bluuebunny/crossref_metadata_2025 huggingface dataset:
An Introduction to Planarians and Their Stem Cells
Authors: Aboukhatwa Ellen , Aboobaker Aziz
Published: January 2015

Of all animals, it is perhaps planarians that have the greatest ability to regenerate. These once classical classroom organisms have now become the subject of advanced molecular genetic studies that have the potential to inform us about our own biology. Regeneration relies upon a population of pluripotent adult stem cells, called neoblasts. These collectively pluripotent stem cells underpin the regenerative capacity of planarians. The underlying molecular mechanisms controlling their proliferation, self‐renewal and differentiation are now being described. In particular, progress has been made in describing the expression profile of these cells and identifying some of the molecular mechanisms that regulate their behaviour leading to a better understanding of how these cells power regeneration.

Key Concepts

Planarians are bilaterians and share many cell and tissue types with other animals including vertebrates.

Planarians are able to mount a profound regenerative response to wounding allowing even small fragments to regenerate whole new worms.

Planarian regeneration requires the proliferation and differentiation of a population of pluripotent stem cell population called neoblasts.

Expression profiling of the neoblast population shows they are a heterogeneous population and express gene regulatory networks in common with both somatic and germline stem cells

Many cell biological and molecular genetic approaches can be used to study gene function in planarians allowing novel biological insights to be made, relevant to our own biology.

Current research has uncovered many important regulatory processes that regulate stem cells, including those regulated by transcription factors, chromatin modification and RNA binding proteins.

Future work will uncover the detailed mechanisms that control stem cell proliferation, self‐renewal and differentiation as well as how missing structures are accurately restored.
Methods for Live Microscopy ofDrosophilaSpermatocytes
Authors: Savoian Matthew S
Published: January 2015

The fruitfly Drosophila melanogaster offers a rich and varied source of differentiated cell types. This and its exceptional experimental tractability make it well suited for cell cycle or other developmental biology investigations. In particular, the sperm‐producing cells of the testes provide a powerful system for studying the mechanics of cell division. These meiotically dividing primary spermatocytes can be easily isolated from the testes of mutant or transgenic animals and maintained in short‐term primary cultures. The cells' large and flat geometry makes them amenable to a variety of live cell light‐microscopy‐based observation methods. Single‐plane transmitted light time‐lapse imaging and more advanced multi‐dimensional widefield or confocal fluorescence microscopy have been used to define the morphological and kinetic changes that accompany processes ranging from meiotic chromosome segregation to microtubule dynamics. The ability to document such dynamic changes underscores the power of live cell imaging in understanding cell physiology and function.

Key Concepts

Drosophilais an experimentally tractable source of different cell types.

Male meiotic primary spermatocytes provide a powerful model system for studying cell division.

These large flat cells are easily cultured for live cell light microscopy.

Transmitted light and fluorescence imaging methods can be used separately or in tandem to record different dynamic processes during cell division.
Tardive Dyskinesia
Authors: Lehosit Jessica B , Pirmohamed Fermina , Vijayakumar Dhanya , Cloud Leslie J
Published: January 2015

Tardive syndromes (TS) are a group of related iatrogenic disorders characterised by persistent abnormal involuntary movements resulting from the use of dopamine receptor blocking medications, which are often used to treat psychiatric and gastrointestinal conditions. The most common of the TS is classic tardive dyskinesia, characterised by involuntary stereotypic movements in the mouth region such as lip smacking or pursing, chewing, facial grimacing and tongue movements. TS can be highly disabling, difficult to treat and have the potential to be permanent, making their prevention of paramount importance. The pathophysiological basis of the TS is poorly understood. Treatment options include oral medications, botulinum toxin injections and deep brain stimulation surgery. More research is needed to determine the best available treatment options and to identify new treatments.

Key Concepts

Tardive syndromes are a group of related iatrogenic disorders characterised by persistent abnormal involuntary movements.

They result from the long‐term use of dopamine receptor blocking medications, which are often used in the treatment of psychiatric and gastroenterological conditions.

Tardive syndromes can persist after discontinuation of the causative drug and have the potential to be permanent.

There are various forms of tardive syndromes, the most common of which is classic tardive dyskinesia, described as repetitive, rhythmic, involuntary movements that are typically present in the mouth region.

Elderly individuals, women, diabetics and non‐whites appear to be most vulnerable to the development of tardive dyskinesia.

Treatment options for tardive syndromes are limited, and more research is needed to determine the best available treatment strategies and to identify potential new therapies.
Breast Cancer Susceptibility Genes
Authors: Apostolou Paraskevi , Vratimos Athanassios , Fostira Florentia
Published: January 2015

Hereditary breast cancer is mainly attributed to loss‐of‐function mutations in
BRCA1
and
BRCA2
genes, which constitute the most important of the known breast cancer susceptibility genes in terms of high penetrance and clinical significance. Such mutations confer elevated breast and ovarian cancer risk, in comparison to the general population, while diagnosis usually occurs in young ages.

The evolution of sequencing technologies led to the identification of additional candidate breast cancer genes, most of which are considered to confer intermediate susceptibility. The majority of these genes are co‐players of
BRCA
genes in major repair mechanisms, which are essential in maintaining genomic integrity. Loss‐of‐function mutations identified in their loci are often associated with rare cancer syndromes that involve a broad spectrum of malignancies.

Genetic testing that involves the molecular analysis of hereditary breast cancer cases provides important information, able to orientate appropriate clinical decisions for the overall benefit of the individual carrying mutations in specific key genes.

Key Concepts

Hereditary breast cancer is associated with loss‐of‐function mutations in cancer‐predisposing genes.

BRCA1
and
BRCA2
are the most commonly mutated genes accounting for 5–10% of hereditary breast cancer cases.

BRCA
mutation carriers face a lifetime risk for both breast and ovarian cancer that can be as high as 82% and 44%, respectively.

A young age of breast cancer diagnosis is often observed in hereditary breast cancer cases.

At least 15 more genes have been associated with breast cancer susceptibility, most of which show intermediate penetrance and are rarely mutated.

Breast cancer genes encode for proteins that maintain genomic integrity through their catalytic role in DNA damage repair pathways (homologous recombination).

Molecular analysis of breast cancer predisposing genes is valuable for diagnosis, customised therapeutics and clinical management.
Policy‐Into‐Practice for Rheumatoid Arthritis: Randomized Controlled Trial and Cohort Study of E‐Learning Targeting Improved Physiotherapy Management
Authors: Fary Robyn E. , Slater Helen , Chua Jason , Ranelli Sonia , Chan Madelynn , Briggs Andrew M.
Published: January 2015

Objective

To examine the effectiveness of a physiotherapy‐specific, web‐based e‐learning platform, “RAP‐el,” in best‐practice management of rheumatoid arthritis (RA) using a single‐blind, randomized controlled trial (RCT) and prospective cohort study.

Methods

Australian‐registered physiotherapists were electronically randomized into intervention and control groups. The intervention group accessed RAP‐eL over 4 weeks. Change in self‐reported confidence in knowledge and skills was compared between groups at the end of the RCT using linear regression conditioned for baseline scores by a blinded assessor, using intent‐to‐treat analysis. Secondary outcomes included physiotherapists’ satisfaction with RA management and responses to RA‐relevant clinical statements and practice‐relevant vignettes. Retention was evaluated in a cohort study 8 weeks after the RCT.

Results

Eighty physiotherapists were randomized into the intervention and 79 into the control groups. Fifty‐six and 48, respectively, provided baseline data. Significant between‐group differences were observed for change in confidence in knowledge (mean difference 8.51; 95% confidence interval [95% CI] 6.29, 10.73; effect size 1.62) and skills (mean difference 7.26; 95% CI 5.1, 9.4; effect size 1.54), with the intervention group performing better. Satisfaction in ability to manage RA, 4 of the 6 clinical statements, and responses to vignettes demonstrated significant improvement in the intervention group. Although 8‐week scores showed declines in most outcomes, their clinical significance remains uncertain.

Conclusion

RAP‐eL can improve self‐reported confidence, likely practice behaviors and satisfaction in physiotherapists’ ability to manage people with RA, and improve their clinical knowledge in several areas of best‐practice RA management in the short term.
Robust set‐membership parameter estimation of the glucose minimal model
Authors: Herrero Pau , Delaunay Benoît , Jaulin Luc , Georgiou Pantelis , Oliver Nick , Toumazou Christofer
Published: January 2015

The minimal model of glucose‐insulin dynamics is currently being used in several diabetes‐related applications, such as investigating the glucose metabolism, and in the developments of model predictive controllers and fault detection techniques for automatic blood glucose control (i.e., artificial pancreas). Different approaches have been proposed to identify this model, but none of them is capable of providing guaranteed robust enclosures for its parameters, something very desired in applications such as the artificial pancreas, where robustness is paramount. This paper presents a novel approach for guaranteed set‐membership parameter estimation of the minimal model based on the well‐renowned Set Inversion via Interval Analysis (SIVIA) algorithm. Because the computational complexity of this algorithm is the main barrier for its applicability, an efficient vectorial implementation of SIVIA was employed. Clinical data from a standard intravenous glucose tolerance test were used to prove the validity of the presented approach. Finally, Modal Interval Analysis was used to reduce the numerical overestimation due to the dependency problem of interval arithmetic and significantly speeding up the computations. Copyright © 2015 John Wiley & Sons, Ltd.
Molecular Recognition in Chemical and Biological Systems
Authors: Persch Elke , Dumele Oliver , Diederich François
Published: January 2015

Structure‐based ligand design in medicinal chemistry and crop protection relies on the identification and quantification of weak noncovalent interactions and understanding the role of water. Small‐molecule and protein structural database searches are important tools to retrieve existing knowledge. Thermodynamic profiling, combined with X‐ray structural and computational studies, is the key to elucidate the energetics of the replacement of water by ligands. Biological receptor sites vary greatly in shape, conformational dynamics, and polarity, and require different ligand‐design strategies, as shown for various case studies. Interactions between dipoles have become a central theme of molecular recognition. Orthogonal interactions, halogen bonding, and amide⋅⋅⋅π stacking provide new tools for innovative lead optimization. The combination of synthetic models and biological complexation studies is required to gather reliable information on weak noncovalent interactions and the role of water.
Structure and Mechanism of the Caseinolytic Protease ClpP1/2 Heterocomplex from Listeria monocytogenes
Authors: Dahmen Maria , Vielberg Marie‐Theres , Groll Michael , Sieber Stephan A.
Published: January 2015

Listeria monocytogenes is a devastating bacterial pathogen. Its virulence and intracellular stress tolerance are supported by caseinolytic protease P (ClpP), an enzyme that is conserved among bacteria. L. monocytogenes expresses two ClpP isoforms that are only distantly related by sequence and differ in catalysis, oligomerization, active‐site composition, and N‐terminal interaction sites for associated AAA+ chaperones. The crystal structure of the ClpP1/2 heterocomplex from L. monocytogenes was solved, and in combination with biochemical studies, it provides insights into the mode of action. The results demonstrate that structural interlocking of LmClpP1 with LmClpP2 leads to the formation of a tetradecamer, aligns all 14 active sites, and enhances proteolytic activity. Furthermore, the catalytic center was identified as being responsible for the transient stability of ClpPs.
Design of Aromatic Helical Polymers for STM Visualization: Imaging of Single and Double Helices with a Pattern of π–π Stacking
Authors: Zhu Junyan , Dong Zeyuan , Lei Shengbin , Cao Lili , Yang Bing , Li Wenfang , Zhang Yuanchao , Liu Junqiu , Shen Jiacong
Published: January 2015

From scanning tunneling microscopy (STM) images of rationally designed helical polymers with a pattern of π–π stacking, we successfully identified the single‐ and double‐helical superstructures. The STM images of the helical structures revealed the smallest helical architecture (diameter ca. 1.3 nm) that has been seen so far. Furthermore, the interconversion of single and double helices was further underpinned by experimental analyses. Significantly, the formation of double helices induced different supramolecular chirality to that observed for the single helices.
Tracing Binding Modes in Hit‐to‐Lead Optimization: Chameleon‐Like Poses of Aspartic Protease Inhibitors
Authors: Kuhnert Maren , Köster Helene , Bartholomäus Ruben , Park Ah Young , Shahim Amir , Heine Andreas , Steuber Holger , Klebe Gerhard , Diederich Wibke E.
Published: January 2015

Successful lead optimization in structure‐based drug discovery depends on the correct deduction and interpretation of the underlying structure–activity relationships (SAR) to facilitate efficient decision‐making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)‐validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X‐ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well‐established surrogate for e.g. renin and β‐secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.
Efficient Synthesis of Sterically Hindered Arenes Bearing Acyclic Secondary Alkyl Groups by Suzuki–Miyaura Cross‐Couplings
Authors: Li Chengxi , Chen Tianyu , Li Bowen , Xiao Guolan , Tang Wenjun
Published: January 2015

Bulky P,PO ligands were designed to inhibit isomerization and reduction side reactions during the cross coupling between sterically hindered aryl halides and alkylboronic acids. Suzuki–Miyaura cross‐couplings between di‐ortho‐substituted aryl bromides and acyclic secondary alkylboronic acids have been achieved with high yields. The method has also enabled the preparation of ortho‐alkoxy di‐ortho‐substituted arenes bearing isopropyl groups in excellent yields. The utility of the synthetic method has been demonstrated in a late‐stage modification of estrone and in the application to a new synthetic route toward gossypol.
Enhanced Luminescent Properties of an Open‐Shell (3,5‐Dichloro‐4‐pyridyl)bis(2,4,6‐trichlorophenyl)methyl Radical by Coordination to Gold
Authors: Hattori Yohei , Kusamoto Tetsuro , Nishihara Hiroshi
Published: January 2015

A gold(I) complex containing an open‐shell luminescent (3,5‐dichloro‐4‐pyridyl)bis(2,4,6‐trichlorophenyl)methyl (PyBTM) radical was prepared. The complex showed fluorescence centered mainly on the coordinated PyBTM ligand. The photophysical and photochemical properties were positively modulated upon coordination to AuI; the photoluminescence quantum yield, fluorescence wavelength, and the stability in the photoexcited state all increased.
Enantioselective Palladium‐Catalyzed Dearomative Cyclization for the Efficient Synthesis of Terpenes and Steroids
Authors: Du Kang , Guo Pan , Chen Yuan , Cao Zhen , Wang Zheng , Tang Wenjun
Published: January 2015

A novel enantioselective palladium‐catalyzed dearomative cyclization has been developed for the efficient construction of a series of chiral phenanthrenone derivatives bearing an all‐carbon quaternary center. The effectiveness of this method in the synthesis of terpenes and steroids was demonstrated by a highly efficient synthesis of a kaurene intermediate, the facile construction of the skeleton of the anabolic steroid boldenone, and the enantioselective total synthesis of the antimicrobial diterpene natural product (−)‐totaradiol.
Design and preparation of cross‐linked α‐methylstyrene acrylonitrile copolymer nanoparticles and their interfacial investigation with rubber
Authors: Zhang Huimei , Lu Ming , Lu Qiuyu , He Bo , Zhang Liqun , Liu Yakang
Published: January 2015

Cross‐linked α‐methylstyrene and acrylonitrile (MStAN) copolymer particles in a latex form were synthesized by free radical emulsion polymerization. The particles showed a narrow size distribution and an average diameter of 65 nm. The amount of the vinyl groups at the surface of the (MStAN) copolymer particles resulted from varied amount of the initiator (APS) and the cross‐linking agent (DVB) was detected by iodine titration method. When filled into ethylene propylene rubber (EPR), the MStAN nano‐particles exhibited excellent reinforcing capabilities, and with the increase of the vinyl groups at the surface of MStAN particles, the tensile stress of MStAN/EPR increased. Results demonstrated that the vinyl groups at the surface of the (MStAN) copolymer particles provided certain chemical interactions between the filler particles and the macromolecular chains of rubber matrix. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41914.
Influence of hydrogen bonding interaction on the damping properties of poly(n‐butyl methacrylate)/small molecule hybrids
Authors: Yin Xiaotong , Liu Chongyang , Lin Yu , Guan Aiguo , Wu Guozhang
Published: January 2015

The hydrogen bonding interactions between poly(n‐butyl methacrylate) and a series of low molecular weight phenols containing two to four hydroxyl groups with different steric effects were investigated by differential scanning calorimetry and Fourier‐transform infrared spectroscopy. Results showed that the hydrogen bonding strength between the two components varies greatly according to the steric effects of the phenolic hydroxyl group. As the size of the group beside the hydroxyl increases, the hydrogen bond strength weakens. The glass transition temperature of binary hybrid systems was put into relation with the corresponding hydrogen bonding interaction strength. Strong hydrogen bonding strength increased Tg to higher values than that predicted by the linear additivity rule; by contrast, Tg of hybrid systems with weak hydrogen bonds showed linear changes. All of the samples showed linear variations at low concentrations of small molecules. The damping properties of five systems were analyzed by dynamic mechanical analysis. Either the loss factor or area of tan δ peak of the five systems increased compared with that of the pure polymer, thereby showing great improvements in the damping properties of the poly(n‐butyl methacrylate)/small molecule hybrid material. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41954.
A Pilot Proteomic Analysis of Salivary Biomarkers in Autism Spectrum Disorder
Authors: Ngounou Wetie Armand G. , Wormwood Kelly L. , Russell Stefanie , Ryan Jeanne P. , Darie Costel C. , Woods Alisa G.
Published: January 2015

Autism spectrum disorder (ASD) prevalence is increasing, with current estimates at 1/68–1/50 individuals diagnosed with an ASD. Diagnosis is based on behavioral assessments. Early diagnosis and intervention is known to greatly improve functional outcomes in people with ASD. Diagnosis, treatment monitoring and prognosis of ASD symptoms could be facilitated with biomarkers to complement behavioral assessments. Mass spectrometry (MS) based proteomics may help reveal biomarkers for ASD. In this pilot study, we have analyzed the salivary proteome in individuals with ASD compared to neurotypical control subjects, using MS‐based proteomics. Our goal is to optimize methods for salivary proteomic biomarker discovery and to identify initial putative biomarkers in people with ASDs. The salivary proteome is virtually unstudied in ASD, and saliva could provide an easily accessible biomaterial for analysis. Using nano liquid chromatography‐tandem mass spectrometry, we found statistically significant differences in several salivary proteins, including elevated prolactin‐inducible protein, lactotransferrin, Ig kappa chain C region, Ig gamma‐1 chain C region, Ig lambda‐2 chain C regions, neutrophil elastase, polymeric immunoglobulin receptor and deleted in malignant brain tumors 1. Our results indicate that this is an effective method for identification of salivary protein biomarkers, support the concept that immune system and gastrointestinal disturbances may be present in individuals with ASDs and point toward the need for larger studies in behaviorally‐characterized individuals. Autism Res 2015, 8: 338–350. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Tracking and sense of futility: the impact of between‐school tracking versus within‐school tracking in secondary education in Flanders (Belgium)
Authors: Van Houtte Mieke , Stevens Peter A. J.
Published: January 2015

It has been established since the 1960s that tracking yields negative consequences for students in lower tracks. As this research has been carried out mainly in the USA and UK, the effects of tracking have been demonstrated in systems of within‐school tracking mostly. However, in many European countries—such as Belgium (Flanders)—tracking is commonly organised between schools. The question then arises whether the specific system of tracking, within‐school vs between‐school tracking, might affect the impact of tracking on students. Although in Flanders between‐school tracking is the norm, there are a number of schools offering a combination of academic tracks with technical and/or vocational tracks, allowing for a comparison of both systems. The present study investigates whether the association between feelings of futility and the specific track a student is enrolled in depends upon whether these tracks are organised between or within schools. Three‐level multilevel analyses (HLM6) of 11,872 3rd‐ and 5th‐grade students clustered in 146 tracks in a representative sample of 85 secondary schools in Flanders are carried out based on the Flemish Educational Assessment (FlEA) data gathered in 2004–2005. Within‐school tracking appears to have a slightly greater impact on the association between track position and sense of futility. So, lower‐track students who are directly confronted with higher‐track students in the same school seem more likely to lose their faith in a meritocratic system, as they put luck above working hard or above merit.
A Bayesian approach to probabilistic sensitivity analysis in structured benefit‐risk assessment
Authors: Waddingham Ed , Mt‐Isa Shahrul , Nixon Richard , Ashby Deborah
Published: January 2015

Quantitative decision models such as multiple criteria decision analysis (MCDA) can be used in benefit‐risk assessment to formalize trade‐offs between benefits and risks, providing transparency to the assessment process. There is however no well‐established method for propagating uncertainty of treatment effects data through such models to provide a sense of the variability of the benefit‐risk balance. Here, we present a Bayesian statistical method that directly models the outcomes observed in randomized placebo‐controlled trials and uses this to infer indirect comparisons between competing active treatments. The resulting treatment effects estimates are suitable for use within the MCDA setting, and it is possible to derive the distribution of the overall benefit‐risk balance through Markov Chain Monte Carlo simulation. The method is illustrated using a case study of natalizumab for relapsing‐remitting multiple sclerosis.
Randomized clinical trial of sacral versus percutaneous tibial nerve stimulation in patients with faecal incontinence
Authors: Thin N N , Taylor S J C , Bremner S A , Emmanuel A V , Hounsome N , Williams N S , Knowles C H , Alam A , Bannister S , Scott S M , Allison M E , Vaizey C J , Thomas G P
Published: January 2015

Background

Sacral nerve stimulation (SNS) is a well established therapy for faecal incontinence (FI). Percutaneous tibial nerve stimulation (PTNS) is a newer, less invasive, treatment. The effectiveness and acceptability of these treatments have not been compared systematically.

Methods

An investigator-blinded randomized pilot trial of PTNSversus SNS with a parallel qualitative study was performed. Quantitative clinical outcomes and qualitative data from patient interviews were collected for both interventions.

Results

Forty patients (39 women; mean age 59 years) met the eligibility criteria; 23 were randomized to receive SNS and 17 to PTNS. Fifteen patients progressed to permanent SNS implantation and 16 received a full course of PTNS. Within-group effect sizes were marginally greater for SNS than for PTNS on available-case analysis. Mean(s.d.) FI episodes per week at baseline, and 3 and 6 months of follow-up were: 11·4(12·0), 4·0(4·0) and 4·9(6·9) respectively for SNS compared with 10·6(11·2), 5·8(6·9) and 6·3(6·9) for PTNS. Mean(s.d.) Cleveland Clinic Incontinence Score values at baseline, and 3 and 6 months were: 16·2(3·0), 11·1(5·2) and 10·4(5·6) for SNSversus 15·1(2·7), 11·7(4·4) and 12·1(5·2) for PTNS. Improvement of at least 50 per cent in FI episodes per week at 6 months was seen in 11 of 18 patients in the SNS group compared with seven of 15 in the PTNS group. Effect estimates for SNS with chronic implanted stimulation were larger (10 of 15 patients at 6 months). Disease-specific and generic quality-of-life improvements complemented clinical outcome data. Qualitative analysis of interview data suggested that both treatments had high acceptability amongst patients.

Conclusion

In the short term, both SNS and PTNS provide some clinical benefit to patients with FI. Registration numbers: 2010-018728-15 and 10479 (http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=10479).
Variability in the reported management of pulmonary metastases in osteosarcoma
Authors: Bhattasali Onita , Vo Andrea T. , Roth Michael , Geller David , Randall R. Lor , Gorlick Richard , Gill Jonathan
Published: January 2015

Nearly 20% of patients with newly diagnosed osteosarcoma have detectable metastases at diagnosis; the majority of which occur in the lungs. There are no established recommendations for the timing and modality of metastasectomy. Members of the Connective Tissue Oncology Society (CTOS) were emailed an anonymous 10‐min survey assessing their management practices for pulmonary findings at the time of an osteosarcoma diagnosis. The questionnaire presented three scenarios and discussed the choice to perform surgery, the timing of resection, and the choice of surgical procedure. Analyses were stratified by medical profession. One hundred and eighty‐three physicians responded to our questionnaire. Respondents were comprised of orthopedic surgeons (37%), medical oncologists (31%), pediatric oncologists (22%), and other medical subspecialties (10%). There was variability among the respondents in the management of the pulmonary nodules. The majority of physicians chose to resect the pulmonary nodules following neoadjuvant chemotherapy (46–63%). Thoracotomy was the preferred technique for surgical resection. When only unilateral findings were present, the majority of physicians did not explore the contralateral lung. The majority of respondents did not recommend resection if the pulmonary nodule disappeared following chemotherapy. The survey demonstrated heterogeneity in the management of pulmonary metastases in osteosarcoma. Prospective trials need to evaluate whether these differences in management have implications for outcomes for patients with metastatic osteosarcoma.
Functional Characterization of MpaG′, the O‐Methyltransferase Involved in the Biosynthesis of Mycophenolic Acid
Authors: Zhang Wei , Cao Shaona , Qiu Li , Qi Fengxia , Li Zhong , Yang Ying , Huang Shaohua , Bai Fali , Liu Changning , Wan Xiaobo , Li Shengying
Published: January 2015

Mycophenolic acid (MPA, 1) is a clinically important immunosuppressant. In this report, a gene cluster mpa′ responsible for the biosynthesis of 1 was identified from Penicillium brevicompactum NRRL 864. The S‐adenosyl‐L‐methionine‐dependent (SAM‐dependent) O‐methyltransferase encoded by the mpaG′ gene was functionally and kinetically characterized in vitro. MpaG′ catalyzes the methylation of demethylmycophenolic acid (DMMPA, 6) to form 1. It also showed significant substrate flexibility by methylating two structural derivatives of 6 prepared by organic synthesis.
A Cascade Synthesis of Aminohydantoins Using In Situ‐Generated N‐Substituted Isocyanates
Authors: Vincent‐Rocan Jean‐François , Clavette Christian , Leckett Kyle , Beauchemin André M.
Published: January 2015

Nitrogen‐substituted isocyanates are rarely utilized but powerful building blocks for the development of cascade reactions in heterocyclic synthesis. These reactive amphoteric intermediates can be accessed in situ via an equilibrium that allows controlled reactivity in the presence of bifunctional partners such as α‐amino esters. A cascade reaction has been carried out that forms 3‐aminohydantoin derivatives using simple phenoxycarbonyl derivatives of hydrazides and hydrazones as precursors of N‐substituted‐isocyanates. This method allows rapid assembly of complex aminohydantoin derivatives, including analogues of medicinally‐relevant compounds, using simple reactants.
Sensing of 2,4,6‐Trinitrotoluene (TNT) and 2,4‐Dinitrotoluene (2,4‐DNT) in the Solid State with Photoluminescent RuII and IrIII Complexes
Authors: Mosca Lorenzo , Khnayzer Rony S. , Lazorski Megan S. , Danilov Evgeny O. , Castellano Felix N. , Anzenbacher Pavel
Published: January 2015

A series of metal–organic chromophores containing RuII or IrIII were studied for the luminometric detection of nitroaromatic compounds, including trinitrotoluene (TNT). These complexes display long‐lived, intense photoluminescence in the visible region and are demonstrated to serve as luminescent sensors for nitroaromatics. The solution‐based behavior of these photoluminescent molecules has been studied in detail in order to identify the mechanism responsible for metal‐to‐ligand charge‐transfer (MLCT) excited state quenching upon addition of TNT and 2,4‐dinitrotoluene (2,4‐DNT). A combination of static and dynamic spectroscopic measurements unequivocally confirmed that the quenching was due to a photoinduced electron transfer (PET) process. Ultrafast transient absorption experiments confirmed the formation of the TNT radical anion product following excited state electron transfer from these metal complexes. Reported for the first time, photoluminescence quenching realized through ink‐jet printing and solid‐state titrations was used for the solid‐state detection of TNT; achieving a limit‐of‐quantitation (LOQ) as low as 5.6 ng cm−2. The combined effect of a long‐lived excited state and an energetically favorable driving force for the PET process makes the RuII and IrIII MLCT complexes discussed here particularly appealing for the detection of nitroaromatic volatiles and related high‐energy compounds.
Synthesis of Bicyclic Proline Derivatives by the Aza‐Cope–Mannich Reaction: Formal Synthesis of (±)‐Acetylaranotin
Authors: Belov Dmitry S. , Ratmanova Nina K. , Andreev Ivan A. , Kurkin Alexander V.
Published: January 2015

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza‐Cope–Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.
Triflic Acid Mediated Cascade Cyclization of Aryldiynes for the Synthesis of Indeno[1,2‐c]chromenes: Application to Dye‐Sensitized Solar Cells
Authors: Jiang Hua , Ferrara Giovanni , Zhang Xuan , Oniwa Kazuaki , Islam Ashraful , Han Liyuan , Sun Ying‐Ji , Bao Ming , Asao Naoki , Yamamoto Yoshinori , Jin Tienan
Published: January 2015

A new triflic acid (TfOH)‐mediated cascade cyclization of ortho‐anisole‐substituted aryldiynes is described for the construction of indeno[1,2‐c]chromenes. The cascade cyclization proceeds through an unusual TfOH‐induced alkyne‐alkyne cyclization followed by nucleophilic attack of the methoxy group on the benzylidene cation, which is completely different to the cyclization of ortho‐aniline‐ or ortho‐thioanisole‐substituted aryldiynes. A new class of organic dyes with the indeno[1,2‐c]chromene framework as both donor and π‐linker were synthesized. These compounds exhibit high photovoltaic performances in dye‐ sensitized solar cells (DSCs).
Dialkylzinc‐Mediated Cross‐Coupling Reactions of Perfluoroalkyl and Perfluoroaryl Halides with Aryl Halides
Authors: Kato Hisano , Hirano Keiichi , Kurauchi Daisuke , Toriumi Naoyuki , Uchiyama Masanobu
Published: January 2015

A highly chemoselective perfluoroalkylation reaction of aromatic halides is reported. Thermally stable perfluoroalkylzinc reagents, generated by a rapid halogen–zinc exchange reaction between diorganozinc and perfluoroalkyl halide species, couple with a wide range of aryl halides in the presence of a copper catalyst, in moderate to high yields. Good stability of the perfluoroalkylzinc species was indicated by DFT calculation and the reagents were storable for at least three months under argon without loss of activity. This method is applicable to gram‐scale synthesis, and its functional group tolerance compares favorably with reported protocols.
Initial Radical Cation Pathway in the Mo2Cl10‐Mediated Dehydrogenative Arene Coupling
Authors: Leppin Jana , Schubert Moritz , Waldvogel Siegfried R. , Heinze Katja
Published: January 2015

Experimental (EPR) and theoretical (DFT) evidence is provided for radical cation formation as initial step in the Mo2Cl10‐mediated dehydrogenative arene coupling. The initial electron transfer from methoxyarenes to molybdenum proceeds via an inner sphere mechanism.
A hybrid model for biofilm growth on a deformable substratum
Authors: Boraey Mohammed A. , Guaily Amr , Epstein Marcelo
Published: January 2015

The mutual interaction between a biofilm growing on a deformable substratum and its deformability is investigated. The interaction process is investigated by a newly developed model based on a hybrid Cellular Automaton/Finite Element approach (CAFE). A quantitative model is proposed that predicts the effect of the substratum deformability on the biofilm growth as well as on the allocation of the newborn cells. In the proposed model, it is suggested that regions of higher positive curvature will act as attractors. The finite element method is used to model the substratum deformability while the biofilm growth is modelled using a semi‐stochastic approach. Numerical examples are presented in two‐ and three‐dimensional settings.
Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties
Authors: Borhade Sanjay R. , Svensson Richard , Brandt Peter , Artursson Per , Arvidsson Per I. , Sandström Anja
Published: January 2015

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa, lipophilicity, in vitro metabolic stability, plasma protein binding, Caco‐2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9–7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.
Augmenting basic colour terms in english
Authors: Mylonas Dimitris , MacDonald Lindsay
Published: January 2015

In an unconstrained colour naming experiment conducted over the web, 330 participants named 600 colour samples in English. The 30 most frequent monolexemic colour terms were analyzed with regards to frequency, consensus among genders, response times, consistency of use, denotative volume in the Munsell and OSA colour spaces and inter‐experimental agreement. Each of these measures served for ranking colour term salience; rankings were then combined to give a composite index of basicness. The results support the extension of English inventory from the 11 basic colour terms of Berlin and Kay to 13 terms by the addition of lilac and turquoise. © 2015 Wiley Periodicals, Inc. Col Res Appl, 41, 32–42, 2016
Stepwise‐refinement for performance: a methodology for many‐core programming
Authors: Hijma P. , van Nieuwpoort R. V. , Jacobs C. J. H. , Bal H. E.
Published: January 2015

Many‐core hardware is targeted specifically at obtaining high performance, but reaching high performance is often challenging because hardware‐specific details have to be taken into account. Although there are many programming systems that try to alleviate many‐core programming, some providing a high‐level language, others providing a low‐level language for control, none of these systems have a clear and systematic methodology as a foundation. In this article, we propose stepwise‐refinement for performance: a novel, clear, and structured methodology for obtaining high performance on many‐cores. We present a system that supports this methodology, offers multiple levels of abstraction to provide programmers a trade‐off between high‐level and low‐level programming, and provides programmers detailed performance feedback. We evaluate our methodology with several widely varying compute kernels on two different many‐core architectures: a Graphical Processing Unit (GPU) and the Xeon Phi. We show that our methodology gives insight in the performance, and that in almost all cases, we gain a substantial performance improvement using our methodology. Copyright © 2015 John Wiley & Sons, Ltd.
Responses of benthic invertebrates to repeated hydropeaking in semi‐natural flume simulations
Authors: Bruno Maria Cristina , Cashman Matthew J. , Maiolini Bruno , Biffi Sofia , Zolezzi Guido
Published: January 2015

We assessed the effects of repeated hydropeaking over five consecutive days on the zoobenthic community by manipulating discharge in five experimental flumes directly fed by an Alpine stream. Treatment consisted of two different hydropeaking intensities which increased discharge two‐ and threefold from baseflow and lasted for 5 h each day. The resulting sudden changes in flow directly affected benthic invertebrates through the induction of catastrophic drift as a direct response to high (hydropeaking) flow conditions, and of behavioural drift in the low, baseflow conditions (at the conclusion of each hydropeaking event) for some taxa. We observed: an initial strong peak in catastrophic drift within the first 3 min of increased discharge, followed by a decreased drift rate throughout the following hours of the experiment; a strong response in the first day of the simulation, with successive days having substantially decreased drift; taxa‐specific responses over the short and long‐time scales: least‐resistant taxa (i.e. Baetis spp.) were removed via the initial catastrophic drift, while more resistant taxa began to behaviourally drift later in each hydropeak (i.e. Simuliidae). Peaks in drift rates corresponded to the initial removal of CPOM which, during low flows, provided habitat and food resource for a high number of individuals and taxa. Quantification of drift responses over time scales larger than the single hydropeaking event underlines the relevance of the typical intermittency and repetition frequency as a stress factor for benthic communities, and that the response to hydropeaking is closely related to the time elapsed since the last perturbation. Copyright © 2015 John Wiley & Sons, Ltd.
Regioselective Nucleophilic Aromatic Substitution Reaction of meso‐Pentafluorophenyl‐Substituted Porphyrinoids with Alcohols
Authors: Golf Hartwig R. A. , Reissig Hans‐Ulrich , Wiehe Arno
Published: January 2015

A detailed study of the nucleophilic aromatic substitution reaction of meso‐pentafluorophenyl‐substituted tetrapyrrole systems with different alcohols is presented. The systematic investigation of various alcohols and bases in two different solvents led to optimized reaction conditions, allowing the selective substitution of the p‐fluorine atoms of meso‐pentafluorophenyl‐substituted porphyrins, their zinc complexes, and a meso‐tris(pentafluorophenyl)corrole with alcohols and a simple base in high yields. When applied to A3B porphyrins in combination with suitable protecting groups, functionalized, polar A3B porphyrins can be prepared in a simple two‐step one‐pot procedure. By using the nucleophilic aromatic substitution reaction, a dimeric porphyrin system was synthesized. In addition, the copper(I)‐catalyzed 1,3‐dipolar cycloaddition of properly functionalized meso‐pentafluorophenyl‐substituted porphyrins led to the corresponding porphyrin dimer with a 1,2,3‐triazole linker. The method described herein allows a simple and fast approach towards multifunctionalized porphyrinoids based on meso‐pentafluorophenyl‐substituted tetrapyrroles.
Synthesis and Electrochemical Properties of the Tetraferrocenyl‐Cavitand in Dimethyl Formamide Solvent Using Platinum and Carbon Working Electrodes
Authors: Filotás Dániel , Nagy Lívia , Kégl Timea R. , Csók Zsolt , Kollár László , Nagy Géza
Published: January 2015

A tetraferrocenyl‐cavitand was synthesized through copper(I)‐catalyzed azide‐alkyne cycloaddition reaction. The electrochemical property of the cavitand possessing four ferrocenyl moieties at the upper rim was investigated in dimethyl formamide solvent using platinum and carbon working electrodes. Quasi reversible redox character was observed and no electrode fouling could be found. Different electrochemical methods were selected for determination of the diffusion coefficient and number of electrons taking part in the redox process of this species. Electrochemical measurements were carried out with ferrocene and the cavitand, utilizing the same cells, electrodes and conditions. The obtained results were compared.
Multiplexed separations for biomarker discovery in metabolomics: Elucidating adaptive responses to exercise training
Authors: Kuehnbaum Naomi L. , Gillen Jenna B. , Kormendi Aleshia , Lam Karen P. , DiBattista Alicia , Gibala Martin J. , Britz‐McKibbin Philip
Published: January 2015

High efficiency separations are needed to enhance selectivity, mass spectral quality, and quantitative performance in metabolomic studies. However, low sample throughput and complicated data preprocessing remain major bottlenecks to biomarker discovery. We introduce an accelerated data workflow to identify plasma metabolite signatures of exercise responsiveness when using multisegment injection‐capillary electrophoresis‐mass spectrometry (MSI‐CE‐MS). This multiplexed separation platform takes advantage of customizable serial injections to enhance sample throughput and data fidelity based on temporally resolved ion signals derived from seven different sample segments analyzed within a single run. MSI‐CE‐MS was applied to explore the adaptive metabolic responses of a cohort of overweight/obese women (BMI > 25, n = 9) performing a 6‐wk high‐intensity interval training intervention using a repeated measures/cross‐over study design. Venous blood samples were collected from each subject at three time intervals (baseline, postexercise, recovery) in their naïve and trained states while completing standardized cycling trials at the same absolute workload. Complementary statistical methods were used to classify dynamic changes in plasma metabolism associated with strenuous exercise and training status. Positive adaptations to exercise were associated with training‐induced upregulation in plasma l‐carnitine at rest due to improved muscle oxidative capacity, and greater antioxidant capacity as reflected by lower circulating glutathionyl‐l‐cysteine mixed disulfide. Attenuation in plasma hypoxanthine and higher O‐acetyl‐l‐carnitine levels postexercise also indicated lower energetic stress for trained women.
Testing the Effect of Rare Compound‐Heterozygous and Recessive Mutations in Case–Parent Sequencing Studies
Authors: Jiang Yu , McCarthy Janice M. , Allen Andrew S.
Published: January 2015

ABSTRACT: Compound heterozygous mutations are mutations that occur on different copies of genes and may completely “knock‐out” gene function. Compound heterozygous mutations have been implicated in a large number of diseases, but there are few statistical methods for analyzing their role in disease, especially when such mutations are rare. A major barrier is that phase information is required to determine whether both gene copies are affected and phasing rare variants is difficult. Here, we propose a method to test compound heterozygous and recessive disease models in case–parent trios. We propose a simple algorithm for phasing and show via simulations that tests based on phased trios have almost the same power as tests using true phase information. A further complication in the study of compound heterozygous mutations is that only families where both parents carry mutations are informative. Thus, the informative sample size will be quite small even when the overall sample size is not, making asymptotic approximations of the null distribution of the test statistic inappropriate. To address this, we develop an exact test that will give appropriate P‐values regardless of sample size. Using simulation, we show that our method is robust to population stratification and significantly outperforms other methods when the causal model is recessive.