bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of sperm flagellar motility activation and chemotaxis caused by egg‐derived substance(s) in sea cucumber
Authors: Morita Masaya , Kitamura Makoto , Nakajima Ayako , Sri Susilo Endang , Takemura Akihiro , Okuno Makoto
Published: February 2009

The sea cucumber Holothuria atra is a broadcast spawner. Among broadcast spawners, fertilization occurs by means of an egg‐derived substance(s) that induces sperm flagellar motility activation and chemotaxis. Holothuria atra sperm were quiescent in seawater, but exhibited flagellar motility activation near eggs with chorion (intact eggs). In addition, they moved in a helical motion toward intact eggs as well as a capillary filled with the water layer of the egg extracts, suggesting that an egg‐derived compound(s) causes motility activation and chemotaxis. Furthermore, demembranated sperm flagella were reactivated in high pH (>7.8) solution without cAMP, and a phosphorylation assay using (γ‐32P)ATP showed that axonemal protein phosphorylation and dephosphorylation also occurred in a pH‐dependent manner. These results suggest that the activation of sperm motility in holothurians is controlled by pH‐sensitive changes in axonemal protein phosphorylation. Ca2+ concentration affected the swimming trajectory of demembranated sperm, indicating that Ca2+‐binding proteins present at the flagella may be associated with regulation of flagellar waveform. Moreover, the phosphorylation states of several axonemal proteins were Ca2+‐sensitive, indicating that Ca2+ impacts both kinase and phosphatase activities. In addition, in vivo sperm protein phosphorylation occurred after treatment with a water‐soluble egg extract. Our results suggest that one or more egg‐derived compounds activate motility and subsequent chemotactic behavior via Ca2+‐sensitive flagellar protein phosphorylation. Cell Motil. Cytoskeleton 2009. © 2009 Wiley‐Liss, Inc.
Gliotoxin reverses age‐dependent nuclear morphology phenotypes, ameliorates motility, but fails to affect lifespan of adult Caenorhabditis elegans
Authors: Bar Daniel Z. , Neufeld Ester , Feinstein Naomi , Gruenbaum Yosef
Published: February 2009

Specific mutations in human LMNA or loss of ZMPSTE26 activity cause abnormal processing of lamin A and early aging diseases, including Hutchinson Gilford progeria syndrome (HGPS). HGPS fibroblasts in culture undergo age‐dependent progressive changes in nuclear architecture. Treating these cells with farnesyl transferase inhibitors (FTIs) reverse these nuclear phenotypes and also extend lifespan of mice HGPS models. Dermal cells derived from healthy old humans also accumulate the abnormally processed lamin A. However, the effect of FTIs on normal aging cells was not tested. Aging adult C. elegans cells show changes in nuclear architecture similar to HGPS fibroblasts and down regulating lamin expression in adult C. elegans reduces their lifespan. Here, we show that nuclei of adult C. elegans, in which lamin is down‐regulated, have similar phenotypes to normal aging nuclei, but at an earlier age. We further show that treating adult C. elegans with the FTI gliotoxin reverses nuclear phenotypes and improves motility of aging worms. However, the average lifespan of the gliotoxin‐treated animals was similar to that of untreated animals. These results suggest that lamins are involved in the process of normal aging in C. elegans. Cell Motil. Cytoskeleton 2009. © 2009 Wiley‐Liss, Inc.
Design, Synthesis, and Biological Evaluation of Levoglucosenone‐Derived Ras Activation Inhibitors
Authors: Müller Christian , Gomez‐Zurita Frau Maria Antonia , Ballinari Dario , Colombo Sonia , Bitto Alessandro , Martegani Enzo , Airoldi Cristina , van Neuren Anske Stephanie , Stein Matthias , Weiser Jörg , Battistini Carlo , Peri Francesco
Published: February 2009

A panel of new potential Ras ligands was generated by decorating a tricyclic levoglucosenone‐derived scaffold with aromatic moieties. Some members of the panel show in vitro inhibitory activity toward the nucleotide exchange process on Ras and are toxic to some human cancer cell lines.

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Low‐dose azacitidine after allogeneic stem cell transplantation for acute leukemia
Authors: Jabbour Elias , Giralt Sergio , Kantarjian Hagop , Garcia‐Manero Guillermo , Jagasia Madan , Kebriaei Partow , de Padua Leandro , Shpall Elizabeth J. , Champlin Richard , de Lima Marcos
Published: February 2009

BACKGROUND:

The authors hypothesized that low doses of the hypomethylating agent 5‐azacitidine may maximize the graft‐versus‐leukemia effect and may be tolerated well after allogeneic transplantation (HSCT).

METHODS:

The drug was given to 17 patients with acute leukemia as salvage for disease recurrence after HSCT (n = 9 patients) or as maintenance therapy (n = 8 patients). 5‐Azacitidine was given subcutaneously daily for 5 days and was repeated every 4 weeks at doses of 16 mg/m2 (n = 4 patients), 24 mg/m2 (n = 9 patients), and 40 mg/m2 (n = 4 patients). A median of 8 cycles was delivered. The median follow‐up was 16 months and 11 months after HSCT and 5‐azacitidine treatment, respectively.

RESULTS:

Five of 9 patients with recurrent disease responded. Four of 13 responding patients developed disease recurrence while they were receiving 5‐azacitidine after a median of 10 months. The actuarial 1‐year event‐free and overall survival rates were 55% and 90%, respectively. There were no extramedullary toxicities, and no graft‐versus‐host disease exacerbation was observed.

CONCLUSIONS:

Low‐dose 5‐azacitidine may induce durable remissions for patients who develop disease recurrence after HSCT. Further follow‐up and a larger group of patients will be necessary to confirm these observations. Cancer 2009. © 2009 American Cancer Society.
The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta
Authors: Jhou Thomas C. , Geisler Stefanie , Marinelli Michela , Degarmo Beth A. , Zahm Daniel S.
Published: February 2009

Prior studies revealed that aversive stimuli and psychostimulant drugs elicit Fos expression in neurons clustered above and behind the interpeduncular nucleus that project strongly to the ventral tegmental area (VTA) and substantia nigra (SN) compacta (C). Other reports suggest that these neurons modulate responses to aversive stimuli. We now designate the region containing them as the “mesopontine rostromedial tegmental nucleus” (RMTg) and report herein on its neuroanatomy. Dense μ‐opioid receptor and somatostatin immunoreactivity characterize the RMTg, as do neurons projecting to the VTA/SNC that are enriched in GAD67 mRNA. Strong inputs to the RMTg arise in the lateral habenula (LHb) and, to a lesser extent, the SN. Other inputs come from the frontal cortex, ventral striatopallidum, extended amygdala, septum, preoptic region, lateral, paraventricular and posterior hypothalamus, zona incerta, periaqueductal gray, intermediate layers of the contralateral superior colliculus, dorsal raphe, mesencephalic, pontine and medullary reticular formation, and the following nuclei: parafascicular, supramammillary, mammillary, ventral lateral geniculate, deep mesencephalic, red, pedunculopontine and laterodorsal tegmental, cuneiform, parabrachial, and deep cerebellar. The RMTg has meager outputs to the forebrain, mainly to the ventral pallidum, preoptic‐lateral hypothalamic continuum, and midline‐intralaminar thalamus, but much heavier outputs to the brainstem, including, most prominently, the VTA/SNC, as noted above, and to medial tegmentum, pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe, and locus ceruleus and subceruleus. The RMTg may integrate multiple forebrain and brainstem inputs in relation to a dominant LHb input. Its outputs to neuromodulatory projection systems likely converge with direct LHb projections to those structures. J. Comp. Neurol. 513:566–596, 2009. © 2009 Wiley‐Liss, Inc.
Three‐dimensional statistical modeling of neuronal populations: Illustration with spatial localization of supernumerary neurons in the locus coeruleus of quaking mutant mice
Authors: Burguet Jasmine , Andrey Philippe , Rampin Olivier , Maurin Yves
Published: February 2009

An algorithm for the three‐dimensional statistical representation of neuronal populations was designed and implemented. Using this algorithm a series of 3D models, calculated from repeated histological experiments, can be combined to provide a synthetic vision of a population of neurons taking into account biological and experimental variability. Based on the point process theory, our algorithm allows computation of neuronal density maps from which isodensity surfaces can be readily extracted and visualized as surface models revealing the statistical organization of the neuronal population under study. This algorithm was applied to the spatial distribution of locus coeruleus (LC) neurons of 30‐ and 90‐day‐old control and quaking mice. By combining 12 3D models of the LC, a region of the nucleus in which a subpopulation of neurons loses its noradrenergic phenotype between 30 and 90 days postnatally was demonstrated in control mice but not in quaking mice, leading to the hyperplasia previously reported in adult mutants. Altogether, this algorithm allows computation of 3D statistical and graphical models of neuronal populations, providing a contribution to quantitative 3D neuroanatomical modeling. J. Comp. Neurol. 513:483–495, 2009. © 2009 Wiley‐Liss, Inc.
Calbindin and S100 protein expression in the developing inner ear in mice
Authors: Buckiová Daniela , Syka Josef
Published: February 2009

Calbindin (CB) and S100 are calcium‐binding proteins expressed in the inner ear in vertebrates. Information about their developmental roles is incomplete. This study investigated the expression patterns of CB and S100 in C3H mice using immunohistochemistry, from embryonic day 11 (E11) to postnatal day 10 (P10). CB was expressed in the otocyst and vestibulocochlear ganglion (VCG) from E11. In the cochlea at E17, CB immunoreactivity clearly labeled the VCG, the outer and inner hair cells, and the stria vascularis. CB staining was also present in the vestibular sensory cells, including their nerve fibers. Two days later, to this expression pattern was added the labeling of Kölliker's organ. Early postnatal CB expression encompassed VCG neurons, auditory hair cells, their afferent nerve fibers, and cells of the cochlear lateral wall. The first signs of S100 immunostaining of cochlear and vestibular epithelial cells appeared at E14. At E17 S100 immunoreactivity was found in a restricted expression pattern in the cochlea. Immunostaining was also present in the sacculus and utriculus and their afferent fibers. The Deiters', pillar and inner hair cells, and the VCG were S100‐positive from E19. Postnatally, S100 staining also appeared in the inner hair cells and Deiters' cells, in some VCG neurons, and, in addition, in the spiral limbus, the spiral prominence, and the intermediate cells of the stria vascularis. This study demonstrates that the sites of CB and S100 expression in the mouse inner ear during embryonic and early postnatal development do not overlap and signal independent developmental patterns. J. Comp. Neurol. 513:469–482, 2009. © 2009 Wiley‐Liss, Inc.
Effect of substrate temperature on structural and materials properties of zirconium nitride films on D9 steel substrates
Authors: Ashok K. , Subramanian B. , Kuppusami P. , Jayachandran M.
Published: February 2009

Thin zirconium nitride (ZrN) films were prepared by using reactive direct current (DC) magnetron sputtering onto D9 steel substrates. XRD technique was employed to study the coatings, observing variations of crystallite size, crystallite texture and lattice constant, as a function of substrate temperature. Chemical states of the ZrN thin films were determined by X‐ray photoelectron microscopy (XPS). AFM picture showed the presence of spherical shaped grains on the top of homogeneous granular surface. The hardness and elastic modulus values were measured by nanoindendation and their values are 18.5 and 343 GPa respectively. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Synthesis, structural and optical properties of well dispersed anatase TiO2 nanoparticles by non‐hydrothermal method
Authors: Christy P. Dennis , Jothi N. S. Nirmala , Melikechi N. , Sagayaraj P.
Published: February 2009

The formation of nanocrystalline TiO2 particles has been investigated via a surfactant‐free synthetic non‐hydrothermal method. Titanium isopropoxide and toluene were used as the starting materials. At a low temperature of 250 °C for 6 h, the reaction mixture turned in to a white precipitate (TiO2) as a result of the thermal decomposition of metal alkoxide. The obtained product was found to crystallize purely in the anatase phase with well defined morphology. The powder XRD study confirms that the average size of the particle is close to ∼15 nm. The TEM analysis indicates the sizes of the primary and secondary particles in the range between 8‐10 nm and 15‐20 nm respectively. The quantum size confinement of the crystallites is evident from the blue shift of the absorption edge in the UV‐Visible absorption spectrum. The luminescence property of the TiO2 nanoparticles studied by the emission spectrum confirms the presence of defect levels caused by the oxygen vacancies. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Role of calcineurin in thrombin‐mediated endothelial cell contraction
Authors: Kolozsvári Bernadett , Szíjgyártó Zsolt , Bai Péter , Gergely Pál , Verin Alexander , Garcia Joe G. N. , Bakó Éva
Published: February 2009

Barrier function and shape changes of endothelial cells (EC) are regulated by phosphorylation/dephosphorylation of key signaling and contractile elements. EC contraction results in intercellular gap formation and loss of the selective vascular barrier to circulating macromolecules. EC dysfunction elicited by thrombin was found to correlate with actin microfilament redistribution. It is known that calcineurin (Cn) is involved in thrombin‐induced EC dysfunction because inhibition of Cn potentiates PKC activity and the phosphorylation state of EC myosin light chain is also affected by Cn activity. Immunofluorescent detection of Cn catalytic subunit (CnA) isoforms coexpressed with GFP was visualized on paraformaldehyde (PFA) fixed bovine pulmonary artery endothelial cells (BPAEC). Actin microfilaments were stained with Texas Red‐phalloidin. Cytotoxic effects of transfections or treatments and the efficiency of transfections were assessed by flow cytometry. Treatment of BPAEC with Cn inhibitors (cyclosporin A and FK506) hindered recovery of the cells from thrombin‐induced EC dysfunction. Inhibition of Cn in the absence of thrombin had no effect on cytoskeletal actin filaments. We detected attenuated thrombin‐induced stress fiber formation and changes in cell shape only when cells were transfected with constitutively active CnA and not with various CnA isoforms. Flow cytometry (FCM) analysis has proved that cytotoxic effect of treatments is negligible. We observed that Cn is involved in the recovery from thrombin‐induced EC dysfunction. Inhibition of Cn caused prolonged contractile effect, while overexpression of constitutively active CnA resulted in reduced thrombin‐induced stress fiber formation. © 2009 International Society for Advancement of Cytometry
A tactile display using phantom sensation with apparent movement together
Authors: Ueda Shintaro , Uchida Masafumi , Nozawa Akio , Ide Hideto
Published: February 2009

When two and more stimuli are arranged in the space, an illusion such as phantom sensation and apparent movement appear in the sense of touch. The foundation research to build a system for presenting two‐dimensional information by using phantom sensation and apparent movement is done in this research. When apparent movement is used, information in the direction can be expressed between two elements of tactile stimulus in two‐dimensional vector information. In this report, the authors propose the technique of information expression using three elements for tactile stimulus that the apparent movement is used with the phantom sensation together. By this technique, two‐dimensional vector information can be expressed by three elements of tactile stimulus. © 2009 Wiley Periodicals, Inc. Electron Comm Jpn, 91(12): 29–38, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecj.10000
3D Image analysis for evaluating internal deformation / fracture characteristics of materials
Authors: Nakazawa Mitsuru , Aoki Yoshimitsu , Toda Hiroyuki , Kobayashi Masakazu
Published: February 2009

In the past, all methods which understand deformation/fracture (D/F) characteristics have been limited on the surface indirectly. D/F characteristics are impacted by nano‐scale structural features like air bubbles (pores); therefore, they need to be analyzed including inside. In this paper, we propose a system which automatically obtains the corresponding relations between pre‐ and post‐D/F pores. Our system enabled analyzing three‐dimensional, local, high‐accuracy D/F characteristics. © 2009 Wiley Periodicals, Inc. Electron Comm Jpn, 91(12): 16–23, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecj.10005
Morphogenesis of CuI Nanocrystals by a TSA‐Assisted Photochemical Route: Synthesis, Optical Properties, and Growth Mechanism
Authors: Zhang Baocheng , Xie Anjian , Shen Yuhua , Yang Liangbao , Huang Yiping , Lu Jingjing
Published: February 2009

Synthesis of nanosized CuI crystals has become more and more important due to their wide range of applications. However, it is usually difficult to control the morphology and size of CuI crystals because of the preferential growth of the (111) face. In this study, single‐crystalline γ‐CuI nanocrystals with diamond and platelet morphologies have been successfully synthesised by utilising UV‐irradiated 12‐tungstosilicate (TSA) as a reducing agent for the reduction of Cu2+ under ambient conditions. A possible growth mechanism has been proposed and this suggests that the formation of diamond‐shaped CuI nanocrystals is in accordance with homogeneous nucleation theory and the formation of CuI platelets is due to reaction‐controlled growth with (111) facets as the basal planes. Both diamond‐shaped and platelet‐shaped CuI nanocrystals have a strong emission band at 365 nm which is different from the previous reports and a high electrical conductivity, indicating their promising applications in optical and electronic nanodevices. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Synthesis and Application of N‐Hydroxylamine Derivatives as Potential Replacements for HOBt
Authors: El‐Faham Ayman , Albericio Fernando
Published: February 2009

Several heterocycles containing N‐hydroxylamine were prepared and tested as coupling additives to replace the use of N‐hydroxybenzotriazole (HOBt) derivatives. On the basis of our results on coupling yield and racemization‐suppressing properties, we propose N‐hydroxyindolin‐2‐one and 6‐chloro‐N‐hydroxy‐2‐phenylbenzimidazole as suitable substitutes for HOBt.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Reconsidering the “relative” in relative ingroup prototypicality
Authors: Ullrich Johannes
Published: February 2009

Relative ingroup prototypicality (RIP) is an important concept in the ingroup projection model (IPM) of social discrimination and tolerance. This paper reviews measures of RIP currently in use and critically examines how the notion of RIP is captured by statistical tests treating RIP as a single variable. It is concluded that composite measures of RIP imply multiple statistical hypotheses that have previously been confounded. The value of an alternative multiple regression approach is illustrated in a study testing the hypothesis of a negative relationship between RIP and outgroup attitudes. Results based on the conventional univariate analyses would have confirmed or disconfirmed the hypothesis depending on the scoring method. In contrast, the multiple regression approach described in this paper resolves this ambiguity by suggesting that only outgroup prototypicality may be necessary to predict outgroup attitudes. Copyright © 2008 John Wiley & Sons, Ltd.
Cofactor engineering of Lactobacillus brevis alcohol dehydrogenase by computational design
Authors: Machielsen Ronnie , Looger Loren L. , Raedts John , Dijkhuizen Sjoerd , Hummel Werner , Hennemann Hans‐Georg , Daussmann Thomas , van der Oost John
Published: February 2009

The R‐specific alcohol dehydrogenase from Lactobacillus brevis (Lb‐ADH) catalyzes the enantioselective reduction of prochiral ketones to the corresponding secondary alcohols. It is stable and has broad substrate specificity. These features make this enzyme an attractive candidate for biotechnological applications. A drawback is its preference for NADP(H) as a cofactor, which is more expensive and labile than NAD(H). Structure‐based computational protein engineering was used to predict mutations to alter the cofactor specificity of Lb‐ADH. Mutations were introduced into Lb‐ADH and tested against the substrate acetophenone, with either NAD(H) or NADP(H) as cofactor. The mutant Arg38Pro showed fourfold increased activity with acetophenone and NAD(H) relative to the wild type. Both Arg38Pro and wild type exhibit a pH optimum of 5.5 with NAD(H) as cofactor, significantly more acidic than with NADP(H). These and related Lb‐ADH mutants may prove useful for the green synthesis of pharmaceutical precursors.
Experimental and analytical study on pounding reduction of base‐isolated highway bridges using MR dampers
Authors: Guo Anxin , Li Zhongjun , Li Hui , Ou Jinping
Published: February 2009

Pounding between adjacent superstructures has been a major cause of highway bridge damage in the past several earthquakes. This paper presents an experimental and analytical study on pounding reduction of highway bridges subjected to earthquake ground motions by using magnetorheological (MR) dampers. An analytical model, which incorporates structural pounding and MR dampers, is developed. A series of shaking table tests on a 1:20 scaled base‐isolated bridge model are performed to investigate the effects of pounding between adjacent superstructures on the dynamics of the structures. Based on the test results, the parameters of the linear and the nonlinear viscoelastic impact models are identified. Performance of the semiactive system for reducing structural pounding is also investigated experimentally, in which the MR dampers are used in conjunction with the proposed control strategy, to verify the effectiveness of the MR dampers. Structural responses are also simulated by using the established analytical model and compared with the shaking table test results. The results show that pounding between adjacent superstructures of the highway bridge significantly increases the structural acceleration responses. For the base‐isolated bridge model considered here, the semiactive control system with MR dampers effectively precludes pounding. Copyright © 2009 John Wiley & Sons, Ltd.
Performance analysis of IDEAL algorithm for three‐dimensional incompressible fluid flow and heat transfer problems
Authors: Sun Dong‐Liang , Qu Zhi‐Guo , He Ya‐Ling , Tao Wen‐Quan
Published: February 2009

Recently, an efficient segregated algorithm for incompressible fluid flow and heat transfer problems, called inner doubly iterative efficient algorithm for linked equations (IDEAL), has been proposed by the present authors. In the algorithm there exist inner doubly iterative processes for pressure equation at each iteration level, which almost completely overcome two approximations in SIMPLE algorithm. Thus, the coupling between velocity and pressure is fully guaranteed, greatly enhancing the convergence rate and stability of solution process. However, validations have only been conducted for two‐dimensional cases. In the present paper the performance of the IDEAL algorithm for three‐dimensional incompressible fluid flow and heat transfer problems is analyzed and a systemic comparison is made between the algorithm and three other most widely used algorithms (SIMPLER, SIMPLEC and PISO). By the comparison of five application examples, it is found that the IDEAL algorithm is the most robust and the most efficient one among the four algorithms compared. For the five three‐dimensional cases studied, when each algorithm works at its own optimal under‐relaxation factor, the IDEAL algorithm can reduce the computation time by 12.9–52.7% over SIMPLER algorithm, by 45.3–73.4% over SIMPLEC algorithm and by 10.7–53.1% over PISO algorithm. Copyright © 2009 John Wiley & Sons, Ltd.
RET‐mediated gene expression pattern is affected by isoform but not oncogenic mutation
Authors: Hickey Jessica G. , Myers Shirley M. , Tian Xuefei , Zhu Shu Jun , V. Shaw Julie L. , Andrew Scott D. , Richardson Douglas S. , Brettschneider Julia , Mulligan Lois M.
Published: February 2009

The inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) is caused by mutations of the RET receptor tyrosine kinase and is characterized by medullary thyroid carcinoma. MEN 2 subtypes have distinct mutational spectrums and vary in severity. The most severe disease subtype, MEN 2B, is associated with a specific RET mutation (M918T) that has been predicted to alter downstream signaling and target gene expression patterns. We used gene expression microarray analysis to identify target genes modulated by RET. We compared two oncogenic RET mutants, associated with MEN 2A (2ARET) or MEN 2B (2BRET) disease subtypes, that are predicted to have distinct downstream target genes. We showed that overall, 2ARET and 2BRET modulated genes with similar functional ontologies. Further, when we validated our microarray data by quantitative real time PCR, we did not detect major differences in gene expression associated with these mutants when differences in receptor activity levels were considered. We did, however, detect differences in gene expression induced by two RET COOH‐terminal isoforms, RET9 and RET51, irrespective of the RET form present (wildtype, 2ARET, or 2BRET). Our data suggest that similar transcriptional programs contribute to all forms of MEN 2 but that differences in target gene expression may contribute to developmental pattern differences observed between RET isoforms. © 2009 Wiley‐Liss, Inc.
Using genome‐wide pathway analysis to unravel the etiology of complex diseases
Authors: Elbers Clara C. , van Eijk Kristel R. , Franke Lude , Mulder Flip , van der Schouw Yvonne T. , Wijmenga Cisca , Onland‐Moret N. Charlotte
Published: February 2009

Several genome‐wide association studies (GWAS) have been published on various complex diseases. Although, new loci are found to be associated with these diseases, still only very little of the genetic risk for these diseases can be explained. As GWAS are still underpowered to find small main effects, and gene‐gene interactions are likely to play a role, the data might currently not be analyzed to its full potential. In this study, we evaluated alternative methods to study GWAS data. Instead of focusing on the single nucleotide polymorphisms (SNPs) with the highest statistical significance, we took advantage of prior biological information and tried to detect overrepresented pathways in the GWAS data. We evaluated whether pathway classification analysis can help prioritize the biological pathways most likely to be involved in the disease etiology. In this study, we present the various benefits and limitations of pathway‐classification tools in analyzing GWAS data. We show multiple differences in outcome between pathway tools analyzing the same dataset. Furthermore, analyzing randomly selected SNPs always results in significantly overrepresented pathways, large pathways have a higher chance of becoming statistically significant and the bioinformatics tools used in this study are biased toward detecting well‐defined pathways. As an example, we analyzed data from two GWAS on type 2 diabetes (T2D): the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC). Occasionally the results from the DGI and the WTCCC GWAS showed concordance in overrepresented pathways, but discordance in the corresponding genes. Thus, incorporating gene networks and pathway classification tools into the analysis can point toward significantly overrepresented molecular pathways, which cannot be picked up using traditional single‐locus analyses. However, the limitations discussed in this study, need to be addressed before these methods can be widely used. Genet. Epidemiol. 33:419–431, 2009. © 2009 Wiley‐Liss, Inc.
Adapting the logical basis of tests for Hardy‐Weinberg Equilibrium to the real needs of association studies in human and medical genetics
Authors: Goddard Katrina A. B. , Ziegler Andreas , Wellek Stefan
Published: February 2009

The standard procedure to assess genetic equilibrium is a χ2 test of goodness‐of‐fit. As is the case with any statistical procedure of that type, the null hypothesis is that the distribution underlying the data is in agreement with the model. Thus, a significant result indicates incompatibility of the observed data with the model, which is clearly at variance with the aim in the majority of applications: to exclude the existence of gross violations of the equilibrium condition. In current practice, we try to avoid this basic logical difficulty by increasing the significance bound to the P‐value (e.g. from 5 to 10%) and inferring compatibility of the data with Hardy Weinberg Equilibrium (HWE) from an insignificant result. Unfortunately, such direct inversion of a statistical testing procedure fails to produce a valid test of the hypothesis of interest, namely, that the data are in sufficiently good agreement with the model under which the P‐value is calculated. We present a logically unflawed solution to the problem of establishing (approximate) compatibility of an observed genotype distribution with HWE. The test is available in one‐ and two‐sided versions. For both versions, we provide tools for exact power calculation. We demonstrate the merits of the new approach through comparison with the traditional χ2 goodness‐of‐fit test in 2×60 genotype distributions from 43 published genetic studies of complex diseases where departure from HWE was noted in either the case or control sample. In addition, we show that the new test is useful for the analysis of genome‐wide association studies. Genet. Epidemiol. 33:569–580, 2009. © 2009 Wiley‐Liss, Inc.
Targeting heat shock protein 90 with non-quinone inhibitors: A novel chemotherapeutic approach in human hepatocellular carcinoma #
Authors: Breinig Marco , Caldas-Lopes Eloisi , Goeppert Benjamin , Malz Mona , Rieker Ralf , Bergmann Frank , Schirmacher Peter , Mayer Matthias , Chiosis Gabriela , Kern Michael André
Published: February 2009

The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro, Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17-desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity. Conclusion: Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity. (Hepatology 2009.)
Social isolation prevents exercise‐induced proliferation of hippocampal progenitor cells in female rats
Authors: Leasure J. Leigh , Decker Linda
Published: February 2009

Social isolation negatively affects the behavior and health of laboratory rats. Recently, it has been found that social isolation retards exercise‐induced neurogenesis in the hippocampal dentate gyrus (DG) of male rats (Stranahan et al. (2006) Nat Neurosci 9:526–533). Since male and female rats react differently to housing changes and exercise opportunities, we investigated whether social isolation would also suppress the exercise‐dependent increase in proliferation of dentate gyrus progenitor cells in females. Accordingly, female rats were housed either alone (isolated) or in groups (social) with (exercise) or without (sedentary) the opportunity to run in an exercise wheel. Proliferating progenitor cells were labeled with bromodeoxyuridine (BrdU). As expected, exercise increased the number of BrdU+ cells in socially housed animals. However, isolation prevented this running‐induced increase. Our results expand upon previous findings by showing that the female brain is also susceptible to the suppressive effect of social isolation on exercise‐induced neurogenesis. © 2009 Wiley‐Liss, Inc.
Secoiridoid Glycosides from the Pitcher Plant Sarracenia alata
Authors: Hu Jin‐Feng , Starks Courtney M. , Williams Russell B. , Rice Stephanie M. , Norman Vanessa L. , Olson Krista M. , Hough Grayson W. , Goering Matt G. , O'Neil‐Johnson Mark , Eldridge Gary R.
Published: February 2009

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The new secoiridoid glycoside alatenoside (6) was isolated along with the known secoiridoid glycosides morroniside (1), (7α)‐7‐O‐methylmorroniside (2), (7β)‐7‐O‐methylmorroniside (3), alpigenoside (4), and kingiside (5). Complete NMR data for 2, 3, and 4 are presented here for the first time. The structure elucidation and de‐replication of the isolates were performed by utilizing a capillary‐scale NMR probe and HR‐ESI‐MS data. Alatenoside (6) represents the first naturally occurring morroniside dimer.
Synthesis and Evaluation of S‐ and C(1)‐Substituted Analogues of Lincomycin
Authors: Collin Marie‐Pierre , Hobbie Sven N. , Böttger Erik C. , Vasella Andrea
Published: February 2009

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New thioglycosides and C(1)‐alkylated thioglycosides (S‐ulosides) of lincomycin were synthesized, and their antibiotic activities were determined. The S‐aryl and S‐arylalkyl analogues 11a–11i were obtained by S‐glycosylation of the sulfoxides 7 with arenethiols, or by S‐alkylation of the thiol 14 with alkyl bromides. Lincomycin derivatives 27, 32a, 32b, 38a, 38b, 44, and 47 were prepared via Henry reaction or Michael addition of the lincosamine‐derived 1‐deoxy‐1‐nitropyranoses 22. The S‐alkyl derivatives showed a similar activity and specificity as lincomycin. Lipophilic S‐uloside analogues were two‐ to fourfold less active than the parent antibiotic, whilst the hydrophilic analogues were inactive.
Pressure drop in liquid–solid circulating fluidized beds
Authors: Hashizume Kenichi , Morita Shinichi , Nakamura Yuki , Wada Akira
Published: February 2009

An experiment was conducted to obtain data for pressure drop in risers of liquid–solid circulating fluidized beds, where two different risers (24 mm and 36 mm in diameter) were used. Tested particles were of glass and ceramics, and their diameter ranged from 2.10 to 4.95 mm. Water under ambient conditions was used as the fluidizing liquid. Pressure drop in the risers was measured using a reversed U‐tube manometer. Based on the experimental data, a calculation method was derived for predicting the pressure drop in the riser, which could reproduce almost all the data with an accuracy of ±20%. Furthermore, the effect of independent parameters was investigated on the pressure drop component ratios consisting of the total pressure drop. © 2009 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/htj.20241
Analogy between pressure drop and heat transfer in liquid–solid circulating fluidized beds
Authors: Hashizume Kenichi , Kimura Yoichi , Morita Shinichi
Published: February 2009

An analogy was found between the frictional pressure drop and the heat transfer in liquid–solid circulating fluidized beds. This investigation is based on the predicting correlations for the particle holdup, the heat transfer coefficient, and the pressure drop, which were all developed by the authors. When the heat transfer coefficients were expressed in terms of the modified j‐factor, then a close mutual relationship was observed between the modified j‐factor and the friction factor of the pressure drop due to liquid and particle flow. A correlation to express this mutual relationship was derived, which consists of the density ratio of particle to liquid and the non‐dimensional riser diameter. The heat transfer coefficient predicted from the derived correlation agreed well with the experimental data by the authors, and with existing data. © 2009 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/htj.20246
Diminished central nervous 5‐HT neurotransmission and mood self‐ratings in children and adolescents with ADHD: no clear effect of rapid tryptophan depletion
Authors: Zepf Florian Daniel , Holtmann Martin , Stadler Christina , Magnus Sophie , Wöckel Lars , Poustka Fritz
Published: February 2009

Introduction

Research on 5‐HT‐functioning in adult patients and healthy subjects using rapid tryptophan depletion (RTD) has indicated weak but stable effects on mood ratings. Altered mood in children and adolescents with attention‐deficit/hyperactivity disorder (ADHD) can confound the differential diagnosis between severe ADHD and mood disorders such as pediatric bipolar disorder. The present study investigated the effects of RTD induced lowered central nervous 5‐HT‐levels on mood self‐ratings in children with ADHD.

Methods

Seventeen boys with ADHD participated in the study in a double‐blind within‐subject crossover‐design. They were administered RTD within an amino acid drink lacking tryptophan, thus lowering central nervous 5‐HT‐synthesis. On another day they received a placebo. Self‐rated mood was assessed on both days at baseline conditions and at three different post‐drink time‐points.

Results

RTD had no clear effect on mood within the whole sample. Low scorers on venturesomeness were more strongly affected by RTD in terms of feelings of inactivity and negative feelings compared to high venture patients.

Conclusions

Our data did not show a significant effect of RTD on mood self‐ratings. However, the findings must be considered as preliminary and require further replication, in particular as they could be due to sampling bias. Copyright © 2009 John Wiley & Sons, Ltd.
Increased frequency of nonconventional double positive CD4CD8 αβ T cells in human breast pleural effusions
Authors: Desfrançois Juliette , Derré Laurent , Corvaisier Murielle , Le Mével Bernard , Catros Véronique , Jotereau Francine , Gervois Nadine
Published: February 2009

Breast cancer remains a leading cause of cancer‐related death within the female population. Immunotherapy is expected to provide additional therapeutic benefits but has met so far limited success. This may be due in part to the poor understanding of immune responses to breast cancer. Although CD4+ and CD8+ T lymphocytes infiltrate these tumors, the phenotype and functions of these cells remain ill defined. This study was designed to investigate further about these questions, taking advantage of multiparameter flow cytometry on lymphocytes derived from peripheral blood, solid tumors, metastatic lymph nodes and pleural effusions samples of patients with breast cancer. Results showed that, in addition to conventional CD4+ and CD8+ αβ T cells, individual tumors and most pleural effusions contained significant fractions of unconventional double positive (DP) CD4+CD8+ αβ T cells. These DP T cells displayed the phenotype and cytotoxic potential of effector/memory activated CD8+ T cells but differed essentially from these cells by a high production of IL‐5 and IL‐13. The increased frequency of DP T cells in advanced breast cancer and their high lytic potential and original cytokine profile suggest that this T‐cell subset may play a specific role in the regulation of immune responses to human breast cancer. © 2009 UICC
Double stranded‐RNA‐mediated activation of P21 gene induced apoptosis and cell cycle arrest in renal cell carcinoma
Authors: Whitson Jared M. , Noonan Emily J. , Pookot Deepa , Place Robert F. , Dahiya Rajvir
Published: February 2009

Small double stranded RNAs (dsRNA) are a new class of molecules which regulate gene expression. Accumulating data suggest that some dsRNA can function as tumor suppressors. Here, we report further evidence on the potential of dsRNA mediated p21 induction. Using the human renal cell carcinoma cell line A498, we found that dsRNA targeting the p21 promoter significantly induced the expression of p21 mRNA and protein levels. As a result, dsP21 transfected cells had a significant decrease in cell viability with a concomitant G1 arrest. We also observed a significant increase in apoptosis. These findings were associated with a significant decrease in survivin mRNA and protein levels. This is the first report that demonstrates dsRNA mediated gene activation in renal cell carcinoma and suggests that forced over‐expression of p21 may lead to an increase in apoptosis through a survivin dependent mechanism. © 2009 UICC.
Gender‐specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood
Authors: Khamly Kenneth K. , Thursfield Vicky J. , Fay Michael , Desai Jayesh , Toner Guy C. , Choong Peter F.M. , Ngan Samuel Y.K. , Powell Gerard J. , Thomas David M.
Published: February 2009

Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender‐related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms. © 2009 UICC
Enhanced insulin production from murine islet beta cells incubated on poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate)
Authors: Yang Xiao‐Di , Li Hong‐Ming , Chen Miao , Zou Xiang‐Hui , Zhu Lin‐Yun , Wei Chi‐ju , Chen Guo‐Qiang
Published: February 2009

Islet transplantation represents an important alternative for the treatment of diabetes. However, the selection of suitable materials is critical for the success of such an implantation application. In this study, cellular migration, aggregation, and insulin production of a murine islet beta‐cell line, NIT‐1 cells on microbially produced polyesters poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate) (PHBHHx), poly(3‐hydroxybutyrate‐co‐4‐hydroxybutyrate) (P3HB4HB) or polylactic acid (PLA) films were investigated. Spherical islet‐like structures were only detected on PHBHHx films after 48 h cultivation. To understand the mechanism underlying the formation of cell aggregates, NIT‐1‐GFP, a stable transfectant of the green fluorescent protein was used in a time‐lapse imaging study. Cell aggregation began on PHBHHx at 2 h, and became obvious at 4 h. Furthermore, cells on PHBHHx displayed higher metabolic activities measured by MTT assay than that on tissue culture plate. More importantly, insulin gene expression as well as extracellular secretion was upregulated after growth on PHBHHx for 72 h. Thus, PHBHHx can be a strong candidate for islet transplantation. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
ERCC1 expression in aseptic loosening after total hip replacement
Authors: Landgraeber Stefan , von Knoch Marius , Löer Franz , Wegner Alexander , Tsokos Michael , Schmid Kurt Werner , Totsch Martin
Published: February 2009

Particle‐induced osteolysis is a major cause of aseptic loosening after total joint replacement. The purpose of the current study was to evaluate the DNA damage repair capacity of macrophages in patients with aseptic hip loosening by determination of ERCC1. Moreover, we wanted to elucidate if the potency of the DNA‐repair mechanisms correlates with the survival of joint implants. For this purpose we compared the immunohistochemical ERCC1 expression in capsules and interface membranes of patients with loosening of a hip replacement in the first 10 years after implantation with those in patients with late loosening. In analogy with ERCC1 studies on cancer in humans we calculated the semi‐quantitative H‐score by multiplying the staining intensity with the proportion score of positive stained macrophages. The level of ERCC1 reaction in the specimens taken from patients with early aseptic loosening (mean H‐score 0.57) was clearly lower in comparison with those from patients undergoing exchange hip arthroplasty later than 10 years after surgery (mean H‐score 2.24). We determined an H‐score for ERCC1 expression of 1 as a cutoff point giving a sensitivity and specificity of 100% for identification of early aseptic loosening after less than 10 years. In summary, lower levels of ERCC1 were found in patients with early aseptic loosening compared to patients with aseptic loosening later than 10 years. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010