bluuebunny/crossref_metadata_2025 huggingface dataset:
A Holistic Framework for Trust in Online Transactions
Authors: Li Feng , Pieńkowski Dariusz , van Moorsel Aad , Smith Chris
Published: May 2011

This paper systematically reviews previous studies of trust from social, economic and technological perspectives and develops a holistic framework for trust, which can be used to analyse the establishment and maintenance of trust in online transactions, and identify the mechanisms that can be used to increase trust. Trust plays a crucial role in the formation of dependent relationships represented by online transactions, and a holistic treatment of trust is necessary because of the gap that exists between the developments in information systems and our understanding of their social and economic implications, and the impact on the perceived trust of the transacting parties. This review enables us to depict an online transaction through its attributes and context, and systematically map these to identified trust antecedents. The key components and processes of the framework are outlined, and three strands of empirical work are discussed to develop it further. The framework highlights the critical role of institutions in the establishment and maintenance of trust in online transactions, which informs the development of e‐commerce and e‐business platforms and the underpinning information systems, and facilitates the establishment of mechanisms to induce additional institutions to increase trust in online transactions.
The ‘Housing Question’ and the State‐Socialist Answer: City, Class and State Remaking in 1950s Bucharest
Authors: CHELCEA LIVIU
Published: May 2011

Housing nationalization as a solution to urban inequalities has a long history in European social thought. This article describes housing nationalization in a state‐socialist context. Using a political economy perspective and relying on recently released archival material about housing in 1950s Romania, I argue that nationalization may be regarded as a special type of urban process. Nationalization raised the occupancy rate and intensified the usage of existing housing, desegregated centrally located neighborhoods, turned some residential space into office space for state institutions, facilitated the degradation of the existing housing stock and gradually produced a socialist gentry. Aside from similarities with other state‐socialist nationalizations from the same period, Romanian nationalization resembled the housing policies of other statist regimes. The data also suggest that, even in the context of revolutionary change, the state is a sum of multiple, often diverging projects, rather than a coherent actor.

Nationaliser le logement pour résoudre les inégalités urbaines n'est pas une solution nouvelle dans la pensée sociale européenne. Cette option est décrite ici dans le contexte du socialisme d'État. Adoptant l'angle de l'économie politique et s'appuyant sur des archives récemment rendues publiques concernant le logement en Roumanie dans les années 1950, cette étude affirme qu'on peut considérer la nationalisation comme un type particulier de processus urbain. Elle a élevé le taux d'occupation et intensifié l'usage de l'habitat disponible, atténué la ségrégation dans les quartiers centraux, transformé une partie de l'espace résidentiel en espace de bureaux pour des institutions étatiques, facilité la dégradation du parc de logements existant, et généré peu à peu une aristocratie socialiste. Hormis des similitudes avec les nationalisations dans d'autres États socialistes à la même époque, la démarche roumaine a ressemblé aux politiques publiques appliquées au logement dans des régimes étatiques différents. Les données suggèrent aussi que, même dans le contexte d'un changement révolutionnaire, l'État est un agrégat de projets multiples, souvent divergents, et non un acteur homogène.
Utilizing hydroglycolic extract from myrobalan fruits to counteract reactive oxygen species
Authors: Chulasiri M. , Wanaswas P. , Sriaum D. , Nakamat S. , Wongkrajang Y. , Kongsaktrakoon B. , Phornchirasilp S. , Songchitsomboon S. , Leelarungrayub D.
Published: May 2011

Synopsis

The hydroglycolic (HG) extract from 70% propylene glycol (PG) extraction of myrobalan fruits showed the most appreciable antioxidant efficiency towards 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) in comparison to the extracts from 30, 50, 70 and 100% ethyl alcohol (EA), and 30, 50 and 100% PG . Its total polyphenols were also higher than others. The additional analysis of antioxidant power revealed that this HG extract was able to counteract the induced oxidation caused by hydrogen peroxide (H2O2) and 2,2′‐azobis(2‐amidinopropane) dihydrochloride (AAPH). The quantification for the antioxidant capacity of the extract showed it was equivalent to 93.78 mg of 6‐hydroxy‐2,5,7,8‐tetramethychroman‐2‐carboxylic acid (Trolox) g−1 by 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐suphonic acid) diammonium (ABTS) assay, and was 140.17 mg ascorbic acid (AA) equivalent g−1 and 107.50 mg Trolox equivalent g−1 by photochemiluminescence (PCL) assay. The incorporation of the HG myrobalan extract into lotion and sunscreen lotion rendered these products to provide the similar antioxidant power as the extract alone.
Patients with early‐onset psoriasis achieve better results following Dead Sea climatotherapy
Authors: Harari M. , Czarnowicki T. , Fluss R. , Ruzicka T. , Ingber A.
Published: May 2011

Background  Plaque psoriasis has recently been divided in two types, which differ in severity and inheritance according to the age of the patient at the onset of the disease.

Aim  To compare the effect of Dead Sea climatotherapy (DSC) on these two types of disease, with early vs. late onset, and to determine the impact of this treatment on the response rate.

Methods  The files of 605 patients who were suffering from plaque psoriasis were retrieved from the database of the Research Institute at the Dead Sea (RIDS) and divided in two groups, types I and II, according to whether the age at the onset of the disease was under or over 40 years, respectively. The primary outcome for the assessment of DSC was Psoriasis Assessment of Severity Index of 95 (PASI 95), which indicates that the PASI improvement percentage reached 95%. Logistical regression was used to identify the factors that related to the observed outcome.

Results  By the end of the study, 74% of the patients in group 1 reached PASI 95 in comparison to 62% in group 2. The 95% confidence interval for the odds ratio (OR) of the effect in group 2 in comparison to that of group 1 was [0.31, 0.99], which implies that group 1 responded better to treatment in comparison to group 2. Cut‐off values for patients who were aged 30 and 20, respectively, exhibited similar trends; 75% vs. 65% and 78% vs. 68% for groups 1 and 2, respectively.

Conclusions  Efficacy rates following DSC were impressively high for plaque psoriasis patients. Contrary to our hypothesis, the treatment effect was found to inversely correlate with the age of the patient at disease onset.
Going, going, . . . gone? The decline of party membership in contemporary Europe
Authors: VAN BIEZEN INGRID , MAIR PETER , POGUNTKE THOMAS
Published: May 2011

This article offers an overview of levels of party membership in European democracies at the end of the first decade of the twenty‐first century and looks also at changes in these levels over time, comparing party membership today with figures from both 1980 and the late 1990s. While relying primarily on the direct and individual membership figures as reported by the parties themselves, the fit of the data with survey data is explored and it is concluded that the two perform well in terms of convergent validity. The differences between large and small democracies are examined, as well as old and new democracies, and it is found that levels of party membership are related to both the size and age of the democratic polity in question. Finally, the implications of the patterns observed in the membership data are discussed, and it is suggested that membership has now reached such a low ebb that it may no longer constitute a relevant indicator of party organisational capacity.
Indication, management, and outcome of brachycephalic dogs requiring mechanical ventilation
Authors: Hoareau Guillaume L. , Mellema Matthew S. , Silverstein Deborah C.
Published: May 2011

Objectives
–
To evaluate the frequency, and need for mechanical ventilation (MV) in a population of brachycephalic dogs (BD) compared with non‐BD. Also, to describe the pre‐MV abnormalities, ventilator settings used, the cardiovascular and pulmonary monitoring results and complications encountered in the same BD population. In addition, we sought to identify factors associated with successful weaning and describe outcomes of BD requiring MV.

Design
–
Retrospective observational study (1990–2008).

Setting
–
University Small Animal Teaching Hospital.

Animals
–
Fifteen BD managed with MV.

Interventions
–
None.

Measurements and Main Results
–
Signalment, indication for MV, ventilator settings, arterial blood gas values, duration of MV, complications, and outcome were recorded for each patient enrolled in study. BD were more likely to receive MV than non‐BD (P=0.036). Out of the 15 dogs that fulfilled the inclusion criteria 7 (47%) underwent MV for impending respiratory fatigue, 6 (40%) for hypoxemia and 2 for hypercapnea. The most common underlying disease was aspiration pneumonia. Duration of MV ranged from 2 to 240 hours (median 15 hours). Seven patients were weaned (47%). Seven dogs had a temporary tracheostomy tube and 5 of them (71%) were weaned. Dogs that were weaned had a significantly greater preweaning trial PaO2/FiO2 ratio than those that were not (359 ± 92 versus 210 ± 57 mm Hg, P=0.025). No significant difference for weaning success between dogs with and those without a tracheostomy was detected (P=0.132). The discharge rate was 27% (all from the respiratory fatigue group).

Conclusion
–
Among all dogs admitted to ICU, BD were more likely to receive MV than non‐BD. Aspiration pneumonia was frequently identified as the underlying cause of respiratory compromise. The survival rate for BD undergoing MV was not markedly different from previous studies. Weaning of BD from MV may be facilitated by employing preemptive strategies such as performing tracheostomy tube placements.
Antidepressant‐like effect induced by systemic and intra‐hippocampal administration of DNA methylation inhibitors
Authors: Sales Amanda J , Biojone Caroline , Terceti Mateus S , Guimarães Francisco S , Gomes Marcus VM , Joca Sâmia RL
Published: May 2011

BACKGROUND AND PURPOSE Epigenetic modifications are thought to play an important role in the neurobiology of depression. Antidepressant treatment induces histone acetylation in the hippocampus, which is associated with transcriptional activation, whereas stress increases DNA methylation, which is associated with transcriptional repression. Because the specific involvement of DNA methylation in the regulation of depressive‐like behaviours is not yet known, we have investigated the effects induced by systemic or intra‐hippocampal administration of inhibitors of DNA methyltransferase (DNMT) in rats submitted to a range of behavioural tests.

EXPERIMENTAL APPROACH Rats received i.p. injections of 5‐aza‐2‐deoxycytidine (5‐azaD, 0.1–0.8 mg·kg−1), 5‐azacytidine (5‐azaC, 0.4–3.2 mg·kg−1), imipramine (15 mg·kg−1) or vehicle and were submitted to the forced swimming test (FST) or open field test (OFT). Other groups of rats received intra‐hippocampal injection of DNMT inhibitors.

KEY RESULTS Systemic administration of DNMT inhibitors induced a dose‐dependent antidepressant‐like effect, which was followed by decreased DNA methylation and increased brain‐derived neurotrophic factor (BDNF) levels in the hippocampus. Hippocampal inhibition of DNA methylation induced similar behavioural effects. No treatment induced any locomotor effects in the OFT. Antidepressant‐like effects of 5‐azaD were confirmed in mice submitted to the FST or the tail suspension test.

CONCLUSIONS AND IMPLICATIONS Systemic, as well as hippocampal, inhibition of DNA methylation induced antidepressant‐like effects. These effects could be associated with increased hippocampal expression of BDNF. Our data give further support to the hypothesis that DNA methylation is an important epigenetic mechanism involved in the development of depressive‐like behaviours.
Cell‐Free Layer Formation in Small Arterioles at Pathological Levels of Erythrocyte Aggregation
Authors: ONG PENG KAI , JAIN SWATI , NAMGUNG BUMSEOK , WOO YEON I. , KIM SANGHO
Published: May 2011

Please cite this paper as: Ong, Jain, Namgung, Woo and Kim (2011). Cell‐Free Layer Formation in Small Arterioles at Pathological Levels of Erythrocyte Aggregation. Microcirculation 18(7), 541–551.

Objective:  To test our hypothesis that an elevation in the aggregation level of red blood cells found in human pathological conditions will significantly enhance cell‐free layer formation in small arterioles.

Methods:  Visualization of arteriolar blood flow in rat cremaster muscle was carried out in both normal and reduced flow conditions before and after Dextran 500 infusion to simulate physiological and pathological levels of red blood cell aggregation in humans.

Results:  Both normalized mean (p < 0.0001) and SD (p < 0.002) of the layer width were significantly enhanced after hyper‐aggregation induction in reduced flow conditions (mean pseudoshear rate = 57.3 ± 7.2/sec). Normalized mean and SD of the layer width generally increased with decreasing vessel radius and this effect was most pronounced with hyper‐aggregation in reduced flow conditions. The threshold pseudoshear rate at which the layer formation became more pronounced when compared with non‐aggregating condition was higher with hyper‐aggregation (217/sec) than normal‐aggregation induction (139/sec).

Conclusion:  Our findings confirmed the formation of a prominent cell‐free layer in the arterioles under higher shear conditions at pathological aggregation levels and this effect became more pronounced in smaller arterioles in normalizing the layer to the vessel radius.
Generic Sorting of Raft Lipids into Secretory Vesicles in Yeast
Authors: Surma Michal A. , Klose Christian , Klemm Robin W. , Ejsing Christer S. , Simons Kai
Published: May 2011

Previous work has showed that ergosterol and sphingolipids become sorted to secretory vesicles immunoisolated using a chimeric, artificial raft membrane protein as bait. In this study, we have extended this analysis to three populations of secretory vesicles isolated using natural yeast plasma membrane (PM) proteins: Pma1p, Mid2p and Gap1*p as baits. We compared the lipidomes of the immunoisolated vesicles with each other and with the lipidomes of the donor compartment, the trans‐Golgi network, and the acceptor compartment, the PM, using a quantitative mass spectrometry approach that provided a complete lipid overview of the yeast late secretory pathway. We could show that vesicles captured with different baits carry the same cargo and have almost identical lipid compositions; being highly enriched in ergosterol and sphingolipids. This finding indicates that lipid raft sorting is a generic feature of vesicles carrying PM cargo and suggests a common lipid‐based mechanism for their formation.
The effect of exploratory talk on the development of sentence structure in able writers
Authors: Robins Gill
Published: May 2011

This one‐term practitioner research study, conducted with 33 Year 5 children, considers the impact of teaching exploratory talk skills on the learning of the class, with particular consideration of the development of the ability of gifted and talented children to manipulate and control sentence structure to create effect. Beginning with metatalk activities, the class defined new talk rules, putting them into practice in an action‐research project. The study then went on to consider the detailed application of these skills in a focus group of six gifted children. In order to meet with the requirements of a wider study, the impact of this focus group on the learning of the whole class was observed. While many children, both those in the focus group and the wider class, appeared to embrace exploratory talk as a route to independence of the class teacher, some children were more reluctant to engage. The article concludes with an evaluation of the impact of exploratory talk.
Greek kindergarten teachers' beliefs and practices in early literacy
Authors: Stellakis Nektarios
Published: May 2011

This work describes a survey conducted in Syros Island in Greece. The intention was to ascertain kindergarten teachers' perceptions about early literacy and the skills and knowledge they consider as important for pre‐school aged children. The participants were all the kindergarten teachers of the island (N = 19) and the data were collected during a workshop where three groups tried to make a conceptual map of ‘literacy’. The results show that, overall, kindergarten teachers adopt a very broad definition of literacy as communication ability but restrict their practices to phonics instruction. Because this attitude differs significantly from the provisions of the official curriculum, which is based on emergent literacy perspective, it is obvious that due to the lack of specialised education and support the participants prefer a hidden curriculum, which is based on the assumption that mere acquaintance with graphophonemic relations is enough for the initial level of education. The findings of this research show that teachers lack awareness of recent research and pedagogy concerning early literacy development and demonstrate the urgent need for development of specialised educational programmes for in‐service kindergarten teachers.
Designing and Engineering of a Site‐specific Incorporation of a Keto Group in Uricase
Authors: Fang Zhengzhi , Liu Yaguang , Liu Jingxian , Sun Renhua , Chen Hai , Gao Xiangdong , Yao Wenbing
Published: May 2011

Urate oxidase is a potential therapeutic protein in the prevention and treatment of tumor lysis syndrome and hyperuricemia. However, its severe immunogenicity limits its clinical application. In our work, several strides have been made toward engineering site‐specific modifications of keto groups in urate oxidase by using evolved Methanocaldococcus jannaschii aminoacyl‐tRNA synthetase(s)/suppressor tRNA pairs to reduce its antigenicity. Our approach, described here, consisted of designing a M. jannaschii tyrosyl‐tRNA synthetase library based on the homology modeling and molecular docking model of the species‐specific TyrRS‐Tyr complex. The active mutation was picked, and pBR‐RS series vectors were constructed to define the relationship between the expression of aaRS and the efficiency of the orthogonal amber suppressor tRNA/synthetase system. Two sites based on the 3D structure of the Candida utilis uricase, Lys21 and Lys248, were substituted for p‐acetyl‐l‐phenylalanine, and the yields were optimized. The products were purified, and their enzyme activities and antigenic properties were analyzed. The mutated uricase exhibited decreased antigenic properties, while its catalytic activities remained unchanged. This method imparts new insights into structure–function relationship research and provides a means by which site‐specific modifications may be achieved by using PEG derivates to improve pharmacological properties of urate oxidase.
Choroidal thickness following extrafoveal photodynamic treatment with verteporfin in patients with central serous chorioretinopathy
Authors: Pryds Anders , Larsen Michael
Published: May 2011

Purpose:  To evaluate the effect of verteporfin photodynamic treatment (PDT) on choroidal thickness in patients with central serous chorioretinopathy (CSC).

Methods:  Choroidal thickness was measured with enhanced depth imaging– optical coherence tomography (EDI–OCT) before and after verteporfin PDT (full‐dose verteporfin, half‐light dose) in 16 eyes in 16 patients with serous detachment of the fovea secondary to extrafoveal angiographic fluorescein leakage. Treatment was confined to the area of leakage, whereas choroidal thickness before and after treatment was assessed over a larger area of the fundus using OCT.

Results:  Complete resolution of the serous detachment was seen in all 16 eyes within 1 month of extrafoveal PDT, while choroidal thickness in the area where PDT was applied decreased from 407 μm [mean; 95% confidence interval (CI95) 356–458 μm] to 349 μm (mean; CI95 300–399 μm; p < 0.0001), and subfoveal choroidal thickness was reduced from 421 μm (mean; CI95 352–489 μm) to 346 μm (mean; CI95 278–414 μm; p = 0.0001). Initially, subfoveal choroidal thickness was significantly increased in the treated eye compared with the healthy fellow eye (mean 324 μm; CI95 273–376 μm; p = 0.0003), but after treatment, the difference was not significant.

Discussion:  Photodynamic therapy of active CSC was followed by choroidal thickness reduction, not only locally but also at considerable distance from the treated area. Thus, the process that causes choroidal thickening in CSC appears to spread laterally within the choroid.
Common dental disorders in the donkey
Authors: du Toit N. , Dixon P. M.
Published: May 2011

Normal dental anatomy and the range of dental disorders found in donkeys are largely similar to those described in horses. Recent studies have shown dental disease to have a high prevalence in donkeys. Some dental disorders, such as diastemata, displaced teeth and wave mouth can have serious clinical consequences by causing oral pain and weight loss and even predispose to colic. Many of these signs can be prevented by regular dental treatment that can slow down or even prevent the progression of these disorders.
Integration of faces and voices, but not faces and names, in person recognition
Authors: O’Mahony Christiane , Newell Fiona N.
Published: May 2011

Recent studies on cross‐modal recognition suggest that face and voice information are linked for the purpose of person identification. We tested whether congruent associations between familiarized faces and voices facilitated subsequent person recognition relative to incongruent associations. Furthermore, we investigated whether congruent face and name associations would similarly benefit person identification relative to incongruent face and name associations. Participants were familiarized with a set of talking video‐images of actors, their names, and their voices. They were then tested on their recognition of either the face, voice, or name of each actor from bimodal stimuli which were either congruent or novel (incongruent) associations between the familiarized face and voice or face and name. We found that response times to familiarity decisions based on congruent face and voice stimuli were facilitated relative to incongruent associations. In contrast, we failed to find a benefit for congruent face and name pairs. Our findings suggest that faces and voices, but not faces and names, are integrated in memory for the purpose of person recognition. These findings have important implications for current models of face perception and support growing evidence for multisensory effects in face perception areas of the brain for the purpose of person recognition.
Effect of Misalignment and Weld Induced Residual Stresses on the Local Buckling Response of Pipelines
Authors: Al-Showaiter Aiman , Taheri Farid , Kenny Shawn
Published: May 2011

The aim of the present study is to develop numerical modeling procedures to simulate and study the effect of girth weld induced residual stresses and geometric imperfections on the behavior of conventional carbon steel oil and gas pipelines. The effect of welding residual stresses was obtained through computational simulations of the multipass girth weld process. The numerical procedures were calibrated using available pubic domain data on stainless steel. The methodology for conducting the welding simulation is presented. A parametric analysis was conducted using the finite element methods to evaluate the effects of welding residual stress due to girth welding processes, joint-to-joint misalignment associated with the girth weld, internal pressure, axial force, and diameter to wall thickness ratio on the local buckling response of pipelines. The pipeline moment-curvature response was examined to determine the influence of these parameters. For the parameters investigated, results from this study have demonstrated the significance of residual stress state due to welding processes and girth weld misalignment on the local buckling response of pipelines subjected to monotonic loading with combined stress state.
Effective Materials Property Information Management for the 21st Century
Authors: Ren Weiju , Cebon David , Arnold Steven M.
Published: May 2011

This paper discusses key principles for the development of material property information management software systems. The growing need for automated material information management is fueled, in part, by the demand for higher efficiency in material testing, product design, and engineering analysis. But equally important, organizations are being driven by the need for consistency, quality, and traceability of data, as well as control of access to proprietary or sensitive information. Further, the use of increasingly sophisticated nonlinear, anisotropic, and multiscale engineering analyses requires both processing of large volumes of test data for the development of constitutive models and complex material data input for computer-aided engineering software. Finally, the globalization of economy often generates great needs for sharing a single “gold source” of material information between members of global engineering teams in extended supply chains. Fortunately, material property management systems have kept pace with the growing user demands and have evolved into versatile data management systems that can be customized to specific user needs. The more sophisticated of these provide facilities for (i) data management functions such as access, version, and quality controls; (ii) a wide range of data import, export, and analysis capabilities; (iii) data “pedigree” traceability mechanisms; (iv) data searching, reporting, and viewing tools; and (v) access to the information via a wide range of interfaces. In this paper, the important requirements for advanced material data management systems, future challenges, and opportunities, such as automated error checking, data quality characterization, identification of gaps in data sets, as well as functionalities and business models to fuel database growth and maintenance are discussed.
FT8-3 Advanced Low Emissions Combustor Design
Authors: Reddy Urmila C. , Blanchard Christine E. , Schlein Barry C.
Published: May 2011

Pratt and Whitney developed a novel water-injected industrial gas turbine combustor liner design that has demonstrated significant reduction in CO emissions when compared with typical film-cooled combustor designs. The CO reduction demonstrated in a prototype test shows that the CO quenching due to cooler film temperatures near the liner wall is a significant source of CO emissions in a conventional water-injected combustor operating on natural gas fuel. This finding paved the way for a combustor design that reduces CO emissions while still maintaining low levels of NOx emissions. This design also has potential for lower NOx since the low CO emissions characteristic enables increased water injection. This paper presents the emissions characteristic measured on prototype hardware and the design of the engine hardware for future validation. Significant reduction in gaseous emissions was demonstrated with the testing of a prototype at the United Technologies Research Center in East Hartford, CT. This reduction in emissions compared with the baseline film-cooled design for a given operating condition has many benefits to the customer, including the reduced need for exhaust catalyst cleanup and extended operating times while still meeting site permits specified in CO tons per year. Other benefits may include the ability to guarantee lower NOx emissions through increased water injection for the current CO emissions output.
The Brayton Cycle Using Real Air and Polytropic Component Efficiencies
Authors: Heiser W. H. , Huxley T. , Bucey J. W.
Published: May 2011

This paper presents the results of a fundamental, comprehensive, and rigorous analytical and computational examination of the performance of the Brayton propulsion and power cycle employing real air as the working fluid. This approach capitalizes on the benefits inherent in closed cycle thermodynamic reasoning and the behavior of the thermally perfect gas to facilitate analysis. The analysis uses a high fidelity correlation to represent the specific heat at constant pressure of air as a function of temperature and the polytropic efficiency to evaluate the overall efficiency of the adiabatic compression and expansion processes. The analytical results are algebraic, transparent, and easily manipulated, and the computational results present a useful guidance for designers and users. The operating range of design parameters considered covers any current and foreseeable application. The results include some important comparisons with more simplified conventional analyses.
Ca
2+
Signaling Tools Acquired from Prostasomes Are Required for Progesterone-Induced Sperm Motility
Authors: Park Kwang-Hyun , Kim Byung-Ju , Kang John , Nam Tae-Sik , Lim Jung Min , Kim Hyoung Tae , Park Jong Kwan , Kim Young Gon , Chae Soo-Wan , Kim Uh-Hyun
Published: May 2011

Prostate-derived vesicles provide sperm with calcium signaling proteins required for progesterone-induced motility.
Network-Based Tools for the Identification of Novel Drug TargetsAdapted from the opening presentation at the International Conference on Systems Biology of Human Disease (SBHD) in Boston, Massachusetts, 16 to 18 June 2010.
Authors: Farkas Illés J. , Korcsmáros Tamás , Kovács István A. , Mihalik Ágoston , Palotai Robin , Simkó Gábor I. , Szalay Kristóf Z. , Szalay-Bekő Máté , Vellai Tibor , Wang Shijun , Csermely Peter
Published: May 2011

Analysis of network topology and dynamics holds promise for identifying new sets of potential drug targets.
Calcium Signaling in Sperm: Help from Prostasomes
Authors: Ren Dejian
Published: May 2011

Proteins involved in calcium signaling are delivered to sperm through fusion with prostate-derived vesicles.
Polycystin-1: A Double-Duty Activator
Authors: Gough Nancy R.
Published: May 2011

Both membrane-bound and cleaved polycystin-1 increase signaling by the transcriptional regulators of the STAT family.
Same Players, Different Roles
Authors: VanHook Annalisa M.
Published: May 2011

Related transcription factors are differentially regulated by auxin to control development of analogous structures in seed plants and mosses.
Phosphoethanolamine Modification of Lipid A in Colistin-Resistant Variants of Acinetobacter baumannii Mediated by the pmrAB Two-Component Regulatory System
Authors: Beceiro Alejandro , Llobet Enrique , Aranda Jesús , Bengoechea José Antonio , Doumith Michel , Hornsey Michael , Dhanji Hiran , Chart Henrik , Bou Germán , Livermore David M. , Woodford Neil
Published: May 2011

Colistin resistance is rare in
Acinetobacter baumannii
, and little is known about its mechanism. We investigated the role of PmrCAB in this trait, using (i) resistant and susceptible clinical strains, (ii) laboratory-selected mutants of the type strain ATCC 19606 and of the clinical isolate ABRIM, and (iii) a susceptible/resistant pair of isogenic clinical isolates, Ab15/133 and Ab15/132, isolated from the same patient.
pmrAB
sequences in all the colistin-susceptible isolates were identical to reference sequences, whereas resistant clinical isolates harbored one or two amino acid replacements variously located in PmrB. Single substitutions in PmrB were also found in resistant mutants of strains ATCC 19606 and ABRIM and in the resistant clinical isolate Ab15/132. No mutations in PmrA or PmrC were found. Reverse transcriptase (RT)-PCR identified increased expression of
pmrA
(4- to 13-fold),
pmrB
(2- to 7-fold), and
pmrC
(1- to 3-fold) in resistant versus susceptible organisms. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry showed the addition of phosphoethanolamine to the hepta-acylated form of lipid A in the resistant variants and in strain ATCC 19606 grown under low-Mg
2+
induction conditions.
pmrB
gene knockout mutants of the colistin-resistant ATCC 19606 derivative showed >100-fold increased susceptibility to colistin and 5-fold decreased expression of
pmrC
; they also lacked the addition of phosphoethanolamine to lipid A. We conclude that the development of a moderate level of colistin resistance in
A. baumannii
requires distinct genetic events, including (i) at least one point mutation in
pmrB
, (ii) upregulation of
pmrAB
, and (iii) expression of
pmrC
, which lead to addition of phosphoethanolamine to lipid A.
SugE, a New Member of the SMR Family of Transporters, Contributes to Antimicrobial Resistance in
Enterobacter cloacae
Authors: He Gui-Xin , Zhang Chu , Crow Robert R. , Thorpe Conner , Chen Huizhong , Kumar Sanath , Tsuchiya Tomofusa , Varela Manuel F.
Published: May 2011

We cloned a gene,
sugE
, from the chromosome of
Enterobacter cloacae
ATCC 13047. Analysis of the susceptibilities of the
sugE
-containing strain (
Escherichia coli
KAM32/pSUGE28) and
sugE
-deficient
E. cloacae
(
Ec
Δ
sugE
) showed that SugE confers resistance to cetyltrimethylammonium bromide, cetylpyridinium chloride, tetraphenylphosphonium, benzalkonium chloride, ethidium bromide, and sodium dodecyl sulfate. We also investigated expression of
sugE
. We confirm here that SugE from
E. cloacae
is an SMR family transporter as determined by observing its energy-dependent drug efflux activity.
Analysis of PBP5 of Early U.S. Isolates of Enterococcus faecium: Sequence Variation Alone Does Not Explain Increasing Ampicillin Resistance over Time
Authors: Galloway-Peña Jessica R. , Rice Louis B. , Murray Barbara E.
Published: May 2011

Recent studies have shown that ampicillin resistance has increased steadily over the past 3 decades within U.S.
Enterococcus faecium
isolates. Analysis of the predicted PBP5 protein of 41 isolates showed a consensus PBP5 pattern for the 9 isolates with MICs of <4 μg/ml that is distinctly different from the PBP5 consensus of the 32 isolates with MICs of >4 μg/ml with ∼5% difference between these; however, there were no consistent amino acid changes that correlated with specific increases in the MICs of ampicillin within the latter group. Analysis of three other genes encoding cell wall/surface proteins also showed that there are two distinct evolutionary groups for each gene, but with occasional mixing of genes, consistent with a species that evolves by recombination.
Discovery of Potent Hepatitis C Virus NS5A Inhibitors with Dimeric Structures
Authors: Lemm Julie A. , Leet John E. , O'Boyle Donald R. , Romine Jeffrey L. , Huang Xiaohua Stella , Schroeder Daniel R. , Alberts Jeffrey , Cantone Joseph L. , Sun Jin-Hua , Nower Peter T. , Martin Scott W. , Serrano-Wu Michael H. , Meanwell Nicholas A. , Snyder Lawrence B. , Gao Min
Published: May 2011

The exceptionalin vitropotency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into anin vivoeffect in proof-of-concept clinical trials. Although the 50% effective concentration (EC50) of the initial lead, the thiazolidinone BMS-824, was ∼10 nM in the replicon assay, it underwent transformation to other inhibitory species after incubation in cell culture medium. The biological profile of BMS-824, including the EC50, the drug concentration required to reduce cell growth by 50% (CC50), and the resistance profile, however, remained unchanged, triggering an investigation to identify the biologically active species. High-performance liquid chromatography (HPLC) biogram fractionation of a sample of BMS-824 incubated in medium revealed that the most active fractions could readily be separated from the parental compound and retained the biological profile of BMS-824. From mass spectral and nuclear magnetic resonance data, the active species was determined to be a dimer of BMS-824 derived from an intermolecular radical-mediated reaction of the parent compound. Based upon an analysis of the structural elements of the dimer deemed necessary for anti-HCV activity, the stilbene derivative BMS-346 was synthesized. This compound exhibited excellent anti-HCV activity and showed a resistance profile similar to that of BMS-824, with changes in compound sensitivity mapped to the N terminus of NS5A. The N terminus of NS5A has been crystallized as a dimer, complementing the symmetry of BMS-346 and allowing a potential mode of inhibition of NS5A to be discussed. Identification of the stable, active pharmacophore associated with these NS5A inhibitors provided the foundation for the design of more potent inhibitors with broad genotype inhibition. This culminated in the identification of BMS-790052, a compound that preserves the symmetry discovered with BMS-346.
Inhibition of Herpes Simplex Virus Type 1 and Type 2 Infections by Peptide-Derivatized Dendrimers
Authors: Luganini Anna , Nicoletto Silvia Fabiole , Pizzuto Lorena , Pirri Giovanna , Giuliani Andrea , Landolfo Santo , Gribaudo Giorgio
Published: May 2011

In response to the need for new antiviral agents, dendrimer-based molecules have been recognized as having a large number of potential therapeutic applications. They include peptide-derivatized dendrimers, which are hyperbranched synthetic well-defined molecules which consist of a peptidyl branching core and covalently attached surface functional peptides. However, few studies have addressed their applications as direct-acting antiviral agents. Here, we report on the ability of the peptide dendrimer SB105 and its derivative, SB105_A10, to directly inhibit herpes simplex virus 1 (HSV-1) and HSV-2
in vitro
replication, with favorable selective indexes discerned for both compounds. An analysis of their mode of action revealed that SB105 and SB105_A10 prevent HSV-1 and HSV-2 attachment to target cells, whereas SB104, a dendrimer with a different amino acid sequence within the functional group and minimal antiviral activity, was ineffective in blocking HSV attachment. Moreover, both SB105 and SB105_A10 retained their ability to inhibit HSV adsorption at pH 3.0 and 4.0 and in the presence of 10% human serum proteins, conditions mimicking the physiological properties of the vagina, a potential therapeutic location for such compounds. The inhibition of HSV adsorption is likely to stem from the ability of SB105_A10 to bind to the glycosaminoglycan moiety of cell surface heparan sulfate proteoglycans, thereby blocking virion attachment to target cells. Finally, when combined with acyclovir in checkerboard experiments SB105_A10 exhibited highly synergistic activity. Taken together, these findings suggest that SB105 and SB105_A10 are promising candidates for the development of novel topical microbicides for the prevention of HSV infections.
Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone
Authors: Ohnishi Makoto , Golparian Daniel , Shimuta Ken , Saika Takeshi , Hoshina Shinji , Iwasaku Kazuhiro , Nakayama Shu-ichi , Kitawaki Jo , Unemo Magnus
Published: May 2011

Recently, the first
Neisseria gonorrhoeae
strain (H041) that is highly resistant to the extended-spectrum cephalosporin (ESC) ceftriaxone, the last remaining option for empirical first-line treatment, was isolated. We performed a detailed characterization of H041, phenotypically and genetically, to confirm the finding, examine its antimicrobial resistance (AMR), and elucidate the resistance mechanisms. H041 was examined using seven species-confirmatory tests, antibiograms (30 antimicrobials),
porB
sequencing,
N. gonorrhoeae
multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of ESC resistance determinants (
penA
,
mtrR
,
penB
,
ponA
, and
pilQ
). Transformation, using appropriate recipient strains, was performed to confirm the ESC resistance determinants. H041 was assigned to serovar Bpyust, MLST sequence type (ST) ST7363, and the new NG-MAST ST4220. H041 proved highly resistant to ceftriaxone (2 to 4 μg/ml, which is 4- to 8-fold higher than any previously described isolate) and all other cephalosporins, as well as most other antimicrobials tested. A new
penA
mosaic allele caused the ceftriaxone resistance. In conclusion,
N. gonorrhoeae
has now shown its ability to also develop ceftriaxone resistance. Although the biological fitness of ceftriaxone resistance in
N. gonorrhoeae
remains unknown,
N. gonorrhoeae
may soon become a true superbug, causing untreatable gonorrhea. A reduction in the global gonorrhea burden by enhanced disease control activities, combined with wider strategies for general AMR control and enhanced understanding of the mechanisms of emergence and spread of AMR, which need to be monitored globally, and public health response plans for global (and national) perspectives are important. Ultimately, the development of new drugs for efficacious gonorrhea treatment is necessary.
Evaluation of Ceftaroline Activity versus Daptomycin (DAP) against DAP-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Strains in an
In Vitro
Pharmacokinetic/Pharmacodynamic Model
Authors: Steed Molly , Vidaillac Celine , Rybak Michael J.
Published: May 2011

The objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin-nonsusceptible (DNS) methicillin-resistant
Staphylococcus aureus
(MRSA) infections. Four clinical DNS MRSA strains, R5717, R5563, R5996 (heteroresistant vancomycin-intermediate
S. aureus
) and R5995 (vancomycin-intermediate
S. aureus
) were evaluated in a two-compartment hollow-fiber
in vitro
pharmacokinetic/pharmacodynamic model at a starting inoculum of 10
7
CFU/ml for 96 h. Simulated regimens were ceftaroline at 600 mg every 12 h (q12h) (maximum free-drug concentration [
f
C
max
], 15.2 μg/ml; serum half-life [
t
1/2
], 2.3 h), daptomycin at 6 mg/kg q24h (
f
C
max
, 7.9 μg/ml;
t
1/2
, 8 h), and daptomycin at 10 mg/kg q24h (
f
C
max
, 15.2 μg/ml;
t
1/2
, 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a ≥3-log
10
CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 μg/ml, and the daptomycin MIC values were 2, 2, 4, and 4 μg/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, −3.1 log
10
CFU/ml; R5563, −2.5 log
10
CFU/ml; R5996, −5.77 log
10
CFU/ml; R5995, −6.38 log
10
CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains,
P
≤ 0.008) and daptomycin at 10 mg/kg q24 h (3 strains,
P
≤ 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.
Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients
Authors: Bazzoli C. , Bénech H. , Rey E. , Retout S. , Salmon D. , Duval X. , Tréluyer J. M. , Mentré F. ,   the COPHAR2-ANRS 111 Study Group
Published: May 2011

The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.
bla
KPC
RNA Expression Correlates with Two Transcriptional Start Sites but Not Always with Gene Copy Number in Four Genera of Gram-Negative Pathogens
Authors: Roth Amanda L. , Kurpiel Philip M. , Lister Philip D. , Hanson Nancy D.
Published: May 2011

Klebsiella pneumoniae
carbapenemase (KPC)-producing organisms are therapeutically and diagnostically challenging. It is possible that
bla
KPC
gene expression plays a role in the variability observed in clinical susceptibility testing.
bla
KPC
transformants together with 10 clinical isolates representing four genera were evaluated for
bla
KPC
copy number and gene expression and correlated with β-lactam MIC data. The data suggest that mechanisms other than gene copy number and expression of
bla
KPC
contribute to variability in susceptibility when testing KPC-producing isolates.
Developmental Pharmacokinetics of Lamivudine in 580 Pediatric Patients Ranging from Neonates to Adolescents
Authors: Bouazza Naïm , Hirt Déborah , Blanche Stéphane , Frange Pierre , Rey Elisabeth , Tréluyer Jean-Marc , Urien Saik
Published: May 2011

Lamivudine concentration-time courses were described for a very large range of ages to study the effects of body weight and maturation on lamivudine pharmacokinetics and to check the consistency of dosing recommendations. Lamivudine concentrations were monitored on a routine basis to produce concentrations similar to the known values in adults. Concentrations were measured in 580 children from 2 days to 18 years old. A total of 2,106 plasma lamivudine concentrations were measured, and a population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.1 software. A two-compartment model adequately described the data. After standardization for a mean standard body weight by using an allometric model, age also had a significant effect on clearance maturation. Typical population estimates (percent interindividual variability) standardized for 70 kg of the apparent clearance, including central and peripheral volumes of distribution, intercompartmental clearance, and absorption rate constant, were 31 liters·h−1(32%), 76.4 liters (77%), 129 liters, 5.83 liters·h−1, and 0.432 h−1, respectively. According to the model, elimination clearance (liters/h/70 kg) increases gradually during the first years of life. Theoretical doses needed to reach the range of 24 h of exposure observed in adults were calculated: to be closer to adult exposure, children should receive 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.