bluuebunny/crossref_metadata_2025 huggingface dataset:
Self‐determination theory, social media and charitable causes: An in‐depth analysis of autonomous motivation
Authors: Ferguson Ronald , Gutberg Jennifer , Schattke Kaspar , Paulin Michèle , Jost Nina
Published: February 2015

Using the framework of the self‐determination theory continuum, we investigated the influence of the distinct autonomous and controlled motivational regulations for engaging participants in online and offline support of charitable events for the causes of breast cancer and homeless youth. Participants were exposed online to Facebook event pages appealing to helping others. When the often omitted integrated autonomous regulation was included in the model, it was the strongest predictor of supportive intentions. Without integrated regulation in the model, we would have overestimated the relatively minor influence of controlled introjected regulation. Furthermore, rather than one overall measure of autonomous intrinsic regulation, we assessed the differential influences of three separate dimensions (to experience stimulation, to learn and to accomplish). Intrinsic motivation to experience stimulation had a unique influence on online and offline supportive intentions. Such was not the case for the dimensions of to learn or to accomplish. Follow‐up meditation analyses of self‐reported behaviours confirmed that autonomous integrated and intrinsic to experience stimulation regulations led to stronger intentions to support online behaviours, which, in turn, increased the likelihood of actual online engagement. The findings in a social media context highlight the importance of analysing distinct regulatory styles within the self‐determination theory continuum. Copyright © 2015 John Wiley & Sons, Ltd.
Origin of Low Detection Limit and High Selectivity of Roche Accu‐Chek Test Strips that Enables Measurement of Tear Glucose Levels
Authors: Cha Kyoung Ha , Qin Yu , Meyerhoff Mark E.
Published: February 2015

Tear glucose measurements have been suggested as a potential alternative to blood glucose monitoring for diabetic patients. While previous work has reported a correlation between blood and tear glucose levels in humans, this link has not been thoroughly established and additional clinical studies are needed. We recently reported that Roche’s electrochemical Accu‐Chek blood glucose test strips exhibit far superior analytical performance over other commercial brands, with the low detection limit and high selectivity required for quantitating tear glucose levels. Herein, we evaluate the origin of the high sensitivity and selectivity of the Roche test strips and show that the use of pyrroloquinoline quinone (PQQ)‐dependent glucose dehydrogenase (GDH) as an active enzyme reagent in combination with a nitrosoaniline derivative as an electron transfer mediator are primarily responsible for the low limit of quantification (LOQ) (ca. 9 µM) and enhanced selectivity achieved with these strips.
Model for understanding consumer textural food choice
Authors: Jeltema Melissa , Beckley Jacqueline , Vahalik Jennifer
Published: February 2015

The current paradigm for developing products that will match the marketing messaging is flawed because the drivers of product choice and satisfaction based on texture are misunderstood. Qualitative research across 10 years has led to the thesis explored in this research that individuals have a preferred way to manipulate food in their mouths (i.e., mouth behavior) and that this behavior is a major driver of food choice, satisfaction, and the desire to repurchase. Texture, which is currently thought to be a major driver of product choice, is a secondary factor, and is important only in that it supports the primary driver—mouth behavior. A model for mouth behavior is proposed and the qualitative research supporting the identification of different mouth behaviors is presented. The development of a trademarked typing tool for characterizing mouth behavior is described along with quantitative substantiation of the tool's ability to group individuals by mouth behavior. The use of these four groups to understand textural preferences and the implications for a variety of areas including product design and weight management are explored.
Increased chronic lymphocytic leukemia proliferation upon IgM stimulation is sustained by the upregulation of miR‐132 and miR‐212
Authors: Tavolaro Simona , Colombo Teresa , Chiaretti Sabina , Peragine Nadia , Fulci Valerio , Ricciardi Maria R. , Messina Monica , Bonina Silvia , Brugnoletti Fulvia , Marinelli Marilisa , Di Maio Valeria , Mauro Francesca R. , Del Giudice Ilaria , Macino Giuseppe , Foà Robin , Guarini Anna
Published: February 2015

To assess the involvement of microRNAs (miRNAs) in B‐cell receptor (BCR) stimulation, we first evaluated miRNA profiling following IgM cross‐linking in chronic lymphocytic leukemia (CLL) cells and in normal B lymphocytes. Second, we combined miRNA and gene expression data to identify putative miRNA functional networks. miRNA profiling showed distinctive patterns of regulation after stimulation in leukemic versus normal B lymphocytes and identified a differential responsiveness to BCR engagement in CLL subgroups according to the immunoglobulin heavy chain variable region mutational status and clinical outcome. The most significantly modulated miRNAs in stimulated CLL are miR‐132 and miR‐212. Notably, these miRNAs appeared regulated in progressive but not in stable CLL. Accordingly, gene profiling showed a significant transcriptional response to stimulation exclusively in progressive CLL. Based on these findings, we combined miRNA and gene expression data to investigate miR‐132 and miR‐212 candidate interactions in this CLL subgroup. Correlation analysis pointed to a link between these miRNAs and RB/E2F and TP53 cascades with proproliferative effects, as corroborated by functional analyses. Finally, basal levels of miR‐132 and miR‐212 were measured in an independent cohort of 20 unstimulated CLL cases and both showed lower expression in progressive compared to stable patients, suggesting an association between the expression of these molecules and disease prognosis. Overall, our results support a model involving miR‐132 and miR‐212 upregulation in sustaining disease progression in CLL. These miRNAs may therefore provide new valuable strategies for therapeutic intervention. © 2015 Wiley Periodicals, Inc.
Neuronal expression of the transcription factor serum response factor modulates myelination in a mouse multiple sclerosis model
Authors: Anastasiadou Sofia , Liebenehm Sophie , Sinske Daniela , Meyer zu Reckendorf Christopher , Moepps Barbara , Nordheim Alfred , Knöll Bernd
Published: February 2015

In multiple sclerosis (MS), neurons in addition to inflammatory cells are now considered to mediate disease origin and progression. So far, molecular and cellular mechanisms of neuronal MS contributions are poorly understood. Herein we analyzed whether neuron‐restricted signaling by the neuroprotective transcription factor serum response factor (SRF) modulates de‐ and remyelination in a rodent MS model. In the mouse cuprizone model, neuron‐ (Srf flox/flox;CaMKCreERT2) but not glia‐specific (Srf flox/flox;PlpCreERT2) SRF depletion impaired demyelination suggesting impaired debris clearance by astrocytes and microglia. This supports an important role of SRF expression in neurons but not oligodendrocytes in de‐ and remyelination. During remyelination, NG2‐ and OLIG2‐positive cells of the oligodendrocyte lineage as well as de novo mRNA synthesis of myelin genes were also reduced in neuron‐specific Srf mutants. Using the stripe assay, we demonstrate that cortices of cuprizone‐fed wild‐type mice elicited astrocyte and microglia activation whereas this was abrogated in cuprizone‐fed neuron‐specific Srf mutants. We identified CCL chemokines (e.g. CCL2) as neuron‐derived SRF‐regulated paracrine signals rescuing immune cell activation upon neuronal SRF deletion. In summary, we uncovered important roles of neurons and neuronally expressed SRF in MS associated de‐ and remyelination. GLIA 2015;63:958–976
Effects of the roots ofCynodon dactylonandSchefflera heptaphyllaon water infiltration rate and soil hydraulic conductivity
Authors: Leung A. K. , Garg A. , Coo J. L. , Ng C. W. W. , Hau B. C. H.
Published: February 2015

Water infiltration rate and hydraulic conductivity in vegetated soil are two vital hydrological parameters for agriculturists to determine availability of soil moisture for assessing crop growths and yields, and also for engineers to carry out stability calculations of vegetated slopes. However, any effects of roots on these two parameters are not well‐understood. This study aims to quantify the effects of a grass species,Cynodon dactylon, and a tree species,Schefflera heptaphylla, on infiltration rate and hydraulic conductivity in relation to their root characteristics and suction responses. The two selected species are commonly used for ecological restoration and rehabilitation in many parts of the world and South China, respectively. A series ofin‐situdouble‐ring infiltration tests was conducted during a wet summer, while the responses of soil suction were monitored by tensiometers. When compared to bare soil, the vegetated soil has lower infiltration rate and hydraulic conductivity. This results in at least 50% higher suction retained in the vegetated soil. It is revealed that the effects of root‐water uptake by the selected species on suction were insignificant because of the small evapotranspiration (<0.2 mm) when the tests were conducted under the wet climate. There appears to have no significant difference (less than 10%) of infiltration rates, hydraulic conductivity and suction retained between the grass‐covered and the tree‐covered soil. However, the grass and tree species having deeper root depth and greater Root Area Index (RAI) retained higher suction. Copyright © 2015 John Wiley & Sons, Ltd.
Evaluation of Genomic Damage in Peripheral Lymphocytes from Occupationally Exposed Anesthetists: Assessment of the Effects of Age, Sex, and GSTT1 Gene Polymorphism
Authors: Santovito Alfredo , Cervella Piero , Delpero Massimiliano
Published: February 2015

Occupational exposure to anaesthetic gases is one of the major hazards to healthcare personnel. We evaluated the cytogenetic effects of chronic exposure to low concentrations of anaesthetic gases in operating theatres. The study included 21 anesthetists and 21 control subjects who matched in age and gender. Chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) assays were performed. All subjects were also genotyped for glutathione S‐transferase T1 (GSTT1) gene polymorphisms. Significant differences were found between exposed and controls in terms of SCEs frequency (P = 0.001) and replication index value (P = 0.005), but not in terms of CAs (P = 0.201) and aberrant cells (P = 0.227) frequencies. Regression analyses indicated that age and the years of employment did not influence the level of chromosomal damage in both groups. Finally, among anesthetists, GSTT1 null individuals showed a significant higher frequency of SCE with respect to GSTT1‐positive subjects.
Cutting‐edge mass spectrometry characterization of originator, biosimilar and biobetter antibodies
Authors: Beck Alain , Debaene François , Diemer Hélène , Wagner‐Rousset Elsa , Colas Olivier , Dorsselaer Alain Van , Cianférani Sarah
Published: February 2015

The approval process for antibody biosimilars relies primarily on comprehensive analytical data to establish comparability and high similarity with the originator. Mass spectrometry (MS) in combination with liquid chromatography (LC) and electrophoretic methods are the corner stone for comparability and biosimilarity evaluation. In this special feature we report head‐to‐head comparison of trastuzumab and cetuximab with corresponding biosimilar and biobetter candidates based on cutting‐edge mass spectrometry techniques such as native MS and ion‐mobility MS at different levels (top, middle and bottom). In addition, we discuss the advantages and the limitations of sample preparation and enzymatic digestion, middle‐up and ‐down strategies and the use of hydrogen/deuterium exchange followed by MS (HDX‐MS). Last but not least, emerging separation methods combined to MS such as capillary zone electrophoresis‐tandem MS (CESI‐MS/MS), electron transfer dissociation (ETD), top down‐sequencing (TDS) and high‐resolution MS (HR‐MS) that complete the panel of state‐of‐the‐art MS‐based options for comparability and biosimilarity evaluation are presented. Copyright © 2015 John Wiley & Sons, Ltd.
Physico‐chemical properties and hypoglycaemic activity of fermented milks prepared with Anemarrhena asphodeloides water extracts
Authors: Zhang Rong , Yang Liu , Ji Jing , Li Bei‐bei , Li Lan , Ye Ming
Published: February 2015

BACKGROUND

In this research, water extract solutions of Anemarrhena asphodeloides (AA) rhizomes were added to reconstituted milk at 5%, 10% and 15% (v/v) to prepare AA fermented milk (AAFM5, AAFM10 and AAFM15). The AAFM10 was selected for investigation of hypoglycaemic activity.

RESULTS

Compared with the control fermented milk, titratable acidity values and water‐holding capacities of AA fermented milk were increased to different extents, but syneresis values were reduced. The viable counts of Streptococcus thermophilus, Lactobacillus bulgaricus and Bifidobacterium adolescentis were significantly increased, respectively. The blood sugar level of streptozotocin diabetic mice taking AAFM10 was reduced by 14.4%, and the food intake was decreased. The contents of malondialdehyde, blood urea nitrogen, serum creatinine, triglycerides, total cholesterol, and low‐density lipoprotein cholesterol were reduced by different degrees, and insulin and total superoxide dismutase were significantly increased.

CONCLUSION

AAFM10 had a significant hypoglycaemic effect and improvement in the complications (such as kidney disease and hyperlipemia) in the mouse model of diabetes. © 2015 Society of Chemical Industry
Sensory characterization during repeated ingestion of small‐molecular‐weight phenolic acids
Authors: Duizer Lisa M , Langfried Allison
Published: February 2015

BACKGROUND

Characterization of the sensory properties of small‐molecular‐weight phenolic acids such as ferulic and vanillic acids has been limited. The objectives of this study were to characterize the sensory perceptions of these acids and the effects of their repeated consumption on sourness, bitterness and astringency. This knowledge will further the understanding of the impact of these acids on the sensory characteristics of foods in which they are typically consumed.

RESULTS

Two time–intensity sensory evaluation experiments were conducted with nine trained panelists: a single‐sip study and a sequential‐sip study. Concentrations of phenolic acids typically found in whole grain bread were tested. For both experiments, vanillic acid was perceived to be significantly more sour than ferulic acid, and ferulic acid was perceived to be significantly more bitter than vanillic acid. Maximum sourness, bitterness and astringency intensities significantly increased with increasing molarity for both acids. During sequential sipping, astringency and bitterness intensity increased with each sip. Sourness, however, increased to sip 3 but did not significantly increase after that point.

CONCLUSION

This research demonstrates that even small quantities of phenolic acids can be perceived as increasingly bitter and astringent with repeated exposures. © 2015 Society of Chemical Industry
1064 nm long‐pulsed Nd:YAG laser treatment of basal cell carcinoma
Authors: Ortiz Arisa E. , Anderson R. Rox , Avram Mathew M.
Published: February 2015

Background and Objective

Standard surgical and destructive treatments for basal cell carcinoma (BCC) can result in significant morbidity and scarring, stimulating the investigation of alternative non‐surgical options. The objective of this study was to determine the safety, clinical, and histological efficacy of pulsed, high‐fluence 1064 nm Nd:YAG laser therapy for the treatment of BCC on the trunk and extremities.

Study Design/Materials and Methods

This was a prospective, non‐randomized, open‐label clinical trial. Ten subjects with a biopsy‐proven BCC less than 1.5 cm in diameter on the trunk or extremities received one treatment with a 10 milliseconds pulsed 1064 nm Nd:YAG laser. Standard excision was performed 1 month after laser treatment to confirm histologic clearance.

Results

The laser treatment was quick and well tolerated. There was complete histologic clearance after one treatment in 92% of the BCC tumors, overall. At higher fluences, there was 100% histologic clearance after one treatment. No significant adverse events were seen, including scarring.

Conclusions

The 1064 nm long‐pulsed Nd:YAG laser may offer a safe alternative for treating BCC off the face. A larger study is highly warranted to confirm these preliminary results. Lasers Surg. Med. 47:106–110, 2015. © 2015 Wiley Periodicals, Inc.
Low‐fluence 585 nm Q‐switched Nd:YAG laser: A novel laser treatment for post‐acne erythema
Authors: Panchaprateep Ratchathorn , Munavalli Girish
Published: February 2015

Background

Persistent post‐acne erythema is one of the most common aesthetic sequelae to arise after active acne resolves. The treatment remains challenging due to lack of effective laser modalities.

Objectives

To evaluate the safety and efficacy of a low‐fluence 585 nm Q‐switched Nd:YAG laser for the treatment of post‐acne erythema.

Materials & Methods

Twenty‐five patients with post‐acne erythema were treated with a low‐fluence Q‐switched Nd:YAG laser using the 585 nm Gold Toning™ handpiece (5 mm spot size, 5–10 ns, 0.30–0.55 J/cm2, 2–4 passes) for three sessions at 2‐week intervals. Erythema lesion (macules) count, inflammatory acne (papules, pustules) count, erythema index, degree of post‐acne erythema and overall improvement in post‐acne erythema and acne scar were assessed at baseline, every 2 weeks and 6 weeks after the last treatment. Subjective degrees of satisfaction were also evaluated. Adverse events were recorded and pain was scored using a visual analog scale (VAS).

Results

At 6 weeks after 3 sessions of laser treatment, all patients demonstrated clinical improvement. Erythema lesion counts decreased by 20.1% (versus baseline) after the first treatment (P = 0.004), by 32.7% after the second treatment, by 46.5% at 2 weeks after the third treatment and by 58.7% at the 6‐week follow‐up (allP < 0.001). Significant improvements were also noted in erythema indices (22.29 ± 2.4 to 17.51 ± 1.8) and mean post‐acne erythema scores after the first treatment (bothP < 0.001). The mean scores of independent physician assessments were 4.04 ± 0.9 in term of the improvement of post‐acne erythema and 3.44 ± 0.9 in the improvement of scaring. In addition, we could observe a significant decrease in inflammatory acne lesion counts after two laser treatments with a decrease in mean lesion counts by 67% at the 6‐week follow‐up. Treatment was well‐tolerated and adverse effects were limited to transient erythema and edema at treatment sites.

Conclusions

Low‐fluence 585 nm Q‐switched Nd:YAG laser treatment is safe and effective for the treatment of post‐acne erythema with minimal discomfort and quantifiable improvement in the appearance of early acne scarring and inflammatory acne. Lasers Surg. Med. 47:148–155, 2015. © 2015 Wiley Periodicals, Inc.
Three‐Layered Biodegradable Micelles Prepared by Two‐Step Self‐Assembly of PLA‐PEI‐PLA and PLA‐PEG‐PLA Triblock Copolymers as Efficient Gene Delivery System
Authors: Abebe Daniel G. , Kandil Rima , Kraus Teresa , Elsayed Maha , Merkel Olivia M. , Fujiwara Tomoko
Published: February 2015

“Three‐layered micelles” (3LM) composed of two triblock copolymers, poly(L‐lactide)‐b‐polyethyleneimine‐b‐poly(L‐lactide) (PLLA‐PEI‐PLLA) and poly(L‐lactide)‐b‐poly(ethylene glycol)‐b‐poly(L‐lactide) (PLLA‐PEG‐PLLA) are designed to combine electrostatic interaction and solvent‐induced condensation of DNA. The low molecular weight PLLA‐PEI‐PLLA is synthesized by a facile amine‐protection/deprotection approach and employed as a gene vector, compacting DNA as a polyplex core in the organo‐micelles. The individual organo‐micelle is further encapsulated within a PLLA‐PEG‐PLLA amphiphilic micelle leading to an aqueous stable colloidal dispersion. The resulting spherical 3LM possess a hydrodynamic diameter of ca. 200 nm and zeta potential close to neutral and display excellent stability to competing polyanions such as dextran sulfate in neutral pH (7.4). Such high stability is attributed to the complete shielding of the PEI/DNA polyplex core with an impermeable hydrophobic intermediate layer. However, greater than 90% of the encapsulated DNA are released within 30 min when exposed to slightly acidic pH (4.5). Based on our findings, a new class of non‐viral delivery system for nucleic acids with superb stability and stealth properties is identified.
The eal truth
Authors: Baratella Stefano , Zambella Domenico
Published: February 2015

We study a real valued propositional logic with unbounded positive and negative truth values that we call ‐valued logic. Such a logic is semantically equivalent to continuous propositional logic, with a different choice of connectives. After presenting the deduction machinery and the semantics of ‐valued logic, we prove a completeness theorem for finite theories. Then we define unital and Archimedean theories, in accordance with the theory of Riesz spaces. In the unital setting, we prove the equivalence of consistency and satisfiability and an approximated completeness theorem similar to the one that holds for continuous propositional logic. Eventually, among unital theories, we characterize Archimedean theories as those for which strong completeness holds. We also point out that ‐valued logic provides alternative calculi for Łukasiewicz logic and for propositional continuous logic.
Identification of a source factor in a control problem for the heat equation with a boundary memory term
Authors: Cavaterra Cecilia , Guidetti Davide
Published: February 2015

We consider a material with thermal memory occupying a bounded region Ω with boundary Γ. The evolution of the temperature u(t,x) is described by an integrodifferential parabolic equation containing a heat source of the form f(t)z0(x). We formulate an initial and boundary value control problem based on a feedback device located on Γ and prescribed by means of a quite general memory operator. Assuming both u and the source factor f are unknown, we study the corresponding inverse and control problem on account of an additional information. We prove a result of existence and uniqueness of the solution (u,f). Copyright © 2015 John Wiley & Sons, Ltd.
The school bus routing and scheduling problem with transfers
Authors: Bögl Michael , Doerner Karl F. , Parragh Sophie N.
Published: February 2015

In this article, we study the school bus routing and scheduling problem with transfers arising in the field of nonperiodic public transportation systems. It deals with the transportation of pupils from home to their school in the morning taking the possibility that pupils may change buses into account. Allowing transfers has several consequences. On the one hand, it allows more flexibility in the bus network structure and can, therefore, help to reduce operating costs. On the other hand, transfers have an impact on the service level: the perceived service quality is lower due to the existence of transfers; however, at the same time, user ride times may be reduced and, thus, transfers may also have a positive impact on service quality. The main objective is the minimization of the total operating costs. We develop a heuristic solution framework to solve this problem and compare it with two solution concepts that do not consider transfers. The impact of transfers on the service level in terms of time loss (or user ride time) and the number of transfers is analyzed. Our results show that allowing transfers reduces total operating costs significantly while average and maximum user ride times are comparable to solutions without transfers. © 2015 Wiley Periodicals, Inc. NETWORKS, Vol. 65(2), 180–203 2015
Concentration, working speed and memory: Cognitive problems in young childhood cancer survivors and their siblings
Authors: Wengenroth L. , Rueegg C. S. , Michel G. , Gianinazzi M. E. , Essig S. , von der Weid N. X. , Grotzer M. , Kuehni Claudia E. ,   for the Swiss Paediatric Oncology Group SPOG
Published: February 2015

Background

Cognitive problems can have a negative effect on a person's education, but little is known about cognitive problems in young childhood cancer survivors (survivors). This study compared cognitive problems between survivors and their siblings, determined if cognitive problems decreased during recent treatment periods and identified characteristics associated with the presence of a cognitive problem in survivors.

Methods

As part of the Swiss Childhood Cancer Survivor Study, a questionnaire was sent to all survivors, aged 8–20 years, registered in the Swiss Childhood Cancer Registry, diagnosed at age <16 years, who had survived ≥5 years. Parent‐reported (aged 8–15 years) and self‐reported (aged 16–20 years) cognitive problems (concentration, working speed, memory) were compared between survivors and siblings. Multivariable logistic regression was used to identify characteristics associated with cognitive problems in survivors.

Results

Data from 840 survivors and 247 siblings were analyzed. More often than their siblings, survivors reported problems with concentration (12% vs. 6%; P = 0.020), slow working speed (20% vs. 8%; P = 0.001) or memory (33% vs. 15%; P < 0.001). Survivors from all treatment periods were more likely to report a cognitive problem than were siblings. Survivors of CNS tumors (OR = 2.82 compared to leukemia survivors, P < 0.001) and those who had received cranial irradiation (OR = 2.10, P = 0.010) were most severely affected.

Conclusion

Childhood cancer survivors, even those treated recently (2001–2005), remain at risk to develop cognitive problems, suggesting a need to improve therapies. Survivors with cognitive problems should be given the opportunity to enter special education programs. Pediatr Blood Cancer 2015;62:875–882. © 2015 Wiley Periodicals, Inc.
Does the average drug exposure in pregnant women affect pregnancy outcome? A comparison of two approaches to estimate the baseline risks of adverse pregnancy outcome
Authors: Wacker Evelin , Navarro Ana , Meister Reinhard , Padberg Stephanie , Weber‐Schoendorfer Corinna , Schaefer Christof
Published: February 2015

Purpose

The results of observational cohort studies on drug effects on pregnancy outcome may depend among others on suitable comparison cohorts. The aim of this investigation was to compare two distinct definitions of maternal exposure status for comparison cohorts.

Methods

We performed an observational cohort study of prospectively ascertained pregnant women who spontaneously contacted the Teratology Information Service (TIS) Berlin for drug risk consultation. The only exclusion criteria were exposures to established teratogens and/or fetotoxicants. Pregnancy outcomes of 3250 women with this “average drug exposure” were compared with 546 non‐exposed or insignificantly exposed pregnancies.

Results

Neither the rate of major birth defects (3.0%; aOR 1.62; 95% CI 0.8–3.3) nor the risk of spontaneous abortion (16.0%; aHR 1.20; 95% CI 0.8–1.7) was significantly increased after average drug exposure, whereas the rate of electively terminated pregnancies was higher (11.1%; aHR 2.05; 95% CI 1.2–3.4). There were no differences in the risk of preterm birth (9.9%; aOR 1.38; 95% CI 0.9–2.0) and infants' birth weight (p = 0.60).

Conclusions

This study does not provide evidence for an increased risk of adverse pregnancy outcome after average drug exposure during pregnancy. Therefore, comparison cohorts with average drug exposure are appropriate for studies on potential teratogens or fetotoxicants based on observational data collected by TIS. Copyright © 2015 John Wiley & Sons, Ltd.
Homo‐double helix formation of an optically active conjugated polymer bearing carboxy groups and amplification of the helicity upon complexation with achiral and chiral amines
Authors: Makiguchi Wataru , Kobayashi Shinzo , Furukawa Keisuke , Iida Hiroki , Furusho Yoshio , Yashima Eiji
Published: February 2015

An optically active, m‐terphenyl‐based π‐conjugated polymer bearing carboxy groups was synthesized by the copolymerization of the diethynyl monomer bearing a carboxy group with (S,S)‐2,5‐bis(2‐methylbutoxy)‐1,4‐dibromobenzene using Sonogashira reaction. The copolymer showed a weak circular dichroism (CD) in the main‐chain chromophore region due to a homo‐double helix formation with an excess helical handedness biased by the chiral alkoxy substituents through self‐association. However, upon complexation with achiral amines, such as piperidine, the CD intensity of the polymer significantly increased resulting in the formation of a greater excess one‐handed homo‐double helix via hydrogen‐bonded inclusion complexation with the achiral amines between each strand, leading to the amplification of the helicity. A preferred‐handed homo‐double helix was also induced in the polymer in the presence of nonracemic amines. The effect of the achiral and chiral amines on the homo‐double helix formation was investigated by comparing the CD spectra of the polymer to those of its model dimer. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 990–999
Aromatic cluster mutations produce focal modulations of β‐sheet structure
Authors: Biancalana Matthew , Makabe Koki , Yan Shude , Koide Shohei
Published: February 2015

Site‐directed mutagenesis is a powerful tool for altering the structure and function of proteins in a focused manner. Here, we examined how a model β‐sheet protein could be tuned by mutation of numerous surface‐exposed residues to aromatic amino acids. We designed these aromatic side chain “clusters” at highly solvent‐exposed positions in the flat, single‐layer β‐sheet of Borrelia outer surface protein A (OspA). This unusual β‐sheet scaffold allows us to interrogate the effects of these mutations in the context of well‐defined structure but in the absence of the strong scaffolding effects of globular protein architecture. We anticipated that the introduction of a cluster of aromatic amino acid residues on the β‐sheet surface would result in large conformational changes and/or stabilization and thereby provide new means of controlling the properties of β‐sheets. Surprisingly, X‐ray crystal structures revealed that the introduction of aromatic clusters produced only subtle conformational changes in the OspA β‐sheet. Additionally, despite burying a large degree of hydrophobic surface area, the aromatic cluster mutants were slightly less stable than the wild‐type scaffold. These results thereby demonstrate that the introduction of aromatic cluster mutations can serve as a means for subtly modulating β‐sheet conformation in protein design.
Target validation and structure–activity analysis of a series of novel PCNA inhibitors
Authors: Dillehay Kelsey L. , Seibel William L. , Zhao Daoli , Lu Shan , Dong Zhongyun
Published: February 2015

Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA‐Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin‐associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA‐I1 was most potent. The purpose of this study is to further establish targeting of PCNA by PCNA‐I1 and to identify PCNA‐I1 analogs with superior potencies. We found that PCNA‐I1 does not affect the level of chromatin‐associated PCNA harboring point mutations at the predicted binding site of PCNA‐I1. Forty‐six PCNA‐I1 analogs with structures of 1‐hydrazonomethyl‐2‐hydroxy (scaffold A), 2‐hydrazonomethyl‐1‐hydroxy (scaffold B), 2‐hydrazonomethyl‐3‐hydroxy (scaffold C), and 4‐pyridyl hydrazine (scaffold D) were analyzed for their effects on cell growth in four tumor cell lines and PCNA trimer stabilization. Compounds in scaffold group A and group B showed the highest trimer stabilization and the most potent cell growth inhibitory activities with a significant potency advantage observed in the Z isomers of scaffold A. The absence of trimer stabilization and growth inhibitory effects in compounds of scaffold group D confirms the essentiality of the hydroxynaphthyl substructure. Compounds structure–activity relationship (SAR)‐6 and SAR‐24 were analyzed for their effects on and found to reduce chromatin‐associated PCNA in tumor cells. This study led to the identification of SAR‐24, a compound with superior potencies and potentially improved solubility, which will be used for future development of PCNA‐targeting cancer therapies.
Long‐lasting oral analgesic effects of N‐protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain
Authors: Bonnard Elisabeth , Poras Hervé , Nadal Xavier , Maldonado Rafael , Fournié‐Zaluski Marie‐Claude , Roques Bernard P.
Published: February 2015

The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain‐evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N‐terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long‐lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through stimulation of peripheral opioid receptors by DENKIs‐protected ENKs as demonstrated by naloxone methiodide reversion. In all tested models, the most efficient prodrug 2a (PL265) was active, at least during 150–180 min, after single oral administration of 25–50 mg/kg in mice and of 100–200 mg/kg in rats. In models of neuropathic pain, both hyperalgesia and allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (PL265) and of the anti‐epileptic drug gabapentin had synergistic effect on neuropathic pain. Pharmacokinetic studies of 2a (PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (PL265) a suitable candidate for clinical development.
Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813
Authors: Lavreysen Hilde , Langlois Xavier , Donck Luc Ver , Nuñez José María Cid , Pype Stefan , Lütjens Robert , Megens Anton
Published: February 2015

JNJ‐40411813/ADX71149 (1‐butyl‐3‐chloro‐4‐(4‐phenylpiperidin‐1‐yl) pyridin‐2(1H)‐one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5‐Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent‐specific metabolite. JNJ‐40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4‐amino‐2‐thiabicyclo [3.1.0] hexane‐4,6‐dicarboxylic acid 2,2‐dioxide), the selective mGlu2 PAM JNJ‐42153605 (3‐(cyclopropylmethyl)‐7‐(4‐phenylpiperidin‐1‐yl)‐8‐(trifluoromethyl)[1,2,4]triazolo[4,3‐a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ‐40411813, JNJ‐42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine‐ and scopolamine‐induced but not d‐amphetamine‐induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine‐induced hyperlocomotion. As measured by 2‐deoxyglucose uptake, all compounds reversed memantine‐induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5‐dimethoxy‐4‐methylamphetamine‐induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ‐40411813.
A floatable formulation and laboratory bioassay of Pandora delphacis (Entomophthoromycota: Entomophthorales) for the control of rice pest Nilaparvata lugens Stål (Hemiptera: Delphacidae)
Authors: Zhou Xiang , Su Xiu , Liu Hongbo
Published: February 2015

BACKGROUND

The brown planthopper (BPH), Nilaparvata lugens (Staparvata luera: Delphacidae), is a serious rice pest that easily develops resistance to chemical insecticides and resistant rice varieties. This study evaluated the infectivity of the BPH fungal pathogen, Pandora delphacis, and developed a novel formulation as an alternative means of BPH control.

RESULTS

In a multiconidial concentration bioassay, P. delphacis‐infected BPH cadavers were observed on day 4, but most occurred between days 5 and 8. BPH mortality depended on the inoculated conidial concentration. The cumulative mortality of adult BPHs reached 81.7% at 192 conidia mm−2 in 8 days. Inoculation with 40.9 conidia mm−2 was sufficient to induce 50% BPH death, based on analysis of a time‐concentration‐mortality model. A floatable P. delphacis‐based formulation was made for use in paddy fields; mycelium‐containing pellets mimicking mycosed cadavers could produce 7–15.7 × 104 infectious conidia pellet−1 at 11–28 °C. In the laboratory bioassay, three floating pellets in a BPH‐rearing jar caused 75.5% BPH mortality within 8 days, similar to the mortality level caused by direct conidial inoculation.

CONCLUSION

P. delphacis is a potential biocontrol agent of BPHs for further research, and the novel floatable formulation holds promise as a method for BPH control. © 2015 Society of Chemical Industry
Evaluation of program success for programs with multiple trials in binary outcomes
Authors: Wang Meihua , Liu G. Frank , Schindler Jerald
Published: February 2015

A late‐stage clinical development program typically contains multiple trials. Conventionally, the program's success or failure may not be known until the completion of all trials. Nowadays, interim analyses are often used to allow evaluation for early success and/or futility for each individual study by calculating conditional power, predictive power and other indexes. It presents a good opportunity for us to estimate the probability of program success (POPS) for the entire clinical development earlier. The sponsor may abandon the program early if the estimated POPS is very low and therefore permit resource savings and reallocation to other products. We provide a method to calculate probability of success (POS) at an individual study level and also POPS for clinical programs with multiple trials in binary outcomes. Methods for calculating variation and confidence measures of POS and POPS and timing for interim analysis will be discussed and evaluated through simulations. We also illustrate our approaches on historical data retrospectively from a completed clinical program for depression. Copyright © 2015 John Wiley & Sons, Ltd.
Human–Nature Relationships in School Science: A Critical Discourse Analysis of a Middle‐Grade Science Textbook
Authors: SHARMA AJAY , BUXTON CORY A.
Published: February 2015

Science education has a central role to play in preparing a scientifically literate citizenry that is capable of understanding complex environmental challenges facing human societies and making well‐informed and evidence‐based decisions that help resolve these challenges. However, evidence suggests that most Americans are poorly equipped with the knowledge necessary for informed environmental action. In this study, we attempted to understand how the language of science textbooks works to represent the world for students in distinct ways that have serious implications for their ecological literacy. Using a methodological framework based on critical discourse analysis and systemic functional linguistics, we focused on clarifying the textual representations of the relationships between natural and social systems as portrayed in a seventh‐grade science textbook that is widely adopted in middle schools in Georgia, United States. Results indicate that this science textbook offers outdated representations of natural systems’ relationships with social systems and the role of human agency in these relationships. We discuss implications of these textual representations and call for reformed science textbooks that underscore the ecological embeddedness of the social world.
Correcting for bias in the selection and validation of informative diagnostic tests
Authors: Robertson David S. , Prevost A. Toby , Bowden Jack
Published: February 2015

When developing a new diagnostic test for a disease, there are often multiple candidate classifiers to choose from, and it is unclear if any will offer an improvement in performance compared with current technology. A two‐stage design can be used to select a promising classifier (if one exists) in stage one for definitive validation in stage two. However, estimating the true properties of the chosen classifier is complicated by the first stage selection rules. In particular, the usual maximum likelihood estimator (MLE) that combines data from both stages will be biased high. Consequently, confidence intervals and p‐values flowing from the MLE will also be incorrect. Building on the results of Pepe et al. (SIM 28:762–779), we derive the most efficient conditionally unbiased estimator and exact confidence intervals for a classifier's sensitivity in a two‐stage design with arbitrary selection rules; the condition being that the trial proceeds to the validation stage. We apply our estimation strategy to data from a recent family history screening tool validation study by Walter et al. (BJGP 63:393–400) and are able to identify and successfully adjust for bias in the tool's estimated sensitivity to detect those at higher risk of breast cancer. © 2015 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.
Let's Get Higher Scores on These New Assessments
Authors: Shanahan Timothy
Published: February 2015

This column explains three ways that teachers can improve reading test performance. Basically, the idea is that instead of teaching students to respond to particular question types as is typical of test preparation despite the ineffectiveness of this practice, it is better to teach students to read the test passages more effectively. Three research‐proven ways to do this are teaching students to interpret word meanings through context, teaching them to reduce or breakdown sentences to make sense of their meanings, and teaching students to sustain effective silent reading for extended periods of time.
Production of tyrosine through phenylalanine hydroxylation bypasses the intrinsic feedback inhibition in Escherichia coli
Authors: Huang Jin , Lin Yuheng , Yuan Qipeng , Yan Yajun
Published: February 2015

Tyrosine is a proteinogenic aromatic amino acid that is often used as a supplement of food and animal feed, as well as a (bio-)synthetic precursor to various pharmaceutically or industrially important molecules. Extensive metabolic engineering efforts have been made towards the efficient and cost-effective microbial production of tyrosine. Conventional strategies usually focus on eliminating intrinsic feedback inhibition and redirecting carbon flux into the shikimate pathway. In this study, we found that continuous conversion of phenylalanine into tyrosine by the action of tetrahydromonapterin (MH4)-utilizing phenylalanine 4-hydroxylase (P4H) can bypass the feedback inhibition in Escherichia coli, leading to tyrosine accumulation in the cultures. First, expression of the P4H from Xanthomonas campestris in combination with an MH4 recycling system in wild-type E. coli allowed the strain to accumulate tyrosine at 262 mg/L. On this basis, enhanced expression of the key enzymes associated with the shikimate pathway and the MH4 biosynthetic pathway resulted in the elevation of tyrosine production up to 401 mg/L in shake flasks. This work demonstrated a novel approach to tyrosine production and verified the possibility to alleviate feedback inhibition by creating a phenylalanine sink.
Leukodystrophy with multiple beaded periventricular cysts: unusual cranial MRI results in Canavan disease
Authors: Drenckhahn Anne , Schuelke Markus , Knierim Ellen
Published: February 2015

A 3‐year‐old boy was admitted with psychomotor delay, spasticity, progressive visual loss, nystagmus, macrocephaly, and epileptic seizures for diagnostics. Cranial magnetic resonance imaging (MRI) revealed leukodystrophy and multicystic changes. Urine excretion of N‐acetylaspartic acid was grossly increased, suggesting Canavan disease. Mutation screening of the ASPA gene confirmed this diagnosis. The underlying enzymatic defect causes accumulation of N‐acetylaspartic acid and subsequent progressive myelin degeneration with characteristic spongy degeneration of the subcortical white matter, normally only seen histologically. We describe this case to show that spongy degeneration in Canavan disease may also be present macroscopically in the form of multiple beaded periventricular cysts on cranial MRI.
Effect of Polyoxyethylene Chain Length on the Physicochemical Properties of N,N‐Dimethyl‐N‐dodecyl Polyoxyethylene Amine Oxide Hybrid Surfactants (C12EOnAO, with n = 1–4)
Authors: Cheng Hui , Zhang Huinian , Liu Xuefeng , Lin Mengchu , Qin Zhirong , Fang Yun
Published: February 2015

In order to determine the structure‐performance relationship of nonionic‐zwitterionic hybrid surfactants, N,N‐dimethyl‐N‐dodecyl polyoxyethylene (n) amine oxides (C12EOnAO) with different polyoxyethylene lengths (EOn, n = 1–4) were synthesized. For homologous C12EOnAO, it was observed that the critical micelle concentration (CMC), the maximum surface excess (Γm), CMC/C20, and the critical micelle aggregation number (Nm,c) decreased on going from 1 to 4 in EOn. However, there were concomitant increases in surface tension at the CMC (γCMC), minimum molecular cross‐sectional area (Amin), adsorption efficiency (pC20), and the polarity ([I1/I3]m) based on the locus of solubilization for pyrene. The values of log CMC and Nm,c decreased linearly with EOn lengthening from 1 to 4, although the impact of each EO unit on the CMC of C12EOnAO (n = 1–4) was much smaller than that typically seen for methylene units in the hydrophobic main chains of traditional surfactants. Compared to the structurally related conventional surfactant N,N‐dimethyl‐N‐dodecyl amine oxide (C12AO), C12EOnAO (n = 1–4) have smaller CMC, Amin, and CMC/C20, but larger pC20, Γm, and Nm,c with a higher [I1/I3]m. This may be attributed to the moderately amphiphilic EOn (n = 1–4) between the hydrophobic C12 tail and the hydrophilic AO head group.