profile methodology. Accurate mass and high resolution provides a robust and highly specific approach to quantify the compounds and minimize tedious sample preparation. The method was finally used to quantify more than 50 perfumes (eaux de toilette, eaux de parfum, extraits). Copyright © 2014 John Wiley & Sons, Ltd.
Complementary molecular approaches reveal heterogeneous CDH1 germline defects in Italian patients with hereditary diffuse gastric cancer (HDGC) syndrome
Authors: Molinaro Valeria , Pensotti Valeria , Marabelli Monica , Feroce Irene , Barile Monica , Pozzi Simonetta , Laghi Luigi , Serrano Davide , Bernard Loris , Bonanni Bernardo , Ranzani Guglielmina Nadia
Published: February 2014

Germline inactivation of the E‐cadherin gene (CDH1) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligation‐dependent probe amplification, single‐nucleotide primer extension, bisulfite sequencing, reverse‐transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six CDH1 constitutive alterations were novel. Our data support the need for a multimethod approach for CDH1 genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from CDH1 genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic CDH1 mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells. © 2014 Wiley Periodicals, Inc.
Gene Expression Signature for Biliary Atresia and a Role for Interleukin-8 in Pathogenesis of Experimental Disease
Authors: Bessho Kazuhiko , Mourya Reena , Shivakumar Pranavkumar , Walters Stephanie , Magee John C. , Rao Marepalli , Jegga Anil G. , Bezerra Jorge A.
Published: February 2014

Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes,

IL8

and

LAMC2

were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in

IL8

was relevant to disease pathogenesis, we inactivated the signaling of

IL8

homologs by genetic targeting of the

Cxcr2

receptor in a murine model of experimental BA. Disruption of

Cxcr2

shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice.

Conclusion :

The hepatic expression of

IL8

and

LAMC2

has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA. (Hepatology 2014;60:211–223)
Incomplete Hepatitis B Immunization, Maternal Carrier Status, and Increased Risk of Liver Diseases: A 20-Year Cohort Study of 3.8 Million Vaccinees
Authors: Chien Yin-Chu , Jan Chyi-Feng , Chiang Chun-Ju , Kuo Hsu-Sung , You San-Lin , Chen Chien-Jen
Published: February 2014

Hepatitis B immunization has been documented to prevent fulminant hepatic failure (FHF) and hepatocellular carcinoma (HCC) by historical comparison studies in Taiwan. This study aimed to assess long-term risks and predictors of various liver diseases associated with incomplete immunization in 3.8 million vaccinees. Profiles of the National Hepatitis B Immunization Registry, National Cancer Registry, and National Death Certification Registry were linked to ascertain newly diagnosed cases of HCC and deaths from FHF and chronic liver diseases (CLDs) from infancy to early adulthood of 3,836,988 newborn vaccinees. Cox's proportional hazards models were used to estimate hazard ratios (HRs) for various risk predictors. There were 49 newly developed cases of HCC, 73 deaths from FHF, and 74 deaths from CLDs during the follow-up of 41,854,715 person-years. There were striking differences between unvaccinated and vaccinated newborns after the launch of a national immunization program for HCC incidence (0.293 vs. 0.117 per 100,000 person-years), FHF mortality (0.733 vs. 0.174 per 100,000 person-years), and CLD mortality (2.206 vs. 0.177 per 100,000 person-years). Among vaccinees, incomplete immunization was the most important risk predictor of HCC, FHF, and CLDs, showing an HR (95% confidence interval,

P

value) of 2.52 (1.25-5.05;

P

= 0.0094), 4.97 (3.05-8.11;

P

< 0.0001), and 6.27 (3.62-10.84;

P

< 0.0001), respectively, after adjustment for maternal hepatitis B serostatus.

Conclusion :

Hepatitis B immunization can significantly prevent the long-term risk of HCC, FHF, and CLDs from infancy to early adulthood. Incomplete immunization with hepatitis B immunoglobulin or vaccines was the most important risk predictor of the liver disease among vaccinees. (Hepatology 2014;60:125–132)
Efficacy of neural network and genetic algorithm techniques in simulating spatio‐temporal fluctuations of groundwater
Authors: Jha Madan K. , Sahoo Sasmita
Published: February 2014

Groundwater modelling has emerged as a powerful tool to develop a sustainable management plan for efficient groundwater utilization and protection of this vital resource. This study deals with the development of five hybrid artificial neural network (ANN) models and their critical assessment for simulating spatio‐temporal fluctuations of groundwater in an alluvial aquifer system. Unlike past studies, in this study, all the relevant input variables having significant influence on groundwater have been considered, and the hybrid ANN technique [ANN‐cum‐Genetic Algorithm (GA)] has been used to simulate groundwater levels at 17 sites over the study area. The parameters of the ANN models were optimized using a GA optimization technique. The predictive ability of the five hybrid ANN models developed for each of the 17 sites was evaluated using six goodness‐of‐fit criteria and graphical indicators, together with adequate uncertainty analyses. The analysis of the results of this study revealed that the multilayer perceptron Levenberg–Marquardt model is the most efficient in predicting monthly groundwater levels at almost all of the 17 sites, while the radial basis function model is the least efficient. The GA technique was found to be superior to the commonly used trial‐and‐error method for determining optimal ANN architecture and internal parameters. Of the goodness‐of‐fit statistics used in this study, only root‐mean‐squared error,r2and Nash–Sutcliffe efficiency were found to be more powerful and useful in assessing the performance of the ANN models. It can be concluded that the hybrid ANN modelling approach can be effectively used for predicting spatio‐temporal fluctuations of groundwater at basin or subbasin scales. Copyright © 2014 John Wiley & Sons, Ltd.
EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer
Authors: Fichter Christiane Daniela , Timme Sylvia , Braun Julia Alexandra , Gudernatsch Verena , Schöpflin Anja , Bogatyreva Lioudmilla , Geddert Helene , Faller Gerhard , Klimstra David , Tang Laura , Hauschke Dieter , Werner Martin , Lassmann Silke
Published: February 2014

Receptor tyrosine kinases (RTKs) are in the focus of targeted therapy for epithelial tumors. Our study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in the context of therapeutic EGFR and HER2 inhibitors. In archival pretreatment biopsies of esophageal carcinomas (n = 110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p = 0.088) and HER2 (34.4%; p < 0.001) with HER3 (91.5%; p < 0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to erlotinib, gefitinib and lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33 and SK‐GT‐4), lapatinib was similarly effective in strongly HER2‐positive (mainly HER2 homodimers and some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2‐targeting antibodies (trastuzumab and pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody‐dependent cellular cytotoxicity in EAC (OE19 and OE33) cells upon co‐culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e.g., with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2‐targeting inhibitors in EACs.
Activating adaptive cellular mechanisms of resistance following sublethal cytotoxic chemotherapy: Implications for diagnostic microdosing
Authors: Wurz Gregory T. , DeGregorio Michael W.
Published: February 2014

As Phase 0 studies have proven to be reasonably predictive of therapeutic dose pharmacokinetics, the application of microdosing has expanded into metabolism, drug–drug interactions and now diagnostics. One potentially serious issue with this application of microdosing that has not been previously discussed is the possibility of activating cellular mechanisms of drug resistance. Here, we provide an overview of Phase 0 microdosing and drug resistance, with an emphasis on cisplatin resistance, followed by a discussion of the potential for inducing acquired resistance to platinum‐based or other types of chemotherapy in cancer patients participating in Phase 0 diagnostic microdosing studies. A number of alternative approaches to diagnostic microdosing, such as the human tumor cloning assay and the use of peripheral blood mononuclear cells as a surrogate for measuring DNA adducts, are discussed that would avoid exposing cancer patients to low doses of first‐line chemotherapy and the possible risk of triggering cellular mechanisms of acquired resistance. Until it has been established that diagnostic microdosing in cancer patients poses no risk of acquired drug resistance, such studies should be approached with caution.
Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6
Authors: Zhu Xiaolan , Li Yuefeng , Xie Chanjuan , Yin Xinming , Liu Yueqin , Cao Yuan , Fang Yue , Lin Xin , Xu Yao , Xu Wenlin , Shen Huiling , Wen Jian
Published: February 2014

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel‐resistant ovarian cancer patients and cell lines had decreased miR‐145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR‐145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P‐gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR‐145, resulting in restoration of P‐gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR‐145. Intriguingly, demethylation with 5‐aza‐dC led to reactivation of miR‐145 expression in drug‐resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR‐145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.
NKG2D signaling in cancer immunosurveillance
Authors: López‐Soto Alejandro , Huergo‐Zapico Leticia , Acebes‐Huerta Andrea , Villa‐Alvarez Mónica , Gonzalez Segundo
Published: February 2014

The immune system is able to detect and eliminate transformed cells. The activating receptor NKG2D is particularly relevant for cancer immunosurveillance. NKG2D ligand expression renders tumor cells more susceptible to be killed by NK and T cells, and correlates with the clinical outcome of the disease. However, tumors develop mechanisms to overcome the NKG2D‐mediated immune response, which has been associated with poor prognosis and impairment of the clinical benefits of immunotherapy in many human cancers. The highly specific pattern of expression displayed by the NKG2D ligands, mainly confined to tumor cells, together with the strong immune response triggered by this receptor clearly supports the idea that the NKG2D‐mediated pathway may be a powerful target for the treatment of cancer. This review draws together the most recent discoveries concerning the biology of the NKG2D signaling and their therapeutic relevance in the context of cancer.
Association between dietary antioxidant vitamins intake/blood level and risk of gastric cancer
Authors: Li Peiwei , Zhang Honghe , Chen Jiamin , Shi Yu , Cai Jianting , Yang Jun , Wu Yihua
Published: February 2014

We aimed to systematically evaluate the association between dietary intake/blood levels of antioxidant vitamins (vitamin C, vitamin E, β‐carotene, and α‐carotene) and gastric cancer risk. Systematic literature searches were conducted until April 2013 in Pubmed and Embase to identify relevant studies. Either a fixed‐ or a random‐effects model was adopted to estimate overall odds ratios (ORs). Dose–response, meta‐regression, subgroup, and publication bias analyses were applied. Forty articles were finally included in the present study. Higher dietary intake of vitamin C, vitamin E, β‐carotene, and α‐carotene was inversely associated with gastric cancer risk (for vitamin C, pooled OR = 0.58, 95% CI 0.51–0.65; for vitamin E, pooled OR = 0.65, 95% CI 0.57–0.74; for β‐carotene, pooled OR = 0.59, 95% CI 0.49–0.70; for α‐carotene, pooled OR = 0.69, 95% CI 0.52–0.93). Subgroup analyses suggested the effects of these antioxidant vitamins were different in gastric cancer subtypes. As indicated by dose–response analysis, a 100 mg/day increment of vitamin C intake conferred an OR of 0.78 (95% CI 0.67–0.90); a 15 mg/day increment of vitamin E intake conferred an OR of 0.79 (95% CI 0.66–0.94); and a 5 mg/day increment in β‐carotene intake conferred an OR of 0.80 (95% CI 0.60–1.04). No significant association was observed between blood vitamin C, α‐tocopherol, γ‐ tocopherol, β‐carotene and α‐carotene levels and gastric cancer risk. In conclusion, dietary intake of vitamin C, vitamin E, β‐carotene and α‐carotene was inversely associated with gastric cancer risk while no such association was observed for blood levels of these antioxidant vitamins, thus the results should be interpreted cautiously.
Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice
Authors: Sasaki Soichiro , Baba Tomohisa , Shinagawa Kei , Matsushima Kouji , Mukaida Naofumi
Published: February 2014

Patients with inflammatory bowel diseases often develop colon carcinoma. Combined treatment of azoxymethane (AOM) and dextran sulfate sodium (DSS) recapitulates colitis‐associated cancer in mice. AOM/DSS‐induced tumor formation was reduced in CCL3‐ or its specific receptor, CCR5‐deficient mice despite the presence of a massive infiltration of inflammatory cells. However, AOM/DSS‐induced type I collagen‐positive fibroblast accumulation in the colon was reduced in CCL3‐ or CCR5‐deficient mice. This was associated with depressed expression of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), which is expressed mainly by fibroblasts. Moreover in vitro, CCL3 induced fibroblasts to proliferate and to enhance HB‐EGF expression. Furthermore, CCR5 blockade reduced tumor formation together with reduced fibroblast accumulation and HB‐EGF expression, even when administered after the development of multiple colon tumors. Thus, CCL3‐CCR5‐mediated fibroblast accumulation may be required, in addition to leukocyte infiltration, to induce full‐blown colitis‐associated carcinogenesis. Our studies shed light on a therapeutic potential of CCR5 antagonist for patients with colitis‐associated cancer.
Rotifers of temporary waters
Authors: Walsh Elizabeth J. , Smith Hilary A. , Wallace Robert L.
Published: February 2014

While ubiquitous, temporary waters vary greatly in geographic distribution, origin, size, connectivity, hydroperiod, and biological composition. However, all terminate as active habitats, transitioning into either dryness or ice, only to be restored when conditions improve. Hydroperiod in some temporary habitats is cyclical and predictable, while in others it is sporadic. Although the rotifer communities of temporary waters are subjected to unique selective pressures within their habitats, species share many of the same adaptive responses. Here, we review temporary waters and their rotiferan inhabitants, examining community composition, life history, and evolutionary strategies that allow rotifers to flourish in these fluctuating environments.
Molecular cloning and localization of GABAA receptor‐associated protein in the rotifer Brachionus plicatilis
Authors: Marcial Helen S. , Suga Koushirou , Kinoshita Shigaheru , Kaneko Gen , Hagiwara Atsushi , Watabe Shugo
Published: February 2014

γ‐Aminobutyric acid receptor type A‐associated protein (GABARAP) and its homologs constitute a protein family found in many eukaryotes from yeast to human, and are known to be involved in intracellular membrane trafficking of GABAA receptors and autophagy. In this study, we cloned cDNA‐encoding GABARAP from the monogonont rotifer Brachionus plicatilis and examined for its tissue distribution at the protein level in neonates, males and females. Using reverse transcription (RT)‐PCR and rapid amplification of cDNA ends (RACE) techniques, we showed that like other GABARAPs, rotifer GABARAP was also composed of 117 amino acids and highly homologous to vertebrate GABARAP2 ortholog (74–76% identity). GABARAP was demonstrated with its specific antibody to be ubiquitously distributed, irrespective of neonates, males, and females, in the coronal area that covers brain and contains most mechano‐ and chemoreceptors. Rotifer GABARAP was also expressed in the mature eggs but not in immature eggs. Double immunostaining with mammalian anti‐GABA γ receptor antibody showed that rotifer GABARAP co‐localized with GABA receptor, suggesting the association of the two proteins. The presence of GABARAP in rotifer implies that it is highly conserved during evolution, and plays important roles in various biological processes.
Development of a multiparametric in vitro model of skin sensitization
Authors: Guyard‐Nicodème Muriel , Gerault Eloise , Platteel Marion , Peschard Olivier , Veron Wilfried , Mondon Philippe , Pascal Svinareff , Feuilloley Marc G. J.
Published: February 2014

Most animal experiments on cosmetics safety are prohibited and since March 2013, this obligation includes sensitization tests. However, until now there has been no validated alternative in vitro method. In this work, 400 compounds used in the cosmetic industry were selected to cover the greatest diversity of structures, biological activities and sensitizing potential. These molecules were submitted to a series of tests aimed at reproducing essential steps in sensitization and to distinguish between sensitization and irritations, i.e., transcutaneous permeation (factor A), haptenation (factor B), sensitization cytokines production (factor C) and acute toxicity (factor D). The transcutaneous diffusion was measured on human skin explants using Franz cells. Haptenation was tested in solution on human serum albumin. Sensitization cytokine production was investigated by measurement of interleukin‐18 release by keratinocytes. Acute toxicity was determined using an 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide75 cell viability test. As only sufficiently stable, soluble and detectable compounds are usable, 33, 72, 68 and 68 molecules were finally tested on factors A, B, C and D, respectively, and 32 were completely screened by the four factors. The individual correlation of the four factors with the reference in vivo tests was limited but the combination of these factors led to a correlation between in vivo and in vitro assays of 81.2% and the safety of the test (risk of false negative) reached 96.8%. The techniques employed are simple and inexpensive and this model of four tests appears as a promising technique to evaluate in vitro the skin sensitization potential of unknown molecules. Copyright © 2014 John Wiley & Sons, Ltd.