bluuebunny/crossref_metadata_2025 huggingface dataset:
Geomagnetic and strong static magnetic field effects on growth and chlorophyll a fluorescence in Lemna minor
Authors: Jan Luka , Fefer Dušan , Košmelj Katarina , Gaberščik Alenka , Jerman Igor
Published: February 2015

The geomagnetic field (GMF) varies over Earth's surface and changes over time, but it is generally not considered as a factor that could influence plant growth. The effects of reduced and enhanced GMFs and a strong static magnetic field on growth and chlorophyll a (Chl a) fluorescence of Lemna minor plants were investigated under controlled conditions. A standard 7 day test was conducted in extreme geomagnetic environments of 4 µT and 100 µT as well as in a strong static magnetic field environment of 150 mT. Specific growth rates as well as slow and fast Chl a fluorescence kinetics were measured after 7 days incubation. The results, compared to those of controls, showed that the reduced GMF significantly stimulated growth rate of the total frond area in the magnetically treated plants. However, the enhanced GMF pointed towards inhibition of growth rate in exposed plants in comparison to control, but the difference was not statistically significant. This trend was not observed in the case of treatments with strong static magnetic fields. Our measurements suggest that the efficiency of photosystem II is not affected by variations in GMF. In contrast, the strong static magnetic field seems to have the potential to increase initial Chl a fluorescence and energy dissipation in Lemna minor plants. Bioelectromagnetics. 36:190–203, 2015. © 2015 Wiley Periodicals, Inc.
Molecular signaling mechanisms of axon–glia communication in the peripheral nervous system
Authors: Grigoryan Tamara , Birchmeier Walter
Published: February 2015

In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron–Schwann cell interactions often results in developmental abnormalities and diseases. Recent investigations have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine‐tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron–Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole.
Camelina as a sustainable oilseed crop: Contributions of plant breeding and genetic engineering
Authors: Vollmann Johann , Eynck Christina
Published: February 2015

Camelina is an underutilized Brassicaceae oilseed plant with a considerable agronomic potential for biofuel and vegetable oil production in temperate regions. In contrast to most Brassicaceae, camelina is resistant to alternaria black spot and other diseases and pests. Sequencing of the camelina genome revealed an undifferentiated allohexaploid genome with a comparatively large number of genes and low percentage of repetitive DNA. As there is a close relationship between camelina and the genetic model plant Arabidopsis, this review aims at exploring the potential of translating basic Arabidopsis results into a camelina oilseed crop for food and non‐food applications. Recently, Arabidopsis genes for drought resistance or increased photosynthesis and overall productivity have successfully been expressed in camelina. In addition, gene constructs affecting lipid metabolism pathways have been engineered into camelina for synthesizing either long‐chain polyunsaturated fatty acids, hydroxy fatty acids or high‐oleic oils in particular camelina strains, which is of great interest in human food, industrial or biofuel applications, respectively. These results confirm the potential of camelina to serve as a biotechnology platform in biorefinery applications thus justifying further investment in breeding and genetic research for combining agronomic potential, unique oil quality features and biosafety into an agricultural production system.
Meta-analysis of prognostic factors for amputation following surgical repair of lower extremity vascular trauma
Authors: Perkins Z B , Yet B , Glasgow S , Cole E , Marsh W , Brohi K , Rasmussen T E , Tai N R M
Published: February 2015

Background

Lower extremity vascular trauma (LEVT) is a major cause of amputation. A clear understanding of prognostic factors for amputation is important to inform surgical decision-making, patient counselling and risk stratification. The aim was to develop an understanding of prognostic factors for amputation following surgical repair of LEVT.

Methods

A systematic review was conducted to identify potential prognostic factors. Bayesian meta-analysis was used to calculate an absolute (pooled proportion) and relative (pooled odds ratio, OR) measure of the amputation risk for each factor.

Results

Forty-five studies, totalling 3187 discrete LEVT repairs, were included. The overall amputation rate was 10·0 (95 per cent credible interval 7·4 to 13·1) per cent. Significant prognostic factors for secondary amputation included: associated major soft tissue injury (26 versus 8 per cent for no soft tissue injury; OR 5·80), compartment syndrome (28 versus 6 per cent; OR 5·11), multiple arterial injuries (18 versus 9 per cent; OR 4·85), duration of ischaemia exceeding 6 h (24 versus 5 per cent; OR 4·40), associated fracture (14 versus 2 per cent; OR 4·30), mechanism of injury (blast 19 per cent, blunt 16 per cent, penetrating 5 per cent), anatomical site of injury (iliac 18 per cent, popliteal 14 per cent, tibial 10 per cent, femoral 4 per cent), age over 55 years (16 versus 9 per cent; OR 3·03) and sex (men 7 per cent versus women 8 per cent; OR 0·64). Shock and nerve or venous injuries were not significant prognostic factors for secondary amputation.

Conclusion

A significant proportion of patients who undergo lower extremity vascular trauma repair will require secondary amputation. This meta-analysis describes significant prognostic factors needed to inform surgical judgement, risk assessment and patient counselling.
Elastic properties of Thiel‐embalmed human ankle tendon and ligament
Authors: Liao Xiaochun , Kemp Sandy , Corner George , Eisma Roos , Huang Zhihong
Published: February 2015

Thiel embalming is recommended as an alternative to formalin‐based embalming because it preserves tissue elasticity, color, and flexibility in the long term, with low infection and toxicity risk. The degree to which Thiel embalming preserves elasticity has so far been assessed mainly by subjective scoring, with little quantitative verification. The aim of this study is to quantify the effect of Thiel embalming on the elastic properties of human ankle tendons and ligament. Biomechanical tensile tests were carried out on six Thiel‐embalmed samples each of the peroneus longus, peroneus brevis, and calcaneal tendons, and the calcaneofibular ligament, with strain rates of 0.25%s−1, 2%s−1, and 8%s−1. The stress−strain relationship was calculated from the force‐extension response with cross‐sectional area and gauge length. Young's modulus was determined from the stress−strain curve. The results showed that the tendon and ligament elasticity were lower after Thiel embalming than the literature values for fresh nonembalmed tendons and ligament. The biomechanical tensile test showed that the measured elasticity of Thiel‐embalmed tendons and ligaments increased with the strain rate. The Thiel embalming method is useful for preserving human ankle tendons and ligaments for anatomy and surgery teaching and research, but users need to be aware of its softening effects. The method retains the mechanical strain rate effect on tendons and ligament. Clin. Anat. 28:917–924, 2015. © 2015 Wiley Periodicals, Inc.
Clinical considerations of the glandular branch of the lacrimal artery
Authors: Kluckman Matthew , Fan Jerry , Balsiger Heather , Scott Gabriel , Gest Thomas
Published: February 2015

The lacrimal artery is classically described as a branch of the ophthalmic artery supplied by the internal carotid. In this study, 25 orbits were dissected to identify variations in glandular branching and to compare them to previously published accounts. The glandular branching patterns of the lacrimal artery fall into two categories, those that branch (56%) and those that do not branch (44%). We found the medial and lateral glandular branches to be equal in diameter with a divergence of 2.67–40.58 mm proximal to the gland parenchyma. The long glandular branches run alongside the superolateral aspect of the orbit. The lateral branch runs lateral to the lateral rectus muscle. The medial branch runs superomedial to the lateral rectus muscle and lateral to the superior rectus muscle. In relation to the lacrimal gland, the medial branch enters the superior aspect of the gland parenchyma and the lateral branch enters its inferior aspect. The average branch lengths were 17.88 mm (medial) and 13.51 mm (lateral) as measured with a Mitutoyo Absolute 1/100 mm caliper. We could not confirm the existence of a third branch supplying the lacrimal gland, as posited by other authors. The key finding in this study is that the lacrimal gland is predominantly supplied by two significant arterial branches, both of which must be identified during procedures involving the lateral orbit. Clin. Anat. 28:844–847, 2015. © 2015 Wiley Periodicals, Inc.
Advances in Experimental Medicine and Biology, Vol. 842: Biochemical Roles of Eukaryotic Cell Surface Macromolecules. Edited by Abhijit Chakrabarti and Avadhesha Surolia.
Authors: Stocker Bridget L.
Published: February 2015

Springer, Heidelberg 2015, 411+IX pp., hardcover, £/€/$ 149.75.—ISBN 978‐3‐319‐11279‐4
Comparative Analysis of Different Control Strategies for a Train of Cryogenic 13C Separation Columns
Authors: Muresan Cristina I. , Dulf Eva H. , Both Roxana
Published: February 2015

Carbon isotopes are widely used in numerous industries, especially in medicine. The advantage of using 13C‐labeled products is only shadowed by the difficulty of increasing the natural concentration. One method available is a train of cryogenic distillation columns. This paper presents a preliminary analysis of three different control strategies for a unit comprising three 7‐m‐high isotope separation columns: a decentralized multivariable proportional‐integral controller and two decoupling control algorithms. For the first one, a single controller is designed for the entire distillation column train, whereas for the second decoupling approach, three separate controllers are designed for each of the three columns. Simulation results show that the last approach provides significantly improved results when compared to the other two control strategies.
Application of Sorbents for Industrial Waste Water Purification
Authors: Matejkova Martina , Soukup Karel , Kastanek Frantisek , Capek Pavel , Grabowski Jacek , Stanczyk Krzysztof , Solcova Olga
Published: February 2015

A sorption technique was tested for decontamination of post‐processing underground coal gasification (UCG) water contaminated by a variety of organic and inorganic substances. Four sorbents (two zeolites and two activated carbons) with nanoiron were chosen for laboratory and pilot sorption experiments. Four main phenol contaminants typical for UCG water served as markers for sorption efficiency. Axial dispersion was evaluated for three pilot channel positions filled with gravel, sand, and sand with stones. Both activated carbons revealed the best sorption efficiency in laboratory as well as in pilot experiments for organic and inorganic contaminants. A sandwich structure of different sorbents was suggested as the optimal design of a reactive bed suitable for tests in the experimental mine.
Energiespeicher – Es gibt keinen Königsweg, aber auch keine Alternative
Authors: Stiller Christoph , Göke Volker , Würtenberger Uwe
Published: February 2015

Der steigende Anteil erneuerbarer Energien erschwert die Regulierung von Angebot und Nachfrage in Stromnetzen. Hier werden Möglichkeiten zur Integration von erneuerbaren Energien in das Energiesystem diskutiert. Denkbare Lösungen sind der überregionale Lastausgleich, die zeitliche Verschiebung von Lasten, die Abregelung von Übererzeugung und insb. die Speicherung von Strom, z. B. in Stromspeichern oder chemischen Produkten. Die Komplexität des Problems und der Lösungsmöglichkeiten sind zugleich Herausforderung und Chance für die Technologiewirtschaft, insb. auch für die Chemiebranche.
The role of families in decisions regarding cancer treatments
Authors: Hobbs Gabriela S. , Landrum Mary Beth , Arora Neeraj K. , Ganz Patricia A. , van Ryn Michelle , Weeks Jane C. , Mack Jennifer W. , Keating Nancy L.
Published: February 2015

BACKGROUND

Shared decision‐making is an important component of patient‐centered care and is associated with improved outcomes. To the authors' knowledge, little is known concerning the extent and predictors of the involvement of a patient's family in decisions regarding cancer treatments.

METHODS

The Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium is a large, multiregional, prospective cohort study of the cancer care and outcomes of patients with lung and colorectal cancer. Participants reported the roles of their families in decision‐making regarding treatment. Multinomial logistic regression was used to assess patient factors associated with family roles in decisions.

RESULTS

Among 5284 patients, 80 (1.5%) reported family‐controlled decisions, with the highest adjusted rates (12.8%) noted among non‐English‐speaking Asians. Among the 5204 remaining patients, 49.4% reported equally sharing decisions with family, 22.1% reported some family input, and 28.5% reported little family input. In adjusted analyses, patients who were married, female, older, and insured more often reported equally shared decisions with family (all P <.001). Adjusted family involvement varied by race/ethnicity and language, with Chinese‐speaking Asian (59.8%) and Spanish‐speaking Hispanic (54.8%) patients equally sharing decisions with family more often than white individuals (47.6%). Veterans Affairs patients were least likely to report sharing decisions with family, even after adjustment for marital status and social support (P <.001).

CONCLUSIONS

The majority of patients with newly diagnosed lung or colorectal cancer involve family members in treatment decisions. Non‐English‐speaking Asians and Hispanics rely significantly on family. Further studies are needed to determine the impact of family involvement in treatment decisions on outcomes; until then, physicians should consider eliciting patients' preferences for family involvement. Cancer 2015;121:1079–1087. © 2015 American Cancer Society.
Efficient Emission Facilitated by Multiple Energy Level Transitions in Uniform Graphitic Carbon Nitride Films Deposited by Thermal Vapor Condensation
Authors: Bian Juncao , Li Jianfu , Kalytchuk Sergii , Wang Yu , Li Qian , Lau Tsz Chun , Niehaus Thomas A. , Rogach Andrey L. , Zhang Rui‐Qin
Published: February 2015

Graphitic carbon nitride (g‐CN) films are important components of optoelectronic devices, but current techniques for their production, such as drop casting and spin coating, fail to deliver uniform and pinhole‐free g‐CN films on solid substrates. Here, versatile, cost‐effective, and large‐area growth of uniform and pinhole‐free g‐CN films is achieved by using a thermal vapor condensation method under atmospheric pressure. A comparison of the X‐ray diffraction and Fourier transform infrared data with the calculated infrared spectrum confirmed the graphitic build‐up of films composed of tri‐s‐triazine units. These g‐CN films possess multiple active energy states including π*, π, and lone‐pair states, which facilitate their efficient (6 % quantum yield in the solid state) photoluminescence, as confirmed by both experimental measurements and theoretical calculations.
Mo‐Doped BiVO4 Photoanodes Synthesized by Reactive Sputtering
Authors: Chen Le , Toma Francesca M. , Cooper Jason K. , Lyon Alan , Lin Yongjing , Sharp Ian D. , Ager Joel W.
Published: February 2015

We report a scalable and reproducible method for reactive co‐sputtering of Mo‐doped BiVO4 thin films with broad compositional control. Optimal photoanode performance is achieved at a Mo concentration of 3 at. %. Incorporation of Mo promotes growth of large grains and reduces majority carrier transport limitations, resulting in maximum AM1.5G photocurrent densities of 3.5 mA cm−2 at 1.23 V vs. RHE in pH 6.8 buffer solution containing 0.1 M Na2SO3 as a hole scavenger. Operation as a front‐illuminated water oxidation photoanode is achieved by balancing the operational stability, catalytic activity, and parasitic optical absorption of a FeOOH oxygen evolution catalyst. FeOOH/Mo:BiVO4 thin film photoanodes enable water oxidation under the front‐side illumination conditions used in integrated tandem water splitting devices.
Natural selection for earlier male arrival to breeding grounds through direct and indirect effects in a migratory songbird
Authors: Velmala William , Helle Samuli , Ahola Markus P. , Klaassen Marcel , Lehikoinen Esa , Rainio Kalle , Sirkiä Päivi M. , Laaksonen Toni
Published: February 2015

For migratory birds, the earlier arrival of males to breeding grounds is often expected to have fitness benefits. However, the selection differential on male arrival time has rarely been decomposed into the direct effect of male arrival and potential indirect effects through female traits. We measured the directional selection differential on male arrival time in the pied flycatcher (Ficedula hypoleuca) using data from 6 years and annual number of fledglings as the fitness proxy. Using structural equation modeling, we were able to take into account the temporal structure of the breeding cycle and the hierarchy between the examined traits. We found directional selection differentials for earlier male arrival date and earlier female laying date, as well as strong selection differential for larger clutch size. These selection differentials were due to direct selection only as indirect selection for these traits was nonsignificant. When decomposing the direct selection for earlier male arrival into direct and indirect effects, we discovered that it was almost exclusively due to the direct effect of male arrival date on fitness and not due to its indirect effects via female traits. In other words, we showed for the first time that there is a direct effect of male arrival date on fitness while accounting for those effects that are mediated by effects of the social partner. Our study thus indicates that natural selection directly favored earlier male arrival in this flycatcher population.
Mitochondrial genetic differentiation and morphological difference of Miniopterus fuliginosus and Miniopterus magnater in China and Vietnam
Authors: Li Shi , Sun Keping , Lu Guanjun , Lin Aiqing , Jiang Tinglei , Jin Longru , Hoyt Joseph R. , Feng Jiang
Published: February 2015

Because of its complicated systematics, the bent‐winged bat is one of the most frequently studied bat species groups. In China, two morphologically similar bent‐winged bat species, Miniopterus fuliginosus and Miniopterus magnater were identified, but their distribution range and genetic differentiation are largely unexplored. In this study, we applied DNA bar codes and two other mitochondrial DNA genes including morphological parameters to determine the phylogeny, genetic differentiation, spatial distribution, and morphological difference of the M. fuliginosus and M. magnater sampled from China and one site in Vietnam. Mitochondrial DNA gene genealogies revealed two monophyletic lineages throughout the Tropic of Cancer. According to DNA bar code divergences, one is M. fuliginosus corresponding to the Chinese mainland and the other is M. magnater corresponding to tropical regions including Hainan and Guangdong provinces of China and Vietnam. Their most recent common ancestor was dated to the early stage of the Quaternary glacial period (ca. 2.26 million years ago [Ma] on the basis of D‐loop data, and ca. 1.69–2.37 Ma according to ND2). A population expansion event was inferred for populations of M. fuliginosus at 0.14 Ma. The two species probably arose in separate Pleistocene refugia under different climate zones. They significantly differed in forearm length, maxillary third molar width, and greatest length of the skull.
Ecological differentiation, lack of hybrids involving diploids, and asymmetric gene flow between polyploids in narrow contact zones of Senecio carniolicus (syn. Jacobaea carniolica, Asteraceae)
Authors: Hülber Karl , Sonnleitner Michaela , Suda Jan , Krejčíková Jana , Schönswetter Peter , Schneeweiss Gerald M. , Winkler Manuela
Published: February 2015

Areas of immediate contact of different cytotypes offer a unique opportunity to study evolutionary dynamics within heteroploid species and to assess isolation mechanisms governing coexistence of cytotypes of different ploidy. The degree of reproductive isolation of cytotypes, that is, the frequency of heteroploid crosses and subsequent formation of viable and (partly) fertile hybrids, plays a crucial role for the long‐term integrity of lineages in contact zones. Here, we assessed fine‐scale distribution, spatial clustering, and ecological niches as well as patterns of gene flow in parental and hybrid cytotypes in zones of immediate contact of di‐, tetra‐, and hexaploid Senecio carniolicus (Asteraceae) in the Eastern Alps. Cytotypes were spatially separated also at the investigated microscale; the strongest spatial separation was observed for the fully interfertile tetra‐ and hexaploids. The three main cytotypes showed highly significant niche differences, which were, however, weaker than across their entire distribution ranges in the Eastern Alps. Individuals with intermediate ploidy levels were found neither in the diploid/tetraploid nor in the diploid/hexaploid contact zones indicating strong reproductive barriers. In contrast, pentaploid individuals were frequent in the tetraploid/hexaploid contact zone, albeit limited to a narrow strip in the immediate contact zone of their parental cytotypes. AFLP fingerprinting data revealed introgressive gene flow mediated by pentaploid hybrids from tetra‐ to hexaploid individuals, but not vice versa. The ecological niche of pentaploids differed significantly from that of tetraploids but not from hexaploids.
A Cationic Polyelectrolyte‐Controlled Liquid Mineral Precursor Process in the BaCO3 System
Authors: Zhu Jianhua , Huang Lei , Cui Mingfang , Ma Li , Cao Fabin
Published: February 2015

Biomimetic BaCO3 materials with various morphologies have been synthesized in a cationic polyelectrolyte‐controlled mineral solution. Investigations showed that the mineral solution initially underwent a phase separation to produce a condensed liquidlike amorphous intermediate. This mineral solution was a typical reaction‐diffusion field, in which concentric ring patterns were frequently observed. Subsequently, overgrowth fibers were seen growing on large microspheres and their growth could be interpreted in terms of a mesocrystal self‐assembly process. This work opens up the possibility of using positively charged polyelectrolytes to design a very wide range of inorganic materials.
A General Synthesis of Bis(o‐azaheteroaryl)methane Derivatives from N‐Oxides of Azines and Azoles
Authors: Szpunar Magdalena , Loska Rafał
Published: February 2015

A general method of preparation of derivatives of bis(o‐azaheteroaryl)methanes from aromatic N‐oxides is reported, the key step of which is a 1,3‐dipolar cycloaddition between N‐oxides of azines or azoles and in situ generated terminal difluoroalkenes containing an o‐azaheteroaryl substituent at the double bond. Selected products were applied for the preparation of two novel unsymmetrical analogues of BODIPY fluorescent dyes, containing both an imidazole and a quinoline or isoquinoline unit.
Development of an Automated Heavy Metal Analyser
Authors: Cases‐Utrera Joana , Escudé‐Pujol Roger , Ibáñez‐Otazua Nora , Javier del Campo F.
Published: February 2015

This article describes the design, fabrication and characterization of a compact and deployable heavy metal analyzer. The system is autonomous and its microcontroller enables the configuration of its four micropumps and the application of different electroanalytical techniques. A range of prototyping and manufacturing techniques have been used in the fabrication of the instrument, including laser sintering, milling, and laser engraving. We present the electrochemical characterization of the system, and provide preliminary results obtained in the determination of Cu and Zn in different waters. The only sample treatment consists in its 1 : 2 dilution in pH 5.6 acetate buffer. Detection limits of 2.2 and 3.8 ppb were found for Cu and Zn, respectively.
Lysine, Arginine, and Histidine Residues in Peptide‐Catalyzed Hydrogen Evolution at Mercury Electrodes
Authors: Dorčák Vlastimil , Vargová Veronika , Ostatná Veronika , Paleček Emil
Published: February 2015

Involvement of hexapeptides composed of lysine (Lys6), arginine (Arg6) or histidine (His6) in the catalytic hydrogen evolution reaction (CHER) was studied. Using McIlvaine buffer, we changed the concentration of citric acid (proton donor in the CHER) either (a) by changing the buffer concentration at constant pH or (b) by changing the pH at constant buffer concentration. These two approaches showed almost the same catalytic behavior of Lys6 and Arg6 but strikingly different ones in the case of His6. The results suggested that at neutral pH His residue is much weaker catalyzer than those of Lys or Arg.
Polyparameter linear free energy relationship for wood char–water sorption coefficients of organic sorbates
Authors: Plata Desiree L. , Hemingway Jordon D. , Gschwend Philip M.
Published: February 2015

Black carbons, including soots, chars, activated carbons, and engineered nanocarbons, have different surface properties, but the extent to which these affect their sorbent properties is not known. To evaluate this for an environmentally ubiquitous form of black carbon, biomass char, the surface of a well-studied wood char was probed using 14 sorbates exhibiting diverse functional groups, and the data were fit with a polyparameter linear free energy relationship to assess the importance of the various possible sorbate–char surface interactions. Sorption from water to water–wet char evolved with the sorbate's degree of surface saturation and depended on only a few sorbate parameters: log Kd(L/kg) = [(4.03 ± 0.14) + (–0.15 ± 0.04) log ai] V + [(–0.28 ± 0.04) log ai] S + (–5.20 ± 0.21) B, where ai is the aqueous saturation of the sorbate i, V is McGowan's characteristic volume, S reflects polarity, and B represents the electron-donation basicity. As is generally observed for activated carbon, the sorbate's size encouraged sorption from water to the char, whereas its electron donation and proton acceptance discouraged sorption from water. The magnitude and saturation dependence differed significantly from what has been seen for activated carbons, presumably reflecting the unique surface chemistries of these 2 black carbon materials and suggesting that black carbon-specific sorption coefficients will yield more accurate assessments of contaminant mobility and bioavailability, as well as evaluation of a site's response to remediation. Environ Toxicol Chem 2015;34:1464–1471. © 2015 SETAC
A component framework for the parallel solution of the incompressible Navier–Stokes equations with Radau‐IIA methods
Authors: Rang J. , Niekamp R.
Published: February 2015

An efficient solution strategy for the simulation of incompressible fluids needs adequate and accurate space and time discretization schemes. In this paper, for the space discretization, we use an inf–sup stable finite element method and for the time discretization, Radau‐IIA methods of higher order, which have the advantage that the pressure component has convergence order s in time, where s is the number of internal stages. The disadvantage of this approach is that we have a high computational amount of work, because large nonlinear systems of equations have to solved. In this paper, we use a transformation of the coefficient matrix and the simplified Newton method. This approach has the effect that our large nonlinear systems split into smaller ones, which can now also be solved in parallel. For the parallelization of the code we use the software component technology and the Component Template Library. Numerical examples show that high order in the pressure component can be achieved and that the proposed solution technique is very effective. Copyright © 2015 John Wiley & Sons, Ltd.
Microarray analysis of differentially expressed genes in ovarian and fallopian tube epithelium from risk‐reducing salpingo‐oophorectomies
Authors: Veskimäe Kristina , Staff Synnöve , Tabaro Francesco , Nykter Matti , Isola Jorma , Mäenpää Johanna
Published: February 2015

Mutations in the BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Ovarian cancer risk can be decreased by risk‐reducing salpingo‐oophorectomy (RRSO). Studies on RRSO material have altered the paradigm of serous ovarian cancer pathogenesis. The purpose of this study was to identify candidate genes possibly involved in the pathogenesis of serous ovarian cancer by carrying out a microarray analysis of differentially expressed genes in BRCA1/2‐ mutation positive ovarian and fallopian tube epithelium derived from RRSO surgery. Freshly frozen ovarian and fallopian tube samples from nine BRCA1/2 mutation carriers scheduled for RRSO were prospectively collected together with five mutation‐negative control patients undergoing salpingo‐oophorectomy for benign indications. Microarray analysis of genome‐wide gene expression was performed on ovarian and fallopian tube samples from the BRCA1/2 and control patients. The validation of microarray data was performed by quantitative real‐time polymerase chain reaction (qRT‐PCR) in selected cases of RRSO samples and also in high grade serous carcinoma samples collected from patients with a BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when compared with controls, pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies. © 2015 Wiley Periodicals, Inc.
A novel zinc finger gene, ZNF465, is inappropriately expressed in acute myeloid leukaemia cells
Authors: Collin Joseph F. , Wells James W. , Czepulkowski Barbara , Lyne Linden , Duriez Patrick J. , Banham Alison H. , Mufti Ghulam J. , Guinn Barbara‐ann
Published: February 2015

To increase our knowledge of leukaemia‐associated antigens, especially in acute myeloid leukaemia (AML) M4, we prepared a phage display cDNA library using mRNA from the bone marrow cells of a patient with AML M4 at diagnosis. We immunoscreened 106 pfu with autologous sera and identified an antigen which we named GKT‐AML8. The cDNA showed more than 99% similarity to a sequence on 2q21.2 and 95% sequence similarity to a sequence on 19q13.3. These genes were named ZNF465 and ZNF466, respectively, following HUGO Gene Nomenclature Committee (HGNC) guidelines. Expressed sequence tag data suggests that both genes are transcriptionally active. ZNF465 and ZNF466 encode a 5′ krüppel associated box domain typical of negative regulators of gene transcription. We have confirmed the translational start site in the +1 frame in a near‐Kozak sequence that produces a 102 amino acid polypeptide from ZNF465. The high level of sequence similarity between ZNF465 and ZNF466 makes their transcripts almost indistinguishable by real‐time polymerase chain reaction (RT‐PCR). However, GKT‐AML8 showed most sequence similarity to ZNF465 and no transcript matching the 3′ ZNF466 sequence could be detected in patient samples or healthy volunteers. ZNF465/466 expression was detectable in 12/13 AML and 10/14 chronic myeloid leukaemia patients' samples but not in normal donor peripheral blood (0/8) or 0/3 bone marrow samples which had been separated into CD34+ and CD34− samples. The altered expression of ZNF465/466 in patients' samples and its absence in healthy donor haematopoietic samples indicate that ZNF465 is overexpressed in early myeloid disease and as such may represent a promising target for immunotherapy. © 2015 Wiley Periodicals, Inc.
Ledipasvir/sofosbuvir regimens for chronic hepatitis C infection: Insights from a work productivity economic model from the United States
Authors: Younossi Zobair M. , Jiang Yushan , Smith Nathaniel J. , Stepanova Maria , Beckerman Rachel
Published: February 2015

Patients with chronic hepatitis C (CHC) exhibit reduced work productivity owing to their disease. Historically, most regimens indicated for CHC genotype 1 (GT1) patients were administered with pegylated interferon (Peg‐IFN) and/or ribavirin (RBV), which further compromised work productivity during treatment. The aim of this study was to model the impact of LDV/SOF (ledipasvir/sofosbuvir), the first Peg‐IFN‐ and RBV‐free regimen for CHC GT1 patients, on work productivity from an economic perspective, compared to receiving no treatment. The WPAI‐SHP (Work Productivity and Activity Index–Specific Health Problem) questionnaire was administered to patients across the ION clinical trials (N = 1,923 U.S. patients). Before initiation of treatment, patients with CHC GT1 in the ION trials exhibited absenteeism and presenteeism impairments of 2.57% and 7.58%, respectively. Patients with cirrhosis exhibited greater work productivity impairment than patients without cirrhosis. In total, 93.21% of U.S. patients in the ION trials achieved SVR; these patients exhibited absenteeism and presenteeism impairments of 2.62% (P = 0.76, when compared to baseline) and 3.53% (P < 0.0001), respectively. Monetizing these data to the entire U.S. population, our model projects an annual societal cost of $7.1 billion owing to productivity loss in untreated GT1 CHC patients. Our model projects that, when compared to no treatment, treating all CHC GT1 patients with a regimen with very high viral eradication rates (LDV/SOF) would translate to annual productivity loss savings of $2.7 billion over a 1‐year time horizon. Conclusions: Patients with untreated HCV impose a substantial societal burden owing to reduced work productivity. As a result of improvements in work productivity, treatment of CHC GT1 patients with LDV/SOF‐based regimens is likely to result in significant cost savings from a societal perspective, relative to no treatment. (Hepatology 2015;61:1471–1478)
Modeling Dyadic Processes Using Hidden Markov Models: A Time Series Approach to Mother–Infant Interactions During Infant Immunization
Authors: Stifter Cynthia A. , Rovine Michael
Published: February 2015

The focus of the present longitudinal study, to examine mother–infant interaction during the administration of immunizations at 2 and 6 months of age, used hidden Markov modelling, a time series approach that produces latent states to describe how mothers and infants work together to bring the infant to a soothed state. Results revealed a four‐state model for the dyadic responses to a 2‐month inoculation whereas a six‐state model best described the dyadic process at 6 months. Two of the states at 2 months and three of the states at 6 months suggested a progression from high‐intensity crying to no crying with parents using vestibular and auditory soothing methods. The use of feeding and/or pacifying to soothe the infant characterized one 2‐month state and two 6‐month states. These data indicate that with maturation and experience, the mother–infant dyad is becoming more organized around the soothing interaction. Using hidden Markov modelling to describe individual differences, as well as normative processes, is also presented and discussed. Copyright © 2015 John Wiley & Sons, Ltd.
Utility of free and total target measurements as target engagement and efficacy biomarkers in biotherapeutic development—Opportunities and challenges
Authors: Zheng Songmao , McIntosh Thomas , Wang Weirong
Published: February 2015

For biotherapeutics directed against soluble targets, most often monoclonal antibodies (mAbs), their therapeutic efficacy theoretically is driven by the magnitude and duration of free target suppression. However, for soluble targets of rapid turnover and low abundance, it can be technically challenging to directly measure the lowering of free target following treatment with biologics. The opportunities, challenges, and practical approaches to assess free and bound soluble targets and the utility of free and bound target measurements as biomarkers for target engagement and efficacy are covered in this review. In particular, case examples are presented to illustrate the interplay between drug and free/bound target, and how an integrated bioanalytical and pharmacokinetic/target engagement/pharmacodynamic (PK/TE/PD) modeling approach can be used to assess the target engagement for biologics directed against soluble targets with rapid turnover. Important caveats of the modeling approach in the absence of free target measurements are also discussed.
Challenges and considerations for development of therapeutic proteins in pediatric patients
Authors: Zhang Yi , Wei Xiaohui , Bajaj Gaurav , Barrett Jeffrey S. , Meibohm Bernd , Joshi Amita , Gupta Manish
Published: February 2015

Target specificity and generally good tolerability of therapeutic proteins (TPs) present desirable treatment opportunities for pediatric patients. However, little is known on the ontogeny of processes related to the pharmacokinetics (PK) and disposition of TPs. The science, regulatory requirements and strategy of developing TPs for children are evolving. Our current review of TPs, (with focus on monoclonal antibodies and fusion proteins) that were approved for pediatric use indicates that dose‐selection for pediatric pivotal studies is often based on adult PK information alone. This approach might not be sufficient if more complex PK properties than simple linear PK are present. Body weight‐based dosing for pediatric patients directly scaled down from adult dosing can lead to under‐exposure in young pediatric patients who are usually in the lowest body‐weight range. Tiered‐fixed dosing can be reasonably effective for TPs in achieving comparable exposure in children over a wide age range. The uniqueness of the pediatric population, the practical challenges in conducting clinical studies in this population, as well as regulations from health authorities warrant including pharmacometrics as an integral component of pediatric drug development. We propose a framework distinct from previous proposals, to guide clinical pharmacology strategy for pediatric drug development specifically for TPs.
Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors
Authors: Ruixo Juan Jose Perez , Doshi Sameer , Sohn Winnie , Chow Andrew
Published: February 2015

Denosumab (XGEVA®) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa‐B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal‐related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target‐mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab. In addition, this review further discusses the clinical relevance of patient covariate effects on denosumab systemic exposure, target engagement and downstream pharmacodynamics biomarkers, and the rationale for dosing regimen selection for Phase 3 studies. Phase 3 clinical studies demonstrated that denosumab was superior to zoledronic acid in inhibiting bone resorption and, consequently, delaying the time to first SRE by a median of 8.2 months in patients with bone metastases from solid tumors. Thus, denosumab may be considered a better alternative treatment than zoledronic acid for the prevention of SRE in patients with bone metastases from solid tumors.
Vaccines: A review of immune‐based interventions to prevent and treat disease
Authors: Alemayehu Demissie , Utt Eric , Knirsch Charles
Published: February 2015

The enormous gains made in public health during the 20th century, through the prevention and treatment of infectious disease, have contributed to dramatic improvements in the quality and length of the human lifespan. Continued advances in medicine are dependent on addressing several challenges including the increase in existing and new resistance to antibiotics, the decrease in productivity of the research and development (R&D) ecosystem, uncertain regulatory pathways, and an economic environment that rewards innovation for developing therapeutics that involve long cycle times from idea to a product. In this article, we consider important issues pertaining to the development of vaccines with particular emphasis on preclinical requirements, optimal dose selection, design, execution, and reporting of clinical trials for regulatory submission, planning and implementation of post‐approval life‐cycle programs, and emerging themes in therapeutic vaccines.
Convenient Synthesis of Novel Quinazoline Congeners via Copper Catalyzed C–N/C–S Coupling and Their Biological Evaluation
Authors: Lakum Harshad P. , Shah Dhruvin R. , Chikhalia Kishor H.
Published: February 2015

A library of novel quinazoline scaffolds endowed with semicarbazide/oxadiazole thiol motif synthesized via an efficient and sustainable copper catalyzed C–N/C–S coupling is reported, making the presented methodology extremely valuable from economic and environmental point of view. Among the all synthesized compounds screened for in vitro antibacterial, antifungal, and anti‐TB activity, 7b, 7c, 7f, 9b, 9c, 9i, and 9j showed excellent inhibitory effect on particular strain of bacteria, fungi, and M. tuberculosis H37Rv as well. All the newly synthesized derivatives were well characterized by their IR, 1H NMR, 13C NMR, mass spectroscopy as well as elemental analysis.
4‐hydroxy‐3‐methoxy‐acetophenone‐mediated long‐lasting memory recovery, hippocampal neuroprotection, and reduction of glial cell activation after transient global cerebral ischemia in rats
Authors: Romanini Cássia Valério , Ferreira Emilene Dias Fiuza , Soares Lígia Mendes , Santiago Amanda Nunes , Milani Humberto , de Oliveira Rúbia Maria Weffort
Published: February 2015

4‐Hydroxy‐3‐methoxy‐acetophenone (apocynin) is a naturally occurring methoxy‐substitute catechol that is isolated from the roots of Apocynin cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae). It has been previously shown to have antioxidant and neuroprotective properties in several models of neurodegenerative disease, including cerebral ischemia. The present study investigates the effects of apocynin on transient global cerebral ischemia (TGCI)‐induced retrograde memory deficits in rats. The protective effects of apocynin on neurodegeneration and the glial response to TGCI are also evaluated. Rats received a single intraperitoneal injection of apocynin (5 mg/kg) 30 min before TGCI and were tested 7, 14, and 21 days later in the eight‐arm aversive radial maze (AvRM). After behavioral testing, the hippocampi were removed for histological evaluation. The present results confirm that TGCI causes memory impairment in the AvRM and that apocynin prevents these memory deficits and attenuates hippocampal neuronal death in a sustained way. Apocynin also decreases OX‐42 and glial fibrillary acidic protein immunoreactivity induced by TGCI. These findings support the potential role of apocynin in preventing neurodegeneration and cognitive impairments following TGCI in rats. The long‐term protective effects of apocynin may involve inhibition of the glial response. © 2015 Wiley Periodicals, Inc.
Musculoskeletal simulation can help explain selective muscle degeneration in Duchenne muscular dystrophy
Authors: Hu Xiao , Blemker Silvia S.
Published: February 2015

Duchenne muscular dystrophy (DMD) is a genetic disease that occurs due to the deficiency of the dystrophin protein. Although dystrophin is deficient in all muscles, it is unclear why degeneration progresses differently across muscles in DMD. We hypothesized that each muscle undergoes a different degree of eccentric contraction during gait, which could contribute to the selective degeneration in lower limb muscle, as indicated by various amounts of fatty infiltration. By comparing eccentric contractions quantified from a previous multibody dynamic musculoskeletal gait simulation and fat fractions quantified in a recent imaging study, our preliminary analyses show a strong correlation between eccentric contractions during gait and lower limb muscle fat fractions, supporting our hypothesis. This knowledge is critical for developing safe exercise regimens for the DMD population. This study also provides supportive evidence for using multiscale modeling and simulation of the musculoskeletal system in future DMD research. Muscle Nerve 52: 174–182, 2015
Electromyographic findings in 37 patients with adult‐onset acid maltase deficiency
Authors: Kassardjian Charles D. , Engel Andrew G. , Sorenson Eric J.
Published: February 2015

Introduction: In acid maltase deficiency (AMD), electrical myotonia (EM) may be restricted to paraspinal muscles. A comprehensive description of the electromyographic (EMG) findings in AMD is lacking. The purpose of this study is to describe the EMG features in adult‐onset AMD, focusing on the distribution of EM. Methods: A retrospective chart review of AMD patients diagnosed at Mayo Clinic over age 18 years. Results: Thirty‐seven patients were included. Twenty‐eight (76%) had EM in at least 1 muscle, and EM was more common in paraspinal and proximal limb muscles. The tensor fasciae latae (TFL) was equally sensitive to the paraspinals for EM. Three of 4 patients had EM identified in the diaphragm. Conclusions: Approximately three‐quarters of adult‐onset AMD patients display EM on EMG. The paraspinal muscles and TFL are the most likely to demonstrate EM, and EM can be detected in the diaphragm of adult onset AMD patients. Muscle Nerve, 2015 Muscle Nerve 51:759–761, 2015