bluuebunny/crossref_metadata_2025 huggingface dataset:
A new hepatocytic isoform of PLZF lacking the BTB domain interacts with ATP7B, the Wilson disease protein, and positively regulates ERK signal transduction
Authors: Ko Jung Ho , Son Wonseok , Bae Gab Yong , Kang Joo Hyun , Oh Wonjun , Yoo Ook Joon
Published: May 2006

The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of the BTB‐domain/zinc‐finger family, and shown to regulate the expression of Hox genes during embryogenesis and the expression of cyclin A in the cell cycle progression. Here, a 45‐kDa isoform of PLZF without a BTB domain was identified via yeast two‐hybrid screening using the C‐terminal region of ATP7B as bait in our determination of the biological roles of the Wilson disease protein outside of its copper‐binding domain. Our immunoprecipitation experiments showed that the hepatocytic isoform of PLZF could specifically interact with the C‐terminal region of ATP7B. The immunostaining of HepG2 cells revealed that the ATP7B and PLZF proteins were apparently colocalized into the trans‐Golgi complexes. It was also determined that disruption of PLZF expression in the HepG2 cells affected an attenuation of ERK activity in a dose‐dependent manner. The hepatocytic activities of ERK kinase were found to be enhanced as the result of PLZF or ATP7B expression, but this enhancement was abrogated by the deletion of the C‐terminal region of ATP7B. Furthermore, a transgenic Drosophila strain that ectopically expressed the hepatocytic ΔBTB‐PLZF exhibited phenotypic changes in eye and wing development, and these alterations were fully recovered as the result of ATP7B expression, indicating the obvious in vivo interaction between the two proteins. Those PLZF‐induced abnormalities were attributed to the enhancement of ERK signaling, as was shown by phenotypic reversions with loss‐of‐function mutations in ERK signal transduction in Drosophila. These data suggest the existence of a mechanism that regulates ERK signaling via the C‐terminus of ATP7B and the ATP7B‐interacting hepatocytic PLZF. J. Cell. Biochem. 99: 719–734, 2006. © 2006 Wiley‐Liss, Inc.
Orthogonal designs via computational algebra
Authors: Kotsireas Ilias S. , Koukouvinos Christos
Published: May 2006

We detail the Williamson array construction based on quaternions, following the description by Baumert and Hall. By analogy, we extend the construction to larger arrays using matrix representations of the algebras of octonions and sedenions. In the case of octonions, we obtain the full orthogonal design OD(8;1,1,1,1,1,1,1,1) or order 8 with 8 variables. In the case of sedenions we obtain the full orthogonal design OD(16;1,1,7,7) of order 16 with 4 variables and the full orthogonal design OD(16;1,1,2,2,2,2,2,2,2) of order 16 with 9 variables. We use OD(16;1,1,2,2,2,2,2,2,2) to search for inequivalent Hadamard matrices of orders 112, 144, 176 and we establish constructively three new lower bounds for the numbers of inequivalent Hadamard matrices of these three orders. © 2006 Wiley Periodicals, Inc. J Combin Designs 14: 351–362, 2006
Cubic s‐regular graphs of order 2p3
Authors: Feng Yan‐Quan , Kwak Jin Ho , Xu Ming‐Yao
Published: May 2006

A graph is s‐regular if its automorphism group acts regularly on the set of its s‐arcs. Malnič et al. (Discrete Math 274 (2004), 187–198) classified the connected cubic edge‐transitive, but not vertex‐transitive graphs of order 2p3 for each prime p. In this article, we determine the s‐regularity of all connected cubic symmetric graphs of order 2p3 for each prime p and each s. © 2006 Wiley Periodicals, Inc. J Graph Theory
Finding a monochromatic subgraph or a rainbow path
Authors: Gyárfás András , Lehel Jenő , Schelp Richard H.
Published: May 2006

For simple graphs G and H, let f(G,H) denote the least integer N such that every coloring of the edges of KN contains either a monochromatic copy of G or a rainbow copy of H. Here we investigate f(G,H) when H = Pk. We show that even if the number of colors is unrestricted when defining f(G,H), the function f(G,Pk), for k = 4 and 5, equals the (k − 2)‐ coloring diagonal Ramsey number of G. © 2006 Wiley Periodicals, Inc. J Graph Theory
Heterozygous P0 deficiency protects mice from vincristine‐induced polyneuropathy
Authors: Üçeyler Nurcan , Kobsar Igor , Biko Lydia , Ulzheimer Jochen , Levinson S. Rock , Martini Rudolf , Sommer Claudia
Published: May 2006

Patients with hereditary neuropathies are more susceptible to vincristine (VIN)‐induced neuropathy than patients without this comorbidity. The heterozygous P0+/– mouse is an animal model of a distinct form of inherited neuropathies. These mice produce only 50% of the major myelin protein protein zero (P0) and display signs of demyelination in motor nerves at 4 months of age. Here we investigated the development of neuropathic signs in P0+/– and wild‐type (wt) mice after VIN treatment. Neuropathy was induced by daily intraperitoneal injections of VIN (0.5 mg/kg body weight) over 10 days. Behavioral and electrophysiological tests were performed at regular time points. Wt mice developed significant hypersensitivity to heat and mechanical stimuli between days 7 and 38 after the first VIN injection. Surprisingly, P0+/– mice did not show sensory or motor signs of neuropathy over the whole testing period. Immunohistochemical analysis showed an increase in macrophage numbers in sciatic nerve sections of wt mice after VIN, whereas P0+/– mice had higher baseline levels of macrophages without changes after VIN treatment. Semithin sections revealed a decrease in the number of small‐diameter myelinated fibers in the sciatic nerves of wt mice after VIN application, whereas P0+/– mice had higher baseline values of this fiber subtype that did not change under treatment. Dorsal root ganglion neurons of both genotypes showed an up‐regulation of voltage‐gated sodium channel immunoreactivity after VIN application without differences between the genotypes. Thus, the P0+/– phenotype seems to be protected against VIN‐induced neuropathy. The mechanism of this neuroprotection remains elusive. © 2006 Wiley‐Liss, Inc.
Micellar electrokinetic capillary chromatography determination of zinc bacitracin and nystatin in animal feed
Authors: Injac Rade , Kac Javor , Mlinaric Ales , Karljikovic‐Rajic Katarina
Published: May 2006

An MEKC procedure was developed for the separation of zinc bacitracin (Zn‐BC) and nystatin (NYS) in mixtures and in animal feedstuff. The running buffer was 15 mM borate/19 mM phosphate, pH 8.2, containing 20 mM SDS and 10% v/v methanol. Samples were run at 25°C, the applied voltage was 25 kV, and an additional pressure of 5 mbar was applied. Both analytes were detected by UV simultaneously at 215 nm, Zn‐BC alone at 192 and 254 nm, and NYS alone at 305 nm. The method was shown to be specific, accurate (recoveries were 100.0 ± 0.6% and 100.1 ± 0.6% for Zn‐BC and NYS, respectively), linear over the tested range (correlation coefficients 0.9991 and 0.9994), and precise (RSD below 1.3% for both analytes). The method was applied to determine Zn‐BC and NYS as additives in animal feed.
Rapid separation of four main taxoids in Taxus species by a combined LLP‐SPE‐HPLC (PAD) procedure
Authors: Zu Yuangang , Fu Yujie , Li Shuangming , Sun Rui , Li Qingyong , Schwarz Günter
Published: May 2006

A method is described for the simultaneous determination of paclitaxel and three related taxoids, 10‐deacetylbaccatin III (10‐DAB III), baccatin III, and cephalomannine, in the extracts from the needles of three Chinese yew species, Taxus cuspidata, T. chinensis, and T. media. SPE was applied as the sample preparation technique and RP‐HPLC with a photodiode array detector (PAD) was used for the analysis of extract samples. The crude extracts were treated with an improved SPE cartridge packed with a combination of 1‐vinyl‐pyrrolidin‐2‐one and divinyl‐benzene. The eluent was 75% methanol. The following separation was achieved with a gradient program on an HIQ SIL C18W column in a system of ACN/water within 60 min. The samples were detected by PAD at wavelengths of 232.1 nm for 10‐DAB III, 229.8 nm for baccatin III and paclitaxel, and 223.9 nm for cephalomannine. The content of 10‐DAB III, baccatin III, cephalomannine, and paclitaxel varied from 0.0277 to 0.0875, 0.0254 to 0.0405, 0.0715 to 0.2486, and 0.0996 to 0.1301 mg/g in fresh needles of the above yew species, respectively. The assay achieved good resolution in the separation between the four compounds, and it can be used for quality control or purity determination for those in bulk and pharmceutical dosage forms.
Characteristics of occupational therapy journals of WFOT member countries: a descriptive survey
Authors: Brown G. Ted
Published: May 2006

There are many occupational therapy journals being published internationally, but little information is available about their characteristics. The purpose of this study was to gather relevant information about these journals. Examined are the journals' characteristics, the audiences they serve, the review process they use, the staff they employ, and the types of articles they publish. The study design was a descriptive survey format using an adapted version of the Survey of Editors Regarding Publishing Practices. Questionnaires were mailed to all the national occupational therapy associations that were members of the World Federation of Occupational Therapists (n=44) in September 1992. The response rate was 86.4% (n=38).

The survey results indicated that a typical occupational therapy journal was published six times a year, with 84% of it being text and 15% of it being advertising. In terms of submission of manuscripts, the preferred average length was 14 pages using American Psychological Association format specifications. Respondents indicated that, on average, occupational therapy journals received 33 manuscripts a year for review, 20 of those being accepted for publication with minor revision, five needing major revision and eight being rejected. Most occupational therapy journals indicated that they were peer‐reviewed/refereed publications. The most frequently cited reasons for rejecting manuscripts submitted for consideration for publication were: (1) content inaccurate; (2) content not important/significant; (3) poorly developed ideas; (4) methodology problems; (5) data interpretation problems; or (6) a poorly written manuscript. Most manuscripts published in occupational therapy journals have a clinical focus in the area of physical medicine or mental health. Results of the survey study are discussed and recommendations for future research are made. Copyright © 1997 Whurr Publishers Ltd.
A study to determine the minimum volume of blood necessary to be discarded from a central venous catheter before a valid sample is obtained in children with cancer
Authors: Cole M. , Price L. , Parry A. , Picton S. , Waters F. , Marshall S. , Goran C. , Parnham A. , Wastell H. , Reid M.M. , Pearson A.D.J. , Boddy A.V. , Veal G.J.
Published: May 2006

Background

The objective of this study was to determine the minimum volume of blood that should be discarded from a range of different types of central venous catheter (CVC), such that the subsequent blood sample was not diluted or contaminated by the residual intra‐luminal fluid.

Procedure

Seventy children aged 1–19 years with central venous access inserted as part of their standard clinical treatment were recruited to this prospective study. Statistical comparison of the extent of variation in biochemical and haematological parameters observed between two blood samples taken following routine 5 ml discard blood volumes, as compared to the extent of variation between samples drawn following a 5 ml discard volume and <5 ml volumes, was carried out.

Results

Data indicate that the measurement error in a clinical sample obtained following a 3 ml discard volume is no different to the measurement error obtained when using a standard 5 ml discard volume. Comparable results were obtained from patients with various different types of CVC or portacath access.

Conclusions

The withdrawal of a 3 ml discard volume is sufficient to ensure that the subsequent blood sample is not diluted or contaminated by residual intra‐luminal fluid. This may have a significant clinical impact in paediatric oncology, where patients frequently require blood transfusions due to the haematological toxicities associated with chemotherapy. It is hoped that these results will impact on hospital policies concerning specified discard volumes taken from CVCs prior to the withdrawal of blood samples for research purposes and routine clinical analysis. Pediatr Blood Cancer 2007;48:687–695. © 2006 Wiley‐Liss, Inc.
Numerical simulations of particulate suspensions via a discretized Boltzmann equation. Part 2. Numerical results
Authors: Ladd Anthony J. C.
Published: May 2006

A new and very general technique for simulating solid–fluid suspensions has been described in a previous paper (Part 1); the most important feature of the new method is that the computational cost scales linearly with the number of particles. In this paper (Part 2), extensive numerical tests of the method are described; results are presented for creeping flows, both with and without Brownian motion, and at finite Reynolds numbers. Hydrodynamic interactions, transport coefficients, and the short-time dynamics of random dispersions of up to 1024 colloidal particles have been simulated.
Direct simulation of interfacial waves in a high-viscosity-ratio and axisymmetric core–annular flow
Authors: Bai Runyuan , Kelkar Kanchan , Joseph Daniel D.
Published: May 2006

A direct numerical simulation of spatially periodic wavy core flows is carried out under the assumption that the densities of the two fluids are identical and that the viscosity of the oil core is so large that it moves as a rigid solid which may nevertheless be deformed by pressure forces in the water. The waves which develop are asymmetric with steep slopes in the high-pressure region at the front face of the wave crest and shallower slopes at the low-pressure region at the lee side of the crest. The simulation gives excellent agreement with the experiments of Bai, Chen & Joseph (1992) on up flow in vertical core flow where axisymmetric bamboo waves are observed. We define a threshold Reynolds number and explore its utility; the pressure force of the water on the core relative to a fixed reference pressure is negative for Reynolds numbers below the threshold and is positive above. The wave length increases with the hold-up ratio when the Reynolds number is smaller than a second threshold and decreases for larger Reynolds numbers. We verify that very high pressures are generated at stagnation points on the wavefront. It is suggested that a positive pressure force is required to levitate the core off the wall when the densities are not matched and to centre the core when they are. A further conjecture is that the principal features which govern wavy core flows cannot be obtained from any theory in which inertia is neglected.
Mechanics of collisional motion of granular materials. Part 4. Expansion wave
Authors: Goldshtein A. , Shapiro M. , Gutfinger C.
Published: May 2006

The problem of expansion into a vacuum of a semi-infinite layer composed of chaotically moving inelastic rough spherical particles is solved analytically. A variant of the matched asymptotic expansion scheme is used to obtain a matched composite solution, which is valid for both small and large times in the wave head, wave tail and intermediate domains of the disturbed part of the layer.

The effects of granular initial energy and particle collisonal properties on their hydrodynamic velocity, temperature, density and pressure are studied in the limit of low initial density of the granular gas. The total granular mass, M, within the disturbed region was found to change with time as log t. This is in contrast with the comparable classical result M ∼ t obtained for conservative (molecular) gases. This logarithmic dependence stems from the influence of kinetic energy losses, which reduce the granular temperature and speed of sound in the wave head region.

The ultimate escape energy and momentum (i.e. those achieved for long times by the expanding part of the layer) are shown to be finite quantities, dependent on the particle restitution coefficient, roughness and the initial granular temperature. The estimated mass of the escaping part of the layer, calculated here for dilute gases, serves as an upper bound on this quantity for all (also dense) comparable granular gases. This mass is determined by the collisional losses, as embodied within the particle restitution and roughness coefficients.
Nonlinear feedback control of the wake past a plate with a suction point on the downstream wall
Authors: Cortelezzi Luca
Published: May 2006

Active circulation control of the two-dimensional unsteady separated flow past a plate with a suction point on the downstream wall is considered. The rolling-up of the separated shear layer is modelled by a pair of point vortices whose time-dependent circulation is predicted by an unsteady Kutta condition. A nonlinear controller able to confine the wake to a single vortex pair of constant circulation is derived in closed form for any free-stream condition. Dynamical system analysis is used to explore the performance of the controlled system. Finally, the control strategy is applied to three different classes of unsteady flows and the results are discussed.
Bioconvection in a suspension of phototactic algae
Authors: Vincent R. V. , Hill N. A.
Published: May 2006

In this paper we develop a new generic model for phototaxis in a suspension of microscopic swimming algae. Phototaxis is a directed swimming response dependent upon the light conditions sensed by the microorganisms. Positive phototaxis consists of motions directed toward the source of illumination and negative phototaxis is motion directed away from it. The model also incorporates the effect ofshadingwhereby microorganisms nearer the light source absorb and scatter the light before it reaches those further away. This model of phototaxis and shading is then used to analyse the linear stability of a suspension of phototactic algae, uniformly illuminated from above, that swim in a fluid which is slightly less dense then they are. In the basic state there are no fluid motions and the up and down swimming caused by positive and negative phototaxis is balanced by diffusion, with the result that a horizontal, concentrated layer of algae forms, the vertical position of which depends on the light intensity. This leads to a bulk density stratification with a gravitationally stable layer of fluid overlying an unstable layer. When the resulting density gradient becomes large enough, a Rayleigh–Taylor type instability initiates fluid motions in the lower, unstable region that subsequently penetrate the upper, locally stable region. The behaviour of the suspension is characterized by four parameters: a layer depth parameterd, a Rayleigh numberR, a Schmidt numberSc, and a sublayer position parameterCthat specifies the vertical position of the sublayer in the fluid. Linear stability analysis of the basic state indicates that initial pattern wavelengths and the critical value ofRat which the suspension becomes unstable are affected by the position of the sublayer, which is determined by the intensity of the light source, and by the type of boundary at the top of the fluid. Oscillatory modes of disturbance are also predicted for certain parameter ranges, driven by cells swimming vigorously upwards towards darker, concentrated downwelling regions and thus creating lower, positively buoyant regions which oppose the fluid motion in the convection patterns.
An energy model for artificially generated bubbles in liquids
Authors: Aitken F. , Mccluskey F. M. J. , Denat A.
Published: May 2006

A mathematical analysis is carried out to model the series of processes following the occurrence of an electron avalanche in a liquid right through to the emission of a pressure transient and the formation of a bubble. The initial energy distribution is chosen to be Gaussian and it is assumed that the electrical energy injected into the system is transformed into thermal and mechanical components. From the mechanical point of view, an outgoing spherical pressure transient is formed at the edge of the plasma region, and at a later time a bubble is also formed. Theoretically, the pressure transient accounts for about 15% of the total injected energy, while it is necessary to revert to experimental results to fix the energy associated with the bubble (about 2%). A minimum such value can, however, be estimated. The maximum pressure amplitude is calculated. Concerning the thermal component of the energy, some is absorbed as internal energy by the liquid, while the remainder is stocked as latent heat of vaporization. The maximum temperature difference is derived as are the different energies as functions of the total injected energy. The advantage of this type of model is that the gas/vapour temperature in the bubble can continue to rise after the phase change takes place. The maximum bubble size following a given energy injection is calculated assuming an adiabatic expansion process. A mathematical expression for the liquid flow induced by the outgoing pressure transient is also found. Comparison between experimental and theoretical results is particularly good.
Bone-anchored hearing aids: results of the first eight years of a programme in a district general hospital, assessed by the Glasgow benefit inventory
Authors: Gillett D , Fairley J W , Chandrashaker T S , Bean A , Gonzalez J
Published: May 2006

Objectives: To report the clinical results of a bone-anchored hearing aid (BAHA) programme in a district general hospital, compared with those in an established, large, university teaching hospital centre.

Design: A retrospective postal questionnaire sent to BAHA patients, with two month waiting time and one reminder, combined with case note analysis. Results compared by appropriate statistical tests with published outcomes data from the largest UK series.

Setting: Public sector (National Health Service) district general hospital, England. Catchment population: 300 000 (mixed rural and small towns).

Participants: Case note analysis of sixty-three patients implanted between 1994 and 2003 (age range, six to 88 years). The commonest indication was chronic otitis media, with inability to wear a conventional hearing aid. Otitis externa, otosclerosis and sensorineural hearing loss were other indications. The questionnaire was sent to 59 patients who had worn their aid for at least six months; it was returned by 41 (69 per cent).

Main outcome measures: Glasgow benefit inventory (GBI, change in health status following otolaryngological intervention); incidence of complications.

Results: Bone-anchored hearing aid implantation significantly improved quality of life as measured by the GBI (p < 0.001). The degree of improvement was similar to that achieved in Birmingham by Proops et al. (p > 0.05, chi-squared test). Minor temporary skin infection was common (33 per cent). Thickening of the skin around the implant occurred in 17 per cent. One implant (2 per cent) failed. There were no serious complications.

Conclusion: The BAHA is a safe, reliable and effective treatment for selected patients. A successful BAHA programme can be run in a district general hospital.
A review of landholder motivations and determinants for participation in conservation covenanting programmes
Authors: KABII THOMAS , HORWITZ PIERRE
Published: May 2006

Conservation covenants (or easements) are flexible but legally enforceable documents attached to a land title restricting the use of that land, providing for the protection of important conservation values, while allowing the landholder to retain possession. Given the attractiveness of covenants to those who seek to expand national and regional nature conservation initiatives, it is important to understand landholder motivations for participation in programmes that covenant for nature conservation. This paper examines the likely influences on landholder decision making when it comes to conservation initiatives. A review of literature highlights key motivations and determinants, such as landholder demographics and the nature of the land tenure in question, their knowledge and awareness of the programme, financial circumstances, and perceptions of financial and other risks and benefits of the programme itself, including incentives and compensation. Underpinning, or mediating, the decision-making processes will be landholder philosophies and values, and five constructs are determined from the review, namely economic dependence on property, private property rights, confidence in perpetual covenant mechanisms, nature conservation equity and nature conservation ethic. Using these constructs, a series of explicit hypotheses is drawn, applicable to agencies dealing with conservation covenants and testable through an adaptive management approach. A conceptual model is presented to show hypothesized relationships between motivational factors and the five constructs that will lead to the uptake of covenants by landholders, providing direction for policy makers and managers of incentive programmes for nature conservation on private lands.
Origin of Mayans according to HLA genes and the uniqueness of Amerindians
Authors: Gómez‐Casado E. , Martínez‐Laso J. , Moscoso J. , Zamora J. , Martin‐Villa M. , Perez‐Blas M. , Lopez‐Santalla M. , Lucas Gramajo P. , Silvera C. , Lowy E. , Arnaiz‐Villena A.
Published: May 2006

Abstract:  The HLA allele frequency distribution of the Mayans from Guatemala was studied and compared with those of other First American Natives and worldwide populations (a total of 12,364 chromosomes and 6182 individuals from 60 different populations). The main conclusions were (1): the closest Amerindian group to Mayans is the Arhuacs, who were the first recorded Caribbean Islands' inhabitants (2). Mayans are not so close to Mesoamerican Zapotec, Mixe and Mixtec Amerindians, who genetically cluster together. Mixe had been related to Mayans only on linguistic bases (3). DRB1*0407 and DRB1*0802 alleles are found in 50% of Mayans; these alleles are also found in other Amerindians, but the Mayans' high frequencies may be showing a founder effect for this Mesoamerican‐Caribbean population (4). Extended Mayan specific HLA haplotypes are described for the first time (5). Language and genes do not completely correlate in microgeographical studies (6). Significant genetic input from outside is not noticed in Meso and South American Amerindians according to the genetic analyses; while all world populations (including Africans, Europeans, Asians, Australians, Polynesians, North American Na‐Dene Indians and Eskimos) are genetically related. Meso and South American Amerindians tend to remain isolated in the neighbour joining analyses.
HLA‐DQA1 polymorphism in autochthonous Basques from Navarre (Spain): Genetic position within European and Mediterranean scopes
Authors: Pérez‐Miranda A.M. , Alfonso‐Sánchez M.A. , Peña J.A. , Calderón R.
Published: May 2006

Abstract: In this work, a sample of 112 individuals from an autochthonous Basque population (Northern Navarre, Spain) were typed at the DNA level for the HLA‐DQA1 locus, with the aim of characterizing its polymorphism and analyzing the genetic relationships of Basque Navarrese with other Caucasian populations. Northern Navarre is a neighboring area with Guipúzcoa, a province located in the core of the Basque territory having the highest proportion of Basque‐speakers. In Navarrese population, the most frequent alleles were DQA1*01 (0.375) and DQA1*02 (0.259). Frequency clines for both DQA1*0103 allele and DQA1*04* allele cluster (including DQA1*0401, DQA1*0501 and DQA1*0601) among the European and Mediterranean populations considered are reported for the first time. Furthermore, a spatial structuring previously described for DQA1*02 allele is corroborated. The information provided by the highly polymorphic HLA‐DQA1 locus was stressed by using genetic distances and non‐metrical multidimensional scaling (MDS). The analysis of genetic relationships among populations showed a high genetic affinity between the Basque subpopulations of Northern Navarre and Guipúzcoa, which in turn tended to plot separately from the remaining European and Mediterranean populations. In the same way, the Basques showed no clear relationship to North African populations, as postulated in several previous HLA studies. The observed genetic heterogeneity seems to be conditioned by the high frequencies of the DQA1*02 allele in Basques from Guipúzcoa and North Navarre. These two subpopulations seem to show low levels of admixture with other non‐Basque neighboring populations, probably because of their deeply rooted ethnicity and the existence of a linguistic barrier to random mating.
Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors
Authors: Ji Hongbin , Zhao Xiaojun , Yuza Yuki , Shimamura Takeshi , Li Danan , Protopopov Alexei , Jung Boonim L. , McNamara Kate , Xia Huili , Glatt Karen A. , Thomas Roman K. , Sasaki Hidefumi , Horner James W. , Eck Michael , Mitchell Albert , Sun Yangping , Al-Hashem Ruqayyah , Bronson Roderick T. , Rabindran Sridhar K. , Discafani Carolyn M. , Maher Elizabeth , Shapiro Geoffrey I. , Meyerson Matthew , Wong Kwok-Kin
Published: May 2006

The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinctEGFRmutation, the variant III (vIII) in-frame deletion of exons 2–7, is commonly found. In this study, we determined thatEGFRvIIImutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of theEGFRvIIImutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression ofEGFRvIIIin the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of theseEGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with theEGFRvIIImutant were relatively resistant to gefitinib and erlotinibin vitrobut proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring theEGFRvIIImutation.
Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias
Authors: Lehnart Stephan E. , Terrenoire Cecile , Reiken Steven , Wehrens Xander H. T. , Song Long-Sheng , Tillman Erik J. , Mancarella Salvatore , Coromilas James , Lederer W. J. , Kass Robert S. , Marks Andrew R.
Published: May 2006

Catecholaminergic polymorphic ventricular tachycardia is a form of exercise-induced sudden cardiac death that has been linked to mutations in the cardiac Ca
2+
release channel/ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR). We have shown that catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutations significantly decrease the binding affinity for calstabin-2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. We have proposed that RyR2-mediated diastolic SR Ca
2+
leak triggers ventricular tachycardia (VT) and sudden cardiac death. In calstabin-2-deficient mice, we have now documented diastolic SR Ca
2+
leak, monophasic action potential alternans, and bidirectional VT. Calstabin-deficient cardiomyocytes exhibited SR Ca
2+
leak-induced aberrant transient inward currents in diastole consistent with delayed after-depolarizations. The 1,4-benzothiazepine JTV519, which increases the binding affinity of calstabin-2 for RyR2, inhibited the diastolic SR Ca
2+
leak, monophasic action potential alternans and triggered arrhythmias. Our data suggest that calstabin-2 deficiency is as a critical mediator of triggers that initiate cardiac arrhythmias.
Structure of the ternary signaling complex of a TGF-β superfamily member
Authors: Allendorph George P. , Vale Wylie W. , Choe Senyon
Published: May 2006

The crystal structure of the complete signaling complex formed between bone morphogenetic protein 2 (BMP-2) and the extracellular domains (ECDs) of its type I receptor [bone morphogenetic protein receptor type Ia (BMPR-Ia)-ECD] and its type II receptor [activin receptor type II (ActRII)-ECD] shows two fundamental structural constraints for receptor assembly. First, the homodimeric BMP-2 ligand assembles two pairs of each receptor symmetrically, where each of the receptor ECDs does not make physical contact. Therefore, conformational communication between receptor ECDs, if any, should be propagated through the central ligand. Second, the type I and II receptor interfaces of the complex, when compared with those of binary complexes such as BMP-2/BMPR Ia–ECD, BMP-7/ActRII-ECD, and activin/ActRIIb-ECD, respectively, show there are common sets of positions repeatedly used by both ligands and receptors. Therefore, specificity-determining amino acid differences at the receptor interfaces should also account for the disparity in affinity of individual receptors for different ligand subunits. We find that a specific mutation to BMP-2 increases its affinity to ActRII-ECD by 5-fold. These results together establish that the specific signaling output is largely determined by two variables, the ligand–receptor pair identity and the mode of cooperative assembly of relevant receptors governed by the ligand flexibility in a membrane-restricted manner.
Protein SRP68 of human signal recognition particle: Identification of the RNA and SRP72 binding domains
Authors: Iakhiaeva Elena , Bhuiyan Shakhawat Hossain , Yin Jiaming , Zwieb Christian
Published: May 2006

The signal recognition particle (SRP) plays an important role in the delivery of secretory proteins to cellular membranes. Mammalian SRP is composed of six polypeptides among which SRP68 and SRP72 form a heterodimer that has been notoriously difficult to investigate. Human SRP68 was purified from overexpressing Escherichia coli cells and was found to bind to recombinant SRP72 as well as in vitro‐transcribed human SRP RNA. Polypeptide fragments covering essentially the entire SRP68 molecule were generated recombinantly or by proteolytic digestion. The RNA binding domain of SRP68 included residues from positions 52 to 252. Ninety‐four amino acids near the C terminus of SRP68 mediated the binding to SRP72. The SRP68–SRP72 interaction remained stable at elevated salt concentrations and engaged ∼150 amino acids from the N‐terminal region of SRP72. This portion of SRP72 was located within a predicted tandem array of four tetratricopeptide (TPR)‐like motifs suggested to form a superhelical structure with a groove to accommodate the C‐terminal region of SRP68.
Cross‐sectional comparison of physical activity and inactivity patterns in Chinese and Filipino youth
Authors: Tudor‐Locke C. , Ainsworth B. E. , Adair L. S. , Du S. , Lee N. , Popkin B. M.
Published: May 2006

Background  To compare and contrast youth physical activity (PA) and inactivity patterns in two developing Asian countries: the Philippines and China.

Methods  Comparative analysis of 1997–1999 Cebu Longitudinal Health and Nutrition Survey and the 1997 China Health and Nutrition Survey, large‐scale surveys that included questions on type, frequency and duration of: commuting mode to school, sports/exercise in and outside of school, select sedentary activities and chores.

Results  Filipino data included 760 males and 872 females aged 14–16 years. The comparable Chinese sample consisted of 202 males and 197 females. Active commuting is proportionately high in both countries (70–71% in the Philippines vs. 77–90% in China), although commuting by bicycling is rare in the Philippines (<1%) vs. China (≈35%). Patterns of school sport/exercise participation differ between countries by gender; more Filipino males report school sport/exercise than females (63 vs. 49%) vs. China, where more females participate than males (75 vs. 69%). Sport/exercise outside of school is proportionately low (6–12%) for youth from both countries with a single exception: 74% of Filipino males participate in extra‐curricular sport/exercise. Although a higher percentage of Filipino youth report watching television >4 h/day (<10%) vs. Chinese youth (<1%), both are lower than comparable US reports.

Conclusion  In the Philippines, continued modernization augurs a decrease in local primary PA sources (chores and active commuting). In China, where youth already are not expected to perform chores, shifts to more passive commuting modes (i.e. increased motorized transportation) are anticipated.
Sure Start graduates: predictors of attainment on starting school
Authors: Schneider J. , Ramsay A. , Lowerson S. A.
Published: May 2006

Background  We report the analysis of the services used and the outcomes for children who used four Sure Start programmes prior to starting school in 2003.

Methods  A cohort study compared the intervention group both to classmates who lived in the areas covered by Sure Start but did not access it, and to a random sample of children in the same Local Education Authority who did not have access because they lived outside these areas. The impact of service use variables on various outcomes for users was explored using multiple linear regression analysis.

Results  No differences were found in school attainment between users and non‐users on average. However, in one of the four areas, users’ outcomes were consistently worse. By contrast, in one area, they appeared to be marginally superior on non‐academic developmental scores. When we controlled for between‐area differences, we also found an association between high use of Sure Start and personal and social development scores.

Implications  Much of the variation in outcomes remains to be explained. Tentative findings suggest stronger associations between Sure Start use and better non‐academic developmental outcomes. These findings add to our understanding of the impact of focused, high‐quality pre‐school provision. Methodological issues raised include rater bias, recruitment bias and a need to measure both frequency and type of service use.
The underpinnings of land‐use history: three centuries of global gridded land‐use transitions, wood‐harvest activity, and resulting secondary lands
Authors: HURTT G. C. , FROLKING S. , FEARON M. G. , MOORE B. , SHEVLIAKOVA E. , MALYSHEV S. , PACALA S. W. , HOUGHTON R. A.
Published: May 2006

To accurately assess the impacts of human land use on the Earth system, information is needed on the current and historical patterns of land‐use activities. Previous global studies have focused on developing reconstructions of the spatial patterns of agriculture. Here, we provide the first global gridded estimates of the underlying land conversions (land‐use transitions), wood harvesting, and resulting secondary lands annually, for the period 1700–2000. Using data‐based historical cases, our results suggest that 42–68% of the land surface was impacted by land‐use activities (crop, pasture, wood harvest) during this period, some multiple times. Secondary land area increased 10–44 × 106 km2; about half of this was forested. Wood harvest and shifting cultivation generated 70–90% of the secondary land by 2000; permanent abandonment and relocation of agricultural land accounted for the rest. This study provides important new estimates of globally gridded land‐use activities for studies attempting to assess the consequences of anthropogenic changes to the Earth's surface over time.
Multiscale model intercomparisons of CO2and H2O exchange rates in a maturing southeastern US pine forest
Authors: SIQUEIRA M. B. , KATUL G. G. , SAMPSON D. A. , STOY P. C. , JUANG J.‐Y. , MCCARTHY H. R. , OREN R.
Published: May 2006

We compared four existing process‐based stand‐level models of varying complexity (physiological principles in predicting growth, photosynthesis and evapotranspiration, biogeochemical cycles, and stand to ecosystem carbon and evapotranspiration simulator) and a new nested model with 4 years of eddy‐covariance‐measured water vapor (LE) and CO2(Fc) fluxes at a maturing loblolly pine forest. The nested model resolves the ‘fast’ CO2and H2O exchange processes using canopy turbulence theories and radiative transfer principles whereas slowly evolving processes were resolved using standard carbon allocation methods modified to improve leaf phenology. This model captured most of the intraannual variations in leaf area index (LAI), net ecosystem exchange (NEE), andLEfor this stand in which maximumLAIwas not at a steady state. The model comparisons suggest strong linkages between carbon production and LAI variability, especially at seasonal time scales. This linkage necessitates the use of multilayer models to reproduce the seasonal dynamics ofLAI,NEE, andLE. However, our findings suggest that increasing model complexity, often justified for resolving faster processes, does not necessarily translate into improved predictive skills at all time scales. Additionally, none of the models tested here adequately captured drought effects on water and CO2fluxes. Furthermore, the good performance of some models in capturing flux variability on interannual time scales appears to stem from erroneous LAI dynamics and from sensitivity to droughts that injects unrealistic flux variability at longer time scales.
Winter climate affects subsequent breeding success of common eiders
Authors: LEHIKOINEN A. , KILPI M. , ÖST M.
Published: May 2006

The phenology of spring migration depends on the severity of the preceding winter and approaching spring. This severity can be quantified using the North Atlantic Oscillation (NAO) index; positive values indicate mild winters. Although milder winters are correlated with earlier migration in many birds in temperate regions, few studies have addressed how climate‐induced variation in spring arrival relates to breeding success. In northern Europe, the NAO‐index correlates with ice cover and timing of ice break‐up of the Baltic Sea. Ice cover plays an important role for breeding waterfowl, since the timing of ice break‐up constrains both spring arrival and onset of breeding. We studied the effects of the winter‐NAO‐index and timing of ice break‐up on spring migration, laying date, clutch size, female body condition at hatching and fledging success of a short‐distance migrant common eider (Somateria mollissima) population from SW Finland, the Baltic Sea, 1991–2004 (migration data 1979–2004). We also examined the correlation between the NAO‐index and the proportion of juvenile eiders in the Danish hunting bag, which reflects the breeding success on a larger spatial scale. The body condition of breeding females and proportion of juveniles in the hunting bag showed significant positive correlations with the NAO, whereas arrival dates showed positive correlations and clutch size and fledging success showed negative correlations with the timing of ice break‐up. The results suggest that climate, which also affects ice conditions, has an important effect on the fledging success of eiders. Outbreaks of duckling disease epidemics may be the primary mechanism underlying this effect. Eider females are in poorer condition after severe winters and cannot allocate as much resources to breeding, which may impair the immune defense of ducklings. Global climate warming is expected to increase the future breeding success of eiders in our study population.
Biodegradable porous calcium polyphosphate scaffolds for the three‐dimensional culture of dental pulp cells
Authors: Wang F.‐M. , Qiu K. , Hu T. , Wan C.‐X. , Zhou X.‐D. , Gutmann J. L.
Published: May 2006

Aim  To develop a three‐dimensional culture model of human dental pulp cells (DPCs) with biodegradable porous calcium polyphosphate (CPP) scaffolds.

Methodology  Human DPCs were isolated from three donors. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assay was used to evaluate the cytotoxicity of CPP compared with hydroxyapatite (HA) and β‐tricalcium phosphate (β‐TCP). Values were analysed using unpaired t‐tests. Cells were seeded onto porous CPP scaffolds with pore sizes in the range of 200–300 μm. The nature of cellular adaptation in the three‐dimensional culture model was then evaluated visually by scanning electronic microscopy (SEM) and confocal laser scanning microscopy (CLSM). The apoptotic property of cells on the scaffolds was also assessed by DNA staining with CLSM.

Results  The cytotoxicity assay indicated that there was no significant difference between CPP and HA for each donor's original cells (P > 0.05). Calcium polyphosphate had no cytotoxic effect on DPCs, whilst SEMs showed that cells successfully adhered to CPP scaffolds and spread amongst pores. On the cell surface, fine processes and matrix secretory granules were found. Confocal laser scanning microscopy showed that cells took on a three‐dimensional structure with signs of vitality.

Conclusion  Porous CPP scaffolds are promising for the establishment of a three‐dimensional culture model of DPCs.
Formation of a hard tissue barrier after pulp cappings in humans. A systematic review
Authors: Olsson H. , Petersson K. , Rohlin M.
Published: May 2006

Aim  To evaluate the evidence on the formation of a hard tissue barrier after pulp capping in humans.

Methodology  A PubMed and CENTRAL literature search with specific indexing terms and a hand search were made. The authors assessed the level of evidence of each publication as high, moderate or low. Based on this, the evidence grade of the conclusions was rated as strong, moderately strong, limited or insufficient.

Results  The initial search process resulted in a total of 171 publications. After reading the abstracts and hand searching the reference lists of the retrieved publications, 107 studies were retrieved in full‐text and interpreted. After the interpretation, 21 studies remained and were included in the systematic review and given a level of evidence. No study had a high level of evidence, one study had moderate and 20 studies had a low level of evidence. There was heterogeneity between the studies; therefore, no meta‐analysis was performed. The majority of studies on pulp capping using calcium hydroxide based materials reported formation of hard tissue bridging, studies on other pulp capping materials such as bonding agents presented inferior results. The evidence grade was insufficient.

Conclusions  Insufficient evidence grade does not necessarily imply that there is no effect of a pulp capping procedure or that it should not be used. Rather, the insufficient evidence underpins the need for high‐quality studies.