bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of retinoid X receptor α (RXRα) on apoptosis in primary cultured porcine pre-adipocytes
Authors: Ya-Qiu Lin , He-Lin Zhuang , Gong-She Yang
Published: January 2010

Using semi-quantitative reverse transcriptase polymerase chain reaction (semi-qRT-PCR), cell transfection, Hoechst 33342, acridine orange (AO) and flow cytometry methods, apoptotic changes in porcine pre-adipocytes treated with 9-cis retinoic acid (9-cisRA)–retinoid X receptor α (RXRα) ligand, transfected with pEnhanced green fluorescent proteins C2–RXRα (pEGFPC2–RXRα) or RXRα–small interfering RNA (RXRα–siRNA), respectively, were investigated. Observations of morphologic changes showed changes in cell structure, cellular shrinkage and condensation of chromatin, pyknosis of the nucleus into a compact body, complete fragmentation within the nuclear membrane, continuous budding and shedding, and, finally conversion of the cell into several apoptotic bodies wrapped in membranes of different sizes. Compared with the control group, the apoptotic rate was significantly lowered in the 10 nmol/l 9-cisRA-treated group, and significantly higher in the 10 μmol/l 9-cisRA-treated group (both P<0.05). Gene expression of RXRα was significantly up-regulated and down-regulated when cultured pre-adipocytes were transfected with pEGFPC2–RXRα or RXRα–siRNA (P<0.05), respectively; the apoptotic rate decreased in the pEGFPC2–RXRα group and significantly increased in the RXRα–siRNA group when compared with a control group (P<0.05). This implies that RXRα inhibits the apoptosis of porcine pre-adipocytes.
Vorsicht! Fehler im FLM 7-13 und im FLM 4-6
Authors: Rost Detlef H. , Bachmann Iris U.
Published: January 2010

Zusammenfassung. Die Auswertungsschablone II des FLM 7–13 („Fragebogen zur Leistungsmotivation für Schüler der 7. bis 13. Klasse”) von Petermann und Winkel (2007a) enthält neun Fehler. Wertet man mit der Schablone aus, werden 30% der Items des FLM 7–13 einer falschen Skala zugeordnet, was zu Fehlinterpretationen bei allen fünf Skalen des FLM 7–13 führt. Auch die Auswertungsfolie des FLM 4–6 („Fragebogen zur Leistungsmotivation für Schüler der 4. bis 6. Klasse”) von Petermann und Winkel (2007b) enthält einen Fehler. Bei beiden Verfahren finden sich zudem grob fehlerhafte Angaben zur Varianzaufklärung in den durchgeführten Faktorenanalysen.
Erfassung von Krankheitsangst mit dem Multidimensional Inventory of Hypochondriacal Traits (MIHT)
Authors: Witthöft Michael , Haaf Andreas , Rist Fred , Bailer Josef
Published: January 2010

Zusammenfassung. Das „Multidimensional Inventory of Hypochondriacal Traits (MIHT)” ( Longley, Watson & Noyes, 2005 ) ist eine Selbstbeurteilungsskala zur mehrdimensionalen Erfassung von Krankheitsangst (KA) in der Allgemeinbevölkerung. Das MIHT basiert auf kognitiv-behavioralen Modellvorstellungen zur KA und umfasst vier Subskalen: Die kognitive Subskala erfasst die „hypochondrische Entfremdung”, die aus der Überzeugung resultiert, an einer schweren Erkrankung zu leiden. Die behaviorale Subskala erfragt die Suche nach Rückversicherungen und sozialer Unterstützung. Die affektive Subskala erfasst Krankheitssorgen und die perzeptuelle Subskala eine habituelle Aufmerksamkeitslenkung auf körperliche Empfindungen. Die Faktorenstruktur und verschiedene Aspekte der externen Validität einer deutschsprachigen Version des MIHT wurden anhand von zwei studentischen Stichproben geprüft. Explorative und konfirmatorische Faktorenanalysen belegen in guter Übereinstimmung mit der englischen Version die vierfaktorielle Subskalenstruktur. Konvergente und diskriminante Beziehungen des MIHT zu etablierten Maßen von KA und anderen psychopathologischen Merkmalen belegen die externe Validität.
Standard-Setting bei C-Tests
Authors: Eckes Thomas
Published: January 2010

Zusammenfassung. C-Tests sind Lückentests zur Messung der allgemeinen Sprachkompetenz. Die vorliegende Arbeit geht der Frage nach, wie sich mittels C-Tests Niveaus der Sprachkompetenz bestimmen lassen. Eine hierzu entwickelte Standard-Setting-Methode verbindet Prinzipien der Rasch-Skalierung von C-Tests mit dem Prototypenkonzept (Prototypgruppenmethode). Experten identifizieren zunächst typische Lernende auf einem von vier Sprachniveaus (A2 bis C1) wie sie im Gemeinsamen europäischen Referenzrahmen für Sprachen (GER; Europarat, 2001 ) beschrieben sind. Anhand der Verteilungen von Fähigkeitsschätzungen der Prototypen je zweier benachbarter Niveaus werden Trennwerte (Cut-Scores) berechnet. Diese Cut-Scores erlauben es, für jede Testperson anzugeben, welches Niveau der allgemeinen Sprachkompetenz sie erreicht hat. Daten aus 23 Erprobungen unterschiedlicher Sets von jeweils 10 C-Test-Texten, bearbeitet von insgesamt 4.842 Testpersonen, illustrieren die Vorgehensweise.
Elternfragebogen zur Erfassung des Unfallrisikos von Jungen
Authors: Brandau Hannes , Daghofer Fedor
Published: January 2010

Zusammenfassung. Ziel der Studie war die Entwicklung einer kurzen deutschsprachigen Adaption des „Tridimensional Personality Questionnaire” nach Cloninger mit 15 Fragen basierend auf der „Injury Behaviour Checklist” mit 13 Fragen, beide konzipiert als Fremdbeurteilungsfragebogen (Elternfragebogen), die im Rahmen der Unfallforschung eingesetzt werden können. In einer Feldstichprobe von 415 Jungen im Alter von vier bis 18 Jahren ergaben sich für alle Skalen zufriedenstellende Reliabilitäten. In einer weiteren Feldstichprobe, bestehend aus 268 Jungen im Alter von vier bis 18 Jahren, zeigte sich in einer multivariaten Analyse, dass die Unfallcheckliste am besten zwischen Unfallwiederholern und Kontrollkindern differenzierte. In einer weiteren Studie zeigte sich, dass die Skala Neugier am besten zwischen klinisch diagnostizierten ADHS-Kindern und Kontrollkindern differenzieren konnte. Mit dem vorliegenden Inventar soll vorerst die Beratung von Eltern unfallgefährdeter Kinder zur Vermeidung weiterer Unfälle differenzierter und gezielter erfolgen, wobei in Zukunft auch weitere Variablen zur Verbesserung der Prognose erhoben werden sollten.
Vermeidung und Depression
Authors: Röthlin Philipp , Grosse Holtforth Martin , Bergomi Claudia , Berking Matthias , Ottenbreit Nicole D. , Caspar Franz
Published: January 2010

Zusammenfassung. Vermeidungsprozesse sind bei der Beschreibung und Erklärung von Angststörungen zentral, spielen aber auch bei Depressionen eine wichtige Rolle. Die Cognitive-Behavioral Avoidance Scale erfasst depressives Vermeiden ( Ottenbreit & Dobson, 2004 ). Die deutsche Übersetzung wurde an einer Stichprobe von insgesamt 657 Probanden (187 ambulante Psychotherapiepatienten, 376 Normalpersonen und 94 Studenten) evaluiert. Die Faktorenstruktur der Originalversion konnte mittels konfirmatorischer Faktorenanalyse bestätigt werden. Psychometrische Analysen ergaben mehrheitlich sehr zufriedenstellende Ergebnisse mit einer internen Konsistenz α = .92 und einer Retestreliabilität von r = .80 (Totalskala). Hinweise auf Konstruktvalidität konnten mittels AAQ und EMOREG gewonnen werden. Zusammenhänge zwischen Vermeidung und Depressivität unabhängig von Angst unterstützen die Spezifität depressiven Vermeidens.
Informationen zum FLM 4-6 und FLM 7-13
Authors: Petermann Franz
Published: January 2010

Zusammenfassung. Die Replik zu Rost und Bachmann (2010) liefert Informationen zur Faktorenanalyse und den Interkorrelationen der Subskalen des FLM 4-6 und FLM 7-3.
Information gap analysis of flood model uncertainties and regional frequency analysis
Authors: Hine Daniel , Hall Jim W.
Published: January 2010

Flood risk analysis is subject to often severe uncertainties, which can potentially undermine flood management decisions. This paper explores the use of information gap theory to analyze the sensitivity of flood management decisions to uncertainties in flood inundation models and flood frequency analysis. Information gap is a quantified nonprobabilistic theory of robustness. To analyze uncertainties in flood modeling, an energy‐bounded information gap model is established and applied first to a simplified uniform channel and then to a more realistic 2‐D flood model. Information gap theory is then applied to the estimation of flood discharges using regional frequency analysis. The use of an information gap model is motivated by the notion that hydrologically similar sites are clustered in the space of their L moments. The information gap model is constructed around a parametric statistical flood frequency analysis, resulting in a hybrid model of uncertainty in which natural variability is handled statistically while epistemic uncertainties are represented in the information gap model. The analysis is demonstrated for sites in the Trent catchment, United Kingdom. The analysis is extended to address ungauged catchments, which, because of the attendant uncertainties in flood frequency analysis, are particularly appropriate for information gap analysis. Finally, the information gap model of flood frequency is combined with the treatment of hydraulic model uncertainties in an example of how both sources of uncertainty can be accounted for using information gap theory in a flood risk management decision.
Frost‐ring chronologies as dendroclimatic proxies of boreal environments
Authors: Payette Serge , Delwaide Ann , Simard Martin
Published: January 2010

Frost rings are formed in tree stems when growing‐season frosts affect immature wood cells, producing collapsed cells within annual tree rings. Open boreal forests are most susceptible to record growing‐season frost because they lack the greenhouse effect commonly observed in closed forests. Here we present a novel method to construct regional frost‐ring chronologies in lichen‐black spruce woodlands of the boreal forest zone. Because the ability of trees to form frost rings depends on several factors (including bark thickness and ring width), we used two models to produce a Frost Composite Index based on a frost susceptibility window of cambial age <30 years. The frost‐ring chronology showed alternating periods of high and low frost activity that were highly consistent within and among sites. Reconstruction of growing‐season frost activity may be used as dendroclimatic proxies of climate variability and may give insights into future risks of frost damage in a warming climate.
Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells
Authors: Ball Stephen G. , Bayley Christopher , Shuttleworth C. Adrian , Kielty Cay M.
Published: January 2010

Using human MSCs (mesenchymal stem cells) lacking VEGF (vascular endothelial growth factor) receptors, we show that the pro-angiogenic receptor neuropilin-1 associates with phosphorylated PDGFRs [PDGF (platelet-derived growth factor) receptors], thereby regulating cell signalling, migration, proliferation and network assembly. Neuropilin-1 co-immunoprecipitated and co-localized with phosphorylated PDGFRs in the presence of growth factors. Neuropilin-1 knockdown blocked PDGF-AA-induced PDGFRα phosphorylation and migration, reduced PDGF-BB-induced PDGFRβ activation and migration, blocked VEGF-A activation of both PDGFRs, and attenuated proliferation. Neuropilin-1 prominently co-localized with both PDGFRs within MSC networks assembled in Matrigel™ and in the chorioallantoic membrane vasculature microenvironment, and its knockdown grossly disrupted network assembly and decreased PDGFR signalling. Thus neuropilin-1 regulates MSCs by forming ligand-specific receptor complexes that direct PDGFR signalling, especially the PDGFRα homodimer. This receptor cross-talk may control the mobilization of MSCs in neovascularization and tissue remodelling.
Dihydroceramide desaturase activity is modulated by oxidative stress
Authors: Idkowiak-Baldys Jolanta , Apraiz Aintzane , Li Li , Rahmaniyan Mehrdad , Clarke Christopher J. , Kraveka Jacqueline M. , Asumendi Aintzane , Hannun Yusuf A.
Published: January 2010

Oxidative stress has been implicated previously in the regulation of ceramide metabolism. In the present study, its effects on dihydroceramide desaturase were investigated. To stimulate oxidative stress, HEK (human embyronic kidney)-293, MCF7, A549 and SMS-KCNR cells were treated with H2O2, menadione or tert-butylhydroperoxide. In all cell lines, an increase in dihydroceramide was observed upon oxidative stress as measured by LC (liquid chromatography)/MS. In contrast, total ceramide levels were relatively unchanged. Mechanistically, dihydroceramide desaturase activity was measured by an in situ assay and decreased in a time- and dose-dependent fashion. Interestingly, no detectable changes in the protein levels were observed, suggesting that oxidative stress does not induce degradation of dihydroceramide desaturase. In summary, oxidative stress leads to potent inhibition of dihydroceramide desaturase resulting in significant elevation in dihydroceramide levels in vivo.
Selective excitation of femtosecond coherent anti-Stokes Raman scattering in the mixture by phase-modulated pump and probe pulses
Authors: Zhang Shian , Zhang Hui , Jia Tianqing , Wang Zugeng , Sun Zhenrong
Published: January 2010

In this paper, we present a feasible method to realize and improve the selective excitation of femtosecond coherent anti-Stokes Raman scattering (CARS) in a mixture. We theoretically show that, by shaping both the pump and probe pulses with the π phase step, the CARS signal from one quantum system can be enhanced and simultaneously that from the other quantum system is effectively suppressed. Comparing with only shaping the probe pulse [D. Oron, N. Dudovich, D. Yelin, and Y. Silberberg, Phys. Rev. Lett., 88, 063004 (2002)], the selectivity of femtosecond CARS by shaping both pump and probe pulses can be greatly improved. Finally, we experimentally compare two shaping schemes by investigating the selective excitation of the femtosecond CARS in the mixture of dibromomethane (CH2Br2) and chloroform (CHCl3).
Energy release and transfer in guide field reconnection
Authors: Birn J. , Hesse M.
Published: January 2010

Properties of energy release and transfer by magnetic reconnection in the presence of a guide field are investigated on the basis of 2.5-dimensional magnetohydrodynamic (MHD) and particle-in-cell (PIC) simulations. Two initial configurations are considered: a plane current sheet with a uniform guide field of 80% of the reconnecting magnetic field component and a force-free current sheet in which the magnetic field strength is constant but the field direction rotates by 180° through the current sheet. The onset of reconnection is stimulated by localized, temporally limited compression. Both MHD and PIC simulations consistently show that the outgoing energy fluxes are dominated by (redirected) Poynting flux and enthalpy flux, whereas bulk kinetic energy flux and heat flux (in the PIC simulation) are small. The Poynting flux is mainly associated with the magnetic energy of the guide field which is carried from inflow to outflow without much alteration. The conversion of annihilated magnetic energy to enthalpy flux (that is, thermal energy) stems mainly from the fact that the outflow occurs into a closed field region governed by approximate force balance between Lorentz and pressure gradient forces. Therefore, the energy converted from magnetic to kinetic energy by Lorentz force acceleration becomes immediately transferred to thermal energy by the work done by the pressure gradient force. Strong similarities between late stages of MHD and PIC simulations result from the fact that conservation of mass and entropy content and footpoint displacement of magnetic flux tubes, imposed in MHD, are also approximately satisfied in the PIC simulations.
Tide-related periodicity of manta rays and sharks to cleaning stations on a coral reef
Authors: O'Shea Owen R. , Kingsford Michael J. , Seymour Jamie
Published: January 2010

Although the movements of fishes on coral reefs have been well studied, there are few data on the movement of elasmobranchs on and around cleaning stations. The visitation to cleaning stations by elasmobranchs was documented by direct observation and remote video capture at an oceanic reef in the Coral Sea and the outer Great Barrier Reef at time scales of hours to weeks. Cleaning was only observed at Osprey Reef and duration of occupancy was recorded for all elasmobranch clients. Strong tidal patterns were detected, with 49% of sharks and 59% of mantas engaging in cleaning interactions on ebb tides. Forty-four per cent of non-cleaned sharks were also observed on ebb tides. Some manta rays (n = 19) were individually identified through ventral skin pigmentation to determine site fidelity; three were seen more than once with repeat observations occurring within days. This was consistent among weeks and days within weeks, regardless of time of day. Hypotheses for tidal behaviour are discussed and we argue that these observations are critical in elucidating previously unknown behaviours in elasmobranch ecology. Our study indicates that observations of large elasmobranchs at cleaning stations are another tool to elucidate elasmobranch ecology.
Retained fishing gear and associated injuries in the east Australian grey nurse sharks (Carcharias taurus): implications for population recovery
Authors: Bansemer C. S. , Bennett M. B.
Published: January 2010

Incidental hooking of Carcharias taurus is a threat to their populations’ recovery on the east coast of Australia. Photo-identification techniques were used to investigate the frequency of hooking at 25 aggregation sites along the east coast of Australia between 2006 and 2008. Of the 673 sharks identified, 113 sharks were identified with signs of 119 incidences of hooking. For sharks with both their left and right flank photographed during a single survey day, up to 29% of females and 52% of males were identified with retained fishing gear or an attributed jaw injury. The largest number of sharks identified (222) were from a year-round aggregation of immature and mature sharks at Fish Rock, New South Wales, Australia. Forty-eight per cent of all sharks identified with retained fishing gear were first identified at this site. Fish Rock, a designated critical habitat for C. taurus, allows most forms of line fishing except fishing with bait or wire trace while anchored or moored. As interactions with fishing gear can result in debilitating disease, morbidity and death, the high incidence of hooked individual C. taurus is considered a key threatening process that is likely to reduce this shark population’s ability to recover.
Recessive mutations in the
INS
gene result in neonatal diabetes through reduced insulin biosynthesis
Authors: Garin Intza , Edghill Emma L. , Akerman Ildem , Rubio-Cabezas Oscar , Rica Itxaso , Locke Jonathan M. , Maestro Miguel Angel , Alshaikh Adnan , Bundak Ruveyde , del Castillo Gabriel , Deeb Asma , Deiss Dorothee , Fernandez Juan M. , Godbole Koumudi , Hussain Khalid , O’Connell Michele , Klupa Thomasz , Kolouskova Stanislava , Mohsin Fauzia , Perlman Kusiel , Sumnik Zdenek , Rial Jose M. , Ugarte Estibaliz , Vasanthi Thiruvengadam ,   Neonatal Diabetes International Group, Johnstone Karen , Flanagan Sarah E. , Martínez Rosa , Castaño Carlos , Patch Ann-Marie , Fernández-Rebollo Eduardo , Raile Klemens , Morgan Noel , Harries Lorna W. , Castaño Luis , Ellard Sian , Ferrer Jorge , de Nanclares Guiomar Perez , Hattersley Andrew T.
Published: January 2010

Heterozygous coding mutations in the
INS
gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive
INS
mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal
INS
transcription, including the deletion of the C1 and E1
cis
regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive
INS
mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant
INS
mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.
Streamlined analysis schema for high-throughput identification of endogenous protein complexes
Authors: Malovannaya Anna , Li Yehua , Bulynko Yaroslava , Jung Sung Yun , Wang Yi , Lanz Rainer B. , O’Malley Bert W. , Qin Jun
Published: January 2010

Immunoprecipitation followed by mass spectrometry (IP/MS) has recently emerged as a preferred method in the analysis of protein complex components and cellular protein networks. Targeting endogenous protein complexes of higher eukaryotes, particularly in large-scale efforts, has been challenging due to cellular heterogeneity, high proteome complexity, and, compared to lower organisms, lack of efficient in-locus epitope-tagging techniques. It is further complicated by variability in nonspecific identifications and cross-reactivity of primary antibodies. Still, the study of endogenous human protein networks is highly desired despite its challenges. Here we describe a streamlined IP/MS protocol for the purification and identification of extended endogenous protein complexes. We investigate the sources of nonspecific protein binding and develop semiquantitative specificity filters that are based on peptide spectral count measurements. We also outline logical constraints for the derivation of accurate complex composition from IP/MS data and demonstrate the effectiveness of this approach by presenting our analyses of different transcriptional coregulator complexes. We show consistent purification of novel components for the Integrator complex, analyze the composition of the Mediator complex solely from our data to demonstrate the wide usability of spectral counts, and deconvolute heterogeneous HDAC1/2 networks into core complex modules and several novel subcomplex interactions.
Basal epithelial stem cells are efficient targets for prostate cancer initiation
Authors: Lawson Devon A. , Zong Yang , Memarzadeh Sanaz , Xin Li , Huang Jiaoti , Witte Owen N.
Published: January 2010

Prevailing theories suggest that luminal cells are the origin of prostate cancer because it is histologically defined by basal cell loss and malignant luminal cell expansion. We introduced a series of genetic alterations into prospectively identified populations of murine basal/stem and luminal cells in an in vivo prostate regeneration assay. Stromal induction of FGF signaling, increased expression of the ETS family transcription factor ERG1, and constitutive activation of PI3K signaling were evaluated. Combination of activated PI3K signaling and heightened androgen receptor signaling, which is associated with disease progression to androgen independence, was also performed. Even though luminal cells fail to respond, basal/stem cells demonstrate efficient capacity for cancer initiation and can produce luminal-like disease characteristic of human prostate cancer in multiple models. This finding provides evidence in support of basal epithelial stem cells as one target cell for prostate cancer initiation and demonstrates the propensity of primitive cells for tumorigenesis.
Structural determinants of growth factor binding and specificity by VEGF receptor 2
Authors: Leppänen Veli-Matti , Prota Andrea E. , Jeltsch Michael , Anisimov Andrey , Kalkkinen Nisse , Strandin Tomas , Lankinen Hilkka , Goldman Adrian , Ballmer-Hofer Kurt , Alitalo Kari
Published: January 2010

Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains, which, upon ligand binding, promote receptor dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis. Here we present the crystal structure of VEGF-C bound to the VEGFR-2 high-affinity-binding site, which consists of immunoglobulin homology domains D2 and D3. This structure reveals a symmetrical 2∶2 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In the VEGFs, receptor specificity is determined by an N-terminal alpha helix and three peptide loops. Our structure shows that two of these loops in VEGF-C bind to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3. Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove separating the two VEGF-C monomers binds to the D2/D3 linker. VEGF-C, unlike VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins to further study receptor specificity. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions.
HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1
Authors: Quintela-Fandino Miguel , Arpaia Enrico , Brenner Dirk , Goh Theo , Yeung Faith Au , Blaser Heiko , Alexandrova Roumiana , Lind Evan F. , Tusche Mike W. , Wakeham Andrew , Ohashi Pamela S. , Mak Tak W.
Published: January 2010

Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Up-regulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.
Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1
Authors: Aoyagi Mariko , Gaspar Miguel , Shenk Thomas E.
Published: January 2010

4EBP1 is phosphorylated by the mTORC1 kinase. When mTORC1 activity is inhibited, hypophosphorylated 4EBP1 binds and sequesters eIF4E, a component of the mRNA cap-binding complex, and blocks translation. As a consequence, mTORC1 activity is needed to maintain active translation. The human cytomegalovirus pUL38 protein preserves mTORC1 activity, keeping most of the E4BP1 in the infected cell in a hyperphosphorylated, inactive state. Here we report that a second viral protein, pUL69, also antagonizes the activity of 4EBP1, but by a separate mechanism. pUL69 interacts directly with eIF4A1, an element of the cap-binding complex, and the poly(A)-binding protein, which binds to the complex. When pUL69 accumulates during infection with wild-type virus, 4EBP1 is excluded from the complex. However, 4EBP1 is present in the cap-binding complex after infection with a pUL69-deficient virus, coincident with reduced accumulation of several late virus-coded proteins. We propose that pUL69 supports translation in human cytomegalovirus-infected cells by excluding hypophosphorylated 4EBP1 from the cap-binding complex.
TheShahnama: Between the Samanids and the Ghaznavids
Authors: Dabiri Ghazzal
Published: January 2010

The paper reconsiders the apocryphal stories regarding theShahnama's initial reception to propose that it was only after long narrative poems gained currency that theShahnamawas recognized as a masterpiece. The paper analyzes the structure and themes of several histories written before and during the Samanid period and compares them with theShahnamaand the content of histories and epics produced immediately afterwards, to argue that the initial reception of theShahnamadid not depend on Sultan Mahmud Ghazni alone. It further argues that theShahnama's aim, content, and execution differed from the histories and poetry produced in the decades immediately preceding and succeeding it, which would account for the lag in its acceptance and popularity. This led later biographers to superimpose their regret over Firdausi's treatment onto Sultan Mahmud Ghazni, who by their accounts denied him the fame and glory he deserved in his lifetime.
Hushang the Dragon-slayer: Fire and Firearms in Safavid Art and Diplomacy
Authors: Lassikova Galina
Published: January 2010

This paper suggests the interpretation of the images woven on Safavid precious textiles in their historical context. The thesis is that the mythical and literary subject of the discovery of fire by Shah Hushang was used by the Safavids in their negotiations concerning the supply of the firearms to Iran. The images of Hushang slaying the dragon on the silks of the third quarter of the sixteenth century reflect different stages of this diplomatic mission and the objects sewn out of these textiles served as meaningful presents to the interested parties.
From Epic to Romance, via Filicide? Rustam's Character Formation
Authors: Clark Fraser
Published: January 2010

Rustam is famed for being one of the most fleshed-out characters of the Shahnama. As such, this article will analyze an episode in his life of extreme emotional turbulence, in order to gain a closer understanding of how much realism Firdausi bestows upon his characters. This episode is the suicide attempt he makes following his act of filicide. I will begin with a discussion of the difficulties involved in interpreting such an ancient text as the Shahnama. An analysis of Rustam's background follows, tracing the development of his personality. I will then take a detailed look at the circumstances surrounding his attempted suicide. After this, I will gauge the extent to which this act may have its roots in his personality. By thus examining how realistic is Rustam's suicide attempt, I hope this paper will contribute to the further study of the literary nature of Firdausi's Shahnama.
The Trickster “Archetype” in the Shahnama
Authors: den Uijl Sebastiaan
Published: January 2010

In this literary analysis of the Akvan Div story in the Shahnama, the author proposes to read the story through the lens of more ancient texts to arrive at a better understanding of the trickster “archetype” in Iranian culture. After a brief introduction to and critique of Jungian archetypal theory and some remarks on the proposed method of “etymological reading,” a structural summary of the story is offered. The analysis that follows shows that in this reading, the story appears in its unity and parts that are usually seen as epic digressions become meaningful.
Why was the Shahnama Illustrated?
Authors: Grabar Oleg
Published: January 2010

A long-standing puzzle in our knowledge of the culture surrounding the Shahnama lies in the fact that its illustrations, which became so well known, postdate the appearance of the text by nearly 300 years. There are several ways of explaining this anomaly. All contribute something to our understanding of Iranian culture, but none is entirely satisfactory. This essay suggests that a solution may lie in a better understanding of the social and ideological consequences of Mongol rule and/or in the peculiarities of urban culture at the time.
Exploring a Neglected Masterpiece: The GulistanShahnamaof Baysunghur
Authors: Hillenbrand Robert
Published: January 2010

The paper begins by summarizing the basic information about theShahnamaproduced in Herat for the Timurid prince Baysunghur, son of Shah Rukh, in 833/1430, one of the three iconic illustrated versions of Firdausi's poem in Persian painting. It then considers in turn the originality of this manuscript, its iconographic program and the intervals at which the images are placed within the text. The themes of enthronement and combat or battle are explored at length, as are the page layout, the role of illumination and the technique and execution of the paintings.
From Tourist to Pilgrim: Iskandar at the Ka‘ba in IllustratedShahnamaManuscripts
Authors: Simpson Marianna Shreve
Published: January 2010

Notwithstanding its brevity, Firdausi's account of Iskandar's visit to the Ka‘ba in Mecca was depicted regularly in illustrated manuscripts of theShahnamafrom the fourteenth century to early modern times. An examination of these illustrations reveals the extent to which poetical and pictorial narratives diverged over the centuries, with an increasing expansion of the shrine's setting and emphasis on ritual performance and with Iskandar evolving from a passive bystander to a devouthajji. This study also offers a telling instance of the way the representation of aShahnamascene could be transformed in response to another poetic text, specifically theKhamsaof Nizami.
Dismantling the “age–prospective memory paradox”: The classic laboratory paradigm simulated in a naturalistic setting
Authors: Bailey Phoebe E. , Henry Julie D. , Rendell Peter G. , Phillips Louise H. , Kliegel Matthias
Published: January 2010

Previous research has identified “the age–prospective memory paradox”—that adult ageing results in reliably poorer performance on laboratory-based tasks of prospective memory (PM), but improved performance on such tasks carried out in real-life settings. We hypothesized that even in their everyday environment, older adults might be worse at PM tasks that are triggered during an experimenter-generated ongoing activity. The present study used a task that captured the key features of the classic laboratory paradigm, but which was completed in a setting that met key criteria to be considered naturalistic. In their everyday setting, participants’ PM was assessed, with the cue to remember occurring either (a) during their day-to-day activities, or (b) during an experimenter-generated ongoing task. The results confirmed previous naturalistic findings, in showing that older adults ( n = 28) exhibited better PM than their younger counterparts ( n = 65) when prompted during their everyday activities. However, older adults were also then subsequently less likely to show effective PM during experimenter-generated ongoing activity. Reproducing the paradox within a single dataset, these data indicate that older adults can effectively act on intentions during everyday activities, but have difficulty in prospective remembering during experimenter-generated ongoing tasks.
Attributable Costs of Surgical Site Infection and Endometritis after Low Transverse Cesarean Delivery
Authors: Olsen Margaret A. , Butler Anne M. , Willers Denise M. , Gross Gilad A. , Hamilton Barton H. , Fraser Victoria J.
Published: January 2010

Background.

Accurate data on costs attributable to hospital-acquired infections are needed to determine their economic impact and the cost-benefit of potential preventive strategies.

Objective.

To determine the attributable costs of surgical site infection (SSI) and endometritis (EMM) after cesarean section by means of 2 different methods.

Design.

Retrospective cohort.

Setting.

Barnes-Jewish Hospital, a 1,250-bed academic tertiary care hospital.

Patients.

There were 1,605 women who underwent low transverse cesarean section from July 1999 through June 2001.

Methods.

Attributable costs of SSI and EMM were determined by generalized least squares (GLS) and propensity score matched-pairs by means of administrative claims data to define underlying comorbidities and procedures. For the matched-pairs analyses, uninfected control patients were matched to patients with SSI or with EMM on the basis of their propensity to develop infection, and the median difference in costs was calculated.

Results.

The attributable total hospital cost of SSI calculated by GLS was $3,529 and by propensity score matched-pairs was $2,852. The attributable total hospital cost of EMM calculated by GLS was $3,956 and by propensity score matched-pairs was $3,842. The majority of excess costs were associated with room and board and pharmacy costs.

Conclusions.

The costs of SSI and EMM were lower than SSI costs reported after more extensive operations. The attributable costs of EMM calculated by the 2 methods were very similar, whereas the costs of SSI calculated by propensity score matched-pairs were lower than the costs calculated by GLS. The difference in costs determined by the 2 methods needs to be considered by investigators who are performing cost analyses of hospital-acquired infections.
Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT
Authors: Singh Amrik , Ye Min , Bucur Octavian , Zhu Shudong , Tanya Santos Maria , Rabinovitz Isaac , Wei Wenyi , Gao Daming , Hahn William C. , Khosravi-Far Roya
Published: January 2010

Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study, we detected a robust interaction between FOXO3a and PP2A. We further demonstrate that 14-3-3, while not impeding the interaction between PP2A and FOXO3a, restrains its activity toward AKT phosphorylation sites T32/S253. Disruption of PP2A function revealed that after AKT inhibition, PP2A-mediated dephosphorylation of T32/S253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of FOXO3a. Our findings reveal that distinct phosphatases dephosphorylate conserved AKT motifs within the FOXO family and that PP2A is entwined in a dynamic interplay with AKT and 14-3-3 to directly regulate FOXO3a subcellular localization and transcriptional activation.
WellReader: a MATLAB program for the analysis of fluorescence and luminescence reporter gene data
Authors: Boyer Frédéric , Besson Bruno , Baptist Guillaume , Izard Jérôme , Pinel Corinne , Ropers Delphine , Geiselmann Johannes , de Jong Hidde
Published: January 2010

Motivation: Fluorescent and luminescent reporter gene systems in combination with automated microplate readers allow real-time monitoring of gene expression on the population level at high precision and sampling density. This generates large amounts of data for the analysis of which computer tools are missing to date.

Results: We have developed WellReader, a MATLAB program for the analysis of fluorescent and luminescent reporter gene data. WellReader allows the user to load the output files of microplate readers, remove outliers, correct for background effects and smooth and fit the data. Moreover, it computes biologically relevant quantities from the measured signals, notably promoter activities and protein concentrations, and compares the resulting expression profiles of different genes under different conditions.

Availability: WellReader is available under a LGPL licence at http://prabi1.inrialpes.fr/trac/wellreader.

Contact:  hidde.de-jong@inria.fr

Supplementary information:  Supplementary data are available at Bioinformatics online.
Computational quantification of metabolic fluxes from a single isotope snapshot: application to an animal biopsy
Authors: Binsl Thomas W. , Alders David J.C. , Heringa Jaap , Groeneveld A.B. Johan , van Beek Johannes H.G.M.
Published: January 2010

Motivation: Quantitative determination of metabolic fluxes in single tissue biopsies is difficult. We report a novel analysis approach and software package for in vivo flux quantification using stable isotope labeling.

Results: We developed a protocol based on brief, timed infusion of 13C isotope-enriched substrates for the tricarboxylic acid (TCA) cycle followed by quick freezing of tissue biopsies. NMR measurements of tissue extracts were used for flux estimation based on a computational model of carbon transitions between TCA cycle metabolites and related amino acids. To this end, we developed a computational framework in which metabolic systems can be flexibly assembled, simulated and analyzed. Flux parameters were quantified from NMR multiplets by a partial grid search followed by repeated Nelder–Mead optimizations implemented on a computer grid. We implemented a model of the TCA cycle and showed by extensive simulations that the timed infusion protocol reliably quantitates multiple fluxes. Experimental validation of the method was done in vivo on hearts of anesthetized pigs under two different conditions: basal state (n = 7) and cardiac stress caused by infusion of dobutamine (n = 7). About nine tissue samples (40–200 mg dry-weight) were taken per heart. TCA cycle flux was 6.11 ± 0.28 (SEM) μmol/min · gdw at baseline versus 9.29 ± 1.03 μmol/min · gdw for dobutamine stress. Oxygen consumption calculated from the TCA cycle flux and from ‘gold standard’ blood gas-based measurements were close, correlating with r=0.88 (P < 10−4). Spatial heterogeneity in metabolic fluxes is detectable amongst the small samples. We propose that our novel isotope snapshot methodology is suitable for flux measurements in biopsies in vivo.

Availability: Non-profit organizations will, upon request, be granted a non-exclusive license to use the software for internal research and teaching purposes at no charge. A web interface for using the software on our computer grid is available under http://www.ibi.vu.nl/programs/

Contact:  hans.van.beek@falw.vu.nl

Supplementary information:  Supplementary data are available at Bioinformatics online.
Exploring classification strategies with the CoEPrA 2006 contest
Authors: Demir-Kavuk Ozgur , Riedesel Henning , Knapp Ernst-Walter
Published: January 2010

Motivation:  In silico methods to classify compounds as potential drugs that bind to a specific target become increasingly important for drug design. To build classification devices training sets of drugs with known activities are needed. For many such classification problems, not only qualitative but also quantitative information of a specific property (e.g. binding affinity) is available. The latter can be used to build a regression scheme to predict this property for new compounds. Predicting a compound property explicitly is generally more difficult than classifying that the property lies below or above a given threshold value. Hence, an indirect classification that is based on regression may lead to poorer results than a direct classification scheme. In fact, initially researchers are only interested to classify compounds as potential drugs. The activities of these compounds are subsequently measured in wet lab.

Results: We propose a novel approach that uses available quantitative information directly for classification rather than first using a regression scheme. It uses a new type of loss function called weighted biased regression. Application of this method to four widely studied datasets of the CoEPrA contest (Comparative Evaluation of Prediction Algorithms, http://coepra.org) shows that it can outperform simple classification methods that do not make use of this additional quantitative information.

Availability: A stand alone application is available at the webpage http://agknapp.chemie.fu-berlin.de/agknapp/index.php?menu=software&page=PeptideClassifier that can be used to build a model for a peptide training set to be submitted.

Contact:  odemir@chemie.fu-berlin.de

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Correcting population stratification in genetic association studies using a phylogenetic approach
Authors: Li Mingyao , Reilly Muredach P. , Rader Daniel J. , Wang Li-San
Published: January 2010

Motivation: The rapid development of genotyping technology and extensive cataloguing of single nucleotide polymorphisms (SNPs) across the human genome have made genetic association studies the mainstream for gene mapping of complex human diseases. For many diseases, the most practical approach is the population-based design with unrelated individuals. Although having the advantages of easier sample collection and greater power than family-based designs, unrecognized population stratification in the study samples can lead to both false-positive and false-negative findings and might obscure the true association signals if not appropriately corrected.

Methods: We report PHYLOSTRAT, a new method that corrects for population stratification by combining phylogeny constructed from SNP genotypes and principal coordinates from multi-dimensional scaling (MDS) analysis. This hybrid approach efficiently captures both discrete and admixed population structures.

Results: By extensive simulations, the analysis of a synthetic genome-wide association dataset created using data from the Human Genome Diversity Project, and the analysis of a lactase-height dataset, we show that our method can correct for population stratification more efficiently than several existing population stratification correction methods, including EIGENSTRAT, a hybrid approach based on MDS and clustering, and STRATSCORE , in terms of requiring fewer random SNPs for inference of population structure. By combining the flexibility and hierarchical nature of phylogenetic trees with the advantage of representing admixture using MDS, our hybrid approach can capture the complex population structures in human populations effectively.

Software Availability: Codes can be downloaded from http://people.pcbi.upenn.edu/∼lswang/phylostrat/

Contact:  mingyao@upenn.edu; iswang@upenn.edu.

Supplementary information:  Supplementary data are available at Bioinformatics online.