bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overcoming resistance to sonic hedgehog inhibition by targeting p90 ribosomal S6 kinase in pediatric medulloblastoma
Authors: Pambid Mary Rose , Berns Rachel , Adomat Hans H. , Hu Kaiji , Triscott Joanna , Maurer Norbert , Zisman Natalia , Ramaswamy Vijay , Hawkins Cynthia E. , Taylor Michael D. , Dunham Christopher , Guns Emma , Dunn Sandra E. 
Published: August 2013

AbstractBackgroundMolecular subtyping has allowed for the beginning of personalized treatment in children suffering from medulloblastoma (MB). However, resistance inevitably emerges against these therapies, particularly in the Sonic Hedgehog (SHH) subtype. We found that children with SHH subtype have the worst outcome underscoring the need to identify new therapeutic targets.ProcedureHigh content screening of a 129 compound library identified agents that inhibited SHH MB growth. Lead molecular target levels, p90 ribosomal S6 kinase (RSK) were characterized by immunoblotting and qRT‐PCR. Comparisons were made to human neural stem cells (hNSC). Impact of inhibiting RSK with the small molecule BI‐D1870 or siRNA was assessed in growth assays (monolayer, neurosphere, and soft agar). NanoString was used to detect RSK in a cohort of 66 patients with MB. To determine BI‐D1870 pharmacokinetics/pharmacodynamics, 100 mg/kg was I.P. injected into mice and tissues were collected at various time points.ResultsDaoy, ONS76, UW228, and UW426 MB cells were exquisitely sensitive to BI‐D1870 but unresponsive to SHH inhibitors. Anti‐tumor growth corresponded with inactivation of RSK in MB cells. BI‐D1870 had no effect on hNSCs. Inhibiting RSK with siRNA or BI‐D1870 suppressed growth, induced apoptosis, and sensitized cells to SHH agents. Notably, RSK expression is correlated with SHH patients. In mice, BI‐D1870 was well‐tolerated and crossed the blood–brain barrier (BBB).ConclusionsRSK inhibitors are promising because they target RSK which is correlated with SHH patients as well as cause high levels of apoptosis to only MB cells. Importantly, BI‐D1870 crosses the BBB, acting as a scaffold for development of more long‐lived RSK inhibitors. Pediatr Blood Cancer 2014;61:107–115. © 2013 Wiley Periodicals, Inc.
Ultrasound‐assisted Extraction with LC–TOF/MS Identification and LC–UV Determination of Imazamox and its Metabolites in Leaves of Wheat Plants
Authors: Rojano‐Delgado Antonia M. , Priego‐Capote Feliciano , Prado Rafael De , de Castro María Dolores Luque 
Published: August 2013

ABSTRACTIntroductionimazamox is a herbicide used in many legominous and cereal crops. There are few methods in the literature for determination of imazamox and its metabolites in plants because of the lack of commercial standards or owing to expensive and/or complex synthesis.ObjectiveTo develop a method based on liquid chromatography and ultraviolet absorption detection for simultaneous determination of imazamox and its metabolites in plants.MethodsSample preparation was based on ultrasound‐assisted extraction (70 W power and duty cycle of 0.7 s/s for 10 min) with subsequent filtration of the extracts and clean‐up and concentration prior to chromatographic separation and detection at 240 nm. The chromatographic analysis was completed in 30 min using a Luna® HILIC column. Identification and confirmatory analysis of the presence of imazamox and its metabolites in extracts from treated plants was performed by LC–TOF/MS in high resolution mode for precursor ions. The metabolites were quantified using a surrogate approach based on an imazamox standard. The method was validated by analysing wheat samples treated with 200 g per hectare of active ingredient imazamox.ResultsThe linear dynamic range of the calibration curve was within 0.27–600 µg/mL, with a correlation coefficient of 0.998 and precision – studied at 0.1 and 2 µg/mL – of 2.9% and 5.0% for repeatability, and 4.7% and 6.9% for reproducibility, respectively.ConclusionThe analytical characteristics of the method make it recommendable for evaluating the metabolism of imazamox in plants. Copyright © 2013 John Wiley & Sons, Ltd.
Vibrational Spectroscopy as a Rapid Quality Control Method for Melaleuca alternifolia Cheel (Tea Tree Oil)
Authors: Tankeu Sidonie , Vermaak Ilze , Kamatou Guy , Viljoen Alvaro 
Published: August 2013

ABSTRACTIntroductionTea tree oil (TTO) is an important commercial oil which has found application in the flavour, fragrance and cosmetic industries. The quality is determined by the relative concentration of its major constituents: 1,8‐cineole, terpinen‐4‐ol, α‐terpineol, α‐terpinene, terpinolene, γ‐terpinene and limonene. Gas chromatography coupled to mass spectrometry (GC–MS) is traditionally used for qualitative and quantitative analyses but is expensive and time consuming.ObjectiveTo evaluate the use of vibrational spectroscopy in tandem with chemometric data analysis as a fast and low‐cost alternative method for the quality control of TTO.MethodsSpectral data were acquired in both the mid‐infrared (MIR) and near infrared (NIR) wavelength regions and reference data obtained using GC–MS with flame ionisation detection (FID). Principal component analysis (PCA) was used to investigate the data by observing clustering and identifying outliers. Partial least squares (PLS) multivariate calibration models were constructed for the quantification of the seven major constituents.ResultsHigh correlation coefficients (R2) of ≥ 0.75 were obtained for the seven major compounds and 1,8‐cineole showed the best correlation coefficients for both MIR and NIR data (R2 = 0.97 and 0.95, respectively). Low values were obtained for the root mean square error of estimation (RMSEE) and root mean square error of prediction (RMSEP) values thereby confirming accuracy.ConclusionThe accurate prediction of the external dataset after introduction into the models confirmed that both MIR and NIR spectroscopy are valuable methods for quantification of the major compounds of TTO when compared with the reference data obtained using GC–MS. Copyright © 2013 John Wiley & Sons, Ltd.
Observed octameric assembly of a Plasmodium yoelii peroxiredoxin can be explained by the replacement of native “ball‐and‐socket” interacting residues by an affinity tag
Authors: Gretes Michael C. , Karplus P. Andrew 
Published: August 2013

AbstractPeroxiredoxins (Prxs) are ubiquitous and efficient antioxidant enzymes crucial for redox homeostasis in most organisms, and are of special importance for disease‐causing parasites that must protect themselves against the oxidative weapons of the human immune system. Here, we describe reanalyses of crystal structures of two Prxs from malaria parasites. In addition to producing improved structures, we provide normalizing explanations for features that had been noted as unusual in the original report of these structures (Qiu et al., BMC Struct Biol 2012;12:2). Most importantly, we provide evidence that the unusual octameric assembly seen for Plasmodium yoelii Prx1a is not physiologically relevant, but arises because the structure is not of authentic P. yoelii Prx1a, but a variant we designate PyPrx1aN* that has seven native N‐terminal residues replaced by an affinity tag. This N‐terminal modification disrupts a previously unrecognized, hydrophobic “ball‐and‐socket” interaction conserved at the B‐type dimer interface of Prx1 subfamily enzymes, and is accommodated by a fascinating two‐residue “β‐slip” type register shift in the β‐strand association at a dimer interface. The resulting change in the geometry of the dimer provides a simple explanation for octamer formation. This study illustrates how substantive impacts can occur in protein variants in which native residues have been altered.
Crystal structure of the Alpha subunit PAS domain from soluble guanylyl cyclase
Authors: Purohit Rahul , Weichsel Andrzej , Montfort William R. 
Published: August 2013

AbstractSoluble guanylate cyclase (sGC) is a heterodimeric heme protein of ∼150 kDa and the primary nitric oxide receptor. Binding of NO stimulates cyclase activity, leading to regulation of cardiovascular physiology and providing attractive opportunities for drug discovery. How sGC is stimulated and where candidate drugs bind remains unknown. The α and β sGC chains are each composed of Heme‐Nitric Oxide Oxygen (H‐NOX), Per‐ARNT‐Sim (PAS), coiled‐coil and cyclase domains. Here, we present the crystal structure of the α1 PAS domain to 1.8 Å resolution. The structure reveals the binding surfaces of importance to heterodimer function, particularly with respect to regulating NO binding to heme in the β1 H‐NOX domain. It also reveals a small internal cavity that may serve to bind ligands or participate in signal transduction.
Substrate‐dependent dynamics of UDP‐galactopyranose mutase: Implications for drug design
Authors: Boechi Leonardo , de Oliveira Cesar Augusto F. , Da Fonseca Isabel , Kizjakina Karina , Sobrado Pablo , Tanner John J. , McCammon J. Andrew 
Published: August 2013

AbstractTrypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that represents one of the major health challenges of the Latin American countries. Successful efforts were made during the last few decades to control the transmission of this disease, but there is still no treatment for the 10 million adults in the chronic phase of the disease. In T. cruzi, as well as in other pathogens, the flavoenzyme UDP‐galactopyranose mutase (UGM) catalyzes the conversion of UDP‐galactopyranose to UDP‐galactofuranose, a precursor of the cell surface β‐galactofuranose that is involved in the virulence of the pathogen. The fact that UGM is not present in humans makes inhibition of this enzyme a good approach in the design of new Chagas therapeutics. By performing a series of computer simulations of T. cruzi UGM in the presence or absence of an active site ligand, we address the molecular details of the mechanism that controls the uptake and retention of the substrate. The simulations suggest a modular mechanism in which each moiety of the substrate controls the flexibility of a different protein loop. Furthermore, the calculations indicate that interactions with the substrate diphosphate moiety are especially important for stabilizing the closed active site. This hypothesis is supported with kinetics measurements of site‐directed mutants of T. cruzi UGM. Our results extend our knowledge of UGM dynamics and offer new alternatives for the prospective design of drugs.
Expanding the frontiers of protein–protein modeling: From docking and scoring to binding affinity predictions and other challenges
Authors: Pallara Chiara , Jiménez‐García Brian , Pérez‐Cano Laura , Romero‐Durana Miguel , Solernou Albert , Grosdidier Solène , Pons Carles , Moal Iain H. , Fernandez‐Recio Juan 
Published: August 2013

ABSTRACTIn addition to protein–protein docking, this CAPRI edition included new challenges, like protein–water and protein–sugar interactions, or the prediction of binding affinities and ΔΔG changes upon mutation. Regarding the standard protein–protein docking cases, our approach, mostly based on the pyDock scheme, submitted correct models as predictors and as scorers for 67% and 57% of the evaluated targets, respectively. In this edition, available information on known interface residues hardly made any difference for our predictions. In one of the targets, the inclusion of available experimental small‐angle X‐ray scattering (SAXS) data using our pyDockSAXS approach slightly improved the predictions. In addition to the standard protein–protein docking assessment, new challenges were proposed. One of the new problems was predicting the position of the interface water molecules, for which we submitted models with 20% and 43% of the water‐mediated native contacts predicted as predictors and scorers, respectively. Another new problem was the prediction of protein–carbohydrate binding, where our submitted model was very close to being acceptable. A set of targets were related to the prediction of binding affinities, in which our pyDock scheme was able to discriminate between natural and designed complexes with area under the curve = 83%. It was also proposed to estimate the effect of point mutations on binding affinity. Our approach, based on machine learning methods, showed high rates of correctly classified mutations for all cases. The overall results were highly rewarding, and show that the field is ready to move forward and face new interesting challenges in interactomics. Proteins 2013; 81:2192–2200. © 2013 Wiley Periodicals, Inc.
Band tail filling effect in MBE‐grown ternary MgZnO epitaxial layers with high Mg content
Authors: Karaliūnas Mindaugas , Šukauskas Vilmantas , Kuokštis Edmundas , Ting Shao‐Ying , Huang Jeng‐Jie , Yang C.‐C. 
Published: August 2013

AbstractIn this work, the carrier localization effect is studied in molecular beam epitaxy grown MgZnO epitaxial layers. The photoluminescence (PL) investigation revealed the S ‐shaped PL peak position dependence on temperature. It is usually related to the carrier localization in randomly distributed potential field fluctuations. We have measured double blue‐shift of the PL peak position with increase of temperature for samples with higher (17–30%) Mg content in the alloys.The two blue‐shifts are attributed to double‐scale potential field fluctuations with different average localization energy. The scanning near optical field microscopy experiment proved the presence of less than 100 nm width Mg rich areas with enhanced PL intensity. The atomic force microscopy and energy dispersive X‐ray diffraction experiments revealed a close relation of structural and optical quality with the evaluated average carriers localization energy. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Defect‐related mechanism of ferromagnetic behaviors for ZnCoO:H films formed by PLD with bias voltage application
Authors: Sasaki Kazuma , Komiyama Takao , Chonan Yasunori , Yamaguchi Hiroyuki , Aoyama Takashi 
Published: August 2013

AbstractFerromagnetic behaviors of Co‐doped ZnO films were investigated by using pulsed laser deposition (PLD) with the bias voltage application technique and by changing the partial pressure of oxygen ambient. The 50 V change in the PLD bias voltage caused the oxygen to zinc (O/Zn) ratio in the film to change by about 7%. Ferromagnetic behaviors were observed after the hydrogenation process. As the the O/Zn ratio in the ZnCoO:H films deviated more from the stoichiometric condition, the saturation magnetization (Ms) significantly decreased but sometimes increased. On the other hand, the deviation from the stoichiometric condition (that is the increase in the native defect concentration) significantly changed the carrier concentration. As the carrier concentration (Fermi level) increased, Ms increased first, then decreased, and finally increased again. Thus, the native defects certainly affected the Ms, but only through the shift of the Fermi level.
The Subventricular Zone Is Able to Respond to a Demyelinating Lesion After Localized Radiation
Authors: Capilla-Gonzalez Vivian , Guerrero-Cazares Hugo , Bonsu Janice M. , Gonzalez-Perez Oscar , Achanta Pragathi , Wong John , Garcia-Verdugo Jose Manuel , Quiñones-Hinojosa Alfredo 
Published: August 2013

AbstractRadiation is a common tool in the treatment of brain tumors that induces neurological deficits as a side effect. Some of these deficits appear to be related to the impact of radiation on the neurogenic niches, producing a drastic decrease in the proliferative capacity of these regions. In the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles is the main neurogenic niche. Neural stem/precursor cells (NSCs) within the SVZ play an important role in brain repair following injuries. However, the irradiated NSCs' ability to respond to damage has not been previously elucidated. In this study, we evaluated the effects of localized radiation on the SVZ ability to respond to a lysolecithin-induced demyelination of the striatum. We demonstrated that the proliferation rate of the irradiated SVZ was increased after brain damage and that residual NSCs were reactivated. The irradiated SVZ had an expansion of doublecortin positive cells that appeared to migrate from the lateral ventricles toward the demyelinated striatum, where newly generated oligodendrocytes were found. In addition, in the absence of demyelinating damage, remaining cells in the irradiated SVZ appeared to repopulate the neurogenic niche a year post-radiation. These findings support the hypothesis that NSCs are radioresistant and can respond to a brain injury, recovering the neurogenic niche. A more complete understanding of the effects that localized radiation has on the SVZ may lead to improvement of the current protocols used in the radiotherapy of cancer. Stem Cells 2014;32:59–69
Low‐temperature thermochronometry along the Kunlun and Haiyuan Faults, NE Tibetan Plateau: Evidence for kinematic change during late‐stage orogenesis
Authors: Duvall Alison R. , Clark Marin K. , Kirby Eric , Farley Kenneth A. , Craddock William H. , Li Chuanyou , Yuan Dao‐Yang 
Published: August 2013

AbstractThe Tibetan Plateau is a prime example of a collisional orogen with widespread strike‐slip faults whose age and tectonic significance remain controversial. We present new low‐temperature thermochronometry to date periods of exhumation associated with Kunlun and Haiyuan faulting, two major strike‐slip faults within the northeastern margin of Tibet. Apatite and zircon (U‐Th)/He and apatite fission‐track ages, which record exhumation from ~2 to 6 km crustal depths, provide minimum bounds on fault timing. Results from Kunlun samples show increased exhumation rates along the western fault segment at circa 12–8 Ma with a possible earlier phase of motion from ~30–20 Ma, along the central fault segment at circa 20–15 Ma, and along the eastern fault segment at circa 8–5 Ma. Combined with previous studies, our results suggest that motion along the Haiyuan fault may have occurred as early as ~15 Ma along the western/central fault segment before initiating at least by 10–8 Ma along the eastern fault tip. We relate an ~250 km wide zone of transpressional shear to synchronous Kunlun and Haiyuan fault motion and suggest that the present‐day configuration of active faults along the northeastern margin of Tibet was likely established since middle Miocene time. We interpret the onset of transpression to relate to the progressive confinement of Tibet against rigid crustal blocks to the north and expansion of crustal thickening to the east during the later stages of orogen development.
Testing Iberian kinematics at Jurassic‐Cretaceous times
Authors: Neres M. , Miranda J. M. , Font E. 
Published: August 2013

AbstractPaleogeographic reconstructions of Iberia at the Mesozoic are still a matter of debate. The incompatibility between kinematic models and paleomagnetic data older than 120 Ma is a major problem for which no cause has yet been determined. Here we use a new method to investigate the origin of this misfit. We solve the inverse problem of finding the Euler poles that fit paleomagnetic poles with the Global Apparent Polar Wander Path (GAPWP) and then test their implications on Iberian reconstructions. We show that Iberian poles from the Early Cretaceous (mean poles for 123 and 130 Ma) are incompatible with the GAPWP, bringing into question their validity. Contrarily, Late Jurassic data (mean pole at 151 Ma) are compatible with the GAPWP and, thus, can be considered reliable. Based on these results, we propose a new magnetic reconstruction of Iberia and surrounding plates at ~150 Ma (M22 anomaly). This work provides new constraints for the kinematic evolution of Iberia during Jurassic‐Cretaceous. However, the development of a detailed and consensual model for the kinematic evolution of Iberia is dependent on the acquisition of new, high‐quality paleomagnetic data and a reevaluation of seafloor magnetic anomalies.
Mutation of the CgPDR16 gene attenuates azole tolerance and biofilm production in pathogenic Candida glabrata
Authors: Culakova Hana , Dzugasova Vladimira , Perzelova Jana , Gbelska Yvetta , Subik Julius 
Published: August 2013

AbstractThe PDR16 gene encodes the homologue of Sec14p, participating in protein secretion, regulation of lipid synthesis and turnover in vivo and acting as a phosphatidylinositol transfer protein in vitro. This gene is also involved in the regulation of multidrug resistance in Saccharomyces cerevisiae and pathogenic yeasts. Here we report the results of functional analysis of the CgPDR16 gene, whose mutation has been previously shown to enhance fluconazole sensitivity in Candida glabrata mutant cells. We have cloned the CgPDR16 gene, which was able to complement the pdr16Δ mutation in both C. glabrata and S. cerevisiae. Along with fluconazole, the pdr16Δ mutation resulted in increased susceptibility of mutant cells to several azole antifungals without changes in sensitivity to polyene antibiotics, cycloheximide, NQO, 5‐fluorocytosine and oxidants inducing the intracellular formation of reactive oxygen species. The susceptibility of the pdr16Δ mutant strain to itraconazole and 5‐fluorocytosine was enhanced by CTBT [7‐chlorotetrazolo(5,1‐c)benzo(1,2,4)triazine] inducing oxidative stress. The pdr16Δ mutation increased the accumulation of rhodamine 6G in mutant cells, decreased the level of itraconazole resistance caused by gain‐of‐function mutations in the CgPDR1 gene, and reduced cell surface hydrophobicity and biofilm production. These results point to the pleiotropic phenotype of the pdr16Δ mutant and support the role of the CgPDR16 gene in the control of drug susceptibility and virulence in the pathogenic C. glabrata. Copyright © 2013 John Wiley & Sons, Ltd.
Alpha‐1 Couples: Interpersonal and Intrapersonal Predictors of Spousal Communication and Stress
Authors: Smith Rachel A. , Wienke Sara , Coffman Donna L. 
Published: August 2013

AbstractCouples often discuss genetic test results, and then manage their implications together. This interdependence can lead to common, shared experiences, similar intrapersonal processes to manage shared stressors, or interpersonal influences between spouses, leading to different outcomes. This study sought to reveal the intracouple, intrapersonal, and interpersonal influences of genetic stigma and negative feelings on spousal communication and perceived stress with 50 couples in which one spouse is a member of a genetic disease registry. The results were analyzed with dyadic analysis, including multilevel modeling. The findings showed that registered members and their spouses were not statistically different in their mean levels of perceived genetic stigma, negative feelings about alpha‐1 antitrypsin deficiency (AATD), conversations with each other about the AATD test results, and their perceived stress. The findings also showed that their intracouple consistencies were not high, and their intrapersonal and interpersonal influences on communication and stress differed. The social implications of genetic research at the interpersonal level are discussed.
Kinetics of Isothermal Crystallization of Hydrogenated Castor Oil‐in‐Water Emulsions
Authors: Yang Dingzheng , Hrymak Andrew N. , Kedzior Stephanie 
Published: August 2013

AbstractKinetics of isothermal crystallization of hydrogenated castor oil in water emulsions exhibiting multiple crystal morphologies have been studied experimentally by DSC and polarized light microscopy. The induction time of nucleation increases with the increase of the isothermal temperature under which crystallization occurred. Crystal growth has been observed by microscopy showing that both crystal morphologies, fibers and rosettes, grow linearly at the initial stage of crystallization and then slow down to reach a plateau value. The Avrami model, which has been widely used in kinetics studies of triacylglycerol systems, was employed to fit experimental results at different isothermal temperatures. It was found that experimental trends could be captured by introducing the volume fraction of each type of morphology into three‐dimensional and one‐dimensional full Avrami models.