bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower-limb growth: How predictable are predictions?
Authors: Kelly Paula M. , Diméglio Alain
Published: August 2008

Purpose

The purpose of this review is to clarify the different methods of predictions for growth of the lower limb and to propose a simplified method to calculate the final limb deficit and the correct timing of epiphysiodesis.

Background

Lower-limb growth is characterized by four different periods: antenatal growth (exponential); birth to 5 years (rapid growth); 5 years to puberty (stable growth); and puberty, which is the final growth spurt characterized by a rapid acceleration phase lasting 1 year followed by a more gradual deceleration phase lasting 1.5 years. The younger the child, the less precise is the prediction. Repeating measurements can increase the accuracy of predictions and those calculated at the beginning of puberty are the most accurate. The challenge is to reduce the margin of uncertainty. Confrontation of the different parameters—bone age, Tanner signs, annual growth velocity of the standing height, sub-ischial length and sitting height—is the most accurate method. Charts and diagrams are only models and templates. There are many mathematical equations in the literature; we must be able to step back from these rigid calculations because they are a false guarantee. The dynamic of growth needs a flexible approach. There are, however, some rules of thumb that may be helpful for different clinical scenarios.

Calculation of limb length discrepancy

For congenital malformations, at birth the limb length discrepancy must be multiplied by 5 to give the final limb length discrepancy. Multiple by 3 at 1 year of age; by 2 at 3 years in girls and 4 years in boys; by 1.5 at 7 years in girls and boys, by 1.2 at 9 years in girls and 11 years in boys and by 1.1 at the onset of puberty (11 years bone age for girls and 13 years bone age for boys).

Timing of epiphysiodesis

For the timing of epiphysiodesis, several simple principles must be observed to reduce the margin of error; strict and repeated measurements, rigorous analysis of the data obtained, perfect evaluation of bone age with elbow plus hand radiographs and confirmation with Tanner signs. The decision should always be taken at the beginning of puberty. A simple rule is that, at the beginning of puberty, there is an average of 5 cm growth remaining at the knee. There are four common different scenarios: (1) A 5-cm discrepancy—epiphysiodesis of both femur and tibia at the beginning of puberty (11 years bone age girls and 13 years in boys). (2) A 4-cm discrepancy—epiphysiodesis of femur and tibia 6 months after the onset of puberty (11 years 6 months bone age girls, 13 years 6 months bone age boys, tri-radiate cartilage open). (3) A 3-cm discrepancy—epiphysiodesis of femur only at the start of puberty, (skeletal age of 11 years in girls and 13 years in boys). (4) A 2-cm discrepancy—epiphysiodesis of femur only, 1 year after the start of puberty (12 years bone age girls and 14 years in boys).
Sucrose in the diet of 3-year-old Finnish children: sources, determinants and impact on food and nutrient intake
Authors: Erkkola Maijaliisa , Kronberg-Kippilä Carina , Kyttälä Pipsa , Lehtisalo Jenni , Reinivuo Heli , Tapanainen Heli , Veijola Riitta , Knip Mikael , Ovaskainen Marja-Leena , Virtanen Suvi M.
Published: August 2008

The aim was to identify the important sources of added sucrose and determinants of high intake, and to evaluate what impact a high proportion of energy from added sucrose has on the intake of foods and nutrients. The subjects consisted of children invited to the nutrition study within the Type 1 Diabetes Prediction and Prevention birth cohort and born in 2001 (n846). Of these, 471 returned 3 d food records at 3 years of age. The average daily intake of added sucrose was 35 (sd17) g (11·3 % of energy intake) and that of total sucrose was 41 (sd18) g (13·3 % of energy intake). Sucrose added by manufacturers accounted for 82 %, naturally occurring sucrose for 15 % and sucrose added by consumers for 3 % of the total sucrose. Juice drinks, yoghurt/cultured milks, and chocolate and confectionery were the main contributors to added sucrose intake. Consumption of rye bread, porridge, fresh vegetables, cooked potatoes, skimmed milk, hard cheeses, margarine and fat spread as well as intake of most nutrients decreased across the quartiles of added sucrose (P < 0·05). Being cared for at home, having a father with a vocational school degree, having at least two siblings and a milk-restricted diet increased the risk for a high-sucrose diet. The study implied that a high proportion of added sucrose in the diet had mainly an unfavourable impact on the intake of recommended foods and key nutrients in Finnish children. The rationale for the recommendation to reduce the intake of refined sugars to ensure adequate intakes of nutrients seems reasonable.
Stress, coping, and health behaviors
Authors: Kohlmann Carl-Walter , Dohnke Birte , Eschenbeck Heike , Gross Cornelia , Heim-Dreger Uwe , Layh Katrin , Meier Stefanie
Published: August 2008

Abstract. Research of the Division of Educational Psychology and Health Psychology has four main topics: 1. Analysis of processing of threat-related information in children is seen as a step towards a better understanding and assessment of vigilant and avoidant coping strategies. 2. Findings concerning gender differences in stress and coping in children and adolescents show that girls in early and middle adolescence display a more favorable coping pattern in social relations than their male peers. Therefore, a focus on the gender-specific development of coping strategies is needed when tailoring programs in stress prevention. 3. Social influences in the context of health behavior change are studied in adults. Cross-sectional and longitudinal studies focus on risk perception, intention formation, and behavior adoption. 4. Aims of the network of school based health promotion are implementation and evaluation of health promoting activities along with the opportunity for networking and training possibilities for schools.
A Euclidean Distance-Based Matching Procedure for Nonrandomized Comparison Studies
Authors: Spiel Christiane , Lapka Dominik , Gradinger Petra , Zodlhofer Eva Maria , Reimann Ralph , Schober Barbara , Wagner Petra , von Eye Alexander
Published: August 2008

For intervention programs that are applied in natural settings, randomization often is difficult or impossible to achieve. If treated individuals are compared with individuals from a nonrandomized comparison group, the inference of causality can be biased. Similar distributions in the relevant characteristics of the treatment and the comparison groups cannot be expected. To adjust between-group comparisons for preexisting differences, this article proposes a simple matching procedure. This procedure involves pairing of treatment and comparison individuals based on observable characteristics, using Euclidean distance scores. Application of the proposed Euclidean-distance matching (EuM) procedure to data from the Viennese E-Lecturing (VEL) project yields satisfying results. Possible generalizations and applications of the EuM procedure are discussed.
Application of Latent Class Analysis to the Investigation of Customer Loyalty in Service Companies
Authors: Varela Mallou Jesús , Rial Boubeta Antonio , Braña Tobío Teresa , Voces López Carmen
Published: August 2008

Loyalty as a strategic goal presents important returns for the organization. The existence of a base of loyal customers shields the company against actions from competitors, thus, ensuring medium- and long-term survival. Unfortunately, detection of truly loyal customers is not an easy task. Current research has clearly shown that the so-called direct or behavioral measurements ( Berné, 1997 ; Jacoby & Chesnut, 1978 ) are not sufficient for this purpose, given that they can lead to identifying as loyalty patterns of repetitive purchasing that do not imply a real commitment to the service providers. It has also been shown that indirect measurements ( Berné, 1997 ) can lead to interpreting as loyalty attitudes and intentions that never materialize in a real purchasing pattern. In our view, both approaches should be combined to reach the goal of detecting and describing different segments of consumers according to their loyalty to the service provided. The most important finding of this research focuses on the identification of different levels of loyalty, based on the attitudinal and behavioral measurements employed. Six different segments of consumers with varying characteristics emerged (true loyalty, latent loyalty, superficial loyalty, repetitive purchasing, forced loyalty and absence of loyalty).
Global characterization of cirrus clouds using CALIPSO data
Authors: Nazaryan Hovakim , McCormick M. Patrick , Menzel W. Paul
Published: August 2008

A global and seasonal distribution of cirrus clouds is presented herein on the basis of measurements made by the lidar aboard the Earth‐orbiting Cloud‐Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) satellite launched in April 2006. The latitude‐longitude and vertical distributions of occurrence frequency of cirrus clouds measured by CALIPSO from June 2006 to June 2007 are presented. The investigation of top‐layer cirrus clouds shows maximum‐occurrence frequency of up to 70% near the tropics over the 100°–180°E longitude band. The results show large latitudinal movement of cirrus cloud cover with the changing seasons. The examination of the vertical distribution of cirrus clouds shows the maximum of cirrus top‐altitude occurrence frequency of approximately 11% at 16 km in the tropics. There are no significant differences in vertical distributions of occurrence frequency of cirrus clouds in the Northern and Southern hemispheric midlatitudes. At latitudes 20°N to 60°N, the maximum frequency of the cirrus top and base altitudes is about 5.1% at 11 and 8 km, respectively.
Extreme hydrometeorological events and the urban environment: Dissecting the 7 July 2004 thunderstorm over the Baltimore MD Metropolitan Region
Authors: Ntelekos Alexandros A. , Smith James A. , Baeck Mary Lynn , Krajewski Witold F. , Miller Andrew J. , Goska Radoslaw
Published: August 2008

Observational analyses and mesoscale modeling studies, using the Weather Research and Forecasting (WRF) model, are used to dissect the mechanisms associated with record lightning, rainfall, and flooding over the Baltimore metropolitan region on 7 July 2004. Storm evolution on 7 July 2004 exhibited characteristic features of warm season thunderstorms producing flash flooding over the Baltimore–Washington DC metropolitan region. The storm system was initiated along the Blue Ridge mountains, with model simulations suggesting that convergence‐induced spin‐up of a meso‐low was responsible for initial thunderstorm development. Observations and model analyses show that thermal effects associated with Chesapeake Bay had a pronounced impact on storm evolution and rainfall distribution. Analyses of radar reflectivity and lightning observations suggest that the urban environment played a significant role in storm evolution and heavy rainfall distribution. Model analyses show that urban canopy effects from both the Baltimore and Washington DC urban regions play an important role in determining the storm environment associated with heavy rainfall. Urban Heat Island effects did not play a significant role in the storm evolution. Observations of aerosols and drop‐size distributions from a vertically pointing LIDAR and a disdrometer and model analyses suggest that the aerosols may have played an important role in stimulating efficient precipitation mechanisms and extreme rainfall rates for the 7 July 2004 storm.
Discrete parameterization of hydrological models: Evaluating the use of parameter sets libraries over 900 catchments
Authors: Perrin Charles , Andréassian Vazken , Rojas Serna Claudia , Mathevet Thibault , Le Moine Nicolas
Published: August 2008

This article describes an alternative to the optimization strategies classically adopted to calibrate the parameters of rainfall‐runoff models. This new method, called discrete parameterization, relies on the sole use of the prior information on parameters gained on other catchments. The optimum parameter set is simply searched within a collection (a library) of predefined optima. This library is composed of parameter sets representing a large number of actual catchments. The method was tested on a set of 900 catchments (from Australia, France, and the United States) using two daily lumped rainfall‐runoff models and was compared to more classical calibration approaches. Results are very similar for both models. Although the discrete parameterization method is not as efficient as a classical global search calibration approach when long time series are available for calibration, it provides more robust parameter sets when flow time series available for calibration becomes shorter than 2 years. This makes the method particularly interesting in the cases of poorly gauged catchments where available flow records are short. In case of limited data, the advantage of the proposed approach over the classical calibration approaches was more significant for the more complex model. On our set of 900 catchments, the optimum parameter set is generally selected among parameter sets from the library corresponding to catchments spatially close to the studied catchment. However other criteria of physical similarity may be relevant to select the donor catchment in the library.
High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial functionin vivo
Authors: Mantena Sudheer K. , Vaughn Denty Paul , Andringa Kelly K. , Eccleston Heather B. , King Adrienne L. , Abrams Gary A. , Doeller Jeannette E. , Kraus David W. , Darley-Usmar Victor M. , Bailey Shannon M.
Published: August 2008

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.
Palladacycles catalyse the oxidation of critical thiols of the mitochondrial membrane proteins and lead to mitochondrial permeabilization and cytochrome c release associated with apoptosis
Authors: Santana Débora P. , Faria Priscila A. , Paredes-Gamero Edgar J. , Caires Antonio C. F. , Nantes Iseli L. , Rodrigues Tiago
Published: August 2008

Permeabilization of the mitochondrial membrane has been extensively associated with necrotic and apoptotic cell death. Similarly to what had been previously observed for B16F10-Nex2 murine melanoma cells, PdC (palladacycle compounds) obtained from the reaction of dmpa (N,N-dimethyl-1-phenethylamine) with the dppe [1,2-ethanebis(diphenylphosphine)] were able to induce apoptosis in HTC (hepatoma, tissue culture) cells, presenting anticancer activity in vitro. To elucidate cell site-specific actions of dmpa:dppe that could respond to the induction of apoptosis in cancer cells in the present study, we investigated the effects of PdC on isolated RLM (rat liver mitochondria). Our results showed that these palladacycles are able to induce a Ca2+-independent mitochondrial swelling that was not inhibited by ADP, Mg2+ and antioxidants. However, the PdC-induced mitochondrial permeabilization was partially prevented by pre-incubation with CsA (cyclosporin A), NEM (N-ethylmaleimide) and bongkreic acid and totally prevented by DTT (dithiothreitol). A decrease in the content of reduced thiol groups of the mitochondrial membrane proteins was also observed, as well as the presence of membrane protein aggregates in SDS/PAGE without lipid and GSH oxidation. FTIR (Fourier-transform IR) analysis of PdC-treated RLM demonstrated the formation of disulfide bonds between critical thiols in mitochondrial membrane proteins. Associated with the mitochondrial permeabilization, PdC also induced the release of cytochrome c, which is sensitive to inhibition by DTT. Besides the contribution to clarify the pro-apoptotic mechanism of PdC, this study shows that the catalysis of specific protein thiol cross-linkage is enough to induce mitochondrial permeabilization and cytochrome c release.
β-Arrestin1 interacts with the G-protein subunits β1γ2 and promotes β1γ2-dependent Akt signalling for NF-κB activation
Authors: Yang Ming , He Rong L. , Benovic Jeffrey L. , Ye Richard D.
Published: August 2008

β-Arrestins are known to regulate G-protein signalling through interactions with their downstream effectors. In the present study, we report that β-arrestin1 associates with the G-protein β1γ2 subunits in transfected cells, and purified β-arrestin1 interacts with Gβ1γ2 derived from in vitro translation. Deletion mutagenesis of β-arrestin1 led to the identification of a region, comprising amino acids 181–280, as being responsible for its interaction with Gβ1γ2. Overexpression of β-arrestin1 facilitates Gβ1γ2-mediated Akt phosphorylation, and inhibition of endogenous β-arrestin1 expression by siRNA (small interfering RNA) diminishes this effect. Through investigation of NF-κB (nuclear factor κB), a transcription factor regulated by Akt signalling, we have found that overexpression of β-arrestin1 significantly enhances Gβ1γ2-mediated nuclear translocation of NF-κB proteins and expression of a NF-κB-directed luciferase reporter. Overexpression of β-arrestin1 also promotes bradykinin-induced, Gβγ-mediated NF-κB luciferase-reporter expression, which is reverted by silencing the endogenous β-arrestin1 with a specific siRNA. These results identify novel functions of β-arrestin1 in binding to the β1γ2 subunits of heterotrimeric G-proteins and promoting Gβγ-mediated Akt signalling for NF-κB activation.
Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor–DNA complexes
Authors: Faist Flavie , Short Stephen , Kneale G. Geoff , Sharpe Colinb R.
Published: August 2008

Signalling by small molecules, such as retinoic acid, is mediated by heterodimers comprising a class II nuclear receptor and an RXR (retinoid X receptor) subunit. The receptors bind to DNA response elements and act as ligand-dependent transcription factors, but, in the absence of signal, the receptors bind the co-repressors SMRT [silencing mediator for RAR (retinoic acid receptor) and TR (thyroid hormone receptor)] and NCoR (nuclear receptor co-repressor) and repress gene expression. Alternative splicing of the SMRT transcript in mammals generates six isoforms containing 1, 2 or 3 CoRNR (co-repressor for nuclear receptor) box motifs which are responsible for the interactions with nuclear receptors. We show that human cell lines express all six SMRT isoforms and then determine the binding affinity of mouse SMRT isoforms for RAR/RXR and three additional class II nuclear receptor–DNA complexes. This approach demonstrates the importance of the full complement of CoRNR boxes within each SMRT protein, rather than the identity of individual CoRNR boxes, in directing the interaction of SMRT with nuclear receptors. Each class of SMRT isoform displays a distinct feature, as the 1-box isoform discriminates between DNA response elements, the 2-box isoforms promote high-affinity binding to TR complexes and the 3-box isoforms show differential binding to nuclear receptors. Consequently, the differential deployment of SMRT isoforms observed in vivo could significantly expand the regulatory capacity of nuclear receptor signalling.
Stretching DNA with electric fields beneath submicron interfacial constriction created by a closely fitting microdroplet in a microchannel
Authors: Hsieh Shu-Fu , Chang Chia-Pu , Juang Yi-Je , Wei Hsien-Hung
Published: August 2008

In this article, we report an alternative strategy for stretching single DNA molecules with electric fields. The approach invokes a closely fitting microdroplet in a microchannel, creating a natural converging geometry for stretching DNA within a submicron interfacial constriction. We demonstrate that DNA molecules can undergo prestretching within the constriction, pseudotethering entropic trap, and rapid extension within the thin film underneath the droplet. An elastic dumbbell model is derived to account for the observed stretch behavior, with predictions in good agreement with the experimental results.
Photoluminescence study of ZnO nanowires grown by thermal evaporation on pulsed laser deposited ZnO buffer layer
Authors: Mohanta Antaryami , Thareja Raj K.
Published: August 2008

The ZnO nanowires are grown by thermal evaporation on pulsed laser deposited ZnO buffer layer on silicon. Photoluminescence of ZnO nanowires is studied at various temperatures in the range from 6 K to room temperature and varying excitation intensities. At 6 K, the photoluminescence profile of ZnO nanowires shows bound exciton, free excitons (FXAn=1,FXAn=2), longitudinal optical phonon replicas (FXAn=1-mLO, m=1, 2, 3) of free exciton (FXAn=1), and donor acceptor pairs. The first longitudinal optical phonon replica (FXAn=1-1LO) dominates at room temperature. Photoluminescence peak shifts by 47 meV from free exciton energy with the increase in temperature to room temperature.
The H3+ rovibrational spectrum revisited with a global electronic potential energy surface
Authors: Velilla Luis , Lepetit Bruno , Aguado Alfredo , Beswick J. Alberto , Paniagua Miguel
Published: August 2008

In this paper, we have computed the rovibrational spectrum of the H3+ molecule using a new global potential energy surface, invariant under all permutations of the nuclei, that includes the long range electrostatic interactions analytically. The energy levels are obtained by a variational calculation using hyperspherical coordinates. From the comparison with available experimental results for low lying levels, we conclude that our accuracy is of the order of 0.1cm−1 for states localized in the vicinity of equilateral triangular configurations of the nuclei, and changes to the order of 1cm−1 when the system is distorted away from equilateral configurations. Full rovibrational spectra up to the H++H2 dissociation energy limit have been computed. The statistical properties of this spectrum (nearest neighbor distribution and spectral rigidity) show the quantum signature of classical chaos and are consistent with random matrix theory. On the other hand, the correlation function, even when convoluted with a smoothing function, exhibits oscillations which are not described by random matrix theory. We discuss a possible similarity between these oscillations and the ones observed experimentally.
Transient buoyancy-driven convection of water around 4 °C in a porous cavity with internal heat generation
Authors: Kandaswamy P. , Eswaramurthi M. , Ng C. O.
Published: August 2008

The transient buoyancy-driven convection in a water saturated porous cavity with internal heat generation is studied numerically. The Brinkman–Forchheimer–extended Darcy model is employed to investigate the average heat transfer rate and to study the effects of density maximum, the Grashof number, porosity, the Darcy number, and the internal heat generation parameter on buoyancy-induced flow and heat transfer. The finite volume method with the power law scheme for convection terms is used to discretize the governing equations for momentum and energy, which are solved by the Gauss–Seidel and successive-over-relaxation methods. A systematic investigation on transient, steady fluid flow, and heat transfer phenomena under different physical conditions is carried out. The results obtained in the steady state regime are presented in the form of streamlines, isotherms, and midheight velocity profiles for various values of Grashof number, porosity, and Darcy number. It is found that the effect of density maximum is to slow down the buoyancy-driven convection and reduce the average heat transfer. The strength of convection and the heat transfer rate become weak due to more flow restriction in the porous medium for small porosity and high internal heat generation parameter.
Dense wavelength conversion and multicasting in a resonance-split silicon microring
Authors: Li Qiang , Zhang Ziyang , Liu Fangfei , Qiu Min , Su Yikai
Published: August 2008

We experimentally demonstrate all-optical wavelength conversions in a 10 μm radius resonance-split silicon microring resonator based on free carrier dispersion effect. The split resonance is caused by the mutual coupling between the two countertraveling modes inside the ring resonator. Dense wavelength conversions are performed at data rates from 500 Mbytes/s to 5 Gbytes/s and a dual-channel wavelength multicasting is realized at a data rate of 1.25 Gbytes/s. The resonance splitting phenomenon opens up opportunities to convert more closely spaced wavelengths, thus effectively increasing the system capacity.
Visualization of weak confinement potentials by near-field optical imaging spectroscopy of exciton and biexciton in a single quantum dot
Authors: Sugimoto Y. , Saiki T. , Nomura S.
Published: August 2008

Imaging spectroscopy of a single GaAs interface fluctuation quantum dot (IFQD) was performed using a near-field scanning optical microscope (NSOM) with a spatial resolution of 40nm. A difference in the emission profiles of an exciton and a biexciton was found for several IFQDs. By comparing with a numerical simulation based on the finite-difference time-domain method, this difference was attributed to the existence of a shallow potential dip in the IFQD. The NSOM wavefunction mapping for excitons and biexcitons as quasiparticles with different masses is a tool for investigating weak confinement potentials to detect local strain and disorder.
Observation of near interface oxide traps in single crystalline Nd2O3 on Si(111) by quasistatic C-V method
Authors: Sun Qing-Qing , Laha Apurba , Ding Shi-Jin , Zhang David Wei , Osten H. Jörg , Fissel A.
Published: August 2008

Single crystalline Nd2O3 based capacitors with proper forming gas annealing treatment are fabricated. By elevating the temperature of substrate to 100°C, near interface oxide traps are observed according to the quasistatic C-V obtained at low frequency. Two types of traps, interface traps and near interface oxide traps, are demonstrated in this gate stack. Using the low-high frequency method, the interface trap density at flatband voltage condition and the near interface oxide trap density are estimated to be 5.17×1011eV−1cm−2 and 3.75×1012cm−2, respectively. The interface trap density is then further confirmed by the conductance method.
Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma
Authors: Qiao Jingbo , Kang JungHee , Ishola Titilope A. , Rychahou Piotr G. , Evers B. Mark , Chung Dai H.
Published: August 2008

Neuroblastoma accounts for nearly 15% of all pediatric cancer-related deaths. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth, and that its cell surface receptor, GRP-R, is overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP/GRP-R on tumorigenesis and metastasis
in vivo
are not clearly elucidated. In the present study, we found that GRP-R knockdown in the aggressive cell line BE(2)-C induced cell morphology changes, reduced cell size, decreased cell proliferation, and inhibited DNA synthesis, corresponding to cell cycle arrest at G
2
/M phase. Activated Akt, a crucial regulator of cell survival and metastasis, was down-regulated by GRP-R silencing. In addition, expression of
p
-p70S6K and its downstream target molecule S6, key regulators of protein synthesis and cell metabolism, were also significantly decreased by GRP-R silencing. GRP-R knockdown also up-regulated the expression of tumor suppressor PTEN, the inhibitor of the PI3K/Akt pathway. Furthermore, silencing GRP-R as well as GRP in BE(2)-C cells suppressed anchorage-independent growth
in vitro
. Conversely, overexpression of GRP-R in less aggressive SK-N-SH neuroblastoma cells resulted in soft agar colony formation, which was inhibited by a GRP-blocking antibody. Moreover, GRP-R deficiency significantly delayed tumor growth and diminished liver metastases
in vivo
. Our findings demonstrate that GRP and GRP-R have important oncogenic properties beyond their established mitogenic functions. Therefore, GRP-R may be an ideal therapeutic target for the treatment of aggressive neuroblastomas.
Short telomeres are a risk factor for idiopathic pulmonary fibrosis
Authors: Alder Jonathan K. , Chen Julian J.-L. , Lancaster Lisa , Danoff Sonye , Su Shu-chih , Cogan Joy D. , Vulto Irma , Xie Mingyi , Qi Xiaodong , Tuder Rubin M. , Phillips John A. , Lansdorp Peter M. , Loyd James E. , Armanios Mary Y.
Published: August 2008

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components,
hTERT
and
hTR
, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced
hTERT
and
hTR.
We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (
P
< 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (
P
< 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as
idiopathic
progressive organ failure in the lung and the liver.
Discovery and measurement of an isotopically distinct source of sulfate in Earth's atmosphere
Authors: Dominguez Gerardo , Jackson Terri , Brothers Lauren , Barnett Burton , Nguyen Bryan , Thiemens Mark H.
Published: August 2008

Sulfate (SO
4
) and its precursors are significant components of the atmosphere, with both natural and anthropogenic sources. Recently, our triple-isotope (
16
O,
17
O,
18
O) measurements of atmospheric sulfate have provided specific insights into the oxidation pathways leading to sulfate, with important implications for models of the sulfur cycle and global climate change. Using similar isotopic measurements of aerosol sulfate in a polluted marine boundary layer (MBL) and primary sulfate (
p
-SO
4
) sampled directly from a ship stack, we quantify the amount of
p
-SO
4
found in the atmosphere from ships. We find that ships contribute between 10% and 44% of the non-sea-salt sulfate found in fine [diameter (D) < 1.5 μm) particulate matter in coastal Southern California. These fractions are surprising, given that
p
-SO
4
constitutes ≈2–7% of total sulfur emissions from combustion sources [Seinfed JH, Pandis SN (2006)
Atmospheric Chemistry and Physics
(Wiley–Interscience, New York)]. Our findings also suggest that the interaction of SO
2
from ship emissions with coarse hydrated sea salt particles may lead to the rapid removal of SO
2
in the MBL. When combined with the longer residence time of
p
-SO
4
emissions in the MBL, these findings suggest that the importance of
p
-SO
4
emissions in marine environments may be underappreciated in global chemical models. Given the expected increase of international shipping in the years to come, these findings have clear implications for public health, air quality, international maritime law, and atmospheric chemistry.
Mcm4 C-terminal domain of MCM helicase prevents excessive formation of single-stranded DNA at stalled replication forks
Authors: Nitani Naoki , Yadani Chie , Yabuuchi Hayato , Masukata Hisao , Nakagawa Takuro
Published: August 2008

The minichromosome maintenance (MCM) helicase, composed of subunits Mcm2–7, is essential for the initiation and elongation phases of DNA replication. Even when DNA synthesis is blocked, MCM continues DNA unwinding to some extent for activation of the replication checkpoint and then stops. However, the mechanism of regulation of MCM-helicase activity remains unknown. Here, we show that truncation of the Mcm4 C-terminal domain (CTD) in fission yeast results in hypersensitivity to replication block caused by dNTP depletion. The truncation
mcm4-c84
does not affect the activation of the replication checkpoint pathway but delays its attenuation during recovery from replication block. Two dimensional gel electrophoresis showed that
mcm4-c84
delays the disappearance of replication intermediates, indicating that the Mcm4 CTD is required for efficient recovery of stalled replication forks. Remarkably, chromatin immunoprecipitation revealed that
mcm4-c84
brings about an increase rather than a decrease in the association of the single-stranded DNA-binding protein RPA to stalled forks, and MCM and the accessory complex GINS are unaffected. These results suggest that the Mcm4 CTD is required to suspend MCM-helicase activity after the formation of single-stranded DNA sufficient for checkpoint activation.
Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line
Authors: Gal-Yam Einav Nili , Egger Gerda , Iniguez Leo , Holster Heather , Einarsson Steingrímur , Zhang Xinmin , Lin Joy C. , Liang Gangning , Jones Peter A. , Tanay Amos
Published: August 2008

Epigenetic reprogramming is commonly observed in cancer, and is hypothesized to involve multiple mechanisms, including DNA methylation and Polycomb repressive complexes (PRCs). Here we devise a new experimental and analytical strategy using customized high-density tiling arrays to investigate coordinated patterns of gene expression, DNA methylation, and Polycomb marks which differentiate prostate cancer cells from their normal counterparts. Three major changes in the epigenomic landscape distinguish the two cell types. Developmentally significant genes containing CpG islands which are silenced by PRCs in the normal cells acquire DNA methylation silencing and lose their PRC marks (epigenetic switching). Because these genes are normally silent this switch does not cause
de novo
repression but might significantly reduce epigenetic plasticity. Two other groups of genes are silenced by either
de novo
DNA methylation without PRC occupancy (5mC reprogramming) or by
de novo
PRC occupancy without DNA methylation (PRC reprogramming). Our data suggest that the two silencing mechanisms act in parallel to reprogram the cancer epigenome and that DNA hypermethylation may replace Polycomb-based repression near key regulatory genes, possibly reducing their regulatory plasticity.
Antagonistic Regulation of Cell-Matrix Adhesion by FosB and ΔFosB/Δ2ΔFosB Encoded by Alternatively Spliced Forms of fosB Transcripts
Authors: Ohnishi Yoshinori N. , Sakumi Kunihiko , Yamazaki Katsuhisa , Ohnishi Yoko H. , Miura Tomofumi , Tominaga Yohei , Nakabeppu Yusaku
Published: August 2008

Among fos family genes encoding components of activator protein-1 complex, only the fosB gene produces two forms of mature transcripts, namely fosB and ΔfosB mRNAs, by alternative splicing of an exonic intron. The former encodes full-length FosB. The latter encodes ΔFosB and Δ2ΔFosB by alternative translation initiation, and both of these lack the C-terminal transactivation domain of FosB. We established two mutant mouse embryonic stem (ES) cell lines carrying homozygous fosB-null alleles and fosBd alleles, the latter exclusively encoding ΔFosB/Δ2ΔFosB. Comparison of their gene expression profiles with that of the wild type revealed that more than 200 genes were up-regulated, whereas 19 genes were down-regulated in a ΔFosB/Δ2ΔFosB-dependent manner. We furthermore found that mRNAs for basement membrane proteins were significantly up-regulated in fosBd/d but not fosB-null mutant cells, whereas genes involved in the TGF-β1 signaling pathway were up-regulated in both mutants. Cell-matrix adhesion was remarkably augmented in fosBd/d ES cells and to some extent in fosB-null cells. By analyzing ES cell lines carrying homozygous fosBFN alleles, which exclusively encode FosB, we confirmed that FosB negatively regulates cell-matrix adhesion and the TGF-β1 signaling pathway. We thus concluded that FosB and ΔFosB/Δ2ΔFosB use this pathway to antagonistically regulate cell matrix adhesion.
Evolution Rescues Folding of Human Immunodeficiency Virus-1 Envelope Glycoprotein GP120 Lacking a Conserved Disulfide Bond
Authors: Sanders Rogier W. , Hsu Shang-Te D. , van Anken Eelco , Liscaljet I. Marije , Dankers Martijn , Bontjer Ilja , Land Aafke , Braakman Ineke , Bonvin Alexandre M.J.J. , Berkhout Ben
Published: August 2008

The majority of eukaryotic secretory and membrane proteins contain disulfide bonds, which are strongly conserved within protein families because of their crucial role in folding or function. The exact role of these disulfide bonds during folding is unclear. Using virus-driven evolution we generated a viral glycoprotein variant, which is functional despite the lack of an absolutely conserved disulfide bond that links two antiparallel β-strands in a six-stranded β-barrel. Molecular dynamics simulations revealed that improved hydrogen bonding and side chain packing led to stabilization of the β-barrel fold, implying that β-sheet preference codirects glycoprotein folding in vivo. Our results show that the interactions between two β-strands that are important for the formation and/or integrity of the β-barrel can be supported by either a disulfide bond or β-sheet favoring residues.
Mitochondrial Serine Acetyltransferase Functions as a Pacemaker of Cysteine Synthesis in Plant Cells
Authors: Haas Florian H. , Heeg Corinna , Queiroz Rafael , Bauer Andrea , Wirtz Markus , Hell Rüdiger
Published: August 2008

Cysteine (Cys) synthesis in plants is carried out by two sequential reactions catalyzed by the rate-limiting enzyme serine acetyltransferase (SAT) and excess amounts of O-acetylserine(thiol)lyase. Why these reactions occur in plastids, mitochondria, and cytosol of plants remained unclear. Expression of artificial microRNA (amiRNA) against Sat3 encoding mitochondrial SAT3 in transgenic Arabidopsis (Arabidopsis thaliana) plants demonstrates that mitochondria are the most important compartment for the synthesis of O-acetylserine (OAS), the precursor of Cys. Reduction of RNA levels, protein contents, SAT enzymatic activity, and phenotype strongly correlate in independent amiSAT3 lines and cause significantly retarded growth. The expression of the other four Sat genes in the Arabidopsis genome are not affected by amiRNA-SAT3 according to quantitative real-time polymerase chain reaction and microarray analyses. Application of radiolabeled serine to leaf pieces revealed severely reduced incorporation rates into Cys and even more so into glutathione. Accordingly, steady-state levels of OAS are 4-fold reduced. Decrease of sulfate reduction-related genes is accompanied by an accumulation of sulfate in amiSAT3 lines. These results unequivocally show that mitochondria provide the bulk of OAS in the plant cell and are the likely site of flux regulation. Together with recent data, the cytosol appears to be a major site of Cys synthesis, while plastids contribute reduced sulfur as sulfide. Thus, Cys synthesis in plants is significantly different from that in nonphotosynthetic eukaryotes at the cellular level.
RESEARCH VULNERABILITY: AN ILLUSTRATIVE CASE STUDY FROM THE SOUTH AFRICAN MINING INDUSTRY
Authors: HORN LYN
Published: August 2008

The concept of ‘vulnerability’ is well established within the realm of research ethics and most ethical guidelines include a section on ‘vulnerable populations’. However, the term ‘vulnerability’, used within a human research context, has received a lot of negative publicity recently and has been described as being simultaneously ‘too broad’ and ‘too narrow’.1 The aim of the paper is to explore the concept of research vulnerability by using a detailed case study – that of mineworkers in post‐apartheid South Africa. In particular, the usefulness of Kipnis’s taxonomy of research vulnerability will be examined.2

In recent years the volume of clinical research on human subjects in South Africa has increased significantly. The HIV and TB pandemics have contributed to this increase. These epidemics have impacted negatively on the mining industry; and mining companies have become increasingly interested in research initiatives that address these problems. This case study explores the potential research vulnerability of mineworkers in the context of the South African mining industry and examines measures that can reduce this vulnerability.
Insulin resistance in subjects with a history of thyrotoxic periodic paralysis (TPP)
Authors: Soonthornpun Supamai , Setasuban Worawong , Thamprasit Atchara
Published: August 2008

Background  Hyperinsulinaemia has been suggested as an important factor for developing hypokalaemic paralysis in patients with thyrotoxic periodic paralysis (TPP). Since hyperinsulinaemia is a common feature of insulin resistance, there may be a causal relationship between insulin resistance and TPP.

Objective  To compare insulin sensitivity between subjects with a history of TPP and others with a history of thyrotoxicosis without periodic paralysis.

Methods  Insulin sensitivity measured by euglycaemic hyperinsulinaemic clamp and 75‐g oral glucose tolerance test (OGTT) were performed nonselectively in 10 subjects with a history of TPP (TPP group) and 10 age‐ and sex‐matched subjects with a history of simple thyrotoxicosis (control group). All participants had euthyroidism and fasting plasma glucose of < 5·55 mmol/l at the time of the study.

Results  Body mass index and waist circumference of the TPP group were higher than that of the control group. One of 10 (10%) subjects in the TPP group and 6 of 10 (60%) in the control group had BMI of < 23 kg/m2. Areas under the curve (AUC) of plasma glucose after OGTT were comparable, while the AUC of serum insulin of the TPP group was higher than in the control group. The TPP group had lower insulin sensitivity than the control group.

Conclusion  The subjects with a history of TPP were more obese and had lower insulin sensitivity than those with a history of simple thyrotoxicosis. Insulin resistance with compensatory hyperinsulinaemia may be a key feature of the pathogenesis of TPP.
Characterization of asphaltene structure using atomic force microscopy
Authors: SABBAGHI S. , SHARIATY‐NIASSAR M. , AYATOLLAHI SH. , JAHANMIRI A.
Published: August 2008

In this study, at the first stage, asphaltene was extracted. The roughness of asphaltene coating at different rpm was studied using an image analysis confocal microscopy. The basics of quantum mechanics and statistical thermodynamics are used to predict the potential energy and the intermolecular forces of asphaltene molecules. The functional forms for the potential energy and intermolecular forces are evaluated. Our final goal is to be able to observe and determine the surface structures of asphaltene micelles with scanning probe microscopes. So, the focus of the work on these unusual molecules is to characterize their structure, dynamics and thermodynamics and to establish the relationship between these properties and petroleum fluid behaviour. The existence of various nanostructures of asphaltene in petroleum has been extensively discussed. A set of fitted data is used to check the validity of the calculated results. The good agreement between the proposed models and the data is promising.
A confident scale–space shape representation framework for cell migration detection
Authors: ZHANG K. , XIONG H. , ZHOU X. , YANG L. , WANG Y.‐L. , WONG S. T. C.
Published: August 2008

Automated segmentation of time‐lapse images is a method to facilitate the understanding of the intricate biological progression, e.g. cancer cell migration. To address this problem, we introduce a shape representation enhancement over popular snake models in the context of confident scale–space such that a higher level of interpretation can hopefully be achieved. Our proposed system consists of a hierarchical analytic framework including feedback loops, self‐adaptive and demand‐adaptive adjustment, incorporating a steerable boundary detail term constraint based on multiscale B‐spline interpolation. To minimize the noise interference inherited from microscopy acquisition, the coarse boundary derived from the initial segmentation with refined watershed line is coupled with microscopy compensation using the mean shift filtering. A progressive approximation is applied to achieve represented as a balance between a relief function of watershed algorithm and local minima concerning multiscale optimality, convergence and robust constraints. Experimental results show that the proposed method overcomes problems with spurious branches, arbitrary gaps, low contrast boundaries and low signal‐to‐noise ratio. The proposed system has the potential to serve as an automated data processing tool for cell migration applications.