bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropathology in progranulin knockout mice
Authors: Wils Hans , Kleinberger Gernot , Pereson Sandra , Janssens Jonathan , Capell Anja , Van Dam Debby , Cuijt Ivy , Joris Geert , De Deyn Peter P , Haass Christian , Van Broeckhoven Christine , Kumar‐Singh Samir 
Published: June 2012

AbstractLoss‐of‐function mutations in progranulin (GRN) are associated with frontotemporal lobar degeneration with intraneuronal ubiquitinated protein accumulations composed primarily of hyperphosphorylated TDP‐43 (FTLD‐TDP). The mechanism by which GRN deficiency causes TDP‐43 pathology or neurodegeneration remains elusive. To explore the role of GRN in vivo, we established Grn knockout mice using a targeted genomic recombination approach and Cre‐LoxP technology. Constitutive Grn homozygous knockout (Grn−/−) mice were born in an expected Mendelian pattern of inheritance and showed no phenotypic alterations compared to heterozygous (Grn+/−) or wild‐type (Wt) littermates until 10 months of age. From then, Grn−/− mice showed reduced survival accompanied by significantly increased gliosis and ubiquitin‐positive accumulations in the cortex, hippocampus, and subcortical regions. Although phosphorylated TDP‐43 could not be detected in the ubiquitinated inclusions, elevated levels of hyperphosphorylated full‐length TDP‐43 were recovered from detergent‐insoluble brain fractions of Grn−/− mice. Phosphorylated TDP‐43 increased with age and was primarily extracted from the nuclear fraction. Grn−/− mice also showed degenerative liver changes and cathepsin D‐positive foamy histiocytes within sinusoids, suggesting widespread defects in lysosomal turnover. An increase in insulin‐like growth factor (IGF)‐1 was observed in Grn−/− brains, and increased IGF‐1 signalling has been associated with decreased longevity. Our data suggest that progranulin deficiency in mice leads to reduced survival in adulthood and increased cellular ageing accompanied by hyperphosphorylation of TDP‐43, and recapitulates key aspects of FTLD‐TDP neuropathology. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis
Authors: Paterson Anna L , O'Donovan Maria , Provenzano Elena , Murray Liam J , Coleman Helen G , Johnson Brian T , McManus Damian T , Novelli Marco , Lovat Laurence B , Fitzgerald Rebecca C 
Published: June 2012

AbstractDespite being common in epithelial malignancies, the timing of receptor tyrosine kinase (RTK) up‐regulation is poorly understood and therefore hampers the identification of the receptor to target for effective treatment. We aimed to determine if RTK expression changes were early events in carcinogenesis. Oesophageal adenocarcinoma and its pre‐invasive lesion, Barrett's oesophagus, were used for immunohistochemical analysis of the RTK panel, EGFR, ErbB2, ErbB3, Met, and FGFR2, by utilizing a cohort of patients with invasive disease ($n = 367$) and two cohorts with pre‐invasive disease, one cross‐sectional ($n = 110$) and one longitudinal in time ($n = 91$). The results demonstrated that 51% of oesophageal adenocarcinomas overexpressed at least one of the RTK panel, with 21% of these overexpressing multiple receptors. Up‐regulation of RTK expression was an early event corresponding with low‐grade dysplasia development (25% in areas without dysplasia versus 63% in low‐grade dysplasia, $p < 0.001$). There was a trend for an increase in the prevalence of concomitant overexpression of multiple receptors as intestinal metaplasia progressed to low‐grade dysplasia, 7% versus 10%; and from low‐grade dysplasia to high‐grade dysplasia, 10% versus 19% ($p = 0.06$ and 0.24, respectively). The timing of receptor up‐regulation varied; FGFR, ErbB2, and Met overexpression occurred as dysplasia first developed, whilst EGFR overexpression was predominately seen in invasive disease and ErbB3 overexpression was uniformly rare. We provide evidence for a frequent and early role for multiple different RTKs in oesophageal carcinogenesis. Given the early timing of receptor deregulation, inhibiting RTKs in pre‐invasive disease may also represent a novel and effective chemopreventive strategy. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction
Authors: Yung Hong wa , Hemberger Myriam , Watson Erica D , Senner Claire E , Jones Carolyn P , Kaufman Randal J , Charnock‐Jones D Stephen , Burton Graham J 
Published: June 2012

AbstractWe recently reported the first evidence of placental endoplasmic reticulum (ER) stress in the pathophysiology of human intrauterine growth restriction. Here, we used a mouse model to investigate potential underlying mechanisms. Eif2s1tm1RjK mice, in which Ser51 of eukaryotic initiation factor 2 subunit alpha (eIF2α) is mutated, display a 30% increase in basal translation. In Eif2s1tm1RjK placentas, we observed increased ER stress and anomalous accumulation of glycoproteins in the endocrine junctional zone (Jz), but not in the labyrinthine zone where physiological exchange occurs. Placental and fetal weights were reduced by 15% (97 mg to 82 mg, p < 0.001) and 20% (1009 mg to 798 mg, p < 0.001), respectively. To investigate whether ER stress affects bioactivity of secreted proteins, mouse embryonic fibroblasts (MEFs) were derived from Eif2s1tm1RjK mutants. These MEFs exhibited ER stress, grew 50% slower, and showed reduced Akt–mTOR signalling compared to wild‐type cells. Conditioned medium (CM) derived from Eif2s1tm1RjK MEFs failed to maintain trophoblast stem cells in a progenitor state, but the effect could be rescued by exogenous application of FGF4 and heparin. In addition, ER stress promoted accumulation of pro‐Igf2 with altered glycosylation in the CM without affecting cellular levels, indicating that the protein failed to be processed after release. Igf2 is the major growth factor for placental development; indeed, activity in the Pdk1–Akt–mTOR pathways was decreased in Eif2s1tm1RjK placentas, indicating loss of Igf2 signalling. Furthermore, we observed premature differentiation of trophoblast progenitors at E9.5 in mutant placentas, consistent with the in vitro results and with the disproportionate development of the labyrinth and Jz seen in placentas at E18.5. Similar disproportion has been reported in the Igf2‐null mouse. These results demonstrate that ER stress adversely affects placental development, and that modulation of post‐translational processing, and hence bioactivity, of secreted growth factors contributes to this effect. Placental dysmorphogenesis potentially affects fetal growth through reduced exchange capacity. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Supportive care needs in newly diagnosed oral cavity cancer patients receiving radiation therapy
Authors: Chen Shu‐Ching , Lai Yeur‐Hur , Liao Chun‐Ta , Chang Joseph Tung‐Chien , Lin Chien‐Yu , Fan Kang‐Hsing , Huang Bing‐Shen 
Published: June 2012

AbstractObjectiveThis study aimed to examine changes in physical symptom severity, functional status, supportive care needs, and related factors in oral cavity cancer patients during 6 months after beginning radiation therapy (RT) or concurrent chemotherapy and radiation therapy (CCRT).MethodsA prospective longitudinal study was conducted involving oral cavity cancer patients from an RT clinic at a medical center in northern Taiwan. Patients were assessed for supportive care needs and physical symptoms at five time points: before the beginning of RT or CCRT and at 1, 2, 3, and 6 months after beginning RT or CCRT. The generalized estimating equation was used to identify predictors of overall needs as well as six specific dimensions of needs.ResultsA total of 82 patients completed the 6 months of follow‐up. Patients had moderate to high levels of supportive care needs over the 6 months. Although the highest information need was at the pretreatment phase, in general, the peak for overall and individual care needs was at 2 months since first receiving RT or CCRT. Patients without religious beliefs as well as those with higher educational level, functional level, overall physical symptom severity, and baseline anxiety reported more supportive care needs. Anxiety level before treatment was the most common factor across most supportive care needs. Individual physical symptoms, including fatigue, swallowing difficulty, and oral mucositis, were significantly related to higher physical and daily living needs.ConclusionsA systematic clinical assessment to detect patients' care needs is necessary to improve the provision of timely cancer care and meet patients' healthcare needs. Copyright © 2012 John Wiley & Sons, Ltd.
Designing redox potential‐controlled protein switches based on mutually exclusive proteins
Authors: Peng Qing , Kong Na , Wang Hui‐Chuan Eileen , Li Hongbin 
Published: June 2012

AbstractSynthetic/artificial protein switches provide an efficient means of controlling protein functions using chemical signals and stimuli. Mutually exclusive proteins, in which only the host or guest domain can remain folded at a given time owing to conformational strain, have been used to engineer novel protein switches that can switch enzymatic functions on and off in response to ligand binding. To further explore the potential of mutually exclusive proteins as protein switches and sensors, we report here a new redox‐based approach to engineer a mutually exclusive folding‐based protein switch. By introducing a disulfide bond into the host domain of a mutually exclusive protein, we demonstrate that it is feasible to use redox potential to switch the host domain between its folded and unfolded conformations via the mutually exclusive folding mechanism, and thus switching the functionality of the host domain on and off. Our study opens a new and potentially general avenue that uses mutually exclusive proteins to design novel switches able to control the function of a variety of proteins.
Use of the novel technique of analytical ultracentrifugation with fluorescence detection system identifies a 77S monosomal translation complex
Authors: Wang Xin , Zhang Chongxu , Chiang Yueh‐Chin , Toomey Shaun , Power Matthew P. , Granoff Mitchell E. , Richardson Roy , Xi Wen , Lee Darren J. , Chase Susan , Laue Thomas M. , Denis Clyde L. 
Published: June 2012

AbstractA fundamental problem in proteomics is the identification of protein complexes and their components. We have used analytical ultracentrifugation with a fluorescence detection system (AU‐FDS) to precisely and rapidly identify translation complexes in the yeast Saccharomyces cerevisiae. Following a one‐step affinity purification of either poly(A)‐binding protein (PAB1) or the large ribosomal subunit protein RPL25A in conjunction with GFP‐tagged yeast proteins/RNAs, we have detected a 77S translation complex that contains the 80S ribosome, mRNA, and components of the closed‐loop structure, eIF4E, eIF4G, and PAB1. This 77S structure, not readily observed previously, is consistent with the monosomal translation complex. The 77S complex abundance decreased with translational defects and following the stress of glucose deprivation that causes translational stoppage. By quantitating the abundance of the 77S complex in response to different stress conditions that block translation initiation, we observed that the stress of glucose deprivation affected translation initiation primarily by operating through a pathway involving the mRNA cap binding protein eIF4E whereas amino acid deprivation, as previously known, acted through the 43S complex. High salt conditions (1M KCl) and robust heat shock acted at other steps. The presumed sites of translational blockage caused by these stresses coincided with the types of stress granules, if any, which are subsequently formed.
Protein flexibility is key to cisplatin crosslinking in calmodulin
Authors: Li Huilin , Wells Stephen A. , Jimenez‐Roldan J. Emilio , Römer Rudolf A. , Zhao Yao , Sadler Peter J. , O'Connor Peter B. 
Published: June 2012

AbstractChemical crosslinking in combination with Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) has significant potential for studying protein structures and protein–protein interactions. Previously, cisplatin has been shown to be a crosslinker and crosslinks multiple methionine (Met) residues in apo‐calmodulin (apo‐CaM). However, the inter‐residue distances obtained from nuclear magnetic resonance structures are inconsistent with the measured distance constraints by crosslinking. Met residues lie too far apart to be crosslinked by cisplatin. Here, by combining FTICR MS with a novel computational flexibility analysis, the flexible nature of the CaM structure is found to be key to cisplatin crosslinking in CaM. It is found that the side chains of Met residues can be brought together by flexible motions in both apo‐CaM and calcium‐bound CaM (Ca4‐CaM). The possibility of cisplatin crosslinking Ca4‐CaM is then confirmed by MS data. Therefore, flexibility analysis as a fast and low‐cost computational method can be a useful tool for predicting crosslinking pairs in protein crosslinking analysis and facilitating MS data analysis. Finally, flexibility analysis also indicates that the crosslinking of platinum to pairs of Met residues will effectively close the nonpolar groove and thus will likely interfere with the binding of CaM to its protein targets, as was proved by comparing assays for cisplatin‐modified/unmodified CaM binding to melittin. Collectively, these results suggest that cisplatin crosslinking of apo‐CaM or Ca4‐CaM can inhibit the ability of CaM to recognize its target proteins, which may have important implications for understanding the mechanism of tumor resistance to platinum anticancer drugs.
Simplified proteomics approach to discover protein–ligand interactions
Authors: Chang Youngil , Schlebach Jonathan P. , VerHeul Ross A. , Park Chiwook 
Published: June 2012

AbstractIdentifying targets of biologically active small molecules is an essential but still challenging task in drug research and chemical genetics. Energetics‐based target identification is an approach that utilizes the change in the conformational stabilities of proteins upon ligand binding in order to identify target proteins. Different from traditional affinity‐based capture approaches, energetics‐based methods do not require any labeling or immobilization of the test molecule. Here, we report a surprisingly simple version of energetics‐based target identification, which only requires ion exchange chromatography, SDS PAGE, and minimal use of mass spectrometry. The complexity of a proteome is reduced through fractionation by ion exchange chromatography. Urea‐induced unfolding of proteins in each fraction is then monitored by the significant increase in proteolytic susceptibility upon unfolding in the presence and the absence of a ligand. Proteins showing a different degree of unfolding with the ligand are identified by SDS PAGE followed by mass spectrometry. Using this approach, we identified ATP‐binding proteins in the Escherichia coli proteome. In addition to known ATP‐binding proteins, we also identified a number of proteins that were not previously known to interact with ATP. To validate one such finding, we cloned and purified phosphoglyceromutase, which was not previously known to bind ATP, and confirmed that ATP indeed stabilizes this protein. The combination of fractionation and pulse proteolysis offers an opportunity to investigate protein–drug or protein–metabolite interactions on a proteomic scale with minimal instrumentation and without modification of a molecule of interest.
The meteorology of Black Saturday
Authors: Engel Chermelle B. , Lane Todd P. , Reeder Michael J. , Rezny Michael 
Published: June 2012

AbstractThe meteorological conditions are investigated over the state of Victoria, Australia on 7 February 2009, the day of the ‘Black Saturday’ fires. Daytime temperatures exceeding 45°C, strong surface winds and extremely dry conditions combined to produce the worst fire weather conditions on record. A high‐resolution nested simulation with the UK Met Office Unified Model and available observations are used to identify the important mesoscale features of the day. The highest resolution domain has horizontal grid spacing of 444 m and reproduces most aspects of the observed meteorological conditions. These include organized horizontal convective rolls, a strong late‐afternoon cool change with many of the characteristics of an unsteady gravity current, a weaker late‐evening cold front and propagating nocturnal bores. These mesoscale phenomena introduce variability in the winds, temperature and humidity at short temporal and spatial scales, which in turn lead to large spatial and temporal variability in fire danger. Copyright © 2012 Royal Meteorological Society
Tight upper tail bounds for cliques
Authors: DeMarco Robert , Kahn Jeff 
Published: June 2012

AbstractWith ξk =ξ the number of copies of Kk in the usual (Erdős‐Rényi) random graph G(n,p), p ≥ n‐2/(k‐1) and η > 0, we show when k > 1

This is tight up to the value of the constant in the exponent. © 2012 Wiley Periodicals, Inc. Random Struct. Alg., 2012
Efficient pairing‐free provably secure identity‐based proxy blind signature scheme
Authors: Tan Zuowen 
Published: June 2012

ABSTRACTIn a proxy signature scheme, an original signer delegates her signing capability to a proxy signer who generates a signature on message on behalf of the original signer. By the combination of a blind signature with a proxy signature, the proxy signer can produce a proxy blind signature on message. Identity‐based public key cryptosystem has an efficient key management as compared with certificate‐based public key settings. In this paper, we propose an efficient identity‐based pairing‐free proxy blind signature scheme. The proxy blind signature scheme is provably secure upon the discrete logarithm assumptions in the random oracle model. Compared with other proxy blind signature schemes in the literature, the proposed proxy blind signature scheme is more efficient. Copyright © 2012 John Wiley & Sons, Ltd.
Magnetic Nanobeads Decorated with Silver Nanoparticles as Cytotoxic Agents and Photothermal Probes
Authors: Di Corato Riccardo , Palumberi Domenico , Marotta Roberto , Scotto Marco , Carregal‐Romero Susana , Rivera_Gil Pilar , Parak Wolfgang J. , Pellegrino Teresa 
Published: June 2012

AbstractA versatile method for decorating magnetic nanobeads (being composite materials from polymers and superparamagnetic nanoparticles) with silver nanoparticles of 3–6 nm size is presented. Control over the silver nanoparticle coverage at the nanobead surface is achieved by changing the reaction parameters. Moreover, the silver‐decorated magnetic nanobeads (Ag‐MNBs) are studied with respect to their in vitro cytotoxicity on two distinct tumour cell lineages under different parameters, i.e., dose, incubation time, magnetic field applied during the culturing, silver ion leakage, and colloidal stability. It is found that enhanced magnetically mediated cellular uptake and silver ion leakage from the Ag‐MNBs surface are the main factors which affect the toxicity of the Ag‐MNBs and allow the half‐maximal inhibitory dose of silver to be reduced to only 32 μg mL−1. Furthermore, a synergic cytotoxicity induced by photo‐activation of silver nanoparticles was also found.
Novel Heneicosadienoic and Tricosadienoic Acid Isomers in Ovaries of Marine Archaeogastropods
Authors: Kawashima Hideki , Ohnishi Masao 
Published: June 2012

AbstractTo investigate unusual odd‐chain fatty acids (FA) from gonads of archaeogastropods, limpets Cellana grata and Cellana toreuma, a subfraction enriched in FA with two double bonds extracted from the gonads was obtained by using argentation thin‐layer chromatography. The resulting fraction was analyzed by using capillary gas chromatography–mass spectrometry of its methyl esters, 3‐pyridylcarbinol esters and pyrrolidide derivatives. Six novel all‐cis diene isomers were identified as 7,18‐heneicosadienoic (21:2Δ7,18), 8,14‐tricosadienoic (23:2Δ8,14), 9,15‐tricosadienoic (23:2Δ9,15), 7,18‐tricosadienoic (23:2Δ7,18), 9,18‐tricosadienoic (23:2Δ9,18), and 9,20‐tricosadienoic (23:2Δ9,20) acids. In the present study, the differences in the proportion of tricosadienoic acid isomers between the ovary lipids of C. grata and C. toreuma were recognized.
B-Cell Ligand Processing Pathways Detected by Large-Scale Comparative Analysis
Authors: Towfic Fadi , Gupta Shakti , Honavar Vasant , Subramaniam Shankar 
Published: June 2012

Abstract
The initiation of B-cell ligand recognition is a critical step for the generation of an immune response against foreign bodies. We sought to identify the biochemical pathways involved in the B-cell ligand recognition cascade and sets of ligands that trigger similar immunological responses. We utilized several comparative approaches to analyze the gene coexpression networks generated from a set of microarray experiments spanning 33 different ligands. First, we compared the degree distributions of the generated networks. Second, we utilized a pairwise network alignment algorithm, BiNA, to align the networks based on the hubs in the networks. Third, we aligned the networks based on a set of KEGG pathways. We summarized our results by constructing a consensus hierarchy of pathways that are involved in B cell ligand recognition. The resulting pathways were further validated through literature for their common physiological responses. Collectively, the results based on our comparative analyses of degree distributions, alignment of hubs, and alignment based on KEGG pathways provide a basis for molecular characterization of the immune response states of B-cells and demonstrate the power of comparative approaches (e.g., gene coexpression network alignment algorithms) in elucidating biochemical pathways involved in complex signaling events in cells.