bluuebunny/crossref_metadata_2025 huggingface dataset:
Resonance and propulsion performance of a heaving flexible wing
Authors: Michelin Sébastien , Llewellyn Smith Stefan G.
Published: July 2009

The influence of the bending rigidity of a flexible heaving wing on its propulsive performance in a two-dimensional imposed parallel flow is investigated in the inviscid limit. Potential flow theory is used to describe the flow over the flapping wing. The vortical wake of the wing is accounted for by the shedding of point vortices with unsteady intensity from the wing’s trailing edge. The trailing-edge flapping amplitude is shown to be maximal for a discrete set of values of the rigidity, at which a resonance occurs between the forcing frequency and a natural frequency of the system. A quantitative comparison of the position of these resonances with linear stability analysis results is presented. Such resonances induce maximum values of the mean developed thrust and power input. The flapping efficiency is also shown to be greatly enhanced by flexibility.
On reflection of solitary waves in a magnetized multicomponent plasma with nonisothermal electrons
Authors: Malik Hitendra K. , Singh Dhananjay K. , Nishida Yasushi
Published: July 2009

Reflection of ion acoustic solitary waves is studied in a magnetized inhomogeneous multicomponent plasma with positive ions, negative ions, and two temperature nonisothermal electrons. Relevant modified Korteweg–de Vries (mKdV) equations corresponding to two oppositely moving solitary waves are coupled to obtain a variable coefficient coupled mKdV equation, which is solved by finding some transformations to investigate the characteristics of the reflected soliton. The reflection of the soliton is possible only when the magnetic field is applied at an angle θ that remains below certain critical value, which shows strong dependence on the concentration and temperature of nonisothermal electrons in addition to the negative ion density. The present plasma model supports compressive solitons only, which reflect strongly in the presence of low temperature electron component in the plasma and are found to downshift after the reflection.
Semi-nonrelativistic limit of the Chern–Simons–Higgs system
Authors: Chae Myeongju , Huh Hyungjin
Published: July 2009

The semi-nonrelativistic limit of Chern–Simons–Higgs system is considered. We obtain several uniform estimates with respect to the light speed c and show the convergence of the solution of Chern–Simons–Higgs system to the solution of Chern–Simons–Schrödinger equations.
Static and dynamic properties of model elastomer with various cross-linking densities: A molecular dynamics study
Authors: Liu Jun , Cao Dapeng , Zhang Liqun
Published: July 2009

The effects of the cross-linking density on the static and dynamic properties of polymer networks are examined by using a molecular dynamics simulation based on a simple elastomer model. Simulation results indicate that the introduced cross-linking junctions show almost no effect on the static structure factor. The glass transition temperature Tg increases slightly with the cross-linking density. By analyzing the mean square displacement of the monomers, the chain diffusion, and the incoherent intermediate dynamic structure factor ϕqs(t) at the chain and segmental length scales, it is found that the mobilities of the monomers and chains are retarded and the relaxation behavior is hindered by the cross linking of polymers. Furthermore, the spatial localization of the monomers is also observed at a long time period for a highly cross-linked system. For the cross-linked system, the time-temperature superposition principle is valid at the segmental length scale but breaks down at the chain length scale. The effect of the cross-linking density on the terminal relaxation is investigated by the end-to-end vector correlation, which is well fitted to the Kohlrauch–William–Watts (KWW) or modified KWW functions. The characteristic relaxation time shows an approximately linear relationship with the cross-linking density. It is demonstrated that the relaxation behavior tends to broaden, attributed to the stronger intermolecular coupling or cooperativity induced by the cross linking, suggesting that the system with a higher cross-linking degree becomes more fragile. For the dynamic properties, the bond orientation and the end-to-end distance along the deformed direction, which is an indicator of the entropic change, and the nonbonded energy are examined during the deformation and relaxation processes, respectively. The results explore the molecular mechanism accounting for the residual stress in the stress relaxation of cross-linked elastomer networks.
On the 1/f noise of triple-gate field-effect transistors with high-k gate dielectric
Authors: Lukyanchikova N. , Garbar N. , Kudina V , Smolanka A. , Put S. , Claeys C. , Simoen E.
Published: July 2009

The low-frequency noise of triple-gate fin field-effect transistors (finFETs) fabricated on silicon-on-insulator (SOI) substrates, with HfO2 or HfSiON gate stacks has been studied. In most cases, 1/fγ noise has been observed with γ<1 for low frequencies f. It is shown that this type of noise can be ascribed to number fluctuations and scales with the effective device area. Based on a simple tunneling model, the noise spectral density has been converted to an oxide trap density profile, exhibiting a decay in Not for larger distances from the Si–SiO2 interface. This stands in contrast with planar bulk devices with a similar high-k gate stack and seems to be typical for the fin processing used, irrespective of further process details, like the use of selective epitaxial growth, strained SOI or strain-inducing cap layers.
Low-frequency electronic noise in the double-gate single-layer graphene transistors
Authors: Liu G. , Stillman W. , Rumyantsev S. , Shao Q. , Shur M. , Balandin A. A.
Published: July 2009

The authors report the results of an experimental investigation of the low-frequency noise in the double-gate graphene transistors. The back-gate graphene devices were modified via addition of the top gate separated by ∼20 nm of HfO2 from the single-layer graphene channels. The measurements revealed low flicker noise levels with the normalized noise spectral density close to 1/f (f is the frequency) and Hooge parameter αH≈2×10−3. The analysis of noise spectral density dependence on the top and bottom gate biases helped to elucidate the noise sources in these devices. The obtained results are important for graphene electronic and sensor applications.
Thermal lens measurement of the Soret coefficient in acetone/water mixtures
Authors: Cabrera Humberto , Martí-López Luis , Sira Eloy , Rahn Kareem , García-Sucre Máximo
Published: July 2009

The Soret coefficient of acetone/water mixtures has been experimentally determined by a recently developed thermal lens technique [Appl. Phys. Lett. 94, 051103 (2009)]. The behavior of the Soret coefficient was reproduced, including its sign change with composition. For concentrations around the equimolar ones, we have also confirmed the disagreement between the experimental and simulation data that had previously been reported by Ning and Wiegand [J. Chem. Phys. 125, 221102 (2006)] using a transient holographic grating technique of thermal diffusion forced Rayleigh scattering. Additionally, we compare our experimental results with the theoretical values predicted by a recently developed viscous energy model [J. Chem. Phys. 130, 064506 (2009)].
Clustering in nondemixing mixtures of repulsive particles
Authors: Overduin Sarah D. , Likos Christos N.
Published: July 2009

Using classical density functional theory (DFT), we investigate the phase behavior of binary mixtures, in which the interactions between all particles are described by ultrasoft, repulsive potentials. In the pure case, one of the species, species 2, forms clusters, and freezes into a cluster crystal at sufficiently high density, while the other, species 1, does not cluster and remains liquid at all densities of interest. For some mixtures, DFT predicts two instabilities in the liquid with respect to modulations of differing periodicities. One instability results from the cluster-crystal forming tendency of species 2. In concentrated species 2 mixtures, we find species 1 clusters in response to species 2 cluster formation, eventually freezing either on, or between the species 2 lattice sites. The second instability arises when the interaction between unlike species is either more favorable, or less favorable, than the interaction between like species; when less favorable, the particles form a highly delocalized cluster crystal. We examine the structure of the liquid and crystal phases. In addition, we explore the effect of the cross-interaction potential on the structure of the cluster crystal.
Wave spectra of two-dimensional Yukawa solids and liquids in the presence of a magnetic field
Authors: Hou Lu-Jing , Shukla P. K. , Piel Alexander , Mišković Z. L.
Published: July 2009

Thermally excited phonon spectra of two-dimensional Yukawa solids and liquids in the presence of an external magnetic field are studied using computer simulations. Special attention is paid to the variation of wave spectra in terms of several key parameters, such as the strength of coupling, the screening parameter, and the intensity of the magnetic field. In addition, comparisons are made with several analytical theories, including random-phase approximation, quasilocalized charge approximation, and harmonic approximation, and the validity of those theories is discussed in the present context.
Resonance-free frequency response of a semiconductor laser
Authors: Feng M. , Then H. W. , Holonyak N. , Walter G. , James A.
Published: July 2009

We show experimentally and analytically that fast spontaneous recombination lifetime, τB,spon, leads to resonance-free frequency response in semiconductor lasers, and as a consequence higher speed operation. Faster τB,spon is obtained by a reverse-bias collector field pinning and tilting a dynamic (removable) charge population in a thin base (τt∼ps), allowing only “fast” recombination. We show resonance-free optical response on a prototype transistor laser (TL) with τB,spon∼29 ps. Based on the TL, a resonance-free tilted-charge diode laser, is demonstrated with a 10.3 Gb/s “clean open-eye” signal achieved with a −3 dB bandwidth device of only 5.6 GHz.
Estimating the density of free-ranging wild horses in rugged gorges using a photographic mark - recapture technique
Authors: Vernes Karl , Freeman Melissa , Nesbitt Brad
Published: July 2009

Estimating the density of large, feral species such as wild horses at landscape scales can present a logistical hurdle for wildlife managers attempting to set density-based management targets. We undertook aerial surveys of wild horses by using a helicopter in Guy Fawkes River National Park in north-eastern New South Wales across 3 years to determine whether meaningful density estimates could be obtained efficiently by a mark–recapture technique based on recognition of individual horses. Horse groups photographed from the air on the first of two surveys conducted each year were ‘marked’ on the basis of a unique combination of colours and natural markings, and ‘recaptured’ if they were photographed and identified on the second survey. Population size was estimated with the program MARK using a range of population estimators; however, because horses appeared to be evading detection on the second survey of each year, we chose a final estimation model that accounted for detection shyness in the study species. In 2005, the density estimate was 3.8 horses per km2 (upper and lower 95% CL = 3.5–5.7 horses per km2). Following horse control in these catchments, the estimate in 2007 was 2.3 horses per km2 (upper and lower 95% CL = 2.1–3.4 horses per km2), and this change in density can be accounted for by the known number of horses removed from the survey area between survey periods. Overall, the technique proved useful for estimating densities of wild horses in deeply dissected gorge country where other estimation techniques (such as line transects) are not practical; however, low recapture rates in one of the years of the study shows that the technique may not always be applicable. Our technique should also be suitable for surveying other large mammals with broad ranges in open environments, provided recognition of individuals from unique marks is possible.
Cyclonic and anthropogenic influences on tern populations
Authors: Devney Carol A. , Short Michael , Congdon Bradley C.
Published: July 2009

Organisms can be strongly affected by a range of natural and anthropogenic stressors in conjunction, making comprehensive assessments of multiple potential drivers of population dynamics essential. An 18-year dataset obtained for Michaelmas Cay in the northern Great Barrier Reef, Australia, was used to assess population trends for three tern species relative to two potential threatening processes, namely human impacts (as either commercial fishing or tourism) and cyclone activity. We found a positive, 2-year lagged relationship between long-line catch per unit effort in the Eastern Tuna and Billfish Fishery in the vicinity of Michaelmas Cay and breeding participation in the two pelagic foraging terns, but not in the inshore foraging tern. The abundance of large pelagic fish may influence recruitment into the breeding populations of the two pelagic terns in the following years through impacts on prey availability. Long-term population trends for all seabirds were not related to localised direct disturbance from cyclones or associated changes in cay size and/or nesting habitat. Current management protocols in place for the tourism industry at the cay appear to be minimising direct human impacts. Other evidence from this breeding location suggesting that climate variation may be driving foraging success and breeding-population dynamics in the two pelagic terns implies that a precautionary approach is warranted to the management of any potential stressors to birds in this system.
Semantic activation and letter search: Blocking or suppression?
Authors: Cinel Caterina , Avons Steve E. , Russo Riccardo
Published: July 2009

Two experiments investigated associative priming with a letter-search prime task where either the prime and letter probe were presented simultaneously, or the letter probe appeared 200 ms (Experiment 1) or 300 ms (Experiment 2) after the prime. Weak associative priming was observed in both experiments, but unlike Stolz and Besner (1996) we found no evidence that priming was increased when the probe was delayed. However, strong associative priming was observed when a semantic decision had to be made on the prime (Experiment 3). Our results are consistent with an account where semantic activation of the prime occurs but its action on the target is suppressed by the prime task. The persistence of weak priming effects with the letter search task is explained in terms of the low-frequency items used.
Magnitude of negative priming varies with conceptual task difficulty: Attentional resources are involved in episodic retrieval processes
Authors: von Hecker Ulrich , Conway Michael
Published: July 2009

In a variant of the negative priming (NP) procedure, the larger of two presented animals is to be named in each trial. Eight animals of different sizes are used, which allows a manipulation of conceptual task difficulty in terms of pair distance (difficult: one step, versus easy: three steps) on the series. Distances are varied for prime pairs and probe pairs orthogonally. NP effects were found for easy (wide) probe distances (Experiments 1 and 2) and, additionally, for easy (wide) prime distances (Experiment 2). This pattern is interpreted in terms of different theories of NP, which emphasize either forward-acting (prime to probe) or backward-acting (probe to prime) processes. The present results are most compatible with a backward-acting mechanism defined by the episodic retrieval perspective; they are less compatible with a forward-acting inhibition perspective. The results have implications for resource requirements of retrieval-based accounts of NP.
Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling
Authors: Brailoiu Eugen , Churamani Dev , Cai Xinjiang , Schrlau Michael G. , Brailoiu G. Cristina , Gao Xin , Hooper Robert , Boulware Michael J. , Dun Nae J. , Marchant Jonathan S. , Patel Sandip
Published: July 2009

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP.
Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease
Authors: Semitekolou Maria , Alissafi Themis , Aggelakopoulou Maria , Kourepini Evangelia , Kariyawasam Harsha H. , Kay Antony B. , Robinson Douglas S. , Lloyd Clare M. , Panoutsakopoulou Vily , Xanthou Georgina
Published: July 2009

Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell–mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor β1 reverses activin-A–induced suppression. Remarkably, transfer of activin-A–induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease.
Evaluation of Patients' Mask Use after the Implementation of Cough Etiquette in the Emergency Department
Authors: Longtin Yves , Akakpo Christophe , Rutschmann Olivier T. , Pittet Didier , Sax Hugo
Published: July 2009

We developed a patient-based survey to evaluate the impact of a respiratory hygiene and cough etiquette implementation strategy on infection control practices in the emergency department. The frequency of self-reported mask use by coughing patients was low (27%) and often inconsistent. The frequency of use was highest among patients who presented with myalgia (odds ratio, 14.7; P = .02) and among patients who visited the emergency department during January (odds ratio, 4.1; P = .04).
Multi-dimensional correlations for gene coexpression and application to the large-scale data of Arabidopsis
Authors: Kinoshita Kengo , Obayashi Takeshi
Published: July 2009

Background: Recent improvements in DNA microarray techniques have made a large variety of gene expression data available in public databases. This data can be used to evaluate the strength of gene coexpression by calculating the correlation of expression patterns among different genes between many experiments. However, gene expression levels differ significantly across various tissues in higher organisms, as well as in different cellular location in eukaryotes in different cell state. Thus the usual correlation measure can only evaluate the difference of tissues or cellular localizations, and cannot adequately elucidate the functional relationship from the coexpression of genes.

Method: We propose a new measure of coexpression by expanding the generally used correlation into a multidimensional one. We used principal component analyses to identify the major factors of gene expression correlation, and then re-calculate the correlation by subtracting the major components in order to remove biases cased by a few experiments. The repeated subtractions of the major components yielded a set of correlation values for each pair of genes. We observed the correlation changes when the first ten principal components were subtracted step-by-step in large-scale Arabidopsis expression data.

Results: We found two extreme patterns of correlation changes, corresponding to stable and fragile coexpression. Our new indexes provided a good means to determine the functional relationships of the genes, by examining a few examples, and higher performance of Gene Ontology term prediction by using the support vector machine and the multidimensional correlation.

Availability: The results are available from the expression detail pages in ATTED-II (http://atted.jp).

Contact:  kinosita@hgc.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
FRODOCK: a new approach for fast rotational protein–protein docking
Authors: Garzon José Ignacio , Lopéz-Blanco José Ramón , Pons Carles , Kovacs Julio , Abagyan Ruben , Fernandez-Recio Juan , Chacon Pablo
Published: July 2009

Motivation: Prediction of protein–protein complexes from the coordinates of their unbound components usually starts by generating many potential predictions from a rigid-body 6D search followed by a second stage that aims to refine such predictions. Here, we present and evaluate a new method to effectively address the complexity and sampling requirements of the initial exhaustive search. In this approach we combine the projection of the interaction terms into 3D grid-based potentials with the efficiency of spherical harmonics approximations to accelerate the search. The binding energy upon complex formation is approximated as a correlation function composed of van der Waals, electrostatics and desolvation potential terms. The interaction-energy minima are identified by a novel, fast and exhaustive rotational docking search combined with a simple translational scanning. Results obtained on standard protein–protein benchmarks demonstrate its general applicability and robustness. The accuracy is comparable to that of existing state-of-the-art initial exhaustive rigid-body docking tools, but achieving superior efficiency. Moreover, a parallel version of the method performs the docking search in just a few minutes, opening new application opportunities in the current ‘omics’ world.

Availability:  http://sbg.cib.csic.es/Software/FRODOCK/

Contact:  Pablo@cib.csic.es

Supplementary information:  Supplementary data are available at Bioinformatics online.
Recruitment and Early Retention of Women with Advanced Breast Cancer in a Complementary and Alternative Medicine Trial
Authors: Sikorskii Alla , Wyatt Gwen K. , Siddiqi Azfar-e-Alam , Tamkus Deimante
Published: July 2009

More than 80% of women with breast cancer are now reported to be using complementary and alternative medicine (CAM) therapies during conventional treatment. A randomized clinical trial (RCT) of reflexology with late stage breast cancer patients serves as the data source for this article. The purposes were to investigate: (i) reasons for refusal to participate in a RCT of reflexology; (ii) the differences between those who completed the baseline interview and those who dropped out before baseline; and (iii) the utility of the Palliative Prognostic Score (PPS) as a prognostic screening tool in minimizing early attrition (before baseline) from the trial. Eligible women (N = 400) approached at 12 cancer centers in the Midwest had advanced breast cancer, were on chemotherapy or hormonal therapy, and had a PPS of 11 or less. Comparisons of those who dropped out early (N = 33) to those who stayed in the trial (N = 240) were carried out using Wilcoxon rank, t‐, chi‐squared and Fisher′s exact tests. The reasons of being “too sick” or “overwhelmed” were given by less than 12% of the women who refused to participate. There was a higher early dropout rate among black women compared to other (primarily white) women (P = .01). Cancer recurrence and metastasis, age, and the PPS were not predictive of early retention of women. Specialized techniques may be needed to ensure black women remain in the trial once consented. Women with advanced disease were likely to enter and remain in the trial despite deterioration in health.
Evaluating Chickpea Genotypes for Resistance to Ascochyta Blight in Nebraska
Authors: Harveson Robert M. , Urrea Carlos A. , Baltensperger David D.
Published: July 2009

Ten irrigated or dryland chickpea field trials in the Nebraska Panhandle over the three year period (2005-2007) assessed parental genotypes and cultivars for disease resistance to Ascochyta blight caused by Aschochyta rabiei. The most promising genotypes for all aspects of disease resistance were the breeding lines PI 17256 and CA0090B347C. PI 17256 had significantly better disease ratings in two of the four dryland trials and five of the six irrigated trials compared to the three standard commercial cultivars (Dylan, Dwelley, and Sierra). Overall, breeding line CA0090B347C was intermediate between PI 17256 and the other entries in terms of disease resistance, with similar ratings to PI 17256 but better than the commercial cultivars in two of the four dryland trials and two of the six irrigated trials. PI 17256 produced the highest yields in three trials, while CA0090347C produced significantly higher yields than the commercial cultivars in three other trials. These two lines should be useful as germplasm sources for ongoing breeding efforts to develop new, adapted blight-tolerant cultivars for Nebraska.

Accepted for publication 11 May 2009. Published 20 July 2009.
PIK3CA amplification is predictive of poor prognosis in Tunisian patients with nasopharyngeal carcinoma
Authors: Fendri Ali , Khabir Abdelmajid , Mnejja Wafa , Sellami‐Boudawara Tahia , Daoud Jamel , Frikha Mounir , Ghorbel Abdelmonem , Gargouri Ali , Mokdad‐Gargouri Raja
Published: July 2009

PI3Ks (phosphatidylinositol 3‐kinases) are lipid kinases that regulate signalling pathways involved in cell proliferation, motility, and adhesion. Somatic mutations and amplification of the PIK3CA gene have been reported in various types of human cancers. However, little is known about the frequency and prognosis role of PIK3CA activation in nasopharyngeal carcinoma (NPC). This study was conducted with the aim to screen for PIK3CA mutations in the two hot spot regions (exons 9 and 20) and to investigate for the PIK3CA gene amplification combined with the expression analysis of the phosphorylated Akt (pAkt). We showed that among 88 specimens, none had mutation in the helical domain (exon 9) and only one (1.13%) had mutation in the kinase domain (exon 20). On the other hand, PIK3CA gene amplification was found in 21.6% of cases and was strongly associated with distant metastasis (P = 0.002), lymph node involvement (P = 0.032), and advanced tumor stage (P < 0.001). Moreover, patients with PIK3CA copy number gain have a significant reduced overall survival time (P log rank = 0.02). We concluded that PIK3CA gene amplification is frequent in NPC and occurs in the advanced stage of NPC. Moreover, our finding emphasizes the association of PIK3CA gene amplification with worse prognosis in nasopharyngeal carcinoma. (Cancer Sci 2009); 00: 000–000)
Decreased expression of germinal center–associated nuclear protein is involved in chromosomal instability in malignant gliomas
Authors: Ohta Kazutaka , Kuwahara Kazuhiko , Zhang Zhenhuan , Makino Keishi , Komohara Yoshihiro , Nakamura Hideo , Kuratsu Jun‐ichi , Sakaguchi Nobuo
Published: July 2009

Malignant glioma (MG) is highly proliferative and invasive, with the malignant characteristics associated with aneuploidy and chromosomal instability (CIN). Here, we found that the level of germinal center–associated nuclear protein (GANP), a mammalian homologue of yeast Sac3, was markedly decreased in MGs with a poor prognosis; and thus we explored the effect of its decrease on cell‐cycle progression of MG cell lines. Glioblastomas showed a significantly lower level of ganp mRNA than anaplastic astrocytomas, as measured by real‐time reverse transcription‐PCR, in 101 cases of adult MG. MGs of ganpLow expression displayed more malignant characteristics, with loss of heterozygosity on chromosome 10, epidermal growth factor receptor gene amplification, and significantly poorer prognosis than the ganpHigh group. Human diploid fibroblasts depleted of ganp mRNA by the RNA interference (RNAi) method showed a decreased percentage of S‐phase cells and a cellular‐senescence phenotype. MG cell lines harboring abnormalities of various cell‐cycle checkpoint molecules displayed slippage of mitotic checkpoints and an increased proportion of hyperploid cells after ganp RNAi‐treatment. These results suggest that GANP protects cells from cellular senescence caused by DNA damage and that a significant decrease in GANP expression leads to malignancy by generating hyperploidy and CIN. (Cancer Sci 2009); 00: 000–000)
Osteoclast‐targeting small molecules for the treatment of neoplastic bone metastases
Authors: Kawatani Makoto , Osada Hiroyuki
Published: July 2009

Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical/biological approach for identifying osteoclast‐targeting small molecular inhibitors. (Cancer Sci2009)
Expression of podoplanin, CD44, and p63 in squamous cell carcinoma of the lung
Authors: Shimada Yoshihisa , Ishii Genichiro , Nagai Kanji , Atsumi Naho , Fujii Satoshi , Yamada Atsushi , Yamane Yuki , Hishida Tomoyuki , Nishimura Mitsuyo , Yoshida Junji , Ikeda Norihiko , Ochiai Atsushi
Published: July 2009

Recent molecular biological studies have identified podoplanin as a candidate cancer stem cell (CSC) marker in squamous cell carcinoma (SqCC). The purpose of this study was to examine the expression pattern of podoplanin, and the other stem cell markers CD44 and p63, and their relationship to clinico‐pathological features including survival in pulmonary SqCC. We examined histologically the expression of podoplanin, CD44, and p63 in 162 consecutive SqCC by immunostaining. Podoplanin expression was observed in 107 (66%) tumors, CD44 in 145 (89.5%), and p63 in 151 (93.2%), respectively. In 95.3% of the podoplanin‐positive tumors, tumor cells showing strong expression were localized in the periphery of the tumor nests. However, this peripheral localization was observed in only 55.9% of the CD44‐positive and 43% of p63‐positive tumors. In 88.8% of the podoplanin‐positive tumors, positive cells were localized more peripherally in the tumor nests than CD44‐ or p63‐positive cells and when CD44 and p63 expressions were compared in these podoplanin‐positive tumors, p63‐positive layers in the periphery of the tumor nests were broader compared to CD44‐positive layers. These findings suggest tumor cells are aligned in the “hierarchical distribution pattern” according to the expression of these three markers. Patients who had podoplanin‐positive tumors with the “hierarchical pattern” resulted in significantly better overall survival than those who had podoplanin‐negative tumors (P = 0.043). These results suggest that podoplanin expression would reflect the most immature status in the differentiation process of SqCC, and SqCC with hierarchical expression would be a well‐organized tumor group with lower biological aggressiveness based on the CSC concept. (Cancer Sci 2009)
The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial
Authors: Dawson Jesse , Quinn Terrence J. , Harrow Craig , Lees Kennedy R. , Walters Matthew R.
Published: July 2009

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• The therapeutic potential of xanthine oxidase inhibition with allopurinol in vascular disease is increasingly apparent.

• Allopurinol has been shown to improve measures of peripheral vascular function in those with and at risk of cardiac disease and stroke.

• It has also been shown to improve cerebrovascular function in those with diabetes, but no study has assessed its effect on cerebrovascular function in those with previous stroke.

WHAT THIS PAPER ADDS

• This study did not confirm a beneficial effect of allopurinol on cerebrovascular reactivity.

• This raises the possibility that previous encouraging findings will not therefore translate into important clinical benefits.

• Results of this and other trials suggest allopurinol may be most effective in those with increased serum uric acid levels, but cast doubt over whether previous positive effects will be sustained over a prolonged period.

AIMS

New preventative strategies for stroke are required. One promising strategy is uric acid reduction and xanthine oxidase inhibition with allopurinol. We sought to investigate whether allopurinol improves cerebrovascular reactivity (CVR) following subcortical stroke.

METHODS

We performed a randomized, double‐blind, controlled study to investigate the effect of a 3‐month course of 300 mg allopurinol once daily vs. placebo on CVR in individuals with recent (within 6 months) subcortical stroke. Participants were randomized on a 1 : 1 basis. CVR was defined as the percentage change in middle cerebral artery flow velocity following an intravenous injection of 15 mg kg−1 of acetazolamide. Our primary end‐point was the CVR difference between baseline and 3 months. Secondary end‐points included measures of peripheral vascular reactivity and blood markers of inflammation and endothelial activation.

RESULTS

We enrolled 50 participants; 45 completed the protocol. Baseline serum urate was 0.35 mmol l−1 (SD 0.1) and 0.34 mmol l−1 (SD 0.1) in the allopurinol and placebo groups, respectively. There were no serious adverse events related to treatment. CVR did not change following treatment with allopurinol [median CVR change 0.89% after allopurinol (n= 20) and −0.68% after placebo (n= 25); 95% confidence interval for estimated difference in medians −13.4, 25.5, P= 0.64]. Urate was significantly lowered by allopurinol but no change in other secondary end‐points was seen.

CONCLUSION

Xanthine oxidase inhibition with allopurinol has previously been shown to improve cerebrovascular function, but no benefit was seen in this study. It may therefore be that previous encouraging findings will not translate into important clinical benefits.
Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite
Authors: Damle Bharat D. , Uderman Howard , Biswas Pinaki , Crownover Penelope , Lin Chang , Glue Paul
Published: July 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The true influence of CYP2C19*2 mutation on the pharmacokinetics of nelfinavir and its active metabolite, M8, is not clear.

• Often, published studies have combined *2 hetero‐ and homozygous poor metabolizers (PMs) and/or have very limited data from *2 homozygotes, which contributes to the lack of clarity.

WHAT THIS STUDY ADDS

• The pharmacokinetics of nelfinavir was delineated using pharmacogenomic data from 66 healthy subjects.

• The exposure of nelfinavir was elevated, whereas that of M8 was reduced, in heterozygous and homozygous PMs in an incremental manner consistent with the loss of functional alleles.

• However, the exposure of active moiety was only modestly elevated in hetero‐ and homozygous PMs.

AIMS

This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6).

METHODS

Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady‐state plasma samples were analysed by high‐performance liquid chromatography/ultraviolet assay to determine pharmacokinetics.

RESULTS

At steady state, the mean Cmax was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean Cmax and AUC were 35% (95% CI 6, 55) and 33% (95% CI −3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean Cmax and AUC values for the active moiety were higher by 30–35% for the *1*2 and *2*2 compared with *1*1 subjects.

CONCLUSIONS

Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype.
Enzyme therapy in Fabry disease: severe adverse events associated with anti‐agalsidase cross‐reactive IgG antibodies
Authors: Tesmoingt Chloe , Lidove Olivier , Reberga Axele , Thetis Marguerite , Ackaert Chloe , Nicaise Pascale , Arnaud Philippe , Papo Thomas
Published: July 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Fabry disease is an X‐linked lysosomal storage disorder related to α‐galactosidase A deficiency.

• Two enzyme replacement therapies were approved by the European Medicines Agency in 2001: agalsidase‐alfa and agalsidase‐beta.

• Patients with Fabry disease and treated with agalsidase‐alfa or ‐beta can develop antibodies against the protein infused.

• IgG antibodies against agalsidase‐alfa and IgG and IgE antibodies against agalsidase‐beta were previously described.

WHAT THIS STUDY ADDS

• Despite two successive treatments with agalsidase in our patient, kidney function declined.

• Cross‐reactivity between the two enzymes could be demonstrated.

• Negative IgE antibodies and skin tests results do not necessarily equate with safety and the ability to continue with enzyme replacement therapies.

AIMS

To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease.

METHODS

Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments.

RESULTS

A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion‐related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin‐test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department.

CONCLUSION

The negativity of immunological tests (specific anti‐agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion.
The effect of soil phosphorus on particulate phosphorus in land runoff
Authors: Withers P. J. A. , Hartikainen H. , Barberis E. , Flynn N. J. , Warren G. P.
Published: July 2009

Accumulation of surplus phosphorus (P) in the soil and the resulting increased transport of P in land runoff contribute to freshwater eutrophication. The effects of increasing soil P (19–194 mg Olsen‐P (OP) kg−1) on the concentrations of particulate P (PP), and sorption properties (Qmax, k and EPCo) of suspended solids (SS) in overland flow from 15 unreplicated field plots established on a dispersive arable soil were measured over three monitoring periods under natural rainfall. Concentrations of PP in plot runoff increased linearly at a rate of 2.6 μg litre−1 per mg OP kg−1 of soil, but this rate was approximately 50% of the rate of increase in dissolved P (< 0.45 μm). Concentrations of SS in runoff were similar across all plots and contained a greater P sorption capacity (mean + 57%) than the soil because of enrichment with fine silt and clay (0.45–20 μm). As soil P increased, the P enrichment ratio of the SS declined exponentially, and the values of P saturation (Psat; 15–42%) and equilibrium P concentration (EPCo; 0.7–5.5 mg litre−1) in the SS fell within narrower ranges compared with the soils (6–74% and 0.1–10 mg litre−1, respectively). When OP was < 100 mg kg−1, Psat and EPCo values in the SS were smaller than those in the soil and vice‐versa, suggesting that eroding particles from soils with both average and high P fertility would release P on entering the local (Rosemaund) stream. Increasing soil OP from average to high P fertility increased the P content of the SS by approximately 10%, but had no significant (P > 0.05) effect on the Psat, or EPCo, of the SS. Management options to reduce soil P status as a means of reducing P losses in land runoff and minimizing eutrophication risk may therefore have more limited effect than is currently assumed in catchment management.
Emerging clinical concerns in the ageing haemophilia patient
Authors: KONKLE B. A. , KESSLER C. , ALEDORT L. , ANDERSEN J. , FOGARTY P. , KOUIDES P. , QUON D. , RAGNI M. , ZAKARIJA A. , EWENSTEIN B.
Published: July 2009

Summary.  The availability of safe replacement clotting factor concentrates together with effective antiviral drugs to treat human immunodeficiency and hepatitis C viruses and the provision of care at designated haemophilia treatment centres have resulted in a new phenomenon in haemophilia management – the ageing patient. Today, increasing numbers of persons with haemophilia (PWH) are middle‐aged and older, and they face the same age‐related health issues as the general population. The impact of these risks on PWH is unclear, however, and there is a paucity of information about how to manage comorbidities in this patient population. This review focuses on five comorbidities that uniquely affect older PWH: cardiovascular disease, liver disease, cancer, renal disease and joint disease. Available research is summarized and potential management approaches are suggested.
Nurturing Nature: Social Experiences and the Brain
Authors: Champagne Frances A.
Published: July 2009

How does ‘nurture’ change the brain? Recent evidence suggests that maternal care may shape the infant brain by turning genes ‘on’ or ‘off’ during development. Some of the genes affected are important for maternal and social behaviour leading to long‐term changes in the nurturing behaviour of offspring. These studies provide new insights into the inheritance of behaviour and the interactions between genes and the social environment across the lifespan.
Combined 17β‐Oestradiol and Progesterone Treatment Prevents Neuronal Cell Injury in Cortical but not Midbrain Neurones or Neuroblastoma Cells
Authors: Lorenz L. , Dang J. , Misiak M. , Tameh Abolfazl A. , Beyer C. , Kipp M.
Published: July 2009

Oestrogens are powerful endogenous and exogenous neuroprotective hormones in animal models of brain injury, including focal cerebral ischaemia. This protective effect has been demonstrated under a variety of different treatments and injury paradigms, such as in vivo and in vitro stroke conditions. Neuroprotection in the central nervous system by progesterone is less defined. In the present study, cultured cortical and midbrain mouse neurones and human neuroblastoma cells (SH‐SY5Y) were exposed to combined glucose‐serum deprivation (CGSD), which is regarded as a reliable model mimicking the effects of ischaemia in vitro. Cell viability was assayed using lactate dehydrogenase release and metabolic activity. Conditions for CGSD treatment were chosen to yield half‐maximal cell death rates. The validity of CGSD in vitro was compared with permanent middle cerebral artery occlusion (MCAO) in vivo. CGSD for 4 h induced half‐maximal neuronal cell death. MCAO in vivo for the same period resulted in significant neuronal loss, also suggesting the validity of CGSD as a suitable stroke‐like in vitro model. Combined steroid treatment (17β‐oestradiol and progesterone) but not the application of single steroids abolished CGSD‐induced cell death of cortical neurones in vitro. By contrast, no cell protection was found in midbrain neurones or neuroblastoma cells. The co‐application of oestrogen (ICI 182,780) or progesterone (RU‐486) receptor antagonists did not obviously counteract the protective steroid effects. This suggests the operation of nonclassical steroid mechanisms and their implication in mediation of hormonal effects. The surplus of combined protective hormonal effects might be a result of the observed influence of progesterone application on neuronal oestradiol synthesis. The data obtained in the present study clearly highlight the potential of a combined steroid treatment under toxic degenerative brain pathologies.