bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognosis of N2b and N2c lymph node disease in oral squamous cell carcinoma is determined by the number of metastatic lymph nodes rather than laterality: Evidence to support a revision of the American Joint Committee on Cancer staging system
Authors: Ebrahimi Ardalan , Gil Ziv , Amit Moran , Yen Tzu‐Chen , Liao Chun‐Ta , Chaturvedi Pankaj , Agarwal Jai Prakash , Kowalski Luiz P. , Kohler Hugo F. , Kreppel Matthias , Cernea Claudio R. , Brandao Jose , Bachar Gideon , Bolzoni Villaret Andrea , Fliss Dan , Fridman Eran , Robbins K. Thomas , Shah Jatin P. , Patel Snehal G. , Clark Jonathan R. ,   The International Consortium for Outcome Research (ICOR) in Head and Neck Cancer.
Published: April 2014

BACKGROUND

A study was conducted to assess for prognostic heterogeneity within the N2b and N2c classifications for oral cancer based on the number of metastatic lymph nodes and to determine whether laterality of neck disease provides additional prognostic information.

METHODS

An international multicenter study of 3704 patients with oral cancer undergoing surgery with curative intent was performed. The endpoints of interest were disease‐specific survival and overall survival. Model fit was assessed by the Akaike Information Criterion and comparison of models with and without the covariate of interest using a likelihood ratio test.

RESULTS

The median number of metastatic lymph nodes was significantly higher in patients with N2c disease compared to those with N2b disease (P < .001). In multivariable analyses stratified by study center, the addition of the number of metastatic lymph nodes improved model fit beyond existing N classification. Next, the authors confirmed significant heterogeneity in prognosis based on the number of metastatic lymph nodes (≤ 2, 3‐4, and ≥ 5) in patients with both N2b and N2c disease (P < .001). A proposed reclassification combining N2b and N2c disease based on the number of metastatic lymph nodes demonstrated significant improvement in prognostic accuracy compared with the American Joint Committee on Cancer staging system, and no improvement was noted with the addition of a covariate for contralateral or bilateral neck disease (P = .472).

CONCLUSIONS

The prognosis of patients with oral cancer with N2b and N2c disease appears to be similar after adequate adjustment for the burden of lymph node metastases, irrespective of laterality. Based on this finding, the authors propose a modified lymph node staging system that requires external validation before implementation in clinical practice. Cancer 2014;120:1968–1974. © 2014 American Cancer Society.
Striking dichotomy in outcome of MYCN‐amplified neuroblastoma in the contemporary era
Authors: Kushner Brian H. , Modak Shakeel , Kramer Kim , LaQuaglia Michael P. , Yataghene Karima , Basu Ellen M. , Roberts Stephen S. , Cheung Nai‐Kong V.
Published: April 2014

BACKGROUND

The authors exploited a large database to investigate the outcomes of patients with high‐risk neuroblastoma in the contemporary era.

METHODS

All patients with high‐risk neuroblastoma aged <12 years who were treated during induction at the authors' institution from 2000 through 2011 were studied, including 118 patients with MYCN‐amplified [MYCN(+)] disease and 127 patients aged >18 months with MYCN‐nonamplified [MYCN(−)] stage 4 disease.

RESULTS

A complete response/very good partial response (CR/VGPR) to induction was correlated with significantly superior event‐free survival (EFS) (P < .001) and overall survival (OS) (P < .001) compared with a partial response or less. Patients with MYCN(+) and MYCN(−) disease had similar rates of CR/VGPR to induction (P = .366), and those with MYCN(+) and MYCN(−) disease who attained a CR/VGPR had similar EFS (P = .346) and OS (P = .542). In contrast, only MYCN(+) patients had progressive disease as a response to induction (P < .001), and early death from progressive disease (<366 days after diagnosis) was significantly more common (P < .001) among those with MYCN(+) disease. Overall, among patients who had a partial response or less, MYCN(+) patients had significantly inferior EFS (P < .001) and OS (P < .001) compared with MYCN(−) patients, which accounted for the significantly worse EFS (P = .008) and OS (P = .002) for the entire MYCN(+) cohort versus the MYCN(−) cohort.

CONCLUSIONS

Patients with MYCN(−), high‐risk neuroblastoma display a broad, continuous spectrum with regard to response and outcome, whereas MYCN(+) patients either have an excellent response to induction associated with good long‐term outcome or develop early progressive disease with a poor outcome. This extreme dichotomy in the clinical course of MYCN(+) patients points to underlying biologic differences with MYCN(+) neuroblastoma, the elucidation of which may have far‐reaching implications, including improved risk classification at diagnosis and the identification of targets for treatment. Cancer 2014;120:2050–2059. © 2014 American Cancer Society.
Fake source‐based source location privacy in wireless sensor networks
Authors: Jhumka Arshad , Bradbury Matthew , Leeke Matthew
Published: April 2014

The development of novel wireless sensor network (WSN) applications, such as asset monitoring, has led to novel reliability requirements. One such property is source location privacy (SLP). The original SLP problem is to protect the location of a source node in a WSN from a single distributed eavesdropper attacker. Several techniques have been proposed to address the SLP problem, and most of them use some form of traffic analysis and engineering to provide enhanced SLP. The use of fake sources is considered to be promising for providing SLP, and several works have investigated the effectiveness of the fake sources approach under various attacker models. However, very little work has been done to understand the theoretical underpinnings of the fake source technique. In this paper, we (i) provide a novel formalisation of the fake sources selection problem; (ii) prove the fake sources selection problem to be NP‐complete; (iii) provide parametric heuristics for three different network configurations; and (iv) show that these heuristics provide (near) optimal levels of SLP under appropriate parameterisation. Our results show that fake sources can provide a high level of SLP. Our work is the first to investigate the theoretical underpinnings of the fake source technique. Copyright © 2014 John Wiley & Sons, Ltd.
Correlation between Temperature Activation of Charge‐Carrier Generation Efficiency and Hole Mobility in Small‐Molecule Donor Materials
Authors: Koerner Christian , Hein Moritz Philipp , Kažukauskas Vaidotas , Sakavičius Andrius , Janonis Vytautas , Fitzner Roland , Bäuerle Peter , Leo Karl , Riede Moritz
Published: April 2014

In organic solar cells, free charge carriers are generated at the interface between an electron‐donating and an electron‐accepting material. The detailed mechanisms of the generation of free charge carriers are still under discussion. In this work, we investigate the influence of temperature on the generation efficiency of free charge carriers in blends of dicyanovinyl substituted oligothiophene (DCVnT) molecules and C60 by quasi‐steady‐state photoinduced absorption (PIA) measurements. The observed positive temperature dependence of charge‐carrier generation can be directly correlated to the charge‐transport behavior. The determined activation energy scales inversely with the hole mobility for all investigated DCVnT derivatives, suggesting higher dissociation probability of bound interfacial charge pairs at high mobility. Furthermore, the energetic disorder parameter, σ, determined by CELIV (charge extraction by linearly increasing voltage) measurements for a DCV6T derivative, matches the activation energy from the PIA measurements. In conclusion, these results underline the need for high‐mobility donor materials for optimal charge‐pair dissociation in organic solar cells.
Order and Conformation of Biphenyl in Cyanobiphenyl Liquid Crystals: A Combined Atomistic Molecular Dynamics and 1H NMR Study
Authors: Pizzirusso Antonio , Di Pietro Maria Enrica , De Luca Giuseppina , Celebre Giorgio , Longeri Marcello , Muccioli Luca , Zannoni Claudio
Published: April 2014

The alignment of biphenyl (2P) in the liquid‐crystal phases of 4‐n‐pentyl‐4′‐cyanobiphenyl (5CB) and 4‐n‐octyl‐4′‐cyanobiphenyl (8CB) is investigated by using a combination of predictive atomistic molecular dynamics (MD) simulations and 1H liquid‐crystal nuclear magnetic resonance (LXNMR) residual dipolar coupling measurements. A detailed comparison and validation of the MD results with LXNMR is provided, showing a good agreement between the simulated and experimental dipolar couplings at the same reduced temperature. MD is then used to examine the location of 2P in the smectic phase, which is unavailable to LXNMR, and 2P is found to be rather uniformly distributed. The combination of MD and NMR spectroscopy provides detailed information about the order, interconnection between orientation and conformation, local positional order, and interactions with the liquid‐crystalline solvent.
Dynamic, small‐world social network generation through local agent interactions
Authors: De Caux Robert , Smith Christopher , Kniveton Dominic , Black Richard , Philippides Andrew
Published: April 2014

To model agent relationships in agent‐based models, it is often necessary to incorporate a social network whose topology is commonly assumed to be “small‐world.” This is potentially problematic, as the classification is broad and covers a wide‐range of network statistics. Furthermore, real networks are often dynamic, in that edges and nodes can appear or disappear, and spatial, in that connections are influenced by an agent's position within a particular social space. These properties are difficult to achieve in current network formation tools. We have, therefore, developed a novel social network formation model, that creates and dynamically adjusts small‐world networks using local spatial interactions, while maintaining tunable global network statistics from across the broad space of possible small‐world networks. It is, therefore, a useful tool for multiagent simulations and diffusion processes, particularly those in which agents and edges die or are constrained in their movement within some social space. We also show, using a simple epidemiological diffusion model, that a range of networks can all satisfy the small‐world criterion, but behave quite differently. This demonstrates that it is problematic to generalize results across the whole space of small‐world networks. © 2014 Wiley Periodicals, Inc. Complexity 19: 44–53, 2014
Highly Efficient Copper–Zinc–Tin–Selenide (CZTSe) Solar Cells by Electrodeposition
Authors: Jeon Jong‐Ok , Lee Kee Doo , Seul Oh Lee , Seo Se‐Won , Lee Doh‐Kwon , Kim Honggon , Jeong Jeung‐hyun , Ko Min Jae , Kim BongSoo , Son Hae Jung , Kim Jin Young
Published: April 2014

Highly efficient copper–zinc–tin–selenide (Cu2ZnSnSe4; CZTSe) thin‐film solar cells are prepared via the electrodepostion technique. A metallic alloy precursor (CZT) film with a Cu‐poor, Zn‐rich composition is directly deposited from a single aqueous bath under a constant current, and the precursor film is converted to CZTSe by annealing under a Se atmosphere at temperatures ranging from 400 °C to 600 °C. The crystallization of CZTSe starts at 400 °C and is completed at 500 °C, while crystal growth continues at higher temperatures. Owing to compromises between enhanced crystallinity and poor physical properties, CZTSe thin films annealed at 550 °C exhibit the best and most‐stable device performances, reaching up to 8.0 % active efficiency; among the highest efficiencies for CZTSe thin‐film solar cells prepared by electrodeposition. Further analysis of the electronic properties and a comparison with another state‐of‐the‐art device prepared from a hydrazine‐based solution, suggests that the conversion efficiency can be further improved by optimizing parameters such as film thickness, antireflection coating, MoSe2 formation, and p–n junction properties.
Significant long‐term, but not short‐term, hippocampal‐dependent memory impairment in adult rats exposed to alcohol in early postnatal life
Authors: Goodfellow Molly J. , Lindquist Derick H.
Published: April 2014

In rodents, ethanol exposure in early postnatal life is known to induce structural and functional impairments throughout the brain, including the hippocampus. Herein, rat pups were administered one of three ethanol doses over postnatal days (PD) 4–9, a period of brain development comparable to the third trimester of human pregnancy. As adults, control and ethanol rats were trained and tested in a variant of hippocampal‐dependent one‐trial context fear conditioning. In Experiment 1, subjects were placed into a novel context and presented with an immediate footshock (i.e., within ∼8 sec). When re‐exposed to the same context 24 hr later low levels of conditioned freezing were observed. Context pre‐exposure 24 hr prior to the immediate shock reversed the deficit in sham‐intubated and unintubated control rats, enhancing freezing behavior during the context retention test. Even with context pre‐exposure, however, significant dose‐dependent reductions in contextual freezing were seen in ethanol rats. In Experiment 2, the interval between context pre‐exposure and the immediate shock was shortened to 2 hr, in addition to the standard 24 hr. Ethanol rats trained with the 2 hr, but not 24 hr, interval displayed retention test freezing levels roughly equal to controls. Results suggest the ethanol rats can encode a short‐term context memory and associate it with the aversive footshock 2 hr later. In the 24 hr ethanol rats the short‐term context memory is poorly transferred or consolidated into long‐term memory, we propose, impeding the memory's subsequent retrieval and association with shock. © 2014 Wiley Periodicals, Inc. Dev Psychobiol 56: 1316–1326, 2014.
No association between vitamin D and β‐cell autoimmunity in Finnish and Estonian children
Authors: Reinert‐Hartwall L. , Honkanen J. , Härkönen T. , Ilonen J. , Simell O. , Peet A. , Tillmann V. , Lamberg‐Allardt C. , Virtanen S. M. , Knip M. , Vaarala O. ,   The DIABIMMUNE Study Group
Published: April 2014

Background

Vitamin D has immunomodulatory properties, such as regulation of FOXP3 expression and regulatory T‐cell activity. Our aim was to investigate whether plasma 25‐hydroxyvitamin D [25(OH)D] concentrations associate with the development of β‐cell autoimmunity and the transcriptional activity of FOXP3 or vitamin D3 convertase gene (CYP27B1) in CD4+ memory T cells.

Methods

We studied 83 Finnish and 32 Estonian children participating in the DIABIMMUNE and DIPP studies. Twenty‐nine Finnish and six Estonian children tested positive for at least one diabetes‐associated autoantibody. The plasma concentrations of 25(OH)D and 1,25(OH)2D were analysed with an enzyme immunoassay. Gene expression of FOXP3 and CYP27B1 in the isolated CD4+ memory T cells was studied with reverse transcription quantitative polymerase chain reaction.

Results

Vitamin D status did not differ between subjects positive and negative for β‐cell autoantibodies. Finnish children had higher vitamin D status than Estonian children (p < 0.001). FOXP3 expression was higher in Estonian CD4+ memory T‐cell samples than in Finnish samples (p < 0.01) even when including in both groups only children with serum 25(OH)D concentrations in the range of 50–80 nmol/L (p < 0.001).

Conclusions

These findings do not support a crucial role of circulating 25(OH)D as a regulator of β‐cell autoimmunity or FOXP3 expression. Copyright © 2014 John Wiley & Sons, Ltd.
Probabilistic maturation reaction norms assessed from mark–recaptures of wild fish in their natural habitat
Authors: Olsen Esben M. , Serbezov Dimitar , Vøllestad Leif A.
Published: April 2014

Reaction norms are a valuable tool in evolutionary biology. Lately, the probabilistic maturation reaction norm approach, describing probabilities of maturing at combinations of age and body size, has been much applied for testing whether phenotypic changes in exploited populations of fish are mainly plastic or involving an evolutionary component. However, due to typical field data limitations, with imperfect knowledge about individual life histories, this demographic method still needs to be assessed. Using 13 years of direct mark–recapture observations on individual growth and maturation in an intensively sampled population of brown trout (Salmo trutta), we show that the probabilistic maturation reaction norm approach may perform well even if the assumption of equal survival of juvenile and maturing fish does not hold. Earlier studies have pointed out that growth effects may confound the interpretation of shifts in maturation reaction norms, because this method in its basic form deals with body size rather than growth. In our case, however, we found that juvenile body size, rather than annual growth, was more strongly associated with maturation. Viewed against earlier studies, our results also underscore the challenges of generalizing life‐history patterns among species and populations.
Effect of age‐based and environment‐based cues on reproductive investment in Gambusia affinis
Authors: Billman Eric J. , Belk Mark C.
Published: April 2014

We examined the multivariate life‐history trajectories of age 0 and age 1 female Gambusia affinis to determine relative effects of age‐based and environment‐based cues on reproductive investment. Age 0 females decreased reproductive investment prior to the onset of fall and winter months, while age 1 females increased reproductive investment as the summer progressed. The reproductive restraint and terminal investment patterns exhibited by age 0 and age 1 females, respectively, were consistent with the predictions from the cost of reproduction hypothesis. Age 0 females responded to environment‐based cues, decreasing reproductive investment to increase the probability of overwinter survival and subsequent reproductive opportunities in the following summer. Age 1 females responded to age‐based cues, or the proximity of death, increasing investment to current reproduction as future reproductive opportunities decreased late in life. Thus, individuals use multiple cues to determine the level of reproductive investment, and the response to each cue is dependent on the age of an individual.
Analysis of trace compounds generated by pressurized oxygen blown entrained flow biomass gasification
Authors: Öhrman Olov G. W. , Molinder Roger , Weiland Fredrik , Johansson Ann‐Christine
Published: April 2014

Trace compounds were measured in synthesis gas and waste water from a pilot scale pressurized entrained flow oxygen blown biomass gasifier. The feedstock used was milled soft stem wood powder. Gaseous trace compounds were analyzed by gas chromatography. Up to 20 ppm of hydrogen sulfide was observed in the cold synthesis gas and the concentration seemed to be independent of the oxygen equivalence ratio (ER). Benzene varied from 30 to 1100 ppm, strongly depended on the ER and correlated well with the methane concentration. The concentrations of acetylene and ethylene increased as the ER was reduced and could have acted as precursors for the observed soot particles which were characterized using thermogravimetric analysis, X‐ray diffraction, and scanning electron microscopy. Common polycyclic aromatic hydrocarbons from high temperature biomass gasification such as pyrene, phenanthrene, fluoranthene, and naphthalene were observed in low concentrations in the soot, in the cold synthesis gas and also in the waste water from the quench. Inorganic elements from the feedstock were observed in the waste water. Comparisons were also made with previous results from a black liquor gasifier. © 2014 American Institute of Chemical Engineers Environ Prog, 33: 699–705, 2014
Risks of neonicotinoid insecticides to honeybees
Authors: Fairbrother Anne , Purdy John , Anderson Troy , Fell Richard
Published: April 2014

The European honeybee, Apis mellifera, is an important pollinator of agricultural crops. Since 2006, when unexpectedly high colony losses were first reported, articles have proliferated in the popular press suggesting a range of possible causes and raising alarm over the general decline of bees. Suggested causes include pesticides, genetically modified crops, habitat fragmentation, and introduced diseases and parasites. Scientists have concluded that multiple factors in various combinations—including mites, fungi, viruses, and pesticides, as well as other factors such as reduction in forage, poor nutrition, and queen failure—are the most probable cause of elevated colony loss rates. Investigators and regulators continue to focus on the possible role that insecticides, particularly the neonicotinoids, may play in honeybee health. Neonicotinoid insecticides are insect neurotoxicants with desirable features such as broad-spectrum activity, low application rates, low mammalian toxicity, upward systemic movement in plants, and versatile application methods. Their distribution throughout the plant, including pollen, nectar, and guttation fluids, poses particular concern for exposure to pollinators. The authors describe how neonicotinoids interact with the nervous system of honeybees and affect individual honeybees in laboratory situations. Because honeybees are social insects, colony effects in semifield and field studies are discussed. The authors conclude with a review of current and proposed guidance in the United States and Europe for assessing the risks of pesticides to honeybees. Environ Toxicol Chem 2014;33:719–731. © 2014 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc., on behalf of SEATC. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.
Late Pleistocene Geology and Paleolithic Archaeology of the Shimaki Site, Hokkaido, Japan
Authors: Buvit Ian , Izuho Masami , Terry Karisa , Shitaoka Yorinao , Soda Tsutomu , Kunikita Dai
Published: April 2014

Here, we assess geochronological, sedimentological, stratigraphic, and stone tool data from Shimaki, an Upper Paleolithic site in southeastern Hokkaido, Japan. Overall, we find that Shimaki's landscape context and flaked‐stone assemblage are similar to sites in Hokkaido that date to just before or at the Last Glacial Maximum (LGM). Based on several numerical ages, we suggest that the artifact‐bearing layer, including a wedge‐shaped core morphologically similar to post‐LGM specimens from Siberia, formed during the LGM, and sites like Shimaki with clear stratigraphy, relatively undisturbed cultural material, and what appear to be transitional artifact forms, may be key to answering questions about the origins of microblades, but, without human fossil remains for ancient DNA comparison, are inadequate to address the fate of Late Pleistocene Siberians.
Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions
Authors: Nijland Philip G. , Michailidou Iliana , Witte Maarten E. , Mizee Mark R. , van der Pol Susanne M. A. , van het Hof Bert , Reijerkerk Arie , Pellerin Luc , van der Valk Paul , de Vries Helga E. , van Horssen Jack
Published: April 2014

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non‐neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co‐transcription factor peroxisome proliferator‐activated receptor gamma co‐activator 1‐alpha (PGC‐1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC‐1α in astrocyte‐like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS. GLIA 2014;62:1125–1141
Communication Maps: Exploring Energy Transport through Proteins and Water
Authors: Agbo Johnson K. , Gnanasekaran Ramachandran , Leitner David M.
Published: April 2014

Frequency‐resolved communication maps provide a coarse‐grained, global mapping of energy transport channels in a protein as a function of frequency of modes that carry energy. We illustrate the approach with a study of the homodimeric hemoglobin of Scapharca inaequivalvis, which exhibits cooperativity during ligand binding. We compare energy transport between the two hemes of the unliganded and oxygenated protein, which is mediated by water as well as residues forming a hydrogen‐bonding network at the interface between the globules, and lies along the pathway for allosteric transitions observed in time‐resolved X‐ray studies. Non‐equilibrium molecular simulations on energy transport from the heme corroborate the energy transport pathways identified by the communication maps.
GLOBAL DISSEMINATION OF MICRO‐IRRIGATION TECHNOLOGIES TO SMALLHOLDER FARMERS
Authors: Andrezejewski Kevin M.
Published: April 2014

Approximately 1.1 billion people in the world live on less than US$1 per day, 800 million of whom are smallholder farmers relying on subsistence agriculture for their livelihood. Moving from reliance on rainfed and bucket irrigation to the use of simple water lifting, application, and storage technologies has a dramatic and positive impact on these families' food security and income stream and contributes to a more efficient use of precious water resources.

iDE designs and disseminates affordable solutions that allow farmers to grow more, higher‐quality crops year‐round while reducing the water, labour, energy and chemical inputs. iDEal's Global Supply serves as the distribution enterprise for these micro‐irrigation technologies, providing sample products, bulk shipments, and technical support for both iDE Country Programmes and other individuals and organizations worldwide. iDEal's standard product offering includes microtube drip kits, water pumps, sprinklers, and water storage bags specifically designed for low‐pressure applications.

To provide widespread access to these affordable, simple, and appropriate micro‐irrigation products, iDEal has established a reliable network of international and local supply chain sources. The key components of this network are:

product support. Sourcing, procurement, new product development, and quality control process;

order fulfilment. Customer service, logistics, basic product support;

marketing. Promotional materials, analysis, and communications planning;

technical assistance. Product specification sheets, training and installation manuals, technical support.

The cornerstone in disseminating these technologies on a global scale is iDE's network of suppliers, logistics relationships, and in‐country expertise. This core competency allows Global Supply to be an innovative leader in last‐mile distribution of micro‐irrigation technologies to farmers worldwide. Copyright © 2014 John Wiley & Sons, Ltd.
Effects of Up to 5 Years of Denosumab Treatment on Bone Histology and Histomorphometry: The FREEDOM Study Extension
Authors: Brown Jacques P , Reid Ian R , Wagman Rachel B , Kendler David , Miller Paul D , Jensen Jens-Erik Beck , Bolognese Michael A , Daizadeh Nadia , Valter Ivo , Zerbini Cristiano AF , Dempster David W
Published: April 2014

Denosumab reduced bone resorption, increased bone mineral density (BMD), and decreased new vertebral, hip, and nonvertebral fracture risk in postmenopausal women with osteoporosis in the FREEDOM trial. Consistent with its mechanism of action, transiliac crest bone biopsies from subjects treated with denosumab for 1 to 3 years demonstrated reduced bone turnover that was reversible upon treatment cessation. Long-term denosumab treatment for up to 6 years in the FREEDOM extension provides sustained bone turnover reduction and continued low fracture incidence. Here, we evaluate 5 years of denosumab treatment on bone remodeling at the tissue level. Transiliac crest bone biopsies were obtained from 41 subjects (13 cross-over and 28 long-term from the FREEDOM placebo and denosumab groups, respectively) at year 2 of the FREEDOM extension, representing up to 5 years of denosumab treatment. Demographics for this subset were comparable to the overall extension cohort. The mean (SD) duration from the last denosumab dose to the first dose of tetracycline was 5.7 (0.5) months. Qualitative bone histology assessed in all biopsy samples was unremarkable, showing normally mineralized lamellar bone. Structural indices, including trabecular bone volume, number, and surface, were similar between cross-over and long-term groups. Bone resorption was decreased as reflected by eroded surface in cross-over and long-term subjects. A total of 11 of 13 (85%) cross-over subjects and 20 of 28 (71%) long-term subjects had specimens with double or single tetracycline label in trabecular and/or cortical compartments; specimens from 5 cross-over subjects and 10 long-term subjects were evaluable for dynamic trabecular bone parameters. Dynamic remodeling indices were low for both groups and consistent with reduced bone turnover with denosumab. In conclusion, denosumab treatment through 5 years resulted in normal bone quality with reduced bone turnover. These observations are consistent with its mechanism of action and associated with continued BMD increases and low fracture incidence. © 2014 American Society for Bone and Mineral Research.
Dlx5 and Mef2 Regulate a Novel Runx2 Enhancer for Osteoblast-Specific Expression
Authors: Kawane Tetsuya , Komori Hisato , Liu Wenguang , Moriishi Takeshi , Miyazaki Toshihiro , Mori Masako , Matsuo Yuki , Takada Yoshio , Izumi Shinichi , Jiang Qing , Nishimura Riko , Kawai Yosuke , Komori Toshihisa
Published: April 2014

Runx2 is essential for osteoblast differentiation and chondrocyte maturation. The expression of Runx2 is the first requisite step for the lineage determination from mesenchymal stem cells to osteoblasts. Although the transcript from Runx2 distal promoter is majorly expressed in osteoblasts, the promoter failed to direct green fluorescent protein (GFP) expression to osteoblasts. To find the regulatory region, we generated GFP reporter mice driven by a bacterial artificial chromosome (BAC) of Runx2 locus, and succeeded in the reproduction of endogenous Runx2 expression. By serially deleting it, we identified a 343-bp enhancer, which directed GFP expression specifically to osteoblasts, about 30 kb upstream of the distal promoter. The sequence of the 343-bp enhancer was highly conserved among mouse, human, dog, horse, opossum, and chicken. Dlx5, Mef2c, Tcf7, Ctnnb1, Sp7, Smad1, and Sox6, which localized on the enhancer region in primary osteoblasts, synergistically upregulated the enhancer activity, whereas Msx2 downregulated the activity in mouse osteoblastic MC3T3-E1 cells. Msx2 was predominantly bound to the enhancer in mouse multipotent mesenchymal C3H10T1/2 cells, whereas Dlx5 was predominantly bound to the enhancer in MC3T3-E1 cells. Dlx5 and Mef2 directly bound to the enhancer, and the binding sites were required for the osteoblast-specific expression in mice, whereas the other factors bound to the enhancer by protein-protein interaction. The enhancer was characterized by the presence of the histone variant H2A.Z, the enrichment of histone H3 mono- and dimethylated at Lys4 and acetylated at Lys18 and Lys27, but the depletion of histone H3 trimethylated at Lys4 in primary osteoblasts. These findings indicated that the enhancer, which had typical histone modifications for enhancers, contains sufficient elements to direct Runx2 expression to osteoblasts, and that Dlx5 and Mef2, which formed an enhanceosome with Tcf7, Ctnnb1, Sp7, Smad1, and Sox6, play an essential role in the osteoblast-specific activation of the enhancer. © 2014 American Society for Bone and Mineral Research.
Characterization of Immortalized Dairy Goat Male Germline Stem Cells (mGSCs)
Authors: Zhu Haijing , Ma Jing , Du Rui , Zheng Liming , Wu Jiang , Song Wencong , Niu Zhiwei , He Xin , Du Enqi , Zhao Shanting , Hua Jinlian
Published: April 2014

Male germline stem cells (mGSCs), in charge for the fertility in male testis, are the only kind of adult stem cells that transmit genetic information to next generation, with promising prospects in germplasm resources preservation and optimization, and production of transgenic animals. Mouse male germline stem cell lines have been established and are valuable for studying the mechanisms of spermatogenesis. However, there is a lack of stable mGSC cell lines in livestock, which restricts the progress of transgenic research and related biotechnology. Here, we firstly established an immortalized dairy goat mGSC cell line to study the biological properties and the signaling pathways associated with mGSCs self‐renewal and differentiation. The ectopic factors SV40 large T antigen and Bmi1 genes were transduced into dairy goat mGSCs, and the results showed that the proliferation of these cells that were named mGSCs‐I‐SB was improved significantly. They maintained the typical characteristics including the expression of mGSC markers, and the potential to differentiate into all three germ layers, sperm‐like cells in vitro. Additionally, mGSCs‐I‐SB survived and differentiated into three germ layer cell types when they were transplanted into chicken embryos. Importantly, the cells also survived in mouse spermatogenesis deficiency model testis which seemed to be the golden standard to examine mGSCs. Conclusively, our results demonstrate that mGSCs‐I‐SB present the characteristics of mGSCs and may promote the future study on goat mGSCs. J. Cell. Biochem. 115: 1549–1560, 2014. © 2014 Wiley Periodicals, Inc.
Determination of Silver in Human Hair by Ionic Liquid‐based Cold‐induced Aggregation Microextraction as a Solvent Extraction Method
Authors: Bahar Soleiman , Hosseini Hamid
Published: April 2014

We report on the determination of silver ion in human hair sample using ionic liquid cold‐induced aggregation combined with spectrophotometric detection. Parameters governing the extraction efficiency (such as concentration of ligand, volume of ionic liquid, pH, temperature, extraction time) were optimized and resulted in enrichment factor of 44.4 for silver ion. The calibration curve was linear with correlation coefficient (R2) of 0.999, in the concentration range from 1.0 to 20 ng mL−1. The relative standard deviation is 2.3% (for n = 10), the limit of detection is 0.262 ng mL−1, and relative recoveries in real samples were more than 93%.
Ultrasound‐Assisted Synthesis of 6‐Methyl‐1,2,3,4‐tetrahydro‐N‐aryl‐2‐oxo/thio‐4‐arylpyrimidine‐5‐carboxamides Catalyzed by Uranyl Nitrate Hexahydrate
Authors: Venkatesan K. , Satyanarayana V. S. V. , Sivakumar A.
Published: April 2014

An efficient and simple method developed for the synthesis of 6‐methyl‐1,2,3,4‐tetrahydro‐N‐aryl‐2‐oxo/thio‐4‐arylpyrimidine‐5‐carboxamide derivatives (4a‐o) using UO2(NO3)2.6H2O catalyst under conventional and ultrasonic conditions. The ultrasound irradiation synthesis had shown several advantages such as milder conditions, shorter reaction times and higher yields. The structures of all the newly synthesized compounds have been confirmed by FT‐IR, 1H NMR, 13C NMR and mass spectra.
Preparation and Application of Fullerene C60‐Polymers in Piezoelectric Quartz Crystal Sensors for Hemoglobin and Olefins
Authors: You Rouah‐Lin , Shih Jeng‐Shong
Published: April 2014

The C60—polycinnamaldehyde (C60—PCA) and C60—polyphenylacetylene (C60—PPA) polymers were synthesized by the Friedel—Craft reaction and applied as piezoelectric (PZ) quartz crystal coating materials. A C60—polycinnamaldehyde (PCA) coated piezoelectric quartz crystal liquid sensor with a homemade computer interface was prepared and applied as a PZ hemoglobin sensor. The adsorption of hemoglobin onto the C60—PCA coated crystal resulted in a decreased oscillating frequency. The variations in crystal frequency were converted to voltage with a frequency to voltage converter, followed by amplification with OPA and data acquisition with an analog to digital converter. The PZ hemoglobin sensor exhibited good sensitivity of 6530 Hz/(mg/mL) with a detection limit at the ppm level for hemoglobin. Further, a C60—polyphenylacetylene (C60—PPA) coated piezoelectric quartz crystal gas sensor with an Intell‐8255 data processing system for various olefin vapors was also made. The aromatic hydrocarbons such as toluene seem to have greater adsorption onto C60—PPA membrane than alkynes, alkenes, and alkanes. The adsorption of polycyclic aromatic hydrocarbons (PAHs) onto the C60—PPA membrane was also examined. The C60—PPA coated PZ crystal gas sensor showed much better sensitivity for PAHs than for other olefins such as toluene, 1‐hexyne and 1‐hexene, and a much larger frequency shift for naphthalene than other PAHs was also found.
Entry‐into‐humans study with ACT‐462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant
Authors: Hoch Matthias , van Gorsel Helene , van Gerven Joop , Dingemanse Jasper
Published: April 2014

A double‐blind, placebo‐ and active comparator‐controlled, randomized, single‐ascending‐dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT‐462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT‐462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400‐mg group received a single oral dose of 400 mg almorexant (two‐way crossover). ACT‐462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose‐dependent. ACT‐462206 was absorbed with a median tmax of 1.5–4.0 hours. The elimination half‐life varied from 4.8 to 11.2 hours. A clinically relevant reduction in vigilance and attention, alertness, and motor coordination was recorded at ACT‐462206 doses ≥200 mg. The onset was between 20 and 45 minutes after drug intake, the maximum effect between 1 and 2 hours after drug administration, and these impairing effects largely disappeared within 8 hours post‐dose. Doses of 400–1,000 mg ACT‐462206 were similarly efficacious to 400 mg almorexant, with a trend for an earlier onset of action with ACT‐462206. The present results confirm the activity of ACT‐462206 as an orexin antagonist.
Linear Free‐Energy Relationships Applied to the 13C NMR Chemical Shifts in 4‐Substituted N‐[1‐(Pyridine‐3‐ and ‐4‐yl)ethylidene]anilines
Authors: Rančić Milica , Trišović Nemanja , Milčić Miloš , Jovanović Maja , Jovanović Bratislav , Marinković Aleksandar
Published: April 2014

Two series of 4‐substituted N‐[1‐(pyridine‐3‐ and ‐4‐yl)ethylidene]anilines have been synthesized using different methods of conventional and microwave‐assisted synthesis, and linear free‐energy relationships have been applied to the 13C NMR chemical shifts of the carbon atoms of interest. The substituent‐induced chemical shifts have been analyzed using single substituent parameter and dual substituent parameter methods. The presented correlations describe satisfactorily the field and resonance substituent effects having similar contributions for C1 and the azomethine carbon, with exception of the carbon atom in para position to the substituent X. In both series, negative ρ values have been found for C1′ atom (reverse substituent effect). Quantum chemical calculations of the optimized geometries at MP2/6‐31G++(d,p) level, together with 13C NMR chemical shifts, give a better insight into the influence of the molecular conformation on the transmission of electronic substituent effects. The comparison of correlation results for different series of imines with phenyl, 4‐nitrophenyl, 2‐pyridyl, 3‐pyridyl, 4‐pyridyl group attached at the azomethine carbon with the results for 4‐substituted N‐[1‐(pyridine‐3‐ and ‐4‐yl)ethylidene]anilines for the same substituent set (X) indicates that a combination of the influences of electronic effects of the substituent X and the π1‐unit can be described as a sensitive balance of different resonance structures.
Radiochemical synthesis of 2′‐[18F]‐labelled and 3′‐[18F]‐labelled nucleosides for positron emission tomography imaging
Authors: Meyer Jan‐Philip , Probst Katrin C. , Westwell Andrew D.
Published: April 2014

This review article considers 2′‐labelled and 3′‐labelled nucleosides, which are of great importance as positron emission tomography (PET) probes in clinical diagnostics and PET research. Although the radiochemical preparation of several [18F]‐labelled nucleosides such as [18F]fluorothymidine or [18F](fluoroarabinofuranosyl)cytosine has been accomplished within the last two decades, a number of potentially interesting nucleoside‐based biomarkers are not yet available for automated good manufacturing practice production due to the lack of fast and efficient synthetic methods for late‐stage [18F]‐introduction. In order to meet recent demands for new PET‐based biomarkers in various clinical applications, appropriate precursors that can easily be fluorinated and deprotected need to be developed.
Social context: Key to understanding culture's effects on creativity
Authors: Nouri Rikki , Erez Miriam , Lee Cynthia , Liang Jian , Bannister Brendan D. , Chiu Warren
Published: April 2014

This paper proposes that the social context moderates the effect of culture on creativity by drawing on the constructivist dynamic approach. We assess creativity by the level of fluency, originality, and elaboration on the usefulness and appropriateness of ideas in three contexts: working under a supervisor, in a group, and alone. We hypothesized that in high power distance cultures, working under a supervisor inhibits creativity, whereas in individualistic cultures, the presence of peers attenuates creativity. Results from two parallel experiments, one in the United States (N = 79) and the other in China (N = 83), partially support the hypotheses. The Chinese originality level was significantly lower when working under a supervisor than when working alone. American subjects generated fewer ideas and elaborated less when working in the presence of peers and elaborated less in the presence of peers than when under a supervisor. We conclude that the social context moderates the culture–creativity relationship by making consensual cultural values more accessible in a social context than when working alone. Copyright © 2014 John Wiley & Sons, Ltd.
An analysis of bivalve larval shell pigments using micro‐Raman spectroscopy
Authors: Thompson Christine M. , North Elizabeth W. , White Sheri N. , Gallager Scott M.
Published: April 2014

Micro‐Raman spectroscopy has been used on adult bivalve shells to investigate organic and inorganic shell components but has not yet been applied to bivalve larvae. It is known that the organic matrix of larval shells contains pigments, but less is known about the presence or source of these molecules in larvae. We investigated Raman spectra of seven species of bivalve larvae to assess the types of pigments present in shells of each species and how the ratio of inorganic : organic material changes in a dorso‐ventral direction. In laboratory experiments, we reared larvae of three clam species in waters containing different organic signatures to determine if larvae incorporated compounds from source waters into their shells. We found differences in spectra and pigments between most species but found less intraspecific differences. A neural network classifier for Raman spectra classified five out of seven species with greater than 85% accuracy. There were slight differences between the amount and type of pigment present along the shell, with the prodissoconch I and shell margin areas being the most variable. Raman spectra of 1‐day‐old larvae were found to be differentiable when larvae were reared in waters with different organic signatures. With micro‐Raman spectroscopy, it may be possible to identify some unknown species in the wild and trace their natal origins, which could enhance identification accuracy of bivalve larvae and ultimately aid management and restoration efforts. Copyright © 2014 John Wiley & Sons, Ltd.
Slab profile encoding (PEN) for minimizing slab boundary artifact in three‐dimensional diffusion‐weighted multislab acquisition
Authors: Van Anh T. , Aksoy Murat , Holdsworth Samantha J. , Kopeinigg Daniel , Vos Sjoerd B. , Bammer Roland
Published: April 2014

Purpose

To propose a method for mitigating slab boundary artifacts in three‐dimensional (3D) multislab diffusion imaging with no or minimal increases in scan time.

Methods

The multislab acquisition was treated as parallel imaging acquisition where the slab profiles acted as the traditional receiver sensitivity profiles. All the slabs were then reconstructed simultaneously along the slab direction using Cartesian‐based sensitivity encoding (SENSE) reconstruction. The slab profile estimation was performed using either a Bloch simulation or a calibration scan.

Results

Both phantom and in vivo results showed negligible slab boundary artifacts after reconstruction using the proposed method. The performance of the proposed method is comparable to the state‐of‐the‐art slab combination method without the scan time penalty that depends on the number of acquired volumes. The obtained g‐factor map of the SENSE reconstruction problem showed a maximum g‐factor of 1.7 in the region of interest.

Conclusion

We proposed a novel method for mitigating slab boundary artifacts in 3D diffusion imaging by treating the multislab acquisition as a parallel imaging acquisition and reconstructing all slabs simultaneously using Cartesian SENSE. Unlike existing methods, the scan time increase, if any, does not scale with the number of image volumes acquired. Magn Reson Med 73:605–613, 2015. © 2014 Wiley Periodicals, Inc.