bluuebunny/crossref_metadata_2025 huggingface dataset:
A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets
Authors: Uitdehaag Joost CM , Verkaar Folkert , Alwan Husam , de Man Jos , Buijsman Rogier C , Zaman Guido JR
Published: January 2012

To establish the druggability of a target, genetic validation needs to be supplemented with pharmacological validation. Pharmacological studies, especially in the kinase field, are hampered by the fact that many reference inhibitors are not fully selective for one target. Fortunately, the initial trickle of selective inhibitors released in the public domain has steadily swelled into a stream. However, rationally picking the most selective tool compound out of the increasing amounts of available inhibitors has become progressively difficult due to the lack of accurate quantitative descriptors of drug selectivity. A recently published approach, termed ‘selectivity entropy’, is an improved way of expressing selectivity as a single‐value parameter and enables rank ordering of inhibitors. We provide a guide to select the best tool compounds for pharmacological validation experiments of candidate drug targets using selectivity entropy. In addition, we recommend which inhibitors to use for studying the biology of the 20 most investigated kinases that are clinically relevant: Abl (ABL1), AKT1, ALK, Aurora A/B, CDKs, MET, CSF1R (FMS), EGFR, FLT3, ERBB2 (HER2), IKBKB (IKK2), JAK2/3, JNK1/2/3 (MAPK8/9/10), MEK1/2, PLK1, PI3Ks, p38α (MAPK14), BRAF, SRC and VEGFR2 (KDR).
Fasitibant chloride, a kinin B2 receptor antagonist, and dexamethasone interact to inhibit carrageenan‐induced inflammatory arthritis in rats
Authors: Valenti Claudio , Giuliani Sandro , Cialdai Cecilia , Tramontana Manuela , Maggi Carlo Alberto
Published: January 2012

BACKGROUND AND PURPOSE Bradykinin, through the kinin B2 receptor, is involved in inflammatory processes related to arthropathies. B2 receptor antagonists inhibited carrageenan‐induced arthritis in rats in synergy with anti‐inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated.

EXPERIMENTAL APPROACH Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra‐articular administration of carrageenan. Their effects on the carrageenan‐induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL‐1β, IL‐6 and the chemokine GRO/CINC‐1), were assessed after 6 h.

KEY RESULTS The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des‐Arg9‐[Leu8]‐bradykinin (B2 receptor, leukotriene, catecholamine and B1 receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des‐Arg9‐[Leu8]‐bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des‐Arg9‐[Leu8]‐bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment.

CONCLUSIONS AND IMPLICATIONS Bradykinin‐mediated inflammatory responses to intra‐articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B2 receptor, or through the indirect effects mediated by release of eicosanoids and cytokines.
Pharmacological dissection of Kv7.1 channels in systemic and pulmonary arteries
Authors: Chadha Preet S , Zunke Friederike , Davis Alison J , Jepps Thomas A , Linders Joannes TM , Schwake Michael , Towart Rob , Greenwood Iain A
Published: January 2012

BACKGROUND AND PURPOSE The aim of this study was to characterize the functional impact of KCNQ1‐encoded voltage‐dependent potassium channels (Kv7.1) in the vasculature.

EXPERIMENTAL APPROACH Mesenteric arteries, intrapulmonary arteries and thoracic aortae were isolated from adult rats. Kv7.1 channel expression was established by fluorescence immunocytochemistry. Wire myography determined functionality of these channels in response to selective blockers and activators. Xenopus oocytes expressing Kv7.1 channels were used to assess the effectiveness of selective Kv7.1 channel blockers.

KEY RESULTS Kv7.1 channels were identified in arterial myocytes by immunocytochemistry. Kv7.1 blockers HMR1556, L‐768,673 (10 µM) and JNJ39490282 (JNJ282; 1 µM) had no contractile effects in arteries, whereas the pan‐Kv7 channel blocker linopirdine (10 µM) evoked robust contractions. Application of two compounds purported to activate Kv7.1 channels, L‐364 373 (R‐L3) and mefenamic acid, relaxed mesenteric arteries preconstricted by methoxamine. These responses were reversed by HMR1556 or L‐768,673 but not JNJ282. Similar effects were observed in the thoracic aorta and intrapulmonary arteries.

CONCLUSIONS AND IMPLICATIONS In contrast to previous assumptions, Kv7.1 channels expressed in arterial myocytes are functional ion channels. Although these channels do not appear to contribute to resting vascular tone, Kv7.1 activators were effective vasorelaxants.
Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model
Authors: Tiller Heidi , Killie Mette Kjaer , Chen Pingguo , Eksteen Mariana , Husebekk Anne , Skogen Bjorn , Kjeldsen‐Kragh Jens , Ni Heyu
Published: January 2012

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA‐1a might therefore be preventable by a prophylactic regimen of inducing antibody‐mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof‐of‐concept study investigated whether passive administration of anti‐β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT.

STUDY DESIGN AND METHODS: A murine model of FNAIT using β3 integrin (GPIIIa)‐deficient (β3−/−) mice was employed for this study. AMIS in β3−/− mice was induced by intravenous administration of human anti‐HPA‐1a immunoglobulin G or murine anti‐β3 antisera given as prophylaxis after transfusion of HPA‐1a–positive human PLTs or murine wild‐type PLTs, respectively.

RESULTS: AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose‐dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead‐born pups in mice receiving high‐dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight.

CONCLUSION: This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.
Riding the Wave: World Trade and Factor‐Based Models of Democratization
Authors: Ahlquist John S. , Wibbels Erik
Published: January 2012

Studies of “waves” of regime change, in which large numbers of countries experience similar political transitions at roughly similar periods of time, though once popular, have fallen from favor. Replacing the “third wave” arguments are several competing models relating domestic social structure—specifically, the distribution of income and factor ownership—to regime type. If any of these distributive models of regime type is correct, then global trade has an important explanatory role to play. Under factor‐based models, changes in the world trading system will have systematic effects on regime dynamics. Trade openness determines labor's factor income and ultimately its political power. As world trade expands and contracts, countries with similar labor endowments should experience similar regime pressures at the same time. We propose a novel empirical specification that addresses the endogeneity and data‐quality problems plaguing previous efforts to examine these arguments. We investigate the conditional impact of the global trading system on democratic transitions across 130 years and all of the states in the international system. Our findings cast doubt on the utility of factor‐based models of democratization, despite their importance in fueling renewed interest in the topic.
The Role of Silica Layer on Sintering Kinetics of Silicon Powder Compact
Authors: Lebrun Jean‐Marie , Pascal Céline , Missiaen Jean‐Michel
Published: January 2012

Sintering of fine silicon powder was studied using thermogravimetric experiments associated with dilatometry. The reduction of the silica layer at the particle surface is consistent with a kinetic model taking into account the powder oxygen content, the partial pressure of oxidizing species, and the pore morphology of the sintered material. The presence of silica at the particle surface inhibits coarsening and promotes densification of the powder compact, which is confirmed by kinetic calculations.
Lung Sound Patterns Help to Distinguish Congestive Heart Failure, Chronic Obstructive Pulmonary Disease, and Asthma Exacerbations
Authors: Wang Zhen , Xiong Ying Xia
Published: January 2012

ACADEMIC EMERGENCY MEDICINE 2012; 19:79–84 © 2012 by the Society for Academic Emergency Medicine

Objectives:  Although congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and asthma patients typically present with abnormal auscultatory findings on lung examination, respiratory sounds are not normally subjected to rigorous analysis. The aim of this study was to evaluate in detail the distribution of respiratory sound intensity in CHF, COPD, and asthma patients during acute exacerbation.

Methods:  Respiratory sounds throughout the respiratory cycle were captured and displayed using an acoustic‐based imaging technique. Breath sound distribution was mapped to create a gray‐scale sequence of two‐dimensional images based on intensity of sound (vibration). Consecutive CHF (n = 22), COPD (n = 19), and asthma (n = 18) patients were imaged at the time of presentation to the emergency department (ED). Twenty healthy subjects were also enrolled as a comparison group. Geographical area of the images and respiratory sound patterns were quantitatively analyzed.

Results:  In healthy volunteers and COPD patients, the median (interquartile range [IQR]) geographical areas of the vibration energy images were similar, at 75.6 (IQR = 6.0) and 75.8 (IQR = 10.8) kilopixels, respectively (p > 0.05). Compared to healthy volunteers and COPD patients, areas for CHF and asthma patients were smaller, at 66.9 (IQR = 9.9) and 53.9 (IQR = 15.6) kilopixels, respectively (p < 0.05). The geographic area ratios between the left and right lungs for healthy volunteers and CHF and COPD patients were 1.0 (IQR = 0.2), 1.0 (IQR = 0.2), and 1.0 (IQR = 0.1), respectively. Compared to healthy volunteers, the geographic area ratio between the left and right lungs for asthma patients was 0.5 (IQR = 0.4; p < 0.05). In healthy volunteers and CHF patients, the ratios of vibration energy values at peak inspiration and expiration (peak I/E ratio) were 4.6 (IQR = 4.4) and 4.7 (IQR = 3.5). In marked contrast, the peak I/E ratios of COPD and asthma patients were 3.4 (= 2.1) and 0.1 (IQR = 0.3; p < 0.05), respectively.

Conclusions:  The pilot data generated in this study support the concept that relative differences in respiratory sound intensity may be useful in distinguishing acute dyspnea caused by CHF, COPD, or asthma.
Material attrition and bone micromorphology after conventional and ultrasonic implant site preparation
Authors: Rashad Ashkan , Sadr‐Eshkevari Pooyan , Weuster Markus , Schmitz Inge , Prochnow Nora , Maurer Peter
Published: January 2012

Objectives

Little is known about the recently introduced ultrasonic implant site preparation. The purpose of this study was to compare material attrition and micromorphological changes after ultrasonic and conventional implant site preparations.

Material and methods

Implant site preparations were performed on fresh bovine ribs using one conventional (Straumann, Freiburg, Germany) and two ultrasonic (Piezosurgery®; Mectron Medical Technology, Carasco, Italy and Variosurg®; NSK, Tochigi, Japan) systems with sufficient saline irrigation. Sections were examined by environmental scanning electron microscopy (ESEM). Energy‐dispersive X‐ray spectroscopy (EDX) was performed to evaluate the metal attrition within the bone and the irrigation fluid.

Results

ESEM: After conventional osteotomy, partially destroyed trabecular structures of the cancellous bone that were loaded with debris were observed, whereas after ultrasonic implant site preparations, the anatomic structures were preserved. EDX: None of the implant site preparation methods resulted in metal deposits in the adjacent bone structures. However, within the irrigation liquid, there was significantly higher metal attrition with ultrasonic osteotomy (P < 0.0001 and P < 0.0001 for Mectron and NSK, respectively). Whereas for Straumann system used, 15.5% of the SEM/EDX findings were drill‐origin metals, this percentage increased to 37.3% and 37.9% with the application of Mectron and NSK, respectively.

Conclusions

Ultrasonic implant site preparation is associated with the preservation of bone microarchitecture and with the increased attrition of metal particles. Therefore, copious irrigation seems to be even more essential for ultrasonic implant site preparation than for the conventional method.
Comparison of microRNA expression using different preservation methods of matched psoriatic skin samples
Authors: Løvendorf Marianne B. , Zibert John R. , Hagedorn Peter H. , Glue Christian , Ødum Niels , Røpke Mads A. , Skov Lone
Published: January 2012

Abstract:  MicroRNAs are non‐coding RNA molecules modulating gene expression post‐transcriptionally. Formalin‐fixed, paraffin‐embedding (FFPE) is a standard preservation method often used in clinical practices, but induces RNA degradation. Extracting high‐quality RNA from human skin can be challenging as skin contains high levels of RNases. As microRNAs are 19‐23 nucleotides long and lack a poly‐A tail, they may be less prone to RNA degradation than mRNAs. We investigated whether microRNAs in psoriatic (FFPE) samples reliably reflect microRNA expression in samples less prone to RNA degradation such as fresh‐frozen (FS) and Tissue‐Tek‐embedding (OCT). We found a strong correlation of the microRNA expression levels between all preservation methods of matched psoriatic skin samples (rs ranging from 0.91 to 0.95 (P < 0.001)). These observations were further confirmed with qRT‐PCR. Our results demonstrate that microRNA detection in human skin is robust irrespective of preservation method; thus, microRNAs offer an appropriate and flexible approach in clinical practices and for diagnostic purposes in skin disorders.
Structural Basis of High‐Affinity Nuclear Localization Signal Interactions with Importin‐α
Authors: Marfori Mary , Lonhienne Thierry G. , Forwood Jade K. , Kobe Bostjan
Published: January 2012

Classical nuclear localization signals (cNLSs), comprising one (monopartite cNLSs) or two clusters of basic residues connected by a 10–12 residue linker (bipartite cNLSs), are recognized by the nuclear import factor importin‐α. The cNLSs bind along a concave groove on importin‐α; however, specificity determinants of cNLSs remain poorly understood. We present a structural and interaction analysis study of importin‐α binding to both designed and naturally occurring high‐affinity cNLS‐like sequences; the peptide inhibitors Bimax1 and Bimax2, and cNLS peptides of cap‐binding protein 80. Our data suggest that cNLSs and cNLS‐like sequences can achieve high affinity through maximizing interactions at the importin‐α minor site, and by taking advantage of multiple linker region interactions. Our study defines an extended set of binding cavities on the importin‐α surface, and also expands on recent observations that longer linker sequences are allowed, and that long‐range electrostatic complementarity can contribute to cNLS‐binding affinity. Altogether, our study explains the molecular and structural basis of the results of a number of recent studies, including systematic mutagenesis and peptide library approaches, and provides an improved level of understanding on the specificity determinants of a cNLS. Our results have implications for identifying cNLSs in novel proteins.
Fixed Implant‐Retained Rehabilitation of the Edentulous Maxilla: 11‐Year Results of a Prospective Study
Authors: Mertens Christian , Steveling Helmut G. , Stucke Kathrin , Pretzl Bernadette , Meyer‐Bäumer Amelie
Published: January 2012

Objectives:The aim of the present study was to assess long‐term survival and success rates of implants in the edentulous maxilla restored with an implant‐supported fixed prosthesis.

Materials and Methods:Seventeen edentulous patients received six to eight implants and implant‐supported fixed prostheses by one surgeon. Yearly recalls were conducted by two examiners over a period of 11 years. Survival and success rates (biological complications) were determined; marginal bone loss was examined radiographically. Furthermore, microbiological tests as well as test for interleukin‐1 composite genotype were assessed and potential risk factors were evaluated.

Results:After a mean time of 11.26 years, 15 patients of 17 could be reexamined. Out of 94 implants, three were lost in one patient. Mean marginal bone loss reached 0.88 mm, two patients (at seven implants) showed bone loss of ≥3.2 mm. Survival rate of implants reached 96.8%. Success rates on implant level hit 92.6% according to the criteria of Albrektsson and colleagues and 83.0% in accordance with Karoussis and colleagues. One prosthesis had to be renewed.

Conclusion:Within the limitation of this study, restoration of the edentulous maxilla with an implant‐supported fixed prosthesis represents an effective tool for rehabilitation over a period of 11 years.
Conventional Multi‐Slice Computed Tomography (CT) and Cone‐Beam CT (CBCT) for Computer‐Assisted Implant Placement. Part I: Relationship of Radiographic Gray Density and Implant Stability
Authors: Arisan Volkan , Karabuda Zihni Cüneyt , Avsever Hakan , Özdemir Tayfun
Published: January 2012

Purpose: The relationship of conventional multi‐slice computed tomography (CT)‐ and cone beam CT (CBCT)‐based gray density values and the primary stability parameters of implants that were placed by stereolithographic surgical guides were analyzed in this study.

Materials and Methods: Eighteen edentulous jaws were randomly scanned by a CT (CT group) or a CBCT scanner (CBCT group) and radiographic gray density was measured from the planned implants. A total of 108 implants were placed, and primary stability parameters were measured by insertion torque value (ITV) and resonance frequency analysis (RFA). Radiographic and subjective bone quality classification (BQC) was also classified. Results were analyzed by correlation tests and multiple regressions (p < .05).

Results: CBCT‐based gray density values (765 ± 97.32 voxel value) outside the implants were significantly higher than those of CT‐based values (668.4 ± 110 Hounsfield unit, p < .001). Significant relations were found among the gray density values outside the implants, ITV (adjusted r2 = 0.6142, p = .001 and adjusted r2 = 0.5166, p = .0021), and RFA (adjusted r2 = 0.5642, p = .0017 and adjusted r2 = 0.5423, p = .0031 for CT and CBCT groups, respectively). Data from radiographic and subjective BQC were also in agreement.

Conclusions: Similar to the gray density values of CT, that of CBCT could also be predictive for the subjective BQC and primary implant stability. Results should be confirmed on different CBCT scanners.
Role of α‐synuclein penetration into the membrane in the mechanisms of oligomer pore formation
Authors: Tsigelny Igor F. , Sharikov Yuriy , Wrasidlo Wolfgang , Gonzalez Tania , Desplats Paula A. , Crews Leslie , Spencer Brian , Masliah Eliezer
Published: January 2012

Parkinson’s disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α‐synuclein (α‐syn) in the central nervous system. Aggregation of α‐syn into oligomers with a ring‐like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms and the potential sequence of events involved in the formation of pore‐like structures are unclear. We utilized computer modeling and cell‐based studies to investigate the process of oligomerization of wild‐type and A53T mutant α‐syn in membranes. The studies suggest that α‐syn penetrates the membrane rapidly, changing its conformation from α‐helical towards a coiled structure. This penetration facilitates the incorporation of additional α‐syn monomers in the complex, and the subsequent displacement of phospholipids and the formation of oligomers in the membrane. This process occurred more rapidly, and with a more favorable energy of interaction, for mutant A53T compared with wild‐type α‐syn. After 4 ns of simulation of the protein–membrane model, α‐syn had penetrated through two‐thirds of the membrane. By 9 ns, the penetration of the annular α‐syn oligomers can result in the formation of pore‐like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant α‐syn in synthetic membranes resulted in the formation of similar pore‐like complexes. Moreover, mutant (A53T) α‐syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures, resulting in greater neuronal permeability, as demonstrated with the calcein efflux assay. These studies provide a sequential molecular explanation for the process of α‐syn oligomerization in the membrane, and support the role of formation of pore‐like structures in the pathogenesis of the neurodegenerative process in PD.
Evolutionarily conserved protein arginine methyltransferases in non‐mammalian animal systems
Authors: Wang Yi‐Chun , Li Chuan
Published: January 2012

Protein arginine methylation is catalyzed by members of the protein arginine methyltransferase (PRMT) family. In the present review, nine PRMTs identified in mammals (human) were used as templates to survey homologous PRMTs in 10 animal species with a completed sequence available in non‐mammalian vertebrates, invertebrate chordates, echinoderms, arthropods, nematodes and cnidarians. We show the conservation of the most typical type I PRMT1 and type II PRMT5 in all of the species examined, the wide yet different distribution of PRMT3, 4 and 7 in non‐mammalian animals, the vertebrate‐restricted distribution of PRMT8 and the special reptile/avian‐deficient distribution of PRMT2 and 6. We summarize the basic functions of each PRMT and focus on the current investigations of PRMTs in the non‐mammalian animal models, including Xenopus, fish (zebrafish, flounder and medaka), Drosophila and Caenorhabditis elegans. Studies in the model systems not only complement the understanding of the functions of PRMTs in mammals, but also provide valuable information about their evolution, as well as their critical roles and interplays.
A non‐cold‐inducible cold shock protein homolog mainly contributes to translational control under optimal growth conditions
Authors: Tanaka Toshiko , Mega Ryosuke , Kim Kwang , Shinkai Akeo , Masui Ryoji , Kuramitsu Seiki , Nakagawa Noriko
Published: January 2012

Cold shock proteins (Csps) include both cold‐induced and non‐cold‐induced proteins, contrary to their name. Cold‐induced Csps are well studied; they function in cold acclimation by controlling transcription and translation. Some Csps have been reported to contribute to other cellular processes. However, the functions of non‐cold‐induced Csps under optimal growth conditions remain unknown. To elucidate these functions, we used transcriptome and proteome analyses as comprehensive approaches and have compared the outputs of wild‐type and non‐cold‐induced Csp‐deletion mutant cells. As a model organism, we selected Thermus thermophilus HB8 because it has only two csp genes (ttcsp1 and ttcsp2); ttCsp1 is the only non‐cold‐induced Csp. Surprisingly, the amount of transcripts and proteins upon deletion of the ttcsp1 gene was quite different. DNA microarray analysis revealed that the deletion of ttcsp1 did not affect the amount of transcripts, although the ttcsp1 gene was constantly expressed in the wild‐type cell. Nonetheless, proteomic analysis revealed that the expression levels of many proteins were significantly altered when ttcsp1 was deleted. These results suggest that ttCsp1 functions in translation independent of transcription. Furthermore, ttCsp1 is involved in both the stimulation and inhibition of translation of specific proteins. Here, we have determined the crystal structure of ttCsp1 at 1.65 Å. This is the first report to present the structure of a non‐cold‐inducible cold shock protein. We also report the nucleotide binding affinity of ttCsp1. Finally, we discuss the functions of non‐cold‐induced Csps and propose how they modulate the levels of specific proteins to suit the prevailing environmental conditions.

Database

Structural data are available in the Protein Data Bank databases under the accession number 3A0J
Review article: Part two: Goal‐directed resuscitation – Which goals? Perfusion targets
Authors: Holley Anthony , Lukin William , Paratz Jennifer , Hawkins Tracey , Boots Robert , Lipman Jeffrey
Published: January 2012

Haemodynamic targets, such as cardiac output, mean arterial blood pressure and central venous oxygen saturations, remain crude predictors of tissue perfusion and oxygen supply at a cellular level. Shocked patients may appear adequately resuscitated based on normalization of global vital signs, yet they are still experiencing occult hypoperfusion. If targeted resuscitation is employed, appropriate use of end‐points is critical. In this review, we consider the value of directing resuscitation at the microcirculation or cellular level. Current technologies available include sublingual capnometry, video microscopy of the microcirculation and near‐infrared spectroscopy providing a measure of tissue oxygenation, whereas base deficit and lactate potentially provide a surrogate measure of the adequacy of global perfusion. The methodology and evidence for these technologies guiding resuscitation are considered in this narrative review.
Review article: Part one: Goal‐directed resuscitation – Which goals? Haemodynamic targets
Authors: Holley Anthony , Lukin William , Paratz Jennifer , Hawkins Tracey , Boots Robert , Lipman Jeffrey
Published: January 2012

Part 2: Goal Directed Resuscitation – Which Goals? Perfusion Targets will follow in the next issue.

The use of appropriate resuscitation targets or end‐points may facilitate early detection and appropriate management of shock. There is a fine balance between oxygen delivery and consumption, and when this is perturbed, an oxygen debt is generated. In this narrative review, we explore the value of global haemodynamic resuscitation end‐points, including pulse rate, blood pressure, central venous pressure and mixed/central venous oxygen saturations. The evidence supporting the reliability of these parameters as end‐points for guiding resuscitation and their potential limitations are evaluated.
Separating Test Artifacts from Material Behavior in the Oxidation Studies of HfB2–SiC at 2000°C and Above
Authors: Carney Carmen M. , Parthasarathy Triplicane A. , Cinibulk Michael K.
Published: January 2012

Oxidation characteristics of HfB2‐15 vol% SiC prepared by field‐assisted sintering was examined at 2000°C by heating it in a zirconia‐resistance furnace and by direct electrical resistance heating of the sample. Limitations of the material and the direct electrical resistance heating apparatus were explored by heating samples multiple times and to temperatures in excess of 2300°C. Oxide scales that developed at 2000°C from both methods were similar in that they consisted of a SiO2/HfO2 outer layer, a porous HfO2 layer, and a HfB2 layer depleted of SiC. But they differed in scale thicknesses, impurities present, scale morphology/complexity. Possible test artifacts are discussed.
Microstructure and Wear Behavior of Plasma‐Sprayed Nanostructured WC–Co Coatings
Authors: Di Girolamo Giovanni , Marra Francesco , Pilloni L. , Pulci Giovanni , Tirillò Jacopo , Valente Teodoro
Published: January 2012

Atmospheric plasma spraying of WC–Co particles with standard gas mixtures (Ar–H2) typically results in largely decarburized coatings with relatively low wear resistance. To fabricate cermet coatings with enhanced tribological properties, nanostructured WC–Co coatings were plasma sprayed using two different process gas mixtures. Phase composition and microstructure were investigated by X‐ray diffraction and scanning electron microscopy, respectively. Microhardness increased by increasing the amount of retained WC grains in coating microstructure. Friction and wear properties, measured under dry sliding conditions, strongly depended on the degree of decarburization. They were comparable to those of conventional coatings produced using identical conditions.
Facile Synthesis of Characteristic Tin Oxide Particulate Films in Aqueous Solution
Authors: Masuda, Yoshitake , Ohji Tatsuki , Kato Kazumi
Published: January 2012

Characteristic tin oxide films were formed on transparent conductive substrates in aqueous solutions. Surface of the films consisted of ellipse‐shaped particles. Particle size in longer or shorter direction was about 300–400 or 200 nm, respectively. In contrast, middle and bottom area of the films were dense structures. Thickness was about 1150 nm. The film was single phase SnO2 with a‐axis orientation. The films had chemical ratio of O/Sn = 1.20–1.37 and F/Sn = 0.088–0.124, suggesting fluorine doping. Facile synthesis of tin oxide particulate films had advantages in ordinary temperature synthesis, water solvent process, and low‐environmental load.
Fabrication and Electrochemical Characterization of Anode‐Supported Microtubular Solid Oxide Fuel Cells Based on Ce0.8Sm0.2O2‐δ Electrolytes
Authors: Xiao Jin , Sun Wenping , Tao Zetian , Zhu Zhiwen , Liu Wei
Published: January 2012

Anode‐supported microtubular solid oxide fuel cells (SOFCs) based on Ce0.8Sm0.2O2‐δ (SDC) electrolytes were prepared using phase inversion and vacuum‐assisted coating techniques. With La0.6Sr0.4Co0.2Fe0.8O3‐δ‐Ce0.8Sm0.2O2‐δ (LSCF‐SDC) as a cathode, the maximum power densities of the cell reached 38, 104, and 168 mW/cm2 at 500°C, 550°C, and 600°C, respectively; and the corresponding open‐circuit voltages (OCVs) were 0.74, 0.73, and 0.71 V. Furthermore, the OCVs could be significantly improved by way of brush painting a BaZr0.1Ce0.8Y0.1O3‐δ‐Ce0.8Sm0.2O2‐δ (BZCY‐SDC) layer on the SDC electrolyte membrane, achieving 0.81, 0.80, and 0.76 V at 500°C, 550°C, and 600°C, respectively.
Emergent Impacts of Ant and Spider Interactions: Herbivory Reduction in a Tropical Savanna Tree
Authors: Nahas Larissa , Gonzaga Marcelo O. , Del‐Claro Kleber
Published: January 2012

Multiple predators often have effects on their common prey populations that cannot be predicted by summing the effects of each predator at a time. When predators forage on the same vegetation substrate, intraguild interactions might cause emergent outcomes for the plants on which the predators co‐occur. We experimentally evaluated the effects of spiders and ants on herbivory and reproduction in the extrafloral nectary‐bearing tree Qualea multiflora (Vochysiaceae). Plants were divided in four experimental groups, depending on the presence or absence of ants and spiders. We compared the effects of each treatment on richness and abundance of chewing and sucking herbivores and on herbivory (leaf area loss). We also evaluated the impact of predators on the production of buds, fruits and seeds, and weight of the fruits. The presence of ants reduced the abundance and richness of spiders, but spiders did not affect the abundance and richness of ants. Only the removal of ants resulted in a significant increase in the abundance of herbivores and herbivore richness. Herbivory, however, was also affected by spiders. In addition, we found a significant interaction effect of ants and spiders on herbivory, indicating an emergent multiple predator effect. Neither ants nor spiders had an impact on the number of buds produced, number of fruits per bud, and seeds per fruits or fruit weight. This study highlights the importance of evaluating the effect of the predator fauna as a whole and not only one specific group on herbivory.
Overview of Regular Dialysis Treatment in Japan (as of 31 December 2009)
Authors: Nakai Shigeru , Iseki Kunitoshi , Itami Noritomo , Ogata Satoshi , Kazama Junichiro James , Kimata Naoki , Shigematsu Takashi , Shinoda Toshio , Shoji Tetsuo , Suzuki Kazuyuki , Taniguchi Masatomo , Tsuchida Kenji , Nakamoto Hidetomo , Nishi Hiroshi , Hashimoto Seiji , Hasegawa Takeshi , Hanafusa Norio , Hamano Takayuki , Fujii Naohiko , Masakane Ikuto , Marubayashi Seiji , Morita Osamu , Yamagata Kunihiro , Wakai Kenji , Wada Atsushi , Watanabe Yuzo , Tsubakihara Yoshiharu
Published: January 2012

A nationwide statistical survey of 4196 dialysis facilities was conducted at the end of 2009, and 4133 facilities (98.5%) responded. The number of patients undergoing dialysis at the end of 2009 was determined to be 290 661, an increase of 7240 patients (2.6%) compared with that of 2008. The number of dialysis patients per million at the end of 2009 was 2279.5. The crude death rate of dialysis patients from the end of 2008 to the end of 2009 was 9.6%. The mean age of the new patients introduced into dialysis was 67.3 years old and the mean age of the entire dialysis patient population was 65.8 years old. Primary diseases such as diabetic nephropathy and chronic glomerulonephritis for new dialysis patients, showed a percentage of 44.5% and 21.9%, respectively. Based on the facilities surveyed, 84.2% of the facilities that responded to the questionnaire satisfied the microbiological quality standard for dialysis fluids for the Japanese Society for Dialysis Therapy (JSDT), with an endotoxin concentration of less than 0.05 EU/mL in the dialysis fluid. Similarly, 98.2% of the facilities surveyed satisfied another standard of the society of a bacterial count of less than 100 cfu/mL in the dialysis fluid. The facility survey indicated that the number of patients who were treated by blood purification by both peritoneal dialysis and extracorporeal circulation, such as hemodialysis, was 1720. Among the total number of patients, 24.8% were satisfied with the management target recommended in the treatment guidelines for secondary hyperparathyroidism. These standards are set by the JSDT, based on the three parameters, i.e. serum calcium concentration, serum phosphorus concentration, and serum intact parathyroid hormone concentration. According to the questionnaire, 9.8% of the patients were considered to have a complication of dementia.
Understanding the Physical Interactions in the FGF21/FGFR/β‐Klotho Complex: Structural Requirements and Implications in FGF21 Signaling
Authors: Yie Junming , Wang Wei , Deng Liying , Tam Lei‐Ting , Stevens Jennitte , Chen Michelle M. , Li Yang , Xu Jing , Lindberg Richard , Hecht Randy , Véniant Murielle , Chen Ching , Wang Minghan
Published: January 2012

The endocrine fibroblast growth factor 21 (FGF21) requires both fibroblast growth factor receptor (FGFR) and β‐Klotho for signaling. In this study, we sought to understand the inter‐molecular physical interactions in the FGF21/FGFR/β‐Klotho complex by deleting key regions in FGFR1c or FGF21. Deletion of the D1 and the D1‐D2 linker (the D1/linker region) from FGFR1c led to β‐Klotho‐independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region‐deficient FGFR1c. Consistent with this, the extracellular portion of FGFR1c lacking the D1/linker region blocked FGF21 action in a reporter assay, presumably by binding to and sequestering FGF21 from acting on cell surface receptor complex. In addition, the D1/linker region‐deficient FGFR1c had enhanced interaction with β‐Klotho. Further, we demonstrated that deletion of the D1/linker region enhanced the formation of the FGF21/β‐Klotho/FGFR1c ternary complex in both Biacore and asymmetrical flow field flow fractionation studies. Finally, we found that the N‐terminus of FGF21 is involved in the interaction with FGFR1c and FGF21/β‐Klotho/FGFR1c ternary complex formation. Taken together, our data suggest that the D1/linker region regulates both the FGF21/FGFR1c and FGFR1c/β‐Klotho interaction, and a direct interaction of FGF21 with FGFR1c may be an important step in receptor‐mediated FGF21 signaling.
When partnerships don't ‘match‐up’: an evaluation of labour–management partnerships in the automotive components and civil aviation industries
Authors: Evans Claire , Harvey Geraint , Turnbull Peter
Published: January 2012

Following the agenda for partnership research set out recently in this journal, ‘exemplar’ case studies from the automotive and civil aviation industries are subject to the litmus (process) test of academic pluralists and the acid (outcomes) test of academic radicals. On both tests, the results have been disappointing, especially for trade unions and their members. However, while mutual gains from partnership agreements are not probable in a UK context, they are still possible, as comparative research in the civil aviation sector serves to illustrate.
Effects of Koji Fermented Phenolic Compounds on the Oxidative Stability of Fish Miso
Authors: Giri Anupam , Osako Kazufumi , Okamoto Akira , Okazaki Emiko , Ohshima Toshiaki
Published: January 2012

Abstract:  In the present study, Aspergillus oryzae‐inoculated koji inhibited lipid oxidation in fermented fish paste rich in polyunsaturated fatty acids following a long fermentation period. The fermentation of koji by A. oryzae liberated several bioactive phenolic compounds, including kojic acid and ferulic acid, which were the most abundant. A linear correlation between several phenolic compounds and their bioactive properties, including their radical‐scavenging activity, reducing power, metal‐chelating activity, and ability to inhibit linoleic acid oxidation was observed. This suggested an important role of koji phenolics in the oxidative stability of fermented fish paste. The activities of different carbohydrate‐cleaving enzymes, including α‐amylase, cellulase, and β‐glucosidase, were positively correlated with the liberation of several phenolic compounds through koji fermentation. Thus, the application of koji offers a novel strategy to enhance the oxidative stability of newly developed fermented fish miso.

Practical Application:  Application of traditional Japanese koji fermentation technique to develop an aroma enriched fish meat bases seasoning has been established. Aspergillus oryzae‐inoculated koji releases several carbohydrate‐cleaving enzymes, including α‐amylase, cellulose, and β‐glucosidase, which led to the liberation of several phenolic compounds during fermentation. Improvement of oxidative stability of the fermented fish meat paste by koji phenolics suggests a useful strategy to uplift the value of different trash fish meat‐based seasoning through proper utilization of the present technique.
Uptake of Divalent Ions (Mn+2 and Ca+2) by Heat‐Set Whey Protein Gels
Authors: Oztop Mecit H. , McCarthy Kathryn L. , McCarthy Michael J. , Rosenberg Moshe
Published: January 2012

Abstract:  Divalent salts are used commonly for gelation of polymer molecules. Calcium, Ca+2, is one of the most common divalent ions that is used in whey protein gels. Manganese, Mn+2, is also divalent, but paramagnetic, enhancing relaxation decay rates in magnetic resonance imaging (MRI) and can be used as a probe to understand the behavior of Ca+2 in whey protein gels. The objective of this study was to investigate the diffusion of Ca+2 and Mn+2 ions in heat‐set whey protein gels by using MRI and nuclear magnetic resonance (NMR) relaxometry. Whey protein gels were immersed in solutions containing MnCl2 and CaCl2 at neutral pH. Images obtained with gels immersed in MnCl2 solution revealed a relaxation sink region in the gel's surface and the thickness of the region increased with time. These “no signal” regions in the MR images were attributed to uptake of Mn+2 by the gel. Results obtained with CaCl2 solution indicated that since Ca+2 did not have the paramagnetic effect, the regions where Ca+2 diffused into the gel exhibited a slight decrease in signal intensity. The relaxation spectrums exhibited 3 populations of protons, for gels immersed in MnCl2 solution, and 2 populations for gels in CaCl2 solution. No significant change in T2 distributions was observed for the gels immersed in CaCl2 solution. The results demonstrated that MRI and NMR relaxometry can be used to understand the diffusion of ions into the whey protein gel, which is useful for designing gels of different physical properties for controlled release applications.

Practical Application:  Design of food systems for delivery of bioactive compounds requires knowledge of diffusion rates and structure. Utilizing magnetic resonance imaging the diffusion rates of ions can be measured. Relaxation spectra could yield information concerning molecular interactions.
Structure and Dynamics of the Excited States of 1,3‐Diarylisobenzofurans: An Experimental and Theoretical Study
Authors: Jacq Jérôme , Tsekhanovich Svetlana , Orio Maylis , Einhorn Cathy , Einhorn Jacques , Bessières Bernard , Chauvin Jérôme , Jouvenot Damien , Loiseau Frédérique
Published: January 2012

The emission properties of a series of substituted 1,3‐diarylisobenzofurans have been studied. Most compounds exhibit very intense emission in the nanosecond timescale at room temperature as well as at 77 K. The room temperature emission is attributed to the deactivation of a twisted intramolecular charge transfer excited state, based on its energy, shape and solvent dependence. The experimental results are strongly supported by a theoretical study on one representative compound. The DFT/TD‐DFT calculations demonstrate that the initial excited state relaxes toward a twisted structure.
Whig Ballads and the Past Passive Jacobite
Authors: HAROL CORRINNE
Published: January 2012

This essay analyses the representation of Jacobitism in ballads about the Hanoverian succession crisis. Focusing on three aspects of Jacobite culture – passive obedience, typological history and the representation of the Stuart heir – it argues that Jacobites and ballads were mutually constructed as nostalgic. The essay thus explores the production of Jacobitism as nostalgic, and the implications of that production, arguing that this formulation was contemporaneous with Jacobitism, that it served both sides and that it contributed to Jacobitism as a modern, rather than an archaic, political identity.
English‐Language Newspapers in Revolutionary France
Authors: MACDONALD SIMON
Published: January 2012

This article examines a series of English‐language newspaper ventures produced in revolutionary France and largely aimed at export to Britain. These enterprises, chief among which was the Paris Mercury (1792), sought to profit from heightened British interest in French events by dispatching ready‐printed newspapers directly from Paris, thus achieving news priority over the domestic British press. New French press freedoms also enabled claims to be made about the superior editorial qualities of such extraterritorial newspapers. This article reconstructs these newspapers' publication history, reviews their contents, discusses their commercial and political rationale and their precursors, and offers explanations for their failure.
The effects of young children's affiliations with prosocial peers on subsequent emotionality in peer interactions
Authors: Fabes Richard A. , Hanish Laura D. , Martin Carol Lynn , Moss Alicia , Reesing Amy
Published: January 2012

Preschoolers’ (60 boys and 64 girls, M age = 50.73 months) affiliations with prosocial peers were observed in naturally occurring interactions and then examined in relation to positive and negative emotionality within their peer interactions one semester later. Greater affiliation with prosocial peers in the fall was related to enhanced positive emotionality (especially for girls) and decreased negative emotionality (especially for boys) in later peer interactions. These findings held when initial levels of the emotion were controlled and were found above and beyond variations in classroom levels of prosociality. The findings suggest that peers exert influence in early childhood and that these effects can positively affect the quality of young children's later peer interactions.
Spontaneous cluster activity in the inferior olivary nucleus in brainstem slices from postnatal mice
Authors: Rekling Jens C. , Jensen Kristian H. R. , Jahnsen Henrik
Published: January 2012

Key points 

The cerebellum is organized in modules, where groups of neurons in the inferior olivary nucleus (IO) are connected to elongated bands of Purkinje neurons in the cerebellar cortex; it is still largely unknown what the specific function of these modules is, and how they are formed.

Here we show that IO neurons spontaneously generate clusters of co‐active neurons in in vitro brain slice preparations from newborn mice, in an age window ranging from birth to two weeks old.

Intracellular recordings revealed that electrical coupling between neighbouring IO neurons may contribute to the synchronization.

The dorsomedial cell column, which is a subregion in the IO involved in the control of balance and posture, showed a high frequency of regular repeating clusters compared to the rest of the IO, suggesting that this system may be on a fast developmental track.

These results increase our understanding of how the circuitry of the cerebellar system develops in the early postnatal period, where animals acquire the ability to produce finely controlled motor acts.
Differential expression and function of nicotinic acetylcholine receptors in the urinary bladder epithelium of the rat
Authors: Beckel Jonathan M. , Birder Lori A.
Published: January 2012

Key points 

It has been previously shown that stimulation of urothelial nicotinic acetylcholine receptors (nAChRs) can alter reflex bladder activity in the rat; the current study examines this further.

Stimulation of rat urothelial cells with an α7 nAChR agonist increases intracellular calcium through internal stores and decreases basal ATP release.

Stimulation with an α3* nAChR agonist increases intracellular calcium through extracellular influx and increases basal ATP release.

Infusion of an α3* agonist into the bladder lumen of the rat increases reflex bladder activity, which is blocked by intra‐arterial administration of a purinergic antagonist.

The cellular effects of α3* stimulation are blocked when the cells are pretreated with an α7 agonist, suggesting cross‐talk between the receptors: this cross‐talk may be mediated through protein kinase A or protein kinase C.