bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrocyte cultures exhibit P2X7 receptor channel opening in the absence of exogenous ligands
Authors: Nagasawa Kazuki , Escartin Carole , Swanson Raymond A.
Published: October 2008

P2X7 receptors (P2X7Rs) gate the opening of large channels when activated by ATP or other ligands. P2X7Rs are expressed by astrocytes in culture and by reactive astrocytes in vivo, and astrocytes in culture have been shown to release glutamate and ATP in response to P2X7R activation. However, P2X7Rs are activated by ATP only at concentrations greater than 1 mM. The conditions under which astrocyte P2X7Rs would be activated in vivo are, thus, unclear. Here we show that astrocytes in culture exhibit basal P2X7R activity. Primary mouse astrocytes were found to take up the P2X7R permeant dyes YO‐PRO‐1 (YP) and propidium iodide in absence of any added ligands. By contrast, cultured rat astrocytes took up very little YP, consistent with their much lower level of P2X7R expression. The uptake by mouse astrocytes was inhibited by oxATP, suramin, KN‐62 and brilliant blue G, and by siRNA knock‐down of P2X7R. Astrocyte uptake of YP was also inhibited by phenol red at concentrations above 50 μM, suggesting that phenol red present in standard cell culture media may influence P2X7R channel activity. Treatment with apyrase, an enzyme that degrades extracellular ATP, partially decreased YP uptake in astrocytes. Conversely, exposure to the ectonucleotidase inhibitor ARL67156 enhanced YP uptake and astrocytes plated without contiguous neighboring astrocytes showed reduced basal YP uptake. These results suggest that the basal uptake of YP may be due to activation of P2X7R by release of ATP by astrocytes themselves into intercellular spaces. © 2008 Wiley‐Liss, Inc.
Climate variability, snow, and physiographic controls on storm hydrographs in small forested basins, western Cascades, Oregon
Authors: Perkins Reed M. , Jones Julia A.
Published: October 2008

Large floods are often attributed to the melting of snow during a rain event. This study tested how climate variability, snowpack presence, and basin physiography were related to storm hydrograph shape in three small (<1 km2) basins with old‐growth forest in western Oregon. Relationships between hydrograph characteristics and precipitation were tested for approximately 800 storms over a nearly 30‐year period. Analyses controlled for (1) snowpack presence/absence, (2) antecedent soil moisture, and (3) hillslope length and gradient. For small storms (<150 mm precipitation), controlling for precipitation, the presence of a snowpack on near‐saturated soil increased the threshold of precipitation before hydrograph rise, extended the start lag, centroid lag, and duration of storm hydrographs, and increased the peak discharge. The presence of a snowpack on near‐saturated soil sped up and steepened storm hydrographs in a basin with short steep slopes, but delayed storm hydrographs in basins with longer or more gentle slopes. Hydrographs of the largest events, which were extreme regional rain and rain‐on‐snow floods, were not sensitive to landform characteristics or snowpack presence/absence. Although the presence of a snowpack did not increase peak discharge in small, forested basins during large storms, it had contrasting effects on storm timing in small basins, potentially synchronizing small basin contributions to the larger basin hydrograph during large rain‐on‐snow events. By altering the relative timing of hydrographs, snowpack melting could produce extreme floods from precipitation events whose size is not extreme. Further work is needed to examine effects of canopy openings, snowpack, and climate warming on extreme rain‐on‐snow floods at the large basin scale. Copyright © 2008 John Wiley & Sons, Ltd.
Aryl hydrocarbon receptor polymorphism modulates DMBA‐induced inflammation and carcinogenesis in phenotypically selected mice
Authors: De Souza Vinicius R.C. , Cabrera Wafa K. , Galvan Antonella , Ribeiro Orlando G. , De Franco Marcelo , Vorraro Francisca , Starobinas Nancy , Massa Solange , Dragani Tommaso A. , Ibañez Olga M.
Published: October 2008

We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,12‐dimethylbenz[a]anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1β, Tnf, Il6, Tgfβ1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high‐affinity ligand‐binding receptor (Ahrb1), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low‐affinity binding receptor (Ahrd), to DMBA. The differential segregation of Ahr functional Ahrdversus Ahrb1 alleles in AIRmax and AIRmin suggests a role for the Ahr gene in the control of inflammatory responsiveness and tumor development of these mouse lines. © 2008 Wiley‐Liss, Inc.
IL‐13 cytotoxin has potent antitumor activity and synergizes with paclitaxel in a mouse model of oral squamous cell carcinoma
Authors: Kioi Mitomu , Shimamura Takeshi , Nakashima Hideyuki , Hirota Makoto , Tohnai Iwai , Husain Syed R. , Puri Raj K.
Published: October 2008

Interleukin‐13 receptor‐targeted cytotoxin (IL13‐PE38) is highly cytotoxic to certain types of human cancers expressing abundant levels of IL‐13Rα2 chain. Although IL13‐PE38 is being tested in a Phase III clinical trial in brain tumors, the activity of IL13‐PE38 alone or when combined with taxane, a chemotherapeutic drug for oral squamous cell carcinoma (OSCC), has not been investigated. Here, we show that approximately 40% of OSCCs (n = 50) in a tissue array are strongly positive for IL‐13Rα2, whereas normal oral mucosa (n = 10) expresses very low or undetectable levels evaluated by immunohistochemistry. IL13‐PE38 was highly cytotoxic to OSCC cell lines, but not cytotoxic to normal oral fibroblasts. IL13‐PE38 mediated a synergistic antitumor effect with paclitaxel in OSC‐19 in vitro and in vivo in the orthotopic OSCC tongue tumor model. Real‐time tumor growth was monitored by optical imaging using a Xenogen‐IVIS imaging system. Treated animals showed significant (p < 0.05) improvement in survival, which correlated with in vivo imaging of tumor response without evidence of visible toxicity. Gene transfer of IL‐13Rα2 in oral cancer cells increased sensitivity of OSCC cell line to IL13‐PE38 in vitro. Retrovirus‐mediated gene‐transfer of IL‐13Rα2 in HSC‐3 into tongue tumors in vivo dramatically enhanced the antitumor activity of IL13‐PE38, providing complete elimination of established tumors and prolonging survival of these animals. These results indicate that IL13‐PE38 in combination with paclitaxel acting via different mechanisms may be a potential treatment option for IL‐13Rα2 expressing OSCC or for the treatment of non–IL‐13Rα2 expressing OSCC combined with gene transfer of IL‐13Rα2. Published 2008 Wiley‐Liss, Inc.
Sensitization of neuroblastoma cells for TRAIL‐induced apoptosis by NF‐κB inhibition
Authors: Ammann Johannes U. , Haag Christian , Kasperczyk Hubert , Debatin Klaus‐Michael , Fulda Simone
Published: October 2008

The transcription factor nuclear factor‐kappaB (NF‐κB) plays a central role in stress‐induced transcriptional activation and has been implicated in chemoresistance of cancers. In the present study, we investigated the role of NF‐κB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP16 and the cytotoxic ligand TRAIL trigger NF‐κB activation, whereas cisplatin and taxol have no impact on NF‐κB activity. Specific inhibition of NF‐κB activation by overexpression of dominant‐negative mutant IκBα‐super‐repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin‐ or VP16‐mediated NF‐κB activation. By comparison, inhibition of TRAIL‐stimulated NF‐κB activation by IκBα‐superrepressor or the small molecule NF‐κB inhibitor BMS‐345541 significantly enhances TRAIL‐induced apoptosis, pointing to an antiapoptotic function of NF‐κB in TRAIL‐mediated apoptosis. Analysis of signaling pathways reveals that NF‐κB inhibition prevents TRAIL‐triggered up‐regulation of Mcl‐1, promoting TRAIL‐induced cytochrome c release and activation of caspases. Accordingly, knockdown of Mcl‐1 by RNA interference significantly enhances TRAIL‐induced apoptosis and also increases sensitivity of neuroblastoma cells to CD95‐ or chemotherapy‐induced apoptosis. In conclusion, NF‐κB regulates apoptosis in a stimulus‐specific manner in neuroblastoma cells and confers protection against TRAIL‐induced apoptosis. By demonstrating that NF‐κB inhibition sensitizes neuroblastoma cells for TRAIL‐induced apoptosis, our findings have important implications. Thus, NF‐κB inhibitors may open new perspectives to potentiate the efficacy of TRAIL‐based protocols in the treatment of neuroblastoma. © 2008 Wiley‐Liss, Inc.
Aberrant expression of proteinase‐activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB‐2 kinase
Authors: Gratio Valérie , Walker Francine , Lehy Thérèse , Laburthe Marc , Darmoul Dalila
Published: October 2008

Thrombin is now recognized as an important factor in many cancers. Here, we examined the expression and role of the recently discovered thrombin receptor PAR4, in human colon cancer cells. PAR4 mRNA was found in 10 out of 14 (71%) human colon cancer cell lines tested but not in epithelial cells isolated from normal human colon. This finding is in line with immunostaining results of PAR4 in human colon tumors and its absence in normal human colonic mucosa. Investigation of the functional significance of the aberrant expression of PAR4 in colon cancer cells revealed (i) a prompt increase in intracellular calcium concentration on challenge with PAR4‐specific agonist AP4 (100 μM) and (ii) marked mitogenic response (2.5‐fold increase in cell number) in a dose‐dependent manner on treatment with AP4 (0.1–300 μM). Analysis of the signaling pathways downstream of PAR4 activation in HT29 cells showed (i) a sustained phosphorylation of extracellular signal‐related kinase 1/2 (ERK1/2) and (ii) the involvement of epidermal growth factor receptor B‐2 (ErbB‐2) but not of epidermal growth factor receptor in PAR4‐induced mitogen‐activated protein kinase activation. Tyrphostin AG1478, the ErbB inhibitor, reversed the action of AP4 on ERK1/2 and ErbB‐2 phosphorylation and HT29 cell growth. Finally, the Src inhibitor PP2 abrogated ErbB‐2 and ERK phosphorylation and HT29 cell proliferation, suggesting the essential role of Src activity in PAR4‐induced phosphorylation of ErbB‐2. These data highlight the role of PAR4 as a new important player in the control of colon tumors and underline the critical role of ErbB‐2 transactivation. © 2008 Wiley‐Liss, Inc.
Dysregulated microRNAs and their predicted targets associated with endometrioid endometrial adenocarcinoma in Hong Kong women
Authors: Chung Tony K.H. , Cheung Tak‐Hong , Huen Ngar‐Yee , Wong Katherine W.Y. , Lo Keith W.K. , Yim So‐Fan , Siu Nelson S.S. , Wong Yin‐Mei , Tsang Po‐Ting , Pang Man‐Wah , Yu Mei‐Yun , To Ka‐Fei , Mok Samuel C. , Wang Vivian W. , Li Chen , Cheung Albert Y.K. , Doran Graeme , Birrer Michael J. , Smith David I. , Wong Yick‐Fu
Published: October 2008

The objective of this study, a parallel study to global gene expression profiling, was to identify dysregulated microRNAs (miRNAs) associated with endometrioid endometrial adenocarcinoma (EEC), examine their correlation with clinico‐pathological characteristics and identify predicted target genes of the dysregulated miRNAs. Using real‐time quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR), profiling of miRNA expression was performed in 30 EECs and 22 normal counterparts in which genome‐wide gene expression had been previously profiled and reported. Clustering analysis identified 30 miRNAs which were significantly dysregulated in EEC. The expression of a sub‐group of miRNAs was significantly correlated with clinico‐pathological characteristics including stage, myometrial invasion, recurrence and lymph node involvement. By searching for predicted miRNA targets that were linked to the dysregulated genes previously identified, 68 genes were predicted as candidate targets of these 30 dysregulated miRNAs. miR‐205 was significantly overexpressed in EECs compared with normal controls. After transfection of a miR‐205 inhibitor, the expression of miR‐205 in endometrial cancer cell line RL95‐2 cells decreased whereas its predicted target gene, JPH4, showed increased protein expression. JPH4 seems to be a real miR‐205 target in vitro and in vivo, and a candidate tumor suppressor gene in EEC. Based on this study in EEC, miRNAs predicted to be involved in tumorigenesis and tumor progression have been identified and placed in the context of the transcriptome of EEC. This work provides a framework on which further research into novel diagnosis and treatment of EEC can be focused. © 2008 Wiley‐Liss, Inc.
HINT1 inhibits β‐catenin/TCF4, USF2 and NFκB activity in human hepatoma cells
Authors: Wang Lin , Li Haiyang , Zhang Yujing , Santella Regina M. , Weinstein I. Bernard
Published: October 2008

In this study we explored the relevance of Hint, a novel tumor suppressor gene, to human hepatoma. The human hepatoma cell lines Hep3B and HepG2 express very low levels of the HINT1 protein but the Huh7 cells express a relatively high level. In Hep3B and HepG2 cells, but not in Huh7 cells, the promoter region of Hint1 is partially methylated and treatment with 5‐azadcdeoxycytidine increased expression of the HINT1 protein and Hint1 mRNA in Hep3B and HepG2 cells. Increased expression of HINT1 in HepG2 cells markedly inhibited their growth. It also inhibited the transcriptional activities of β‐catenin/TCF4, and USF2, and inhibited the expression of endogenous cyclin D1 and TGFβ2. Furthermore, HINT1 co‐immunoprecipitated with USF2 in extracts of Hep2 cells. HINT1 also inhibited NFκB transcription factor reporter activity and inhibited translocation of the endogenous p65 protein to the nucleus of HepG2 cells. Therefore, decreased expression of the Hint1 gene through epigenetic silencing may play a role in enhancing the growth of a subset of human hepatoma by increasing the expression of genes controlled by the transcription factors β‐catenin, USF2, and NFκB. © 2008 Wiley‐Liss, Inc.
Hormone escape is associated with genomic instability in a human prostate cancer model
Authors: Legrier Marie‐Emmanuelle , Guyader Charlotte , Céraline Jocelyn , Dutrillaux Bernard , Oudard Stéphane , Poupon Marie‐France , Auger Nathalie
Published: October 2008

Lack of hormone dependency in prostate cancers is an irreversible event that occurs through generation of genomic instability induced by androgen deprivation. Indeed, the cytogenetic profile of hormone‐dependent (HD) prostate cancer remains stable as long as it received a hormone supply, whereas the profile of hormone‐independent (HID) variants acquired new and various alterations. This is demonstrated here using a HD xenografted model of a human prostate cancer, PAC120, transplanted for 11 years into male nude mice and 4 HID variants obtained by surgical castration. Cytogenetic analysis, done by karyotype, FISH, CGH and array‐CGH, shows that PAC120 at early passage presents numerous chromosomal alterations. Very few additional alterations were found between the 5th and 47th passages, indicating the stability of the parental tumor. HID variants largely maintained the core of chromosomal alterations of PAC120 — losses at 6q, 7p, 12q, 15q and 17q sites. However, each HID variant displayed a number of new alterations, almost all being specific to each variant and very few shared by all. None of the HID had androgen receptor mutations. Our study indicates that hormone castration is responsible for genomic instability generating new cytogenetic abnormalities susceptible to alter the properties of cancer cell associated with tumor progression, such as increased cell survival and ability to metastasize. © 2008 Wiley‐Liss, Inc.
Over‐expression of phosphatase of regenerating liver‐3 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma
Authors: Zhou Jun , Wang Shuang , Lu Juan , Li Jianming , Ding Yanqing
Published: October 2008

This study aimed at clarifying the expression of phosphatase of regenerating liver‐3 (PRL‐3), one member of protein tyrosine phosphatase (PTP) superfamily, in nasopharyngeal carcinoma (NPC) and its correlation with clinicopathologic features, including the survival of patients with NPC. Real‐time PCR and Western blot showed that the expression level of PRL‐3 was markedly higher in NPC cell lines than that in the normal nasopharyngeal epithelial cell at both mRNA and protein levels. Immunohistochemical analysis revealed overexpression of PRL‐3 in 97 of 174 (55.7%) paraffin‐embedded archival NPC biopsies. Statistical analysis showed that PRL‐3 expression was positively correlated with N classification (p = 0.033), distant metastasis (M classification, p = 0.048) and clinical stage (p = 0.005) of patients. Patients with higher PRL‐3 expression had shorter overall survival time, whereas patients with lower level of PRL‐3 had better survival. Multivariate analysis suggested that PRL‐3 expression might be an independent prognostic indicator for the survival of patients with NPC. Disruption of endogenous PRL‐3 protein through a siRNA knockdown technique was shown to suppress the invasion ability and migration potency of 5‐8F and HONE1 cells, substantially. Interestingly, we also found that no significant effect on the proliferation of 5‐8F and HONE1 cells was observed after PRL‐3 was down‐regulated. Our results suggest that PRL‐3 protein is a valuable marker for progression of NPC patients. High PRL‐3 expression is associated with poor overall survival in patients with NPC. © 2008 Wiley‐Liss, Inc.
Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells
Authors: Schwinn Nicole , Vokhminova Daria , Sucker Antje , Textor Sonja , Striegel Sandra , Moll Iris , Nausch Norman , Tuettenberg Jochen , Steinle Alexander , Cerwenka Adelheid , Schadendorf Dirk , Paschen Annette
Published: October 2008

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of αβ CD8+ T cells. Ligands of NKG2D, the MHC class I chain‐related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon‐γ (IFN‐γ) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I‐negative and ‐positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN‐γ treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down‐regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT‐PCR revealed a decrease of MICA‐specific mRNA levels upon IFN‐γ treatment and siRNA experiments pointed to an involvement of STAT‐1 in this process. Importantly, IFN‐γ‐treated MHC class I‐negative melanoma cells were less susceptible to NKG2D‐mediated NK cell cytotoxicity. Our study suggests that IFN‐γ, by down‐regulating ligand expression, might facilitate escape of MHC class I‐negative melanoma cells from NKG2D‐mediated killing by NK cells. © 2008 Wiley‐Liss, Inc.
Response of two legume crops to soil salinity in gypsiferous soils
Authors: Webber Heidi , Madramootoo Chandra , Bourgault Maryse , Horst Mikhail , Stulina Galina , Smith Donald
Published: October 2008

Competition for water resources, increasing land salinization and the need to feed a growing population are challenges facing irrigated agriculture in the Fergana Valley of Uzbekistan. Growing short‐season legumes with water‐saving irrigation technologies is one strategy for increasing food production and land productivity using relatively less water. However, little information is available to assess how these crops will respond when produced with deficit irrigation on the gypsiferous soils of the region. This greenhouse study evaluated various growth components of common bean and green gram irrigated with deficit irrigation in soils with and without gypsum and at three levels of soil salinity. Results showed that biomass and leaf area decreased by approximately 20% for both crops, as ECe increased from 2.8 to 7 dS m−1. Yields were higher at all salinities for green gram than in common bean. However, relative yield reductions with increasing salinity were greater for green gram (43%) compared to common bean (19–31%). The presence of gypsum enabled both crops to maintain reasonable yield at ECe values which would be lethal in soils dominated both other salts. The effect of increasing salinity was the same at all levels of deficit irrigation. Copyright © 2008 John Wiley & Sons, Ltd.
Water for food as food for thought: case study of applying the PODIUMSim model to Uzbekistan
Authors: Yakubov Murat , Manthrithilake Herath
Published: October 2008

Uzbekistan, being historically one of the most populated and agriculture‐based republics in the former Soviet Union, still features quite high annual population growth rates and great dependence on agriculture as a backbone for the rest of the economic reforms. With water playing an extremely important role in producing a sufficient food base for the country's growing population and earning much needed foreign exchange for the government to ensure overall economic development, the pressures on this scarce resource will obviously and inevitably grow, putting it much at risk over a long‐term perspective. So would available water be enough to meet ever‐increasing demands from major economic uses in the foreseeable future, and what can be the options for meeting such demands – these are the key questions raised and researched in this article. As such the research concentrates on the two major country‐specific scenarios with water and its multiple uses for Uzbekistan – the business as usual and the best case. Both scenarios discuss possible future implications for the next quarter‐century given certain assumptions. Finally when summarizing the findings, the paper provides conclusions and recommendations as to how the model and further scenarios can be better optimized given the trans‐boundary nature of most water resources in Central Asia where Uzbekistan geographically belongs. Copyright © 2008 John Wiley & Sons, Ltd.
Beware expense reimbursement schemes!
Authors: McGee Jo Ann , Byington J. Ralph
Published: October 2008

Your employees may be stealing your cash with clever expense reimbursement schemes that are difficult to spot. Reports of this kind of cash fraud appear in the press on a daily basis. What kinds of schemes are out there, and what can you do to prevent and detect them? © 2008 Wiley Periodicals, Inc.
Prevent large cash losses from small business fraud
Authors: Johnson Leigh Redd , Rudolph Holly R.
Published: October 2008

Over the past few years, the spotlight has been on large corporate frauds. These resulted from cash management systems devoid of adequate controls and governance.

But about half of all frauds occur in small businesses—and the effect is often devastating. The average loss for any small business fraud scheme was found to be greater than in any other business‐size category.

Since fraud generally starts small—even in large companies—everyone can benefit from sharpening their cash management fraud prevention. This article examines five cases of smaller frauds that could lead to large cash losses. And the authors give advice on how to better detect and prevent such frauds in the future. © 2008 Wiley Periodicals, Inc.
Treasury products for mid‐to‐small corporations
Authors: Sagner James S.
Published: October 2008

The treasury and noncredit services market for mid‐size and smaller corporations is significantly different from the one for Fortune 500 companies—although the banks have focused mostly on the latter. As a result, bankers and other financial service professionals usually approach a “mid‐to‐small” business project using the wrong assumptions and techniques.

The author examines this situation and suggests other ways for mid‐to‐small companies and banks to establish relationships. © 2008 Wiley Periodicals, Inc.
Grappling with global compliance
Authors: Simon Gary , Krause Delbert
Published: October 2008

Since the onset of Sarbanes‐Oxley and other new compliance regulations, global businesses have faced a bewildering tide of new regulations. What you don't know can—and will—hurt you.

So, how can you stay ahead of the curve? © 2008 Wiley Periodicals, Inc.
Simple, effective performance management: A top‐down and bottom‐up approach
Authors: Muras Andrew , Smith Thomas , Meyers Deborah
Published: October 2008

Performance management systems sometimes confuse rather than enlighten managers and employees. The combination of complex processes, competing IT systems, and multiple dashboards often fails to provide the insight needed to bring change, so the metrics become irrelevant. Using a back‐to‐basics approach and employing two well‐known processes—activity analysis and balanced scorecards—overcomes this irrelevance. Employing a simple, straightforward, and linked approach provides the information necessary to measure and improve performance from both an operational and strategic perspective. This article provides an overview of the linked concept and two case studies of implementations. © 2008 Wiley Periodicals, Inc.
Automated exploration of stable isomers of H+(H2O)n (n = 5–7) via ab initio calculations: An application of the anharmonic downward distortion following algorithm
Authors: Luo Yi , Maeda Satoshi , Ohno Koichi
Published: October 2008

Isomers of protonated water clusters H+(H2O)n (n = 5–7) have been explored on ab initio potential energy surfaces by means of the anharmonic downward distortion following algorithm. Totally, 9, 24, and 131 isomers for n = 5, 6, and 7, respectively, were located by the automatic exploration, and all of known important isomers previously reported by conventional geometry optimization approaches have been included in the present results. Moreover, structure transitions depending on n and temperature, which were observed by experimental studies, could be reproduced via thermodynamic simulation on the basis of the superposition approach and the present isomer sets. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
tCONCOORD‐GUI: Visually supported conformational sampling of bioactive molecules
Authors: Seeliger Daniel , De Groot Bert L.
Published: October 2008

Conformational flexibility of bioactive molecules poses a major challenge to computational biology. tCONCOORD generates structure ensembles based on geometrical considerations and has been successfully applied to predict protein conformational flexibility and essential degrees of freedom. We have now developed a graphical user interface (GUI) for tCONCOORD, which substantially facilitates the simulation setup and provides valuable insights into the structure analysis and constraint definition process in tCONCOORD. Moreover, users can influence the constraint definition process by interactively turning interactions on and off, defining completely rigid or flexible regions, or by applying artifical constraints that cause a biased sampling of the conformational space. This interface offers a versatile environment not only for the setup and analysis of tCONCOORD simulations, but also for molecular modeling and structure analysis in general. Both tCONCOORD* and the tCONCOORD‐GUI† are distributed freely. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
Probing the free energy landscape of the FBP28WW domain using multiple techniques
Authors: Periole Xavier , Allen Lucy R. , Tamiola Kamil , Mark Alan E. , Paci Emanuele
Published: October 2008

The free‐energy landscape of a small protein, the FBP 28 WW domain, has been explored using molecular dynamics (MD) simulations with alternative descriptions of the molecule. The molecular models used range from coarse‐grained to all‐atom with either an implicit or explicit treatment of the solvent. Sampling of conformation space was performed using both conventional and temperature‐replica exchange MD simulations. Experimental chemical shifts and NOEs were used to validate the simulations, and experimental ϕ values both for validation and as restraints. This combination of different approaches has provided insight into the free energy landscape and barriers encountered by the protein during folding and enabled the characterization of native, denatured and transition states which are compatible with the available experimental data. All the molecular models used stabilize well defined native and denatured basins; however, the degree of agreement with the available experimental data varies. While the most detailed, explicit solvent model predicts the data reasonably accurately, it does not fold despite a simulation time 10 times that of the experimental folding time. The less detailed models performed poorly relative to the explicit solvent model: an implicit solvent model stabilizes a ground state which differs from the experimental native state, and a structure‐based model underestimates the size of the barrier between the two states. The use of experimental ϕ values both as restraints, and to extract structures from unfolding simulations, result in conformations which, although not necessarily true transition states, appear to share the geometrical characteristics of transition state structures. In addition to characterizing the native, transition and denatured states of this particular system in this work, the advantages and limitations of using varying levels of representation are discussed. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
WebMTA: A web‐interface for ab initio geometry optimization of large molecules using molecular tailoring approach
Authors: Kavathekar Ritwik , Khire Subodh , Ganesh V. , Rahalkar Anuja P. , Gadre Shridhar R.
Published: October 2008

A web‐interface for geometry optimization of large molecules using a linear scaling method, i.e., cardinality guided molecular tailoring approach (CG‐MTA), is presented. CG‐MTA is a cut‐and‐stitch, fragmentation‐based method developed in our laboratory, for linear scaling of conventional ab initio techniques. This interface provides limited access to CG‐MTA‐enabled GAMESS. It can be used to obtain fragmentation schemes for a given spatially extended molecule depending on the maximum allowed fragment size and minimum cut radius values provided by the user. Currently, we support submission of single point or geometry optimization jobs at Hartree‐Fock and density functional theory levels of theory for systems containing between 80 to 200 first row atoms and comprising up to 1000 basis functions. The graphical user interface is built using HTML and Python at the back end. The back end farms out the jobs on an in‐house Linux‐based cluster running on Pentium‐4 Class or higher machines using an @Home‐based parallelization scheme (http://chem.unipune.ernet.in/∼tcg/mtaweb/). © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
Novel bi‐transition metallic encapsulated naphthalene‐like Si20 prismatic cage: A DFT investigation
Authors: Wang Jin , Liu Jin Huai
Published: October 2008

A theoretical investigation of stabilities and electronic properties of novel transition bimetallic atoms (BTMAs) encapsulated naphthalene‐like Si20 prismatic cage is being reported for the first time. The symmetry and electronic state of naphthalene‐like TMA2@Si20 is significantly affected by the type of encapsulated TMA from 3d, 4d to 5d series. Because of high binding energies, relative high HOMO‐LUMO gaps, large charge‐reverse transferring from naphthalene‐like Si20 cage to BTMAs at the centre of the 5d series, the most stable species of TMA2@Si20 cage is favorable to form new 1D‐TMAn@Sim nanotube, which is based on array of the novel naphthalene‐like structure. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
The importance of aromatic‐type interactions in serotonin synthesis: Protein–ligand interactions in tryptophan hydroxylase and aromatic amino acid decarboxylase
Authors: Hofto Laura R. , Lee Caroline E. , Cafiero Mauricio
Published: October 2008

The biosynthesis of serotonin requires aromatic substrates to be bound in the active sites of the enzymes tryptophan hydroxylase and aromatic amino acid decarboxylase. These aromatic substrates are held in place partially by dispersion and induction interactions with the enzymes' aromatic amino acid residues. Mutations that decrease substrate binding can result in a decrease in serotonin production and thus can lead to depression and related disorders. We use optimized crystal structures of these two enzymes to examine pair‐wise electronic interaction energies between aromatic residues in the active sites and the aromatic ligands. We also perform in silico mutations on the aromatic residues to determine the change in interaction energies as mutations occur. Our second‐order Moller‐Plessett perturbation theory calculations show that drastic changes in interaction energy can occur and, in light of our previous work, we are able to use these data to offer predictions on the loss of protein function and on the possibility of disease upon mutation. We also examine local and gradient corrected density functional theory methods to evaluate their ability to predict these induction/dispersion‐dominated interaction energies. We find that the hybrid B3LYP cannot model these interactions well, whereas the GGA HCTH407 offers largely qualitatively correct results, and the local functional SVWN quantitatively mimics the MP2 results rather well. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009
Skeletal morphogenesis of the vertebral column of the miniature hylid frog Acris crepitans, with comments on anomalies
Authors: Pugener L. Analía , Maglia Anne M.
Published: October 2008

Although the vertebral columns of anurans have received much study in the last 150 years, few detailed descriptions exist of the skeletal morphogenesis of this anatomical unit. Herein, the ontogeny of the vertebral skeleton of the hylid frog Acris crepitans is described based on cleared and double‐stained specimens, radiographs, and 3D reconstructions generated from synchrotron microCT scans. The adult axial formula is 1‐7‐1‐1, and the vertebral centra are epichordal and procoelous. The neural arches are nonimbricate, and there is a medial articulation between the laminae of Presacrals I and II. Free ribs are absent. The sacral diapophyses are uniform in width or slightly expanded distally. The urostyle is slender, round in cross section, and about equal in length to the presacral region. Presacral vertebrae are the first to form, developing in a cephalic‐to‐caudal sequence. However, development and growth are decoupled and growth is fastest initially in the posterior presacrals and sacrum. In addition, there is a time lag between the formation of the presacral/sacral region and the postsacral region. More than 8.5% of the specimens examined have vertebral anomalies, and about 50% display small variants from the typical vertebral column morphology. However, these malformations do not seem to have been so severe as to have affected survival. J. Morphol., 2009. © 2008 Wiley‐Liss, Inc.
Ultrastructure of spermatozoa and spermatophores of old world freshwater crabs (Brachyura: Potamoidea: Gecarcinucidae, Potamidae, and Potamonautidae)
Authors: Klaus Sebastian , Schubart Christoph D. , Brandis Dirk
Published: October 2008

We investigated the ultrastructure of spermatozoa and spermatophores of 19 palaeotropical freshwater crab species [12 species of the Gecarcinucidae, 6 of the Potamidae (Potamiscinae), and 1 species of the Potamonautidae (Deckeniinae: Hydrothelphusini)]. The investigated Potamiscinae have densely packed coenospermic spermatophores with the exception of Thaiphusa sirikit and Johora singaporensis that exhibit cleistospermia. In contrast, in the Gecarcinucidae the spermatozoa are loosely embedded in a mucous matrix. The gecarcinucid and potamiscine sperm differ, furthermore, in acrosomal structure and size. The acrosome in the Gecarcinucidae is much smaller and spherical, while the larger acrosome in the Potamiscinae has the tendency to be depressed. In the Potamiscinae, an additional middle acrosomal zone evolved between the acrosome ray zone and the outer acrosomal zone. Within the Gecarcinucidae, a differentiation into two groups (Gecarcinucinae and Parathelphusinae) is not supported by the present spermatological data. The sperm morphology of Hydrothelphusa aff. madagascariensis (Potamonautidae: Deckeniinae) differs from Potamonautes sidneyi (Potamonautidae: Potamonautinae) in acrosomal size and shape, and in the absence of a periopercular rim. A closer relationship of Deckeniinae and Gecarcinucidae cannot be confirmed by spermatology. J. Morphol., 2009. © 2008 Wiley‐Liss, Inc.
Structure and evolution of the pharynx simplex in acoel flatworms (Acoela)
Authors: Todt Christiane
Published: October 2008

The homology of pharynges within the mostly pharynx‐less Acoela has been a matter of discussion for decades and even the basic question of whether a pharynx is a primitive trait within the Acoela and homologous to the pharynx of platyhelminth turbellarians is open. By using fluorescence staining of musculature, as well as conventional histological techniques and transmission electron microscopy, the present study sets focus on the mouth and pharynx (where present) of seven species of Acoela within Paratomellidae, Solenofilomorphidae, Hofsteniidae, Proporidae, and Convolutidae, as well as one species of Nemertodermatida and Catenulida, respectively. It is shown that among the investigated families of acoels there is a great variability in muscle systems associated with the mouth and pharynx and that pharynx histology and ultrastructural characters are widely diverse. There are no close similarities between the acoel pharynges and the catenulid pharynx but there is a general resemblance of the musculature associated with the mouth in the representatives of Paratomellidae and Nemertodermatida. On the basis of the profound differences in pharynx morphology, three major conclusions are drawn: 1) the pharynges as present in Recent acoels are not homologous to the pharynx simplex characteristic for Catenulida and Macrostomida within the Platyhelminthes; 2) the different muscular pharynx types of acoels are not homologous between higher taxa and thus a single acoel‐type pharynx simplex cannot be defined; 3) the presence of a muscular pharynx most likely does not represent the ancestral state. J. Morphol, 2009. © 2008 Wiley‐Liss, Inc.
Electrospray ionization from an adjustable gap between two silicon chips
Authors: Ek Patrik , Schönberg Tommy , Sjödahl Johan , Jacksén Johan , Vieider Christian , Emmer Åsa , Roeraade Johan
Published: October 2008

In this paper, a silicon chip–based electrospray emitter with a variable orifice size is presented. The device consists of two chips, with a thin beam elevating from the center of each of the chips. The chips are individually mounted to form an open gap of a narrow, uniform width between the top areas of the beams. The electrospray is generated at the endpoint of the gap, where the spray point is formed by the very sharp intersection between the crystal planes of the < 100 > silicon chips. Sample solution is applied to the rear end of the gap from a capillary via a liquid bridge, and capillary forces ensure a spontaneous imbibition of the gap. The sample solution is confined to the gap by means of a hydrophobic treatment of the surfaces surrounding the gap, as well as the geometrical boundaries formed by the edges of the gap walls. The gap width could be adjusted between 1 and 25 µm during electrospray experiments without suffering from any interruption of the electrospray process. Using a peptide sample solution, a shift toward higher charge states and increased signal‐to‐noise ratios was observed when the gap width was decreased. The limit of detection for the peptide insulin (chain B, oxidized) was approximately 4 nM. We also show a successful interfacing of the electrospray setup with capillary electrophoresis. Copyright © 2008 John Wiley & Sons, Ltd.
Very‐high‐dose α‐tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke‐prone spontaneously hypertensive rats
Authors: Miyamoto Kaori , Shiozaki Motoko , Shibata Masahiro , Koike Masato , Uchiyama Yasuo , Gotow Takahiro
Published: October 2008

Tocopherols and tocotrienols constitute the vitamin E family. Although α‐tocotrienol is the most neuroprotective form of vitamin E proved to be effective against stroke, α‐tocopherol is the most abundant in nature and is used most often for disease prevention/treatment. A recent metaanalysis of human studies suggested that α‐tocopherol supplementation increases all‐cause mortality. Therefore, we investigated the effects of α‐tocopherol (∼44 mg/kg body weight; equivalent to 2,600 mg/human/day) on the central nervous system (CNS) of stroke‐prone spontaneously hypertensive rats (SHRSP). SHRSP treated with high dose α‐tocopherol had significantly higher blood pressure than untreated controls fed a basal diet that contained ∼4 mg tocopherols/kg body weight, but neither group experienced a change in degree of lipid peroxidation in serum or CNS tissue. Biochemical/immunohistochemical analyses demonstrated that expressions of phosphorylated neurofilament H protein, glial fibrillary acidic protein and cathepsin D in the CNS tissue were significantly enhanced in α‐tocopherol‐supplemented rats, whereas expressions of SOD2 and Bcl‐xL were diminished in response to α‐tocopherol supplementation. Similarly, the frequency of cathepsin D‐positive cells, corresponding mostly to microglial cells, was significantly increased in α‐tocopherol‐supplemented rats. α‐Tocopherol supplementation also increased the number of lysosomes and lipofuscin granules in perikarya of both hippocampal pyramidal and Purkinje cells. Furthermore, α‐tocopherol supplementation increased the frequency of glial filaments and lipofuscin granules in astrocytes and lysosomes in microglial cells that were frequently occupied with phagocytosed inclusion structures. The present results are the first to suggest that a very high dose of α‐tocopherol supplementation increases blood pressure in SHRSP rats and influences the CNS tissue in a manner that seems adverse. © 2008 Wiley‐Liss, Inc.
Climate perspective on the large‐scale circulation associated with the transition of the first South Atlantic hurricane
Authors: Pezza Alexandre Bernardes , Simmonds Ian , Pereira Filho Augusto Jose
Published: October 2008

The landfall of Cyclone Catarina on the Brazilian coast in March 2004 became known as the first documented hurricane in the South Atlantic Ocean, promoting a new view on how large‐scale features can contribute to tropical transition. The aim of this paper is to put the large‐scale circulation associated with Catarina's transition in climate perspective. This is discussed in the light of a robust pattern of spatial correlations between thermodynamic and dynamic variables of importance for hurricane formation. A discussion on how transition mechanisms respond to the present‐day circulation is presented. These associations help in understanding why Catarina was formed in a region previously thought to be hurricane‐free.

Catarina developed over a large‐scale area of thermodynamically favourable air/sea temperature contrast. This aspect explains the paradox that such a rare system developed when the sea surface temperature was slightly below average. But, although thermodynamics played an important role, it is apparent that Catarina would not have formed without the key dynamic interplay triggered by a high latitude blocking. The blocking was associated with an extreme positive phase of the Southern Annular Mode (SAM) both hemispherically and locally, and the nearby area where Catarina developed is found to be more cyclonic during the positive phase of the SAM. A conceptual model is developed and a ‘South Atlantic index’ is introduced as a useful diagnostic of potential conditions leading to tropical transition in the area, where large‐scale indices indicate trends towards more favourable atmospheric conditions for tropical cyclone formation. Copyright © 2008 Royal Meteorological Society
Fluctuations in autumn–winter severe storms over the British Isles: 1920 to present
Authors: Allan Rob , Tett Simon , Alexander Lisa
Published: October 2008

An examination of extreme storms across the British Isles over the last 85 years during the boreal autumn [October, November, December (OND)] and winter [January, February, March (JFM)] shows that large‐scale natural climate variability plays an important role in modulating the intensity and frequency of these events.

Severe storms across the British Isles were most prominent in the 1920s and 1990s in OND, and in the 1920s, 1980s and 1990s in JFM. There is a significant correlation between JFM severe storminess across the British Isles and both the Gibraltar–South‐West (SW) Iceland and Azores–Iceland indices of the North Atlantic Oscillation (NAO), but this relationship fluctuates over the 85 years of data. Strongest NAO relationships occur during 1970–1990 and 1940–1960, with a weaker correlation in the 1920s–1940s, and effectively no correlation in 1950–1970. There is no significant relationship between the Gibraltar–SW Iceland NAO and severe storms in OND, but a significant correlation exists with the Azores–Iceland NAO and there is a clear link to a pattern in mean sea level pressure (MSLP) extending from the tropical Atlantic to higher latitudes of the North Atlantic. El Niño Southern Oscillation (ENSO) influences from the Pacific Ocean also appear to play a role in modulating OND severe storms over the British Isles. Importantly, severe storms in OND and JFM seasons respond to different physical mechanisms.

Future work is needed to extend this study back into the late 19th century in order to evaluate fully any changes in severe storms across the British Isles using a longer instrumental record. This may be best achieved through long historical surface‐observations‐only global reanalyses, which can reconstruct tropospheric weather variables using longer instrumental records of daily to sub‐daily MSLP. Copyright © 2008 Royal Meteorological Society