bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunophenotyping of Paucicellular Samples
Authors: Stacchini Alessandra , Demurtas Anna , Aliberti Sabrina
Published: April 2014

Immunophenotyping of paucicellular samples may represent a diagnostic challenge in the flow cytometry (FC) laboratory routine, as the scarcity of cells limits the number of tests that can be performed. Specimens such as fine needle aspirates (FNA), human body fluids (BF), cerebrospinal fluid (CSF), or ocular fluid (OF) sent for FC investigations in the case of suspicion of lymphoma, or for lymphoma monitoring, may contain very low numbers of cells. In these cases, it is mandatory to obtain the largest amount possible of useful information from a single tube. The basic protocol described in this unit provides a method that combines the use of multiple monoclonal antibodies (MAbs) with a Boolean gating strategy to identify and quantify the main lymphocyte populations, as well as to detect lymphomatous B cells or any aberrant T cell expression, if present, in paucicellular samples. Curr. Protoc. Cytom. 68:9.46.1‐9.46.14. © 2014 by John Wiley & Sons, Inc.
How useful are complex flood damage models?
Authors: Schröter Kai , Kreibich Heidi , Vogel Kristin , Riggelsen Carsten , Scherbaum Frank , Merz Bruno
Published: April 2014

We investigate the usefulness of complex flood damage models for predicting relative damage to residential buildings in a spatial and temporal transfer context. We apply eight different flood damage models to predict relative building damage for five historic flood events in two different regions of Germany. Model complexity is measured in terms of the number of explanatory variables which varies from 1 variable up to 10 variables which are singled out from 28 candidate variables. Model validation is based on empirical damage data, whereas observation uncertainty is taken into consideration. The comparison of model predictive performance shows that additional explanatory variables besides the water depth improve the predictive capability in a spatial and temporal transfer context, i.e., when the models are transferred to different regions and different flood events. Concerning the trade‐off between predictive capability and reliability the model structure seem more important than the number of explanatory variables. Among the models considered, the reliability of Bayesian network‐based predictions in space‐time transfer is larger than for the remaining models, and the uncertainties associated with damage predictions are reflected more completely.
White House Climate Data Initiative Kicks Off
Authors: Showstack Randy
Published: April 2014

A newly launched White House Climate Data Initiative includes nearly 20 U.S. government federal agency and private sector projects to leverage vast stores of government data to support climate change preparedness efforts.
First assessment of noctilucent cloud variability at midlatitudes
Authors: Schultz Colin
Published: April 2014

As the Sun dips below the horizon, the last rays of light can glint off crystals of ice high in the atmosphere, lighting up the sky with an electric blue glow. Known as noctilucent clouds, these collections of ice crystals occur most often at high latitudes, but the long polar days make them difficult to see. With the eye, noctilucent clouds can best be seen at night between 50° and 60° latitude in both hemispheres.
Supporting Adult Independence in the Community for Individuals With High‐Functioning Autism Spectrum Disorders
Authors: Loomis James W.
Published: April 2014

Research finds that outcomes related to independence for adults with autism are generally fair to poor. For adults with high‐functioning autism, functional independence in adulthood is one of the most important long‐term goals to pursue in our educational and clinical programming. With these skills, individuals can lead more self‐determined, satisfying, and productive lives while reducing the burden on families and agencies to provide care. Independence rests on the ability to master functional skills that allow them to care for themselves, live in their own residence, support themselves through employment, and successfully participate in chosen social and recreational activities. Studies find that cognitive abilities, social skills, communication ability, and adaptive competencies predict better outcomes and greater independence in adulthood. Programming for independence should start early in childhood, become the primary focus during adolescence, and continue as needed throughout the adult years. Comprehensive educational and clinical programming should emphasize communication, initiation, self‐regulation, motivation, higher‐order cognition/judgment, and adaptive skills.
Construct Validity of the Patient‐Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales in Systemic Sclerosis
Authors: Nagaraja Vivek , Hays Ron D. , Khanna Puja P. , Spiegel Brennan M. R. , Chang Lin , Melmed Gil Y. , Bolus Roger , Khanna Dinesh
Published: April 2014

Objective

Gastrointestinal (GI) involvement is common in patients with systemic sclerosis (SSc; scleroderma). The Patient‐Reported Outcomes Measurement Information System (PROMIS) GI symptom item bank captures upper and lower GI symptoms (reflux, disrupted swallowing, nausea/vomiting, belly pain, gas/bloating/flatulence, diarrhea, constipation, and fecal incontinence). The objective of this study was to evaluate the construct validity of the PROMIS GI bank in SSc.

Methods

A total of 167 patients with SSc were administered the PROMIS GI bank and the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Scale (GIT 2.0) instrument. GIT 2.0 is a multi‐item instrument that measures SSc‐associated GI symptoms. Product‐moment correlations and a multitrait–multimethod analysis of the PROMIS GI scales with the GIT 2.0 symptom scales were used to evaluate convergent and discriminant validity.

Results

Patients with SSc GI involvement had PROMIS GI scale scores 0.2–0.7 SD worse than the US general population. Correlations among scales measuring the same domains for the PROMIS GI and GIT 2.0 measures were large, ranging from 0.61 to 0.87 (average r = 0.77). The average correlation between different symptom scales was 0.22, supporting discriminant validity.

Conclusion

This study provides support for the construct validity of the PROMIS GI scales in SSc. Future research is needed to assess the responsiveness to change of these scales in patients with SSc.
Relationship Between Homocysteine Levels and Hypertension in Systemic Lupus Erythematosus
Authors: Sabio José Mario , Vargas‐Hitos José Antonio , Martinez‐Bordonado Josefina , Navarrete‐Navarrete Nuria , Díaz‐Chamorro Antonio , Olvera‐Porcel Carmen , Zamora‐Pasadas Mónica , Jiménez‐Alonso Juan
Published: April 2014

Objective

Homocysteine has been linked to atherosclerosis and hypertension (HT) in the general population. However, there is limited evidence regarding the effect of homocysteine on blood pressure and arterial stiffness in systemic lupus erythematosus (SLE). We examined whether homocysteine is associated with HT and arterial stiffness in women with SLE.

Methods

In total, 99 women with SLE without a history of cardiovascular disease or diabetes mellitus and 101 matched controls were included in this cross‐sectional study. Participants were analyzed for homocysteine levels, cardiovascular risk factors, and arterial stiffness assessed by means of carotid–femoral pulse wave velocity (PWV). Associations between homocysteine, systolic blood pressure (SBP), PWV, and HT were tested using univariate and multivariate analyses.

Results

Homocysteine levels (mean ± SD 12.3 ± 4.8 versus 9.3 ± 3.8 μmoles/liter), PWV (mean ± SD 7.54 ± 1.1 versus 7.10 ± 1.1 meters/second), SBP (mean ± SD 119 ± 13 versus 115 ± 12 mm Hg), and the prevalence of hyperhomocysteinemia (23% versus 7%) and HT (43% versus 12%) were significantly higher in women with SLE (P< 0.050 for all). In the univariate analysis, homocysteine correlated positively with SBP (P= 0.001) and PWV (P= 0.023) in women with SLE but not in controls. In the multiple linear regression analysis, SBP was independently associated with homocysteine and body mass index (BMI) in women with SLE. Similarly, in the multivariate logistic regression analysis, homocysteine levels (or hyperhomocysteinemia), BMI, and daily prednisone dose were independently associated with HT in women with SLE.

Conclusion

Homocysteine was independently associated with SBP and HT in women with SLE, but not in controls. Elevated homocysteine levels could increase the risk of HT in SLE.
Cubic Phase GaN on Nano‐grooved Si (100) via Maskless Selective Area Epitaxy
Authors: Bayram Can , Ott John A. , Shiu Kuen‐Ting , Cheng Cheng‐Wei , Zhu Yu , Kim Jeehwan , Razeghi Manijeh , Sadana Devendra K.
Published: April 2014

A method of forming cubic phase (zinc blende) GaN (referred as c‐GaN) on a CMOS‐compatible on‐axis Si (100) substrate is reported. Conventional GaN materials are hexagonal phase (wurtzite) (referred as h‐GaN) and possess very high polarization fields (∼MV/cm) along the common growth direction of <0001>. Such large polarization fields lead to undesired shifts (e.g., wavelength and current) in the performance of photonic and vertical transport electronic devices. The cubic phase of GaN materials is polarization‐free along the common growth direction of <001>, however, this phase is thermodynamically unstable, requiring low‐temperature deposition conditions and unconventional substrates (e.g., GaAs). Here, novel nano‐groove patterning and maskless selective area epitaxy processes are employed to integrate thermodynamically stable, stress‐free, and low‐defectivity c‐GaN on CMOS‐compatible on‐axis Si. These results suggest that epitaxial growth conditions and nano‐groove pattern parameters are critical to obtain such high quality c‐GaN. InGaN/GaN multi‐quantum‐well structures grown on c‐GaN/Si (100) show strong room temperature luminescence in the visible spectrum, promising visible emitter applications for this technology.
Understanding and Controlling the Self‐Folding Behavior of Poly (N‐Isopropylacrylamide) Microgel‐Based Devices
Authors: Li Xue , Serpe Michael J.
Published: April 2014

Poly(N‐isopropylacrylamide) (pNIPAm) microgel‐based materials can be fabricated that self‐fold into three‐dimensional structures in response to changes in the environmental humidity. The materials are composed of a semi‐rigid polymer substrate coated with a thin layer of Au; the Au layer is subsequently coated with a pNIPAm‐based microgel layer and finally covered with a solution of polydiallyldimethylammonium chloride (pDADMAC). The pDADMAC layer contracts upon drying causing the material to deform (typically bending); this deformation is completely reversible over many cycles as the environmental humidity is systematically varied. Here, by varying the size and aspect ratio of the polymer substrate, it is possible to develop a set of empirical rules that can be applied to predict the material's self‐folding behavior. From these rules, materials that self‐fold from two‐dimensional, flat objects into discrete three‐dimensional structures, which are fully capable of unfolding and folding multiple times in response to humidity, are designed.
Multifunctional Graphene Oxide‐based Triple Stimuli‐Responsive Nanotheranostics
Authors: Chen Yu , Xu Pengfei , Shu Zhu , Wu Meiying , Wang Lianzhou , Zhang Shengjian , Zheng Yuanyi , Chen Hangrong , Wang Jin , Li Yaping , Shi Jianlin
Published: April 2014

Construction of multifunctional stimuli‐responsive nanosystems intelligently responsive to inner physiological and/or external irradiations based on nanobiotechnology can enable the on‐demand drug release and improved diagnostic imaging to mitigate the side‐effects of anticancer drugs and enhance the diagnostic/therapeutic outcome simultaneously. Here, a triple‐functional stimuli‐responsive nanosystem based on the co‐integration of superparamagnetic Fe3O4 and paramagnetic MnOx nanoparticles (NPs) onto exfoliated graphene oxide (GO) nanosheets by a novel and efficient double redox strategy (DRS) is reported. Aromatic anticancer drug molecules can interact with GO nanosheets through supramolecular π stacking to achieve high drug loading capacity and pH‐responsive drug releasing performance. The integrated MnOx NPs can disintegrate in mild acidic and reduction environment to realize the highly efficient pH‐responsive and reduction‐triggered T1‐weighted magnetic resonance imaging (MRI). Superparamagnetic Fe3O4 NPs can not only function as the T2‐weighted contrast agents for MRI, but also response to the external magnetic field for magnetic hyperthermia against cancer. Importantly, the constructed biocompatible GO‐based nanoplatform can inhibit the metastasis of cancer cells by downregulating the expression of metastasis‐related proteins, and anticancer drug‐loaded carrier can significantly reverse the multidrug resistance (MDR) of cancer cells.
Phenylalanine Ammonia Lyase Catalyzed Synthesis of Amino Acids by an MIO‐Cofactor Independent Pathway
Authors: Lovelock Sarah L. , Lloyd Richard C. , Turner Nicholas J.
Published: April 2014

Phenylalanine ammonia lyases (PALs) belong to a family of 4‐methylideneimidazole‐5‐one (MIO) cofactor dependent enzymes which are responsible for the conversion of L‐phenylalanine into trans‐cinnamic acid in eukaryotic and prokaryotic organisms. Under conditions of high ammonia concentration, this deamination reaction is reversible and hence there is considerable interest in the development of PALs as biocatalysts for the enantioselective synthesis of non‐natural amino acids. Herein the discovery of a previously unobserved competing MIO‐independent reaction pathway, which proceeds in a non‐stereoselective manner and results in the generation of both L‐ and D‐phenylalanine derivatives, is described. The mechanism of the MIO‐independent pathway is explored through isotopic‐labeling studies and mutagenesis of key active‐site residues. The results obtained are consistent with amino acid deamination occurring by a stepwise E1cB elimination mechanism.
Room‐Temperature Carbide‐Derived Carbon Synthesis by Electrochemical Etching of MAX Phases
Authors: Lukatskaya Maria R. , Halim Joseph , Dyatkin Boris , Naguib Michael , Buranova Yulia S. , Barsoum Michel W. , Gogotsi Yury
Published: April 2014

Porous carbons are widely used in energy storage and gas separation applications, but their synthesis always involves high temperatures. Herein we electrochemically selectively extract, at ambient temperature, the metal atoms from the ternary layered carbides, Ti3AlC2, Ti2AlC and Ti3SiC2 (MAX phases). The result is a predominantly amorphous carbide‐derived carbon, with a narrow distribution of micropores. The latter is produced by placing the carbides in HF, HCl or NaCl solutions and applying anodic potentials. The pores that form when Ti3AlC2 is etched in dilute HF are around 0.5 nm in diameter. This approach forgoes energy‐intensive thermal treatments and presents a novel method for developing carbons with finely tuned pores for a variety of applications, such as supercapacitor, battery electrodes or CO2 capture.
Pd(l‐proline)2complex: an efficient catalyst for Suzuki–Miyaura coupling reaction in neat water
Authors: Zhang Guofu , Luan Yuxin , Han Xingwang , Wang Yong , Wen Xin , Ding Chengrong
Published: April 2014

An efficient catalytic system for Suzuki–Miyaura coupling reactions in neat water has been developed by using a water‐soluble Pd(l‐proline)2catalyst. Under the optimized conditions, various biaryl compounds were obtained in good to excellent yields and a wide range of functional groups on the tested substrates were well tolerated. The catalytic system could be reused at least six times with no significant loss in its activity. Copyright © 2014 John Wiley & Sons, Ltd.
Optoacoustic Imaging and Staging of Inflammation in a Murine Model of Arthritis
Authors: Beziere N. , von Schacky C. , Kosanke Y. , Kimm M. , Nunes A. , Licha K. , Aichler M. , Walch A. , Rummeny E. J. , Ntziachristos V. , Meier R.
Published: April 2014

Objective

Rheumatoid arthritis (RA) is one of the most frequent inflammatory diseases, causing pain and disability in the affected joints. Early diagnosis is essential for the efficiency of symptom‐targeting treatments, but its diagnosis requires careful clinical, serologic, and imaging examinations, such as magnetic resonance imaging (MRI), which is both expensive and time consuming. In an effort to provide the biomedical community with a more accessible way to assess the advancement of arthritis, this study sought to investigate the use of multispectral optoacoustic tomography (MSOT) in a murine arthritis model, to visualize the extent of inflammation in vivo through an L‐selectin/P‐selectin–targeting contrast agent.

Methods

Mice with collagen‐induced arthritis were studied as a model of RA. MSOT was performed using an L‐selectin/P‐selectin–targeting contrast agent, polyanionic dendritic polyglycerol sulfate (dPGS) labeled with a near‐infrared (NIR) fluorophore, to increase the contrast of the arthritic joint. The signal intensity ratios between healthy legs and arthritic legs were calculated. Findings on contrast‐enhanced MRI, clinical observations, the lymphocyte:granulocyte ratio, and histologic findings served as referents for comparison.

Results

MSOT using an inflammation‐targeting contrast agent, dPGS‐NIR, allowed for accurate diagnosis of inflammation in the mouse joints. In addition, use of this technique resulted in significant differentiation of the inflamed joints from the healthy joints (P = 0.023). The observed advancement of arthritis on the MSOT images was confirmed by clinical observation, blood analysis, contrast‐enhanced MRI, and ex vivo histologic examinations.

Conclusion

This study demonstrates that the combination of an inflammation‐targeting contrast agent and optoacoustic tomographic imaging presents a promising means for the diagnosis of RA and the staging of arthritis‐related inflammation.
An arts‐informed study of information using the draw‐and‐write technique
Authors: Hartel Jenna
Published: April 2014

There are untold conceptions of information in information science, and yet the nature of information remains obscure and contested. This article contributes something new to the conversation as the first arts‐informed, visual, empirical study of information utilizing the draw‐and‐write technique. To approach the concept of information afresh, graduate students at a North American iSchool were asked to respond to the question “What is information?” by drawing on a 4‐ by 4‐inch piece of paper, called an iSquare. One hundred thirty‐seven iSquares were produced and then analyzed using compositional interpretation combined with a theoretical framework of graphic representations. The findings indicate how students visualize information, what was drawn, and associations between the iSquares and prior renderings of information based on words. In the iSquares, information appears most often as pictures of people, artifacts, landscapes, and patterns. There are also many link diagrams, grouping diagrams, symbols, and written text, each with distinct qualities. Methodological reflections address the relationship between visual and textual data, and the sample for the study is critiqued. A discussion presents new directions for theory and research on information, namely, the iSquares as a thinking tool, visual stories of information, and the contradictions of information. Ideas are also provided on the use of arts‐informed, visual methods and the draw‐and‐write technique in the classroom.
Dynamic topic detection and tracking: A comparison of HDP, C‐word, and cocitation methods
Authors: Ding Wanying , Chen Chaomei
Published: April 2014

Cocitation and co‐word methods have long been used to detect and track emerging topics in scientific literature, but both have weaknesses. Recently, while many researchers have adopted generative probabilistic models for topic detection and tracking, few have compared generative probabilistic models with traditional cocitation and co‐word methods in terms of their overall performance. In this article, we compare the performance of hierarchical Dirichlet process (HDP), a promising generative probabilistic model, with that of the 2 traditional topic detecting and tracking methods—cocitation analysis and co‐word analysis. We visualize and explore the relationships between topics identified by the 3 methods in hierarchical edge bundling graphs and time flow graphs. Our result shows that HDP is more sensitive and reliable than the other 2 methods in both detecting and tracking emerging topics. Furthermore, we demonstrate the important topics and topic evolution trends in the literature of terrorism research with the HDP method.
BIM – Erfahrungen bei der Anwendung einer neuen Methode im Ingenieurbüro
Authors: Mansperger Tobias , Jung Rolf , Thiele Tobias , Steinberg Andrea
Published: April 2014

Das Ingenieurbüro Leonhardt, Andrä und Partner konnte in den letzten Jahren weitreichende Erfahrungen mit der Anwendung von Building Information Modeling (BIM) sammeln. Dabei wurde nicht nur in der Praxis BIM der ersten und zweiten Stufe angewandt, sondern auch im Zuge von Forschungsprojekten an der Weiterentwicklung der Methode auf höheren Ebenen gearbeitet.

Bei der praktischen Anwendung kommen zurzeit hauptsächlich geschlossene Methoden, also mit einer speziellen Software bzw. Partnersoftware und deren spezifischer Schnittstelle zum Einsatz. Bereits bei dieser sog. ersten Stufe von BIM ergeben sich auch schon in frühen Projektphasen zahlreiche Vorteile, die dessen Einsatz lohnenswert machen. Bei der Anwendung der offenen Methode mit Datenaustausch via IFC wurde wiederholt deutlich, dass die Funktionalitäten der beteiligten Software dadurch eingeschränkt werden, dass bestimmte Modellparameter nicht ausgetauscht werden können oder die Schnittstellen noch fehlerbehaftet sind.

Bei der Beteiligung an Forschungsprojekten wird ersichtlich, welche weitreichenden Chancen open BIM bietet, aber auch welche technischen Hürden zu überwinden sind. Durch die Weiterentwicklung der Schnittstellen sowie die Verwendung von Cloud bzw. Grid Computing werden hochkomplexe und rechenaufwändige Analysen der Bauwerke ermöglicht. Webbasierte Plattformen erlauben effizientes Zusammenarbeiten verschiedener Fachdisziplinen sowie ein optimiertes Zusammenspiel unterschiedlichster Analysesoftware.

BIM – Experiences of the application of a new method in an engineering company

Consulting engineers Leonhardt Andrä and Partners were able to gather extensive experiences in the application of BIM. Not only first and second level BIM was used in practice, but also by contributing to research projects, the method was developed on higher levels.

At daily practice, mainly closed BIMs are worked on by using proprietary software with a specific interface. Already on this first level BIM, many advantages are becoming obvious that also pay off on early project stages. It became apparent, that the application of open BIM with data exchange via IFC limits the functionalities of the participating software, as some model parameters can't be exchanged, or interfaces are defective.

The participation in research projects shows on the one hand the chances of open BIM, on the other hand what problems have to be resolved. By developing the interfaces and Cloud/Grid computing, highly complex and computing time consuming analyses are made feasible. Web‐based platforms allow efficient co‐working of different disciplines and an optimized cooperation of different tools.
4‐O‐methylhonokiol Inhibits Serious Embryo Anomalies Caused by Nicotine via Modulations of Oxidative Stress, Apoptosis, and Inflammation
Authors: Lin Chunmei , Yon Jung‐Min , Hong Jin Tae , Lee Jong Kwon , Jeong Jayoung , Baek In‐Jeoung , Lee Beom Jun , Yun Young Won , Nam Sang‐Yoon
Published: April 2014

BACKGROUND

Since the increasing smoking rate among women has resulted in higher rates of embryonic malformations, it is important to search for an efficient and inexpensive agent that can help reduce the rate of serious fetal anomalies caused by maternal cigarette smoking. In this study, the bioavailability of 4‐O‐methylhonokiol isolated from Magnolia officinalis was first demonstrated in the mouse embryos exposed to nicotine using a whole embryo culture system.

METHODS

Mouse embryos on embryonic day 8.5 were cultured with 1 mM nicotine and/or 4‐O‐methylhonokiol (1 × 10−4 or 1 × 10−3 μM) for 48 hr and were analyzed on the viewpoints of embryo developmental changes, oxidative damages, and apoptotic and inflammatory changes.

RESULTS

Embryos exposed to 1 mM nicotine developed not only severe morphological anomalies, increased expressions of tumor necrosis factor‐α, interleukin‐1β, and caspase 3 mRNAs; and elevated levels of lipid peroxidation, but also decreased levels of cytoplasmic superoxide dismutase, cytosolic glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, hypoxia inducible factor‐1α, and B‐cell lymphoma‐extra large mRNAs, and reduced superoxide dismutase activity. However, these parameters were significantly improved when embryos exposed to the nicotine were concurrently treated with 4‐O‐methylhonokiol (1 × 10−4 or 1 × 10−3 μM).

CONCLUSIONS

These findings indicate that 4‐O‐methylhonokiol reduces serious embryo anomalies caused by nicotine in mouse embryos via the modulations of oxidative stress, apoptosis, and inflammation, suggesting that 4‐O‐methylhonokiol may be a preventive and therapeutic agent against the dysmorphology induced by maternal smoking during pregnancy.
Embryofetal Development Study of Vismodegib, a Hedgehog Pathway Inhibitor, in Rats
Authors: Morinello Eric , Pignatello Michael , Villabruna Loris , Goelzer Petra , Bürgin Heinrich
Published: April 2014

Vismodegib (Erivedge) is a first‐in‐class small‐molecule hedgehog pathway inhibitor for the treatment of adults with advanced basal‐cell carcinoma. Because this pathway is known to play key roles in patterning and growth during vertebrate development, vismodegib was anticipated to be embryotoxic. To support marketing applications, an embryofetal development study was completed in which a limited number of pregnant rats (n = 6/group) was administered vismodegib by oral gavage on gestation days 6 to 17. When vismodegib was administered at ≥60 mg/kg/day, doses associated with evidence of pharmacologic activity in previous rat toxicity studies, all conceptuses were resorbed at an early embryonic stage in the absence of significant maternal toxicity. When administered at 10 mg/kg/day, corresponding to an exposure (AUC0–24h) approximately 15% of the median in patients at steady state, a variety of malformations were observed, including absent/fused digits in the hindlimb of multiple fetuses, multiple craniofacial abnormalities in one fetus, and an anorectal defect in one fetus. In addition, the incidence of variations, including dilated renal pelvis or ureter and incompletely or unossified skeletal elements, was significantly greater when compared with the controls. These results confirmed that vismodegib is likely to be embryotoxic at clinically relevant maternal exposures, and doses ≥60 mg/kg/day resulted in a 100% incidence of embryolethality that likely resulted from severe defects in early embryonic development. In contrast, craniofacial defects typically associated with hedgehog pathway inhibition were only observed in one fetus at the low dose of 10 mg/kg/day, which likely reflected minimal or intermittent pathway inhibition at low exposures.
Absence of Irreversible Effects of Aliskiren in Standard Juvenile Rat Toxicity Studies
Authors: Beckman David , Barbeau Stephanie , McLean Lee Anne , Yan Jing‐He , Hoffmann Peter
Published: April 2014

BACKGROUND

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population.

METHODS

In Study 1, aliskiren oral administration was initiated on postpartum day (PPD) 14, after nephrogenesis was completed, and continued through PPD 70 at doses of 0, 30, 100, and 300 mg/kg/day. In‐life, clinical pathology, anatomic pathology, developmental, behavioral, reproductive, and toxicokinetics evaluations were performed. In Study 2, oral administration was initiated on PPD 8, before completion of nephrogenesis, and continued through PPD 35/36. In‐life, clinical pathology, anatomic pathology, developmental, and toxicokinetics evaluations were performed.

RESULTS

With dosing initiated on PPD 8, mortality at 100 and 300 mg/kg/day and slightly increased kidney weight at 100 mg/kg/day occurred. Decreased absolute lymphocyte count at 300 mg/kg/day at the end of dosing occurred with dosing initiated on PPD 14. There were clinical signs and transient effects on body weight gains in both studies. There were no changes in other parameters. Systemic exposure was much higher on PPD 8 and 14 compared with adult rats on PPD 64.

CONCLUSIONS

All effects produced by aliskiren, including kidney effects, were reversible. Increased exposure in very young animals is considered to be the result of immature drug transporter systems.
Juveniles Who Have Committed Sexual Offenses: A Special Group?
Authors: Fanniff Amanda M. , Kimonis Eva R.
Published: April 2014

Juveniles who have committed sexual offenses (JSOs) are subject to specialized interventions and public policies based on the assumption that they constitute a unique group distinct from other delinquents. Previous research has demonstrated considerable similarities between these groups, though some consistent differences have been found and some theory‐relevant constructs have been inadequately studied. The current study compares 119 delinquents and 108 JSOs on a number of theory‐relevant constructs. Consistent with theories positing a unique etiology for sexual offending, JSOs reported higher rates of sexual abuse and anxiety as well as fewer consensual sexual partners, less delinquent activity, and lower callous‐unemotional traits; however, there were no differences detected in the majority of characteristics examined (e.g., attachment, sensation‐seeking). Physical and emotional abuse did not predict sex offending after controlling for sexual abuse, but lower callous‐unemotional traits did predict sex offending after controlling for total delinquent behavior. Additional research on constructs little studied in previous research (e.g., sexual history and development, attachment) is needed, but evidence to date suggests considerable overlap between these populations. Perhaps subgroups of JSOs are distinct from generally delinquent youth; however, a focus on offender characteristics or trajectories of behavior problems may prove more fruitful than categorizing youth based on a single behavior. Copyright © 2014 John Wiley & Sons, Ltd.
Control of galactosylated glycoforms distribution in cell culture system
Authors: McCracken Neil A. , Kowle Ronald , Ouyang Anli
Published: April 2014

Cell culture process conditions including media components and bioreactor operation conditions have a profound impact on recombinant protein quality attributes. Considerable changes in the distribution of galactosylated glycoforms (G0F, G1F, and G2F) were observed across multiple CHO derived recombinant proteins in development at Eli Lilly and Company when switching to a new chemically defined (CD) media platform condition. In the new CD platform, significantly lower G0F percentages and higher G1F and G2F were observed. These changes were of interest as glycosylation heterogeneity can impact the effectiveness of a protein. A systematic investigation was done to understand the root cause of the change and control strategy for galactosylated glycoforms distribution. It was found that changes in asparagine concentration could result in a corresponding change in G0F, G1F, and G2F distribution. A follow‐up study examined a wider range of asparagine concentration and it was found that G0F, G1F, and G2F percentage could be titrated by adjusting asparagine concentration. The observed changes in heterogeneity from changing asparagine concentration are due to resulting changes in ammonium metabolism. Further study ascertained that different integrated ammonium level during the cell culture process could control G0F, G1F, and G2F percentage distribution. A mechanism hypothesis is proposed that integrated ammonium level impacts intracellular pH, which further regulates β‐1, 4 galactosyltransferase activity. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:547–553, 2014
Biochemical Investigations of Two 6‐DMATS Enzymes from Streptomyces Reveal New Features of L‐Tryptophan Prenyltransferases
Authors: Winkelblech Julia , Li Shu‐Ming
Published: April 2014

Two putative prenyltransferase genes, SAML0654 and Strvi8510, were identified in Streptomyces ambofaciens and Streptomyces violaceusniger, respectively. Their deduced products share 63 % sequence identity. Biochemical investigations with recombinant proteins demonstrated that L‐tryptophan and derivatives, including D‐tryptophan, 4‐, 5‐, 6‐ and 7‐methyl‐dl‐tryptophan, were well accepted by both enzymes in the presence of DMAPP. Structural elucidation of the isolated products revealed regiospecific prenylation at C‐6 of the indole ring and proved unequivocally the identification of two very similar 6‐dimethylallyltryptophan synthases (6‐DMATS). Detailed biochemical investigations with SAML0654 proved L‐tryptophan to be the best substrate (Km 18 μm, turnover 0.3 s−1). Incubation with different prenyl donors showed that they also accepted GPP and catalyzed the same specific prenylation. Utilizing GPP as a prenyl donor has not been reported for tryptophan prenyltransferases previously. Both enzymes also catalyzed prenylation of some hydroxynaphthalenes; this has not previously been described for bacterial indole prenyltransferases. Interestingly, SAML0654 transferred prenyl moieties onto the unsubstituted ring of hydroxynaphthalenes.
Mukaiyama–Michael Reactions with trans‐2,5‐Diarylpyrrolidine Catalysts: Enantioselectivity Arises from Attractive Noncovalent Interactions, Not from Steric Hindrance
Authors: Kemppainen Eeva K. , Sahoo Gokarneswar , Piisola Antti , Hamza Andrea , Kótai Bianka , Pápai Imre , Pihko Petri M.
Published: April 2014

The scope of the enantioselective Mukaiyama–Michael reactions catalyzed by trans‐2,5‐diphenylpyrrolidine has been expanded to include both α‐ and β‐substituted enals. However, the rationalization of the observed enantioselectivity is far from obvious since the catalyst is not very sterically hindered. DFT calculations were carried out to rationalize the observed stereoselectivities. Transition states of the CC bond formation between iminium intermediates and silyloxyfurans were located and their relative energies were used to estimate the stereoselectivity data. We find excellent agreement between the predicted and observed stereoselectivities. The analysis of intermolecular forces reveals that the enantioselectivity is mostly due to stabilizing noncovalent interactions between the reacting partners, not due to steric hindrance. The role of attractive noncovalent interactions in enantioselective catalysis may be underappreciated.
Development of Fluorescent Film Sensors Based on Electropolymerization for Iron(III) Ion Detection
Authors: Li Peng , Ji Changyin , Ma Hongwei , Zhang Ming , Cheng Yunfei
Published: April 2014

Two electroactive materials, M1 and M2, are synthesized and their fluorescent electropolymerized (EP) films are prepared and used to detect metal ions. From the tested metal ions, M1 and M2 are demonstrated to be sensitive and selective for Fe3+ ions. In particular, M2 exhibits higher sensitivity towards Fe3+ ions. The fluorescent detection ranges from 10−5 M to 4×10−4 M. The excellent performance of the EP fluorescent films is mainly due to the strong metal‐chelated properties of M2 and the intrinsic porous cross‐linked‐network microstructure of the EP films. This study, thus, provides a promising Fe3+ sensing candidate and a potential preparation method for fluorescent sensing films.
Inhibition of Amyloid Fibril Growth and Dissolution of Amyloid Fibrils by Curcumin–Gold Nanoparticles
Authors: Palmal Sharbari , Maity Amit Ranjan , Singh Brijesh Kumar , Basu Sreetama , Jana Nihar R. , Jana Nikhil R.
Published: April 2014

Inhibition of amyloid fibrillation and clearance of amyloid fibrils/plaques are essential for the prevention and treatment of various neurodegenerative disorders involving protein aggregation. Herein, we report curcumin‐functionalized gold nanoparticles (Au‐curcumin) of hydrodynamic diameter 10–25 nm, which serve to inhibit amyloid fibrillation and disintegrate/dissolve amyloid fibrils. In nanoparticle form, curcumin is water‐soluble and can efficiently interact with amyloid protein/peptide, offering enhanced performance in inhibiting amyloid fibrillation and dissolving amyloid fibrils. Our results imply that nanoparticle‐based artificial molecular chaperones may offer a promising therapeutic approach to combat neurodegenerative disease.
Stickstofffixierung in Lösung durch einen Eisenkomplex
Authors: Jaenicke Lothar
Published: April 2014

Als Fritz Haber in den noch‐Friedensjahren kurz vor dem ersten Weltkrieg die katalytische bergauf‐Ammoniak‐Synthese unter hohem Druck und ziemlich hoher Temperatur ersann, war man noch wenig energiebewusst, befand sich noch buchstäblich im Dampfmaschinen‐Zeitalter. In den hundert Jahren seither sind wir ökonomisch einsichtiger geworden, auch tätiger, das Haber‐Bosch‐Verfahren durch naturnähere Synthesen zu ersetzen. Denn Mikoorganismen, besonders die in Symbiose mit Pflanzenwurzeln lebenden Rhizobium‐Knöllchenbakterien, hydrogenieren N2 zu NH3 unter Umweltbedingungen durch spezielle Übergangsmetall(FeMo)‐Coenzyme in einem von uns noch immer nicht recht verstandenen Prozess.
Kohlenhydrate spielen Protein
Authors: Groß Michael
Published: April 2014

Viele wichtige Proteine, etwa der Blutfarbstoff Hämoglobin, assoziieren sich in reversibler Reaktion zu wohldefinierten Oligomeren. Erst jetzt wurde ein solches Verhalten mittels der analytischen Ultrazentrifugation auch für Kohlenhydrate nachgewiesen.
Was hat Tryptophan mit Krebs und Parkinson zu tun?
Authors: Heiland Ines
Published: April 2014

Tryptophan ist den meisten Chemikern bekannt als essentielle Aminosäure und damit Basis für die Synthese von Proteinen. Allerdings wird selbst in Geweben mit hoher Zellteilungsaktivität nur ein Bruchteil des mit der Nahrung aufgenommenen Tryptophans in Proteine integriert. Der überwiegende Teil wird verstoffwechselt und dadurch in andere biologisch aktive Substanzen umgewandelt (Abbildung 1). Abnormalitäten im Tryptophanstoffwechsel wurden bei neurodegenerativen Erkrankungen und Hirntumoren beobachtet.
A spline‐based semiparametric sieve likelihood method for over‐dispersed panel count data
Authors: Hua Lei , Zhang Ying , Tu Wanzhu
Published: April 2014

In this article we study a Gamma‐Frailty inhomogeneous Poisson process model for analysing over‐dispersed panel count data. A cubic B‐spline function is used to approximate the logarithm of the baseline mean function in the semiparametric proportional mean model. The regression parameters and spline coefficients are jointly estimated by maximizing a spline‐based sieve pseudo‐likelihood and by replacing the nuisance over‐dispersion parameter with its moment estimate. The asymptotic properties of the proposed maximum pseudo likelihood estimator, including its consistency, convergence rate and the asymptotic normality of the estimated regression parameters, are thoroughly studied using modern empirical process theory. A spline‐based least‐squares standard error estimator is developed to facilitate robust inference for the regression parameters. Simulation studies are conducted to investigate finite sample performance of the proposed method and robustness of the Gamma‐Frailty inhomogeneous Poisson process model. Finally, for illustration, the method is used to analyse data from an observational study of sexually transmitted infection (STI) in young women. The Canadian Journal of Statistics 42: 217–245; 2014 © 2014 Statistical Society of Canada
Choline phosphate cytidylyltransferase‐α is a novel antigen detected by the anti‐ERCC1 antibody 8F1 with biomarker value in patients with lung and head and neck squamous cell carcinomas
Authors: Vaezi Alec E. , Bepler Gerold , Bhagwat Nikhil R. , Malysa Agnes , Rubatt Jennifer M. , Chen Wei , Hood Brian L. , Conrads Thomas P. , Wang Lin , Kemp Carolyn E. , Niedernhofer Laura J.
Published: April 2014

BACKGROUND

The determination of in situ protein levels of ERCC1 with the 8F1 monoclonal antibody is prognostic of survival in patients with non‐small cell lung cancer (NSCLC). The authors previously demonstrated that 8F1 recognizes a second nuclear antigen. This antigen was identified and its value as a biomarker of clinical outcomes analyzed.

METHODS

The second antigen was identified by mass spectrometry. Protein identity and antibody specificity were confirmed through knockdown and overexpression experiments. Immunohistochemistry of 187 early‐stage NSCLC samples and 60 head and neck squamous cell carcinomas (HNSCCs) was used to examine the influence of the second antigen on 8F1 immunoreactivity and its association with patient outcomes.

RESULTS

Choline phosphate cytidylyltransferase‐α (CCTα, also known as phosphate cytidylyltransferase 1 choline alpha [PCYT1A], a phospholipid synthesis enzyme regulated by RAS) is the second antigen recognized by 8F1. In NSCLC samples, CCTα contributed (rho, 0.38) to 8F1 immunoreactivity. In samples of squamous cell carcinomas of the lung, CCTα was found to be the dominant determinant of 8F1 immunoreactivity, whereas its contribution in other subtypes of lung cancer was negligible. High expression of CCTα, but not ERCC1, was found to be prognostic of longer disease‐free survival (log‐rank P = .002) and overall survival (log‐rank P = .056). Similarly, in patients with HNSCC, CCTα contributed strongly to 8F1 immunoreactivity (rho, 0.74), and high CCTα expression was found to be prognostic of survival (log‐rank P = .022 for disease‐free survival and P = .027 for overall survival).

CONCLUSIONS

CCTα is the second antigen detected by 8F1. High CCTα expression appears to be prognostic of survival in patients with NSCLC who are treated by surgery alone and patients with HNSCC. CCTα is a promising biomarker of patient survival and deserves further study. Cancer 2014;120:1898–1907. © 2014 American Cancer Society.
Influence of conformal radiotherapy technique on survival after chemoradiotherapy for patients with stage III non‐small cell lung cancer in the National Cancer Data Base
Authors: Sher David J. , Koshy Matthew , Liptay Michael J. , Fidler Mary Jo
Published: April 2014

BACKGROUND

Definitive chemoradiotherapy is a core treatment modality for patients with stage III non‐small cell lung cancer (NSCLC). Although radiotherapy (RT) technologies have advanced dramatically, to the authors' knowledge relatively little is known regarding the importance of irradiation technique on outcome, particularly given the competing risk of distant metastasis. The National Cancer Data Base was used to determine predictors of overall survival (OS) in patients with AJCC stage III NSCLC who were treated with chemoradiotherapy, focusing on the importance of conformal RT (CRT).

METHODS

Patients with stage III NSCLC who were treated with chemoradiotherapy between 2003 and 2005 in the National Cancer Data Base were included. RT technique was defined as conventional, 3‐dimensional–conformal, or intensity‐modulated RT (IMRT), the latter 2 combined as CRT. Cox proportional hazards regression was performed for univariable and multivariable analyses of OS.

RESULTS

The median, 3‐year, and 5‐year survival outcomes for the 13,292 patients were 12.9 months, 19%, and 11%, respectively. The 3‐year and 5‐year survival probabilities of patients receiving CRT versus no CRT were 22% versus 19% and 14% versus 11%, respectively (P < .0001). On multivariable analysis, CRT was found to be significantly associated with improved OS (hazards ratio, 0.89). This effect was confirmed on sensitivity analyses, including restricting the cohort to minimum 6‐month survivors, young patients with stage IIIA disease, and propensity score‐matching. Institutional academic status and patient volume were not found to be associated with OS.

CONCLUSIONS

CRT was found to be independently associated with a survival advantage. These results reflect the importance of optimal locoregional therapy in patients with stage III NSCLC and provide motivation for further study of advanced RT technologies in patients with NSCLC. Cancer 2014;120:2060–2068. © 2014 American Cancer Society.
Mechanistic Investigation into the Cleavage of a Phosphomonoester Mediated by a Symmetrical Oxyimine‐Based Macrocyclic Zinc(II) Complex
Authors: Zhang Xuepeng , Xu Xianyan , Xu Huiying , Zhang Xiting , Phillips David Lee , Zhao Cunyuan
Published: April 2014

Density functional calculations are utilized to explore the hydrolysis mechanisms of the phosphomonoester 4‐nitrophenyl phosphate catalyzed by a symmetrical zinc(II) complex. The formation process and properties of the active catalyst are verified. Eight plausible mechanisms are proposed and categorized into three groups. All of the proposed mechanisms, except for Mechanism 7 (see text), are SN2‐type addition–substitution reaction pathways. Nucleophilic attack at the ortho position occurs in Mechanism 7 with a relatively high reaction barrier. Mechanisms 1 and 2 in the monocatalyst model, Mechanisms 5 to 7 in the sandwich‐dual‐catalyst model, as well as the nucleophilic addition–substitution step in Mechanism 8 are concerted reaction pathways, whereas the rest appear to occur in a stepwise manner. Meanwhile, the explicit solvent model is utilized to consider direct hydrogen bonds and solvation interactions and these results indicate that the added water molecule is involved in the hydrolysis process, but does not change the mechanisms significantly. Mechanism 8, with the lowest reaction barrier, is the most favored reaction pathway of the eight proposed mechanisms, although Mechanisms 1, 4, and 6 are in competition with Mechanism 8. In consideration of the zinc(II) complex concentration, Mechanism 1 is only the predominant reaction pathway at a low zinc(II) complex concentration; Mechanisms 4 and 6 tend to be more competitive with increasing concentration of the zinc(II) complexes, and Mechanism 8 is favored at high zinc(II) complex concentrations. Our calculated results are consistent with, and can be used to systematically interpret, experimental observations. More importantly, insightful suggestions are made regarding the catalyst design and selection of the reaction environment.
Ag@Fe3O4 nanowire: fabrication, characterization and peroxidase‐like activity
Authors: Chen Junzhi , Liu Yuanjun , Zhu Guoxing , Yuan Aihua
Published: April 2014

With a facile solvothermal method, Ag@Fe3O4 nanowire was successfully prepared and characterized by X‐ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The obtained Ag@Fe3O4 nanowire posses enhanced peroxidase‐like activity with good stability and high absorbance. The optimization of pH, H2O2 concentration and loading capacity were carried out. The result of kinetic analysis indicates that the catalyzed reaction followed a Michaelis‐Menten behavior. The good peroxidase‐like activity makes Ag@Fe3O4 nanowire be promising for real application in biomedicine.