bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing a Playground Injury Prevention Plan
Authors: Olsen Heather M. , Hudson Susan D. , Thompson Donna
Published: August 2008

Playgrounds are a major source of unintentional injuries in the school environment. In fact, 80% of all injuries on public playground equipment happen at school. Thus, the need for developing a playground injury prevention plan is critical to provide safe educational outdoor environments for children. The S.A.F.E.™ framework for injury prevention is the first step in preventing playground injuries. This article highlights suggestions that school nurses can implement in creating an effective playground injury prevention program at their schools.
Living as a Chameleon: Girls, Anger, and Mental Health
Authors: van Daalen-Smith Cheryl
Published: August 2008

One’s practice as a school nurse affords numerous privileges. One that stands out in my mind is the privilege of bearing witness to the lives of countless girls as they navigated their own aspirations and the expectations of the culture. The stories they iterated to me in my school nurse office form the basis for this discussion regarding the relationship between anger and mental health. I’ve come to realize that as a school nurse, I was an anger-story listener. In so being, I was given the opportunity and responsibility to influence positive mental health for numerous girls and young women. This feminist qualitative research project explored girls’ lived experiences of anger. The findings suggest that experiences of disrespect, dismissal, denied agency, and a denial of the right to verbalize anger eventually led to self-silencing and an eventual disconnect from this important emotion. The girls described strategies associated with the societal response to their anger that are likened here to the ultra-adaptive strategies that chameleons show to survive.
Are Patient-Administered Attention Deficit Hyperactivity Disorder Scales Suitable for Adults?
Authors: Rogers Edwin S. , Spalding Steven L. , Eckard Alexis A. , Wallace Lorraine S.
Published: August 2008

Objective: This primary purpose of this study was to examine cognitive complexity and readability of patient-administered ADHD scales. The secondary purpose was to estimate variation in readability of individual ADHD scale items. Method: Using comprehensive search strategies, we identified eight English-language ADHD scales for inclusion in our study. A complete copy of each ADHD scale was obtained from the most current publication. Cognitive complexity of individual ADHD scale items were assessed using three techniques (number of items, number of words, and linguistic problems), while readability was calculated using the Flesch-Kinkaid formula. Results: Total number of ADHD scale items ranged from 6 to 66. The ADHD scale items averaged from a low of 4.4±2.9 to a high of 18.7±4.4 words. Most individual ADHD scale items had between 1 to 3 linguistic problems. Although readability of ADHD scales ranged from approximately 5th to 8th grade, there was notable variation in readability across individual statements and questions. Conclusion: Formatting characteristics, including linguistic problems and high readability, may interfere with patients’ ability to accurately complete ADHD scales. (J. of Att. Dis. 2009; 13(2) 168-174)
“The WarGames Scenario”
Authors: Schulte Stephanie Ricker
Published: August 2008

WarGames (1983), the first mass-consumed, visual representation of the internet, served as both a vehicle and framework for America's earliest discussion of the internet. WarGames presented the internet simultaneously as a high-tech toy for teenagers and a weapon for global destruction. In its wake, major news media focused on potential realities of the “ WarGames Scenario.” In response, Congress held hearings, screened WarGames, and produced the first internet-regulating legislation. WarGames engaged a “teenaged technology” discourse, which cast both internet technology itself and its users as rebellious teenagers in need of parental control. This discourse enabled policy makers to equate government internet regulation with parental guidance rather than with suppression of democracy and innovation, a crucial distinction within 1980s cold war context. Thus, this article historicizes the internet as a cultural text, examining how technology and its regulation shaped and were shaped by cultural representations.
Effect of AlCl3, CH3SO3H on thickness, current efficiency and corrosion properties of brush plated Cr(III) formate urea baths
Authors: Saravanan G. , Mohan S. , Gnanamuthu R. M. , Vijayakumar J.
Published: August 2008

Brush plating technique was used to deposit trivalent Cr for the first time and effects of AlCl3 and methane sulphonic acid (CH3SO3H) in the trivalent Cr bath was studied. Advantages of brush plated Cr on suitable substrate produced by selective area deposition process with required thickness was investigated. Owing to its portability, flexibility and easy to operate, brush plating has found increasing use in industry. The main applications are for repair and resizing purposes. Brush plated Cr on brass substrate has been investigated using XRD, SEM and AFM. X-ray diffraction analysis revealed that the brush plated Cr(110) was crystalline. Uniform surface coverage of the substrate by granular morphology was observed from SEM and AFM. CH3SO3H increases the hydrogen overpotential on Cr deposition, therefore current efficiency and thickness increased. Cr coated from bath containing both AlCl3 and CH3SO3H have better corrosion resistance due to high charge transfer resistance R ct and very low I corr than Cr(III) bath without these additives.
Study on nanomechanical and high temperature tribological behaviour of Ti2AlNb based alloys by plasma surface alloying
Authors: Wu H. Y. , Zhang P. Z. , Xu Z.
Published: August 2008

Plasma chromising and carburisation following plasma chromising (duplex treatment) were carried out on the Ti2AlNb based (O phase) alloys by the double glow plasma process. The dynamic ultramicro hardness and elastic modulus of the alloyed layers were investigated by the nano-indentation technique. Dry sliding friction tests on the samples against silicon nitride (Si3N4) balls were completed at high temperature by a ball-on-disc tribometer. The results indicated that the duplex-treated layer was mainly composed of Cr23C6 and Cr2Nb, while the chromised layer was consisted of Al8Cr5 and Cr2Nb phases. The ultramicro hardness of the duplex-treated layer was higher than that of the chromised layer, whereas the elastic modulus of the duplex-treated layer was lower than that of the chromised layer. The wear rates of the duplex-treated layer and the chromised layer were ∼6˙6 and 2˙5 times respectively, lower than that of substrate. The duplex-treated layer exhibited excellent high temperature wear resistance.
Electrophoretic deposition of manganese oxide films
Authors: Cheong M. , Zhitomirsky I.
Published: August 2008

Electrophoretic deposition method has been developed for the fabrication of manganese oxide films for applications in electrochemical supercapacitors. Submicrometre particles of manganese oxide were obtained by reduction of KMnO4 solutions with ethanol. As prepared particles were amorphous and crystallised in a birnessite structure after annealing at 400°C during 1 h. The use of sodium alginate as a dispersant, enabled electrosteric stabilisation of the nanoparticles in aqueous suspensions. It was shown that binding properties and pH dependent charge of alginate enabled electrophoretic deposition of crack free films. The thickness of the films prepared from stable suspensions, containing 1–10 g L−1 manganese oxide, was varied in the range of 2–100 μm by variation in deposition time and applied voltage. The composition of the films can be varied by the variation in suspension composition. Cyclic voltammetry and chronopotentiometry data for the films tested in the 0·1M Na2SO4 solutions showed capacitive behaviour in the voltage window of 0·9 V. The highest specific capacitance of ∼150 F g−1 was obtained at a scan rate of 2 mV s−1. The deposition mechanism, kinetics of deposition and charge storage properties of the films are discussed.
MYC stimulates EZH2 expression by repression of its negative regulator miR-26a
Authors: Sander Sandrine , Bullinger Lars , Klapproth Kay , Fiedler Katja , Kestler Hans A. , Barth Thomas F. E. , Möller Peter , Stilgenbauer Stephan , Pollack Jonathan R. , Wirth Thomas
Published: August 2008

The MYC oncogene, which is commonly mutated/amplified in tumors, represents an important regulator of cell growth because of its ability to induce both proliferation and apoptosis. Recent evidence links MYC to altered miRNA expression, thereby suggesting that MYC-regulated miRNAs might contribute to tumorigenesis. To further analyze the impact of MYC-regulated miRNAs, we investigated a murine lymphoma model harboring the MYC transgene in a Tet-off system to control its expression. Microarray-based miRNA expression profiling revealed both known and novel MYC targets. Among the miRNAs repressed by MYC, we identified the potential tumor suppressor miR-26a, which possessed the ability to attenuate proliferation in MYC-dependent cells. Interestingly, miR-26a was also found to be deregulated in primary human Burkitt lymphoma samples, thereby probably being of clinical relevance. Although today only few miRNA targets have been identified in human disease, we could show that ectopic expression of miR-26a influenced cell cycle progression by targeting the bona fide oncogene EZH2, a Polycomb protein and global regulator of gene expression yet unknown to be regulated by miRNAs. Thus, in addition to directly targeting protein-coding genes, MYC modulates genes important to oncogenesis via deregulation of miRNAs, thereby vitally contributing to MYC-induced lymphomagenesis.
Thalidomide and rituximab in Waldenstrom macroglobulinemia
Authors: Treon Steven P. , Soumerai Jacob D. , Branagan Andrew R. , Hunter Zachary R. , Patterson Christopher J. , Ioakimidis Leukothea , Briccetti Frederick M. , Pasmantier Mark , Zimbler Harvey , Cooper Robert B. , Moore Maria , Hill John , Rauch Alan , Garbo Lawrence , Chu Luis , Chua Cynthia , Nantel Stephen H. , Lovett David R. , Boedeker Hans , Sonneborn Henry , Howard John , Musto Paul , Ciccarelli Bryan T. , Hatjiharissi Evdoxia , Anderson Kenneth C.
Published: August 2008

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m2 per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, ≤ 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www.clinicaltrials.gov as #NCT00142116.
Biologic properties and enucleation of red blood cells from human embryonic stem cells
Authors: Lu Shi-Jiang , Feng Qiang , Park Jennifer S. , Vida Loyda , Lee Bao-Shiang , Strausbauch Michael , Wettstein Peter J. , Honig George R. , Lanza Robert
Published: August 2008

Human erythropoiesis is a complex multistep process that involves the differentiation of early erythroid progenitors to mature erythrocytes. Here we show that it is feasible to differentiate and mature human embryonic stem cells (hESCs) into functional oxygen-carrying erythrocytes on a large scale (1010-1011 cells/6-well plate hESCs). We also show for the first time that the oxygen equilibrium curves of the hESC-derived cells are comparable with normal red blood cells and respond to changes in pH and 2,3-diphosphoglyerate. Although these cells mainly expressed fetal and embryonic globins, they also possessed the capacity to express the adult β-globin chain on further maturation in vitro. Polymerase chain reaction and globin chain specific immunofluorescent analysis showed that the cells increased expression of β-globin (from 0% to > 16%) after in vitro culture. Importantly, the cells underwent multiple maturation events, including a progressive decrease in size, increase in glycophorin A expression, and chromatin and nuclear condensation. This process resulted in extrusion of the pycnotic nuclei in up to more than 60% of the cells generating red blood cells with a diameter of approximately 6 to 8 μm. The results show that it is feasible to differentiate and mature hESCs into functional oxygen-carrying erythrocytes on a large scale.
Transhiatal esophagectomy in a high volume institution
Authors: Davies Andrew R , Forshaw Matthew J , Khan Aadil A , Noorani Alia S , Patel Vanash M , Strauss Dirk C , Mason Robert C
Published: August 2008

Background

The optimal operative approach for carcinoma at the lower esophagus and esophagogastric junction remains controversial. The aim of this study was to assess a single unit experience of transhiatal esophagectomy in an era when the use of systemic oncological therapies has increased dramatically.

Study Design

Between January 2000 and November 2006, 215 consecutive patients (182 males, 33 females, median age = 65 years) underwent transhiatal esophagectomy; invasive malignancy was detected preoperatively in 188 patients. 90 patients (42%) received neoadjuvant chemotherapy. Prospective data was obtained for these patients and cross-referenced with cancer registry survival data.

Results

There were 2 in-hospital deaths (0.9%). Major complications included: respiratory complications in 65 patients (30%), cardiovascular complications in 31 patients (14%) and clinically apparent anastomotic leak in 12 patients (6%). Median length of hospital stay was 14 days. The radicality of resection was inversely related to T stage: an R0 resection was achieved in 98–100% of T0/1 tumors and only 14% of T4 tumors. With a median follow up of 26 months, one and five year survival rates were estimated at 81% and 48% respectively.

Conclusion

Transhiatal esophagectomy is an effective operative approach for tumors of the infracarinal esophagus and the esophagogastric junction. It is associated with low mortality and morbidity and a five survival rate of nearly 50% when combined with neoadjuvant chemotherapy.
Rac regulates the interaction of fascin with protein kinase C in cell migration
Authors: Parsons Maddy , Adams Josephine C.
Published: August 2008

Fascin is an actin-bundling protein that is low or absent in normal epithelia; its upregulation correlates with poor prognosis in many human carcinomas. We have recently demonstrated in mouse xenograft models that fascin contributes to tumour development and metastasis through its dual actin-bundling and active PKC-binding activities. Rac was implicated as a regulator of fascin-dependent colon carcinoma cell migration in vitro. Here, we tested the hypothesis that Rac regulates the interaction of fascin with active PKC. The major conventional PKC in colon carcinoma cells is protein kinase Cγ (PKCγ). Endogenous PKCγ, fascin and Rac1 colocalised at lamellipodial margins of migrating cells. Colocalisation of fascin and PKCγ depended on Rac activity, and inhibition of Rac decreased PKCγ activity in cell extracts but not in vitro. Fluorescence resonance energy transfer/fluorescence lifetime imaging microscopy uncovered that fascin and PKCγ interact in protrusions and filopodia of migrating cells. Mechanistically, the interaction depended on phosphorylated fascin, active PKCγ and active Rac, but not on active Cdc42. The activity of Rac on the fascin/PKC complex was mediated in part by Pak. Elucidation of this novel pathway for regulation of the fascin/PKCγ complex in migrating carcinoma cells suggests novel targets for therapeutic intervention in metastasis.
VRK1 phosphorylates CREB and mediates CCND1 expression
Authors: Kang Tae-Hong , Park Do-Young , Kim Wanil , Kim Kyong-Tai
Published: August 2008

Vaccinia virus B1 kinase plays a key role in viral DNA replication. The homologous mammalian vaccinia-related kinases (VRKs) are also implicated in the regulation of DNA replication, although direct evidence remains elusive. Here we show that VRK1 regulates cell cycle progression in the DNA replication period by inducing cyclin D1 (CCND1) expression. Furthermore, depletion of VRK1 in human cancer cells reduces the fraction of cells in S phase at a given time. VRK1 specifically enhances activity of the cAMP-response element (CRE) in the CCND1 promoter by facilitating the recruitment of phospho-CREB to this locus. VRK1 phosphorylates CREB at Ser133 in vitro and the expression of a kinase-dead mutant of VRK1 or knockdown of VRK1 using siRNA fails to activate CREB and subsequently activate CRE. Finally, we show that VRK1 is a critical link in the CCND1 gene expression pathway stimulated by Myc overexpression. Our results indicate that VRK1 is a novel regulator of CCND1 expression.
Heat shock causes a decrease in polysomes and the appearance of stress granules in trypanosomes independently of eIF2α phosphorylation at Thr169
Authors: Kramer Susanne , Queiroz Rafael , Ellis Louise , Webb Helena , Hoheisel Jörg D. , Clayton Christine , Carrington Mark
Published: August 2008

In trypanosomes there is an almost total reliance on post-transcriptional mechanisms to alter gene expression; here, heat shock was used to investigate the response to an environmental signal. Heat shock rapidly and reversibly induced a decrease in polysome abundance, and the consequent changes in mRNA metabolism were studied. Both heat shock and polysome dissociation were necessary for (1) a reduction in mRNA levels that was more rapid than normal turnover, (2) an increased number of P-body-like granules that contained DHH1, SCD6 and XRNA, (3) the formation of stress granules that remained largely separate from the P-body-like granules and localise to the periphery of the cell and, (4) an increase in the size of a novel focus located at the posterior pole of the cell that contain XRNA, but neither DHH1 nor SCD6. The response differed from mammalian cells in that neither the decrease in polysomes nor stress-granule formation required phosphorylation of eIF2α at the position homologous to that of serine 51 in mammalian eIF2α and in the occurrence of a novel XRNA-focus.
Synapsin-I- and synapsin-II-null mice display an increased age-dependent cognitive impairment
Authors: Corradi Anna , Zanardi Alessio , Giacomini Caterina , Onofri Franco , Valtorta Flavia , Zoli Michele , Benfenati Fabio
Published: August 2008

Synapsin I (SynI) and synapsin II (SynII) are major synaptic vesicle (SV) proteins that function in the regulation of the availability of SVs for release in mature neurons. SynI and SynII show a high level of sequence similarity and share many functions in vivo, although distinct physiological roles for the two proteins have been proposed. Both SynI–/– and SynII–/– mice have a normal lifespan, but exhibit a decreased number of SVs and synaptic depression upon high-frequency stimulation. Because of the role of the synapsin proteins in synaptic organization and plasticity, we studied the long-lasting effects of synapsin deletion on the phenotype of SynI–/– and SynII–/– mice during aging. Both SynI–/– and SynII–/– mice displayed behavioural defects that emerged during aging and involved emotional memory in both mutants, and spatial memory in SynII–/– mice. These abnormalities, which were more pronounced in SynII–/– mice, were associated with neuronal loss and gliosis in the cerebral cortex and hippocampus. The data indicate that SynI and SynII have specific and non-redundant functions, and that synaptic dysfunctions associated with synapsin mutations negatively modulate cognitive performances and neuronal survival during senescence.
Influence of counterface topography on sliding friction and wear of some elastomers under dry sliding conditions
Authors: Mofidi M , Prakash B
Published: August 2008

In this work, the friction and wear behaviour of acrylonitrile butadiene rubber (NBR), hydrogenated acrylonitrile butadiene rubber (HNBR), acrylate rubber (ACM), and fluoroelastomer (FKM) against steel surfaces under unidirectional dry sliding conditions have been studied. The influence of surface roughness of the steel counterface on friction and wear was studied using a block-on-ring test configuration. At low load, the friction coefficient decreased after a running-in period and the wear was insignificant, especially for the ACM and FKM. The running-in time in terms of achieving a stable dry friction for the different elastomers, from longest to shortest, is in the order HNBR, NBR, FKM, and ACM, with an exception in case of FKM sliding against a smooth steel counterface. At higher contact pressure, powdery worn particles on the ACM and a decrease in friction coefficient were observed, but for FKM and HNBR, worn particles with roll shapes were produced. The worn particles of FKM were significantly larger than those of the other tested materials, and a considerably higher wear in FKM was observed.
Verification of a spherical plain bearing finite-element model using scattered light photoelasticity tests
Authors: Germaneau A , Peyruseigt F , Mistou S , Dalverny O , Doumalin P , Dupré J-C
Published: August 2008

Spherical plain bearings are used on many components of Airbus aircrafts like engine-to-pylon and pylon-to-wing links. Their design is based on contact pressure distribution on spherical surfaces. Until now, empirical laws are applied to determine it, and the aim of this work is to develop a numerical modelling in order to validate the use of these laws. The assumptions on the numerical model and their significance have been verified and meas-ured by scattered light photoelasticity (SLP) on an epoxy replica of the bearing. The analysis of this type of bearing is difficult due to its three-dimensional behaviour and its spherical confined contact. The SLP technique allows getting information on stress fields inside an epoxy specimen with the analysis of photoelastic fringes. Comparing photoelastic fringes with simulated results, the finite-element model has been improved to be more representative of the real life bearing. In addition, some critical factors on the bearing behaviour have been obtained.
Nanoscience and nanotechnology: The bottom-up construction of molecular devices and machines
Authors: Balzani Vincenzo
Published: August 2008

The bottom-up approach to miniaturization, which starts from molecules to build up nanostructures, enables the extension of the macroscopic concepts of a device and a machine to molecular level. Molecular-level devices and machines operate via electronic and/or nuclear rearrangements and, like macroscopic devices and machines, need energy to operate and signals to communicate with the operator. Examples of molecular-level photonic wires, plug/socket systems, light-harvesting antennas, artificial muscles, molecular lifts, and light-powered linear and rotary motors are illustrated. The extension of the concepts of a device and a machine to the molecular level is of interest not only for basic research, but also for the growth of nanoscience and the development of nanotechnology.
Chemoselective reactions: Toward the synthesis of biologically active natural products with anticancer activities
Authors: Reymond Sébastien , Ferrié Laurent , Guérinot Amandine , Capdevielle Patrice , Cossy Janine
Published: August 2008

Leucascandrolide A and migrastatin were synthesized efficiently by using chemoselective reactions such as olefin metatheses. The use of an iron-catalyzed cross-coupling reaction overcame difficulties encountered with palladium-catalyzed processes in our synthetic approach toward spirangien A.
Multitarget drugs: Focus on the NO-donor hybrid drugs
Authors: Gasco Alberto , Boschi Donatella , Chegaev Konstantin , Cena Clara , Di Stilo Antonella , Fruttero Roberta , Lazzarato Loretta , Rolando Barbara , Tosco Paolo
Published: August 2008

The article addresses the design of multitarget drugs, namely, compounds capable of interacting with more than one target simultaneously. These agents could be useful tools in the therapy of complex diseases such as cardiovascular and inflammatory diseases. An interesting case of multitarget compounds are nitric oxide (NO)-donor hybrids, structures which combine the physiological properties of NO with those of a lead drug. In particular, the authors discuss the symbiotic approach used to design NO-donor nonsteroidal anti-inflammatory drugs (NO-NSAIDs) and NO-donor antioxidants. The former could be useful agents in the treatment of anti-inflammatory diseases being devoid of gastro- and cardiotoxicity, the latter could be a valid approach to the treatment of many cardiovascular diseases.
Oxidation-responsiveness of nanomaterials for targeting inflammatory reactions
Authors: Khutoryanskiy Vitaliy V. , Tirelli Nicola
Published: August 2008

Oxidation is an almost ubiquitous feature of inflammatory reactions. We discuss the development of nanocarriers that respond to the presence of oxidants with profound physical reorganization, which could in perspective allow their use for delivering anti-inflammatory principles in an inflammation-responsive fashion. We also present a study demonstrating that the response of polysulfide nanoparticles has a bulk character, i.e., the odixation reactions happen homogeneously throughout the nanoparticles, and not interfacially.
Synthesis of substituted conjugated polymers: Tuning properties by functionalization
Authors: Farinola Gianluca M. , Babudri Francesco , Cardone Antonio , Hassan Omar Omar , Naso Francesco
Published: August 2008

The review addresses features of special interest concerning two classes of functionalized semiconducting polymers: poly(aryleneethynylene)s (PAEs) bearing biomolecules as chiral nonracemic pendant groups and poly(phenylenevinylene)s (PPVs), which are fluorinated in various positions of the repeating units. Molecular design and choice of specific substituents, synthetic protocols, and the effect of functionalization on properties of the polymers both in solution and in the solid state are discussed.
Total synthesis of cytotoxic marine macrolides: Callipeltoside A, aurisides A and B, and dolastatin 19
Authors: Paterson Ian , Findlay Alison D.
Published: August 2008

Synthetic studies pertaining to a novel class of structurally related glycosidic 14-membered macrolides of marine origin are reported. The evolution of a versatile aldol-based strategy that culminated in the total syntheses of callipeltoside A and aurisides A and B is detailed. Using a combination of biogenetic considerations and conformational analysis, a revised stereochemical assignment for the related polyketide dolastatin 19 was proposed and validated by total synthesis.
Discovery of leishmanicidal agents from medicinal plants
Authors: Atta-ur-Rahman  , Samreen  , Atia-tul-Wahab  , Choudhary M. Iqbal
Published: August 2008

Antileishmanial activity of several classes of natural compounds was evaluated by using an in vitro parasitic assay model. This has led to the discovery of new antileishmanial agents with potential to be useful in the treatment of visceral and cutaneous leishmaniasis.
Chemical wizardry? The generation of diversity in terpenoid biosynthesis
Authors: Allemann Rudolf K.
Published: August 2008

Terpene synthases catalyze the conversion of linear prenyl-diphosphates to a multitude of hydrocarbon skeletons with often high regio- and stereoselectivity. These remarkable enzymes all rely on a shared fold for activity, namely, the class I terpene cyclase fold. Recent work has illuminated the catalytic strategy used by these enzymes to catalyze the arguably most complex chemical reactions found in Nature. Terpene synthases catalyze the formation of a reactive carbocation and provide a template for the cyclization reactions while at the same time providing the necessary stability of the carbocationic reaction intermediates as well as strictly controlling water access.
Catalytic metallodrugs
Authors: Cowan James A.
Published: August 2008

Drug discovery remains a top priority in medical science. The phenomenon of drug resistance has heightened the need for both new classes of pharmaceutical, as well as novel modes of action. A new paradigm for drug activity is presented, which includes both recognition and subsequent irreversible inactivation of therapeutic targets. Application to both RNA and enzyme therapeutic targets has been demonstrated, while incorporation of both binding and catalytic centers provides a double-filter mechanism for improved target selectivity and lower dosing. In contrast to RNA targets that are subject to strand scission chemistry mediated by ribose H-atom abstraction, proteins appear to be inactivated through oxidative damage to amino acid side chains around the enzyme active site. Methods to monitor both intracellular delivery and activity against RNA targets have been developed based on plasmid expression of the green fluorescent protein (GFP). Herein, the activity of representative metallodrugs is described in the context of both in vitro and cellular assays, and the mechanism of action is discussed. Studies with scavengers of reactive oxygen species (ROS) confirmed hydrogen peroxide to be an obligatory diffusible intermediate, prior to formation of a Cu-bound hydroxyl radical species generated from Fenton-type chemistry.
Adenine-based calcium signal pathway messengers: Synthesis and agonistic properties of cyclic ADP-ribose analogs
Authors: Zhang Liangren , Yang Zhenjun , Guse Andreas H. , Zhang Lihe
Published: August 2008

A series of cyclic ADP-ribose (cADPR) analogs, in which modifications mainly focused on riboses, was synthesized in order to explore the molecular mechanism of calcium release regulated by cADPR. Biological activities investigated in intact T-lymphocytes showed that the structurally simplified analogs, N1-ethoxymethyl-substituted cyclic inosine diphosphoribose (cIDPRE), N1,N9-diethoxymethyl-substituted cyclic inosine diphosphoribose (cIDPDE), and N1-ethoxymethyl-substituted cyclic adenosine diphosphoribose (cADPRE) in which the northern ribose or both northern and southern riboses were replaced by ether linkages are membrane-permeant and induce calcium release from intracellular stores. This research has provided novel molecules to probe cADPR-mediated calcium signaling and enlarges our knowledge of the structure-activity relationships of cADPR analogs.
On the role of aromatic-sugar interactions in the molecular recognition of carbohydrates: A 3D view by using NMR
Authors: Díaz M. Dolores , Fernández-Alonso María del Carmen , Cuevas Gabriel , Cañada F. Javier , Jiménez-Barbero Jesús
Published: August 2008

This revision describes an up-to-date review of our efforts to investigate the interaction of carbohydrates with aromatic moieties at different levels of complexity. Protein-sugar interactions have been studied using NMR experiments on a variety of hevein/chitooligosaccharide systems. In addition, NMR and computational methods have also been used to evaluate the interaction of simple aromatic entities with simple monosaccharides. In between, the stacking features of aromatic-containing glycomolecules have also been described by using an analogous experimental-theoretical approach.
Antibody-catalyzed water-oxidation pathway
Authors: Wentworth Paul , Witter Daniel P.
Published: August 2008

The intrinsic ability of all antibodies to generate hydrogen peroxide (H2O2) from singlet dioxygen (1O2*) via the antibody-catalyzed water-oxidation pathway (ACWOP) has triggered a rethink of the potential role of antibodies both in immune defense, inflammation, and disease. It has been shown that photochemical activation of this pathway is highly bactericidal. More recently, cholesterol oxidation by-products that may arise from the ACWOP have been discovered in vivo and are receiving a great deal of attention as possible key players in atherosclerosis and diseases of protein misfolding, such as Alzheimer's disease and Parkinson's disease.
Bisphosphonate Therapy Ameliorates Hearing Loss in Mice Lacking Osteoprotegerin
Authors: Kanzaki Sho , Takada Yasunari , Ogawa Kaoru , Matsuo Koichi
Published: August 2008

Three auditory ossicles including the malleus, incus, and stapes conduct sound in the middle ear from the tympanic membrane to the inner ear. Auditory ossicles are massively resorbed by osteoclasts in Opg−/− mice, which lack osteoprotegerin (OPG), a soluble decoy receptor for the osteoclastogenic cytokine RANKL. Opg−/− mice exhibit progressive hearing loss and are a model for juvenile Paget's disease. However, effects of antiresorptive treatment on auditory ossicles and on hearing function in Opg−/− mice are unknown. We intraperitoneally injected Opg−/− mice with bisphosphonate risedronate 5 d/wk for 9 wk. Morphology of auditory ossicles was examined microscopically, radiographically, and histologically. Hearing function was monitored by measuring the auditory brain stem response (ABR). Control Opg−/− mice exhibited thinning of all three ossicles and tibia. In contrast, risedronate treatment significantly inhibited bone loss in auditory ossicles as well as in long bones of Opg−/− mice. Bony fusion of the junction between the stapes and the otic capsule was reduced after treatment. Moreover, ABR measurement showed that hearing in Opg−/− mice was significantly improved by risedronate treatment. These data suggest that hearing loss in pathologies characterized by excessive resorption of the auditory ossicles may be prevented by bisphosphonates.
Successful Skeletal Aging: A Marker of Low Fracture Risk and Longevity. The Study of Osteoporotic Fractures (SOF)
Authors: Cauley Jane A , Lui Li-Yung , Barnes Deborah , Ensrud Kristine E , Zmuda Joseph M , Hillier Teresa A , Hochberg Marc C , Schwartz Ann V , Yaffe Kristine , Cummings Steven R , Newman Anne B
Published: August 2008

Successful aging is multidimensional, and many phenotypes have been proposed. We examined a biomarker of aging based on repeated measures of BMD for up to 15 yr and hypothesized that maintenance of BMD will be associated with low fracture risk and disability and improved survival. We studied 9704 women recruited at four U.S. clinical centers and enrolled in the Study of Osteoporotic Fractures, a longitudinal cohort study. Of these, 8224 women had at least one hip BMD measurement. Hip BMD was measured a maximum of five times over 15 yr. Random effects regression was used to determine a BMD slope for each subject. Three groups were formed—“maintained” BMD: slope ≥0, n = 724 (9%); “expected” BMD loss: slope <0 to <1 SD below mean, n = 6478 (79%); and “accelerated” BMD loss: slope ≥1 SD below mean, n = 1022 (12%). Cox proportional hazards models were used to compare the relative hazard (RH; 95% CI) of fracture, incident mobility disability, and mortality in the maintained and accelerated groups compared with the expected. A 1 SD decrease in the BMD slope was associated with an increased risk of all outcomes. In multivariate models, the RH of nonspine fracture was 0.81 (0.71–0.93) and of hip fracture was 0.36 (0.25–0.53) for women in the maintained compared with the expected group. The incidence of mobility disability was lower in the maintained versus expected group (RH = 0.70; 95% CI = 0.59–0.83), but this was largely explained by other factors. Women who experienced accelerated bone loss were more likely to develop disability (RH = 1.56; 95% CI: 1.33–1.84). Mortality risks were lower in the maintained compared with the expected group (RH = 0.49; 95% CI: 0.42–0.58). In conclusion, a subset of older women maintained their BMD up to 15 yr, suggesting that bone loss is not an inevitable consequence of aging. These women experienced a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging.
Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Is Associated With Spinal BMD in 9-Year-Old Children
Authors: Steer Colin D , Emmett Pauline M , Lewis Sarah J , Smith George Davey , Tobias Jon H
Published: August 2008

The C677T MTHFR polymorphism has been associated with lumbar spine and hip BMD. In older adults, the genetic effect has been reported in women only. However, in younger adults, this influence may only be present in men. This study is the first to investigate associations between the C677T MTHFR polymorphism and bone phenotypes in children. Regression analyses were used to study the relationship between MTHFR genotype and bone phenotypes derived from total body DXA scans in children 9.9 yr of age from the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 5816 children had both genetic and DXA data for the total body less head region (TBLH) and 3196 for the spine. A strong association was observed between the C677T MTHFR genotype and spine BMD (p < 0.001; 0.10 SD decrease per T allele). There was some evidence that this genetic effect was stronger in boys compared with girls (p = 0.04 for sex interaction). In contrast, there was no association between the C677T MTHFR genotype and TBLH BMD. The association between MTHFR genotype and spine BMD was attenuated particularly in girls by high maternal dietary intakes of vitamin B6 and folate during pregnancy but not by child dietary intakes at 7 yr. To the extent that these findings reflect known influences of C677T MTHFR genotype on plasma homocysteine levels, our results suggest that the latter is an important regulator of spinal BMD in childhood.
Functional Characterization of Genetic Variation in the Frizzled 1 (FZD1) Promoter and Association With Bone Phenotypes: More to the LRP5 Story?
Authors: Yerges Laura M , Zhang Yingze , Cauley Jane A , Kammerer Candace M , Nestlerode Cara S , Wheeler Victor W , Patrick Alan L , Bunker Clareann H , Moffett Susan P , Ferrell Robert E , Zmuda Joseph M
Published: August 2008

WNT signaling is an important determinant of bone formation. The WNT co-receptor, Frizzled homolog 1 (FZD1), initiates WNT signal transduction. To study the influence of FZD1 genetic variation on measures of bone health, we first sequenced a 6.8-kb region surrounding FZD1 in 48 samples of African ancestry. We genotyped all common polymorphisms and performed association analysis with bone phenotypes in a larger sample. Only 3 of 35 SNPs identified were present in ≥5% of the sample and assayed further in 1084 men of African ancestry. Two of these SNPs were in the FZD1 promoter (rs2232157, rs2232158) and were associated with femoral neck areal BMD (p = 0.041 and 0.009, respectively). The minor alleles of these two SNPs were also associated with larger bone size at the radius (p < 0.05 for both), and rs2232158 was associated with greater strength-strain index, an indicator of bone's ability to withstand torsion. Functional experiments were completed to assess the influence of the rs2232158 promoter polymorphism on transcriptional regulation of FZD1. The minor C allele in rs2232158 creates a binding site for the transcription factor Egr1, has higher Egr1 binding affinity, and has greater FZD1 promoter activity in MG63 and SaOS-2 cells, providing a plausible molecular mechanism for the population associations. This study indicates that a cis-regulatory polymorphism in the FZD1 promoter region may have a functional role in determining bone structural geometry.
Diaminobutane (DAB) Dendrimers Are Potent Binders of Oral Phosphate
Authors: Williams Katie B , Barycka Katarzyna , Zella Julia B , DeLuca Hector F
Published: August 2008

Reduction of blood phosphorus is a critical component in the management of secondary hyperparathyroidism in chronic kidney disease patients. In addition to dialysis treatment and dietary phosphorus restriction, oral phosphate binders are often consumed with meals to reduce the availability of food phosphorus. Several oral phosphate binders are approved for use in chronic kidney disease patients, but all have practical limitations because of toxicity, poor efficacy, or high cost. Using an in vivo method to measure intestinal phosphate absorption in rats using radiolabeled phosphate, we found that first-, second-, third-, and fifth-generation diaminobutane dendrimer compounds, DAB-4-Cl, DAB-8-Cl, DAB-16-Cl, and DAB-64-Cl, respectively, drastically reduce the absorption of inorganic phosphate in a dose-dependent manner. To avoid complications of metabolic acidosis caused by hydrochloride salts, an acetate salt, DAB-9-AcOH, was prepared and shown to be equally effective at binding radiolabeled phosphate as DAB-8-Cl. DAB-8-AcOH was further shown to increase fecal phosphorus and decrease serum phosphorus in a dose-dependent manner when fed to rats. These data suggest that dendrimer compounds are of great potential use in the binding of food phosphate for the management of hyperparathyroidism secondary to chronic kidney disease.
Knock-In Mice Lacking the PDZ-Ligand Motif of mGluR7a Show Impaired PKC-Dependent Autoinhibition of Glutamate Release, Spatial Working Memory Deficits, and Increased Susceptibility to Pentylenetetrazol
Authors: Zhang Chuan-Sheng , Bertaso Federica , Eulenburg Volker , Lerner-Natoli Mireille , Herin Greta Ann , Bauer Liane , Bockaert Joel , Fagni Laurent , Betz Heinrich , Scheschonka Astrid
Published: August 2008

The metabotropic glutamate receptor 7 (mGluR7) is widely expressed throughout the brain and primarily localized at presynaptic active zones, where it is thought to regulate neurotransmitter release. Protein interacting with C kinase 1 (PICK1), a postsynaptic density protein-95/disc-large tumor suppressor protein/zonula occludens-1 (PDZ)-domain protein, binds to the three C-terminal amino acids (-LVI) of the predominant mGluR7 splice variant, mGluR7a, and has been implicated in the synaptic clustering of this receptor. Here, we generated knock-in mice in which the C-terminal LVI coding sequence of exon 10 of the mGluR7 gene was replaced by three alanine codons (-AAA). Immunoprecipitation showed that the PICK1–mGluR7a interaction is disrupted inmGluR7aAAA/AAAmice. However, the synaptic localization of mGluR7a was not altered in cultured hippocampal neurons and brain sections prepared from the knock-in animals. In cerebellar granule cell cultures, the group III mGluR agonistl-AP-4 decreased the frequency of spontaneous excitatory currents in neurons derived from wild-type but notmGluR7aAAA/AAAmice, consistent with the interaction between mGluR7a and PICK1 being required for protein kinase C-mediated inhibition of glutamate release. At the behavioral level, themGluR7aAAA/AAAmice showed no deficits in motor coordination, pain sensitivity, and anxiety but exhibited significant defects in hippocampus-dependent spatial working memory. In addition, they displayed a high susceptibility to the convulsant drug pentylenetetrazole. Together, these results indicate that PICK1 binding to the C-terminal region of mGluR7a is crucial for agonist-triggered presynaptic signalingin vivo.
Downregulation of DendriticIhin CA1 Pyramidal Neurons after LTP
Authors: Campanac Emilie , Daoudal Gaël , Ankri Norbert , Debanne Dominique
Published: August 2008

Hyperpolarization-activated (h)-channels occupy a central position in dendritic function. Although it has been demonstrated that these channels are upregulated after large depolarizations to reduce dendritic excitation, it is not clear whether they also support other forms of long-term plasticity. We show here that nearly maximal long-term potentiation (LTP) induced by theta-burst pairing produced upregulation in h-channel activity in CA1 pyramidal neurons. In contrast, moderate LTP induced by spike-timing-dependent plasticity or high-frequency stimulation (HFS) downregulated the h-current (Ih) in the dendrites. After HFS-induced LTP, the h-conductance (Gh) was reduced without changing its activation. Pharmacological blockade ofIhhad no effect on LTP induction, but occluded EPSP-to-spike potentiation, an input-specific facilitation of dendritic integration. Dynamic-clamp reduction ofGhlocally in the dendrite mimicked the effects of HFS and enhanced synaptic integration in an input-selective way. We conclude that dendriticIhis locally downregulated after induction of nonmaximal LTP, thus facilitating integration of the potentiated input.
Dissociable Roles for Cortical and Subcortical Structures in Memory Retrieval and Acquisition
Authors: Mitchell Anna S. , Browning Philip G. F. , Wilson Charles R. E. , Baxter Mark G. , Gaffan David
Published: August 2008

The relationship between anterograde and retrograde amnesia remains unclear. Previous data from both clinical neuropsychology and monkey lesion studies suggest that damage to discrete subcortical structures leads to a relatively greater degree of anterograde than retrograde amnesia, whereas damage to discrete regions of cortex leads to the opposite pattern of impairments. Nevertheless, damage to the medial diencephalon in humans is associated with both retrograde and anterograde amnesia. In the present study, we sought to reconcile this by assessing retention as well as subsequent relearning and new postoperative learning. Rhesus monkeys learned 300 unique scene discriminations preoperatively, and retention was assessed in a preoperative and postoperative one-trial retrieval test. Combined bilateral subcortical lesions to the magnocellular mediodorsal thalamus and fornix impaired postoperative retention of the preoperatively acquired information. In addition, subsequent relearning and new postoperative learning were also impaired. This contrasts with the effects of a discrete lesion to just one of these structures, after which retention is intact in both cases. Discrete bilateral ablations to the entorhinal cortex impaired retention but had no effect on new learning. Combined with previous work from our laboratory, these results support the hypothesis that subcortical damage has a relatively greater effect on new learning, and cortical damage has a relatively greater effect on retention. Furthermore, the results demonstrate that retrograde amnesia occurs as a result of subcortical damage only if it is widespread, leading to an extensive disruption of cortical functioning. Damage of this nature may account for dense amnesia.