bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta
Authors: Jacobsen Christina M , Barber Lauren A , Ayturk Ugur M , Roberts Heather J , Deal Lauren E , Schwartz Marissa A , Weis MaryAnn , Eyre David , Zurakowski David , Robling Alexander G , Warman Matthew L 
Published: February 2014

ABSTRACT

The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5p.A214V) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5+/p.A214V mice to Col1a2+/p.G610C mice, which model human type IV OI. We found that Col1a2+/p.G610C;Lrp5+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2+/p.G610C;Lrp5+/+ littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research.
METTL21C Is a Potential Pleiotropic Gene for Osteoporosis and Sarcopenia Acting Through the Modulation of the NF-κB Signaling Pathway
Authors: Huang Jian , Hsu Yi-Hsiang , Mo Chenglin , Abreu Eduardo , Kiel Douglas P , Bonewald Lynda F , Brotto Marco , Karasik David 
Published: February 2014

ABSTRACT

Sarcopenia and osteoporosis are important public health problems that occur concurrently. A bivariate genome-wide association study (GWAS) identified METTL21c as a suggestive pleiotropic gene for both bone and muscle. The METTL21 family of proteins methylates chaperones involved in the etiology of both myopathy and inclusion body myositis with Paget's disease. To validate these GWAS results, Mettl21c mRNA expression was reduced with siRNA in a mouse myogenic C2C12 cell line and the mouse osteocyte-like cell line MLO-Y4. At day 3, as C2C12 myoblasts start to differentiate into myotubes, a significant reduction in the number of myocytes aligning/organizing for fusion was observed in the siRNA-treated cells. At day 5, both fewer and smaller myotubes were observed in the siRNA-treated cells as confirmed by histomorphometric analyses and immunostaining with myosin heavy chain (MHC) antibody, which only stains myocytes/myotubes but not myoblasts. Intracellular calcium (Ca2+) measurements of the siRNA-treated myotubes showed a decrease in maximal amplitude peak response to caffeine, suggesting that less Ca2+ is available for release due to the partial silencing of Mettl21c, correlating with impaired myogenesis. In siRNA-treated MLO-Y4 cells, 48 hours after treatment with dexamethasone there was a significant increase in cell death, suggesting a role of Mettl21c in osteocyte survival. To investigate the molecular signaling machinery induced by the partial silencing of Mettl21c, we used a real-time PCR gene array to monitor the activity of 10 signaling pathways. We discovered that Mettl21c knockdown modulated only the NF-κB signaling pathway (ie, Birc3, Ccl5, and Tnf). These results suggest that Mettl21c might exert its bone-muscle pleiotropic function via the regulation of the NF-κB signaling pathway, which is critical for bone and muscle homeostasis. These studies also provide rationale for cellular and molecular validation of GWAS, and warrant additional in vitro and in vivo studies to advance our understanding of role of METTL21C in musculoskeletal biology. © 2014 American Society for Bone and Mineral Research
Cancer biomarker discovery for cholangiocarcinoma: the high‐throughput approaches
Authors: Silsirivanit Atit , Sawanyawisuth Kanlayanee , Riggins Gregory J. , Wongkham Chaisiri 
Published: February 2014

Abstract Cholangiocarcinoma (CCA) is difficult to diagnose at an early stage and most tumors are detected at late stage where surgery or other therapy is ineffective. Many advanced techniques are applied to diagnose CCA; however, most are expensive and have varying degrees of accuracy. A less invasive and simpler procedure such as serum markers would be of substantial clinical benefit for diagnosis, monitoring, and predicting outcome for CCA patients. Recent advances in “Omics” technologies offer remarkable opportunities for establishment of biomarker‐related to diseases. In this review, the potential biomarkers obtained from proteomics and glycomic studies are evaluated. Several protein markers were discovered from patient specimen, using two dimensional‐differential gel electrophoresis couple with liquid chromatography tandem mass spectrometry (2D‐DIGE/LC‐MS‐MS), matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry (MALDI‐TOF‐MS), surface enhanced laser desorption/ionization (SELDI)‐TOF‐MS and capillary electrophoresis (CE)‐MS, etc. Newly reported CCA‐associated glyco‐biomarkers were identified using lectin‐assisted, monoclonal antibody‐assisted or specific‐target strategies. The combination between carbohydrate binding‐lectin and core protein‐binding mAb significantly increased the values for detection of the glyco‐biomarkers for CCA. Searching for specific and sensitive molecular markers to be used for population screening is worth being evaluated. This could lead to earlier diagnosis and improve outcome. Further investigation of those biomarker functions is also of value in order to better understand the tumor biology and use them as targets for future therapeutic agents.
Formation of adherens and communicating junctions coordinate the differentiation of the shedding‐layer and beta‐epidermal generation in regenerating lizard epidermis
Authors: Alibardi Lorenzo 
Published: February 2014

ABSTRACTIn the lizard epidermis, the formation of a stratified alpha‐ and beta‐layer, separated by a shedding complex for molting, suggests that keratinocytes communicate in a coordinated manner after they leave the basal layers during the shedding cycle. I have therefore studied the localization of cell junctional proteins such as beta‐catenin and connexins 43 and 26 during scale regeneration in lizard using immunocytochemistry. Beta‐catenin is also detected in nuclei of basal cells destined to give rise to the Oberhäutchen and beta‐cells suggesting activation of the Wnt‐pathway during beta‐cell differentiation. The observations show that cells of the entire shedding layer (clear and Oberhäutchen) and beta‐layer are connected by beta‐catenin (adherens junctions) and connexins (communicating junctions) during their differentiation. This likely cell coupling determines the formation of a distinct shedding and beta‐layer within the regenerating epidermis. The observed pattern of cell junctional stratification suggests that after departing from the basal layer Oberhäutchen and beta‐cells form a continuous communicating compartment that coordinates the contemporaneous differentiation along the entire scale. While the beta‐layer matures the junctions are lost while other cell junctions are formed in the following mesos‐ and alpha‐cell layers. This process determines the formation of layers with different texture (harder or softer) and the precise localization of the shedding layer within lizard epidermis. J. Morphol. 275:693–702, 2014. © 2014 Wiley Periodicals, Inc.
Autumn Eurasian snow depth, autumn Arctic sea ice cover and East Asian winter monsoon
Authors: Li Fei , Wang Huijun 
Published: February 2014

ABSTRACTWe present observational evidence and model simulation demonstrating a significant change in the early 1990s in the relationships of the autumn Eurasian snow depth (AESD) and the autumn Arctic sea ice cover (ASIC) with the East Asian winter monsoon (EAWM). A weakening of the AESD–EAWM relationship occurs over a period when the ASIC–EAWM relationship strengthens. The possible physical process can be described as follows: before the early 1990s, the positive AESD anomaly tends to persist into winter. In contrast, after the early 1990s, the negative ASIC anomaly tends to excite a stationary Rossby wave across the North America–Atlantic sector in autumn. This wave train propagates eastward in winter and favours the winter Eurasian snow depth (WESD) increase. The WESD anomaly is associated with the strengthening and expansions of the Siberian high west and north across the pole and the zonally elongated cold anomalies from Europe to the Far East. It has a stable connection with the EAWM throughout the period observed (1979–2006) and may serve as a bridge linking AESD or ASIC with the EAWM.
Multimodel ensemble forecasting of rainfall over East Asia: regularized regression approach
Authors: Lim Yaeji , Jo Seongil , Lee Jaeyong , Oh Hee‐Seok , Lee Sang‐Goo , Park Yongtae , Kang Hyun‐Suk 
Published: February 2014

ABSTRACTThis paper considers the problem of predicting the rainfall over East Asia from multimode outputs. For this purpose, we propose a new multimode ensemble method based on regularized regression approach, which consists of two steps, the pre‐processing step and the ensemble step. In the pre‐processing step, we improve prediction from each model output using regularized regression, and in the ensemble step, we apply regularization‐based regression method to combine the result from the pre‐processing step. The main benefits of the proposed method are that it improves prediction accuracy, and it is capable of solving the singularity problem so that it can integrate many climate variables from multimode outputs for a better prediction. The proposed method is applied to monthly outputs from nine general circulation models (GCMs) on boreal summer (June, July, and August) over 20 years (1983–2002). The prediction ability of the proposed ensemble forecast is compared with the observations and the outputs (prediction) from eachGCM. The results show that the proposed method is capable of improving forecast accuracy by adjusting each model before combining.
Distortion conspicuity on stereoscopically viewed 3D images may correlate to scene content and distortion type
Authors: Chen Ming‐Jun , Cormack Lawrence K. , Bovik Alan C. 
Published: February 2014

AbstractWe describe two studies that were aimed towards increasing our understanding of how the visibility of distortions on stereoscopically viewed 3D images is affected by scene content and distortion types. By assuming that subjects' performance would be highly correlated with the visibility of local distorted patches, we analyzed subjects' performance in locating distortion patches when viewing stereoscopic 3D images. Subjects' performances are measured by whether they successfully locate a local distorted patch, the times they spent to finish the task, and subjective quality ratings given by subjects. The visual data used in this work are co‐registered stereo images with co‐registered “ground truth” range (depth) data. Varied statistical analysis methods were used to discuss the significance of our observations. Three observations are drawn from our analyses. First, blur, JPEG, and JP2K distortions in stereo 3D images may be suppressed if one of the left or right views is undistorted. Second, contrast masking does not occur, or is reduced, while viewing white noise distorted stereo 3D images. Third, there is no depth/disparity masking effect when viewing stereo 3D images, but there may be (conversely) depth‐related facilitation effects for blur, JPEG, and JP2K distorted stereo 3D images.
Pixel structures using the negative feedback method for high‐resolution active matrix organic light‐emitting diode displays
Authors: Keum Nack‐Hyeon , Kwon Oh‐Kyong 
Published: February 2014

AbstractNovel two pixel structures are proposed for high‐resolution active matrix organic light‐emitting diode displays. The proposed two pixels (pixel structures A and B) use the negative feedback method for high‐resolution displays that requires to have small‐sized storage capacitance. The proposed pixel structures A and B improve the luminance uniformity by reducing the voltage distortion in the storage capacitor. However, the proposed pixel structure A is vulnerable to the organic light‐emitting diode (OLED) degradation because the anode voltage of the OLED affects the emission current. In order to compensate the OLED degradation, the proposed pixel structure B stores the turn‐on voltage of OLEDs in the storage capacitor. The simulation results show that the emission current error of the proposed pixel structure B is improved by four times in comparison with the proposed pixel structure A when the OLED turn‐on voltage increases by 0.1 V. Also, the emission current error of the proposed pixel structure B when the threshold voltage of driving thin‐film transistors varies from −2.2 to −1.8 V is from −0.69 least significant bit (LSB) to 0.13 LSB, which shows the excellent luminance uniformity. The proposed pixels are designed for 5.5‐in. full high‐definition displays.
Consecutive Chemical Activation Steps in the OH‐Initiated Atmospheric Degradation of Isoprene: An Analysis with Coupled Master Equations
Authors: Pfeifle Mark , Olzmann Matthias 
Published: February 2014

ABSTRACTThe influence of a two‐step chemical activation on 1,5‐H and 1,6‐H shift reactions of hydroxyl‐peroxy radicals formed in the atmospheric photooxidation of isoprene was investigated by means of a master equation analysis. To account for multiple chemical activation processes, three master equations were coupled. The general approach of this coupling is described, and consequences for steady‐state regimes are examined. The specific calculations show that chemical activation has no substantial influence on the rate coefficients of the above‐mentioned reactions under tropospheric conditions. However, it is demonstrated that high‐pressure limits of the thermal rate coefficients instead of the falloff‐corrected values have to be used for kinetic modeling. This is a consequence of the continuous population of the high‐energy part of the isoprene‐OH‐O2 adduct distribution by the forming reactions under steady‐state conditions. The rate coefficients of the isomerization reactions at T = 298 K were calculated to be k3a∞ = 1.5 × 10−3 s−1 (1,5‐H‐shift of the 1,2‐isomer) and k4a∞ = 6.5 s−1 (1,6‐H‐shift of the (Z)‐1,4‐isomer). The calculated value of k4a∞ is three orders of magnitude larger than a recently reported experimentally observed rate coefficient for the hydrogen shift reactions of the hydroxyl‐peroxy intermediates. It is shown that this discrepancy is in part due to the fact that the experiment does not distinguish between different structural isomers. A comparison of the experimentally determined isotope effect with the calculated value shows a reasonable agreement.
Latent and Delayed Action Polymerization Systems
Authors: Naumann Stefan , Buchmeiser Michael R. 
Published: February 2014

Various approaches to latent polymerization processes are described. In order to highlight recent advances in this field, the discussion is subdivided into chapters dedicated to diverse classes of polymers, namely polyurethanes, polyamides, polyesters, polyacrylates, epoxy resins, and metathesis‐derived polymers. The described latent initiating systems encompass metal‐containing as well as purely organic compounds that are activated by external triggers such as light, heat, or mechanical force. Special emphasis is put on the different chemical venues that can be taken to achieve true latency, which include masked N‐heterocyclic carbenes, latent metathesis catalysts, and photolatent radical initiators, among others. Scientific challenges and the advantageous application of latent polymerization processes are discussed.
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ABT‐089 and ABT‐894 reduce levodopa‐induced dyskinesias in a monkey model of Parkinson's disease
Authors: Zhang Danhui , Bordia Tanuja , McGregor Matthew , McIntosh J. Michael , Decker Michael W. , Quik Maryka 
Published: February 2014

ABSTRACTLevodopa‐induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT‐089 and ABT‐894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle‐treated group, an nAChR agonist‐treated group, and a nicotine‐treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug‐primed), whereas Set B monkeys were initially nAChR drug‐naive. Both sets were administered the partial agonist ABT‐089 (range, 0.01‐1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT‐089 decreased LIDs by 30% to 50% compared with vehicle‐treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT‐894 (range, 0.0001‐0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT‐894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT‐089 was 30 to 60 times less potent than ABT‐894. Tolerance did not develop for the time periods tested (range, 3‐4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT‐894 and ABT‐089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society
Safety and tolerability of carbamylated erythropoietin in Friedreich's ataxia
Authors: Boesch Sylvia , Nachbauer Wolfgang , Mariotti Caterina , Sacca Francesco , Filla Alessandro , Klockgether Thomas , Klopstock Thomas , Schöls Ludger , Jacobi Heike , Büchner Boriana , vom Hagen Jennifer Müller , Nanetti Lorenzo , Manicom Karen 
Published: February 2014

ABSTRACTBackgroundErythropoietin (EPO) derivatives have been found to increase frataxin levels in Friedreich's ataxia (FRDA) in vitro. This multicenter, double‐blind, placebo‐controlled, phase II clinical trial aimed to evaluate the safety and tolerability of Lu AA24493 (carbamylated EPO; CEPO).MethodsThirty‐six ambulatory FRDA patients harboring >400 GAA repeats were 2:1 randomly assigned to either CEPO in a fixed dose (325 µg thrice‐weekly) or placebo. Safety and tolerability were assessed up to 103 days after baseline. Secondary outcome measures of efficacy (exploration of biomarkers and ataxia ratings) were performed up to 43 days after baseline.ResultsAll patients received six doses of study medication. Adverse events were equally distributed between CEPO and placebo. There was no evidence for immunogenicity of CEPO after multiple dosing. Biomarkers, such as frataxin, or measures for oxidative stress and ataxia ratings did not differ between CEPO and placebo.ConclusionCEPO was safe and well tolerated in a 2‐week treatment phase. Secondary outcome measures remained without apparent difference between CEPO and placebo. © 2014 International Parkinson and Movement Disorder Society
The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation
Authors: Nikolaienko Tymofii Yu. , Bulavin Leonid A. , Sukhodub Leonid F. 
Published: February 2014

AbstractNon‐covalent complexes of methylated nitrogenous DNA base guanine (m9Gua) with 1 to 6 molecules of anticancer drug ThioTEPA (1,1′,1′′‐phosphorothioyltriaziridine) have been investigated by molecular modeling techniques (molecular docking and DFT geometry optimization), ab initio wavefunction calculations and the quantum theory of atoms in molecules (QTAIM). The accuracy of complex structures predicted by standard molecular docking techniques have been assessed by comparing them with ab initio calculations, and the most important differences have been discussed. Obtained stabilization enthalpies (kcal/mol) for the m9Gua⋅⋅⋅(ThioTEPA)n complexes with n=1…6 have been found to be −15.6, −26.5, −38.4, −49.6, −60.5 and −69.3 respectively. The non‐covalent interactions revealed by the QTAIM method have been shown to be a dominating factor responsible for the complex stability, with hydrogen bonds of NH⋅⋅⋅N type being the most important interactions in small (n=1 to 4) and CH⋅⋅⋅N bonds – in large (n=5, 6) complexes. The obtained results may help to understand ThioTEPA‐DNA interactions and clarify the mechanism of the drug action.
eFindSite: Enhanced Fingerprint‐Based Virtual Screening Against Predicted Ligand Binding Sites in Protein Models
Authors: Feinstein Wei P. , Brylinski Michal 
Published: February 2014

AbstractA standard practice for lead identification in drug discovery is ligand virtual screening, which utilizes computing technologies to detect small compounds that likely bind to target proteins prior to experimental screens. A high accuracy is often achieved when the target protein has a resolved crystal structure; however, using protein models still renders significant challenges. Towards this goal, we recently developed eFindSite that predicts ligand binding sites using a collection of effective algorithms, including meta‐threading, machine learning and reliable confidence estimation systems. Here, we incorporate fingerprint‐based virtual screening capabilities in eFindSite in addition to its flagship role as a ligand binding pocket predictor. Virtual screening benchmarks using the enhanced Directory of Useful Decoys demonstrate that eFindSite significantly outperforms AutoDock Vina as assessed by several evaluation metrics. Importantly, this holds true regardless of the quality of target protein structures. As a first genome‐wide application of eFindSite, we conduct large‐scale virtual screening of the entire proteome of Escherichia coli with encouraging results. In the new approach to fingerprint‐based virtual screening using remote protein homology, eFindSite demonstrates its compelling proficiency offering a high ranking accuracy and low susceptibility to target structure deformations. The enhanced version of eFindSite is freely available to the academic community at http://www.brylinski.org/efindsite.