bluuebunny/crossref_metadata_2025_split huggingface dataset:
Melphalan‐flufenamide is cytotoxic and potentiates treatment with chemotherapy and the Src inhibitor dasatinib in urothelial carcinoma
Authors: Viktorsson Kristina , Shah Carl-Henrik , Juntti Therese , Hååg Petra , Zielinska-Chomej Katarzyna , Sierakowiak Adam , Holmsten Karin , Tu Jessica , Spira Jack , Kanter Lena , Lewensohn Rolf , Ullén Anders 
Published: January 2016

Background: Chemotherapy options in advanced urothelial carcinoma (UC) remain limited. Here we evaluated the peptide‐based alkylating agent melphalan‐flufenamide (mel‐flufen) for UC.Methods: UC cell lines J82, RT4, TCCsup and 5637 were treated with mel‐flufen, alone or combined with cisplatin, gemcitabine, dasatinib or bestatin. Cell viability (MTT assay), intracellular drug accumulation (liquid chromatography) apoptosis induction (apoptotic cell nuclei morphology, western blot analysis of PARP‐1/caspase‐9 cleavage and Bak/Bax activation) were evaluated. Kinome alterations were characterized by PathScan array and phospho‐Src validated by western blotting. Aminopeptidase N (ANPEP) expression was evaluated in UC clinical specimens in relation to patient outcome.Results: In J82, RT4, TCCsup and 5637 UC cells, mel‐flufen amplified the intracellular loading of melphalan in part via aminopeptidase N (ANPEP), resulting in increased cytotoxicity compared to melphalan alone. Mel‐flufen induced apoptosis seen as activation of Bak/Bax, cleavage of caspase‐9/PARP‐1 and induction of apoptotic cell nuclei morphology. Combining mel‐flufen with cisplatin or gemcitabine in J82 cells resulted in additive cytotoxic effects and for gemcitabine also increased apoptosis induction. Profiling of mel‐flufen‐induced kinome alterations in J82 cells revealed that mel‐flufen alone did not inhibit Src phosphorylation. Accordingly, the Src inhibitor dasatinib sensitized for mel‐flufen cytotoxicity. Immunohistochemical analysis of the putative mel‐flufen biomarker ANPEP demonstrated prominent expression levels in tumours from 82 of 83 cystectomy patients. Significantly longer median overall survival was found in patients with high ANPEP expression (P = 0.02).Conclusion: Mel‐flufen alone or in combination with cisplatin, gemcitabine or Src inhibition holds promise as a novel treatment for UC.
Development and regeneration of salivary gland toward for clinical application
Authors: Sakai Takayoshi 
Published: January 2016

AbstractSalivary gland hypofunction, also termed as xerostomia, is caused by radiation therapy for head and neck cancer or Sjögren's syndrome, leading to a detrimental impact on oral health and quality of life. This review describes current studies on salivary gland development and the translational approaches of basic science to treating patients with dysfunction and hypofunction of the salivary gland. Here, we review the most recent studies that have offered better insight into the mechanisms of salivary gland development and regeneration. Furthermore, we highlight proposed approaches with the aim of recovering salivary gland function using both gene‐ and cell‐based therapy. A thorough understanding of the mechanisms involved in salivary gland development is necessary in order to design effective therapies for regeneration and repair of damaged salivary glands.
ShapeCluster: Applying parametric regression to analyse time-series gene expression data
Authors: Law Philip , Buchanan-Wollaston Vicky , Mead Andrew 
Published: January 2016

1ABSTRACTHigh-throughput technologies have made it possible to perform genome-scale analyses to investigate a variety of research areas. From these analyses, vast amounts of data are generated. However, this data can be noisy, which could obscure the underlying signal. Here, a high-throughput regression analysis approach was developed, where a variety of linear and nonlinear parametric models were fitted to gene expression profiles from time course experiments. These models include the logistic, Gompertz, exponential, critical exponential, linear+exponential, Gaussian and linear functions. The fitted parameters from these models reflect aspects of the model shape, and thus allowed for the interpretation of gene expression profiles in terms of the underlying biology, such as the time of initial gene expression. This provides a potentially more mechanistic approach to studying the genetic responses to stimuli. Together with a cluster analysis, termed ShapeCluster, it was possible to group genes based on these aspects of the expression profiles. By investigating different combinations of parameters, this added flexibility to the analysis and allowed for the investigation of the data in multiple ways, including the identification of groups of genes that may be co-regulated, or participate in response to the biological stress in question. Clusters from these methods were assessed for significance through the use of over-represented annotation terms and motifs, and found to produce biologically relevant sets of genes. The ShapeCluster package is available fromhttps://sourceforge.net/projects/shapecluster/.
Genome-wide Prediction of DNase I Hypersensitivity Using Gene Expression
Authors: Zhou Weiqiang , Sherwood Ben , Ji Zhicheng , Du Fang , Bai Jiawei , Ji Hongkai 
Published: January 2016

ABSTRACTWe evaluate the feasibility of using a biological sample’s transcriptome to predict its genome-wide regulatory element activities measured by DNase I hypersensitivity (DH). We develop BIRD, Big Data Regression for predicting DH, to handle this high-dimensional problem. Applying BIRD to the Encyclopedia of DNA Element (ENCODE) data, we found that gene expression to a large extent predicts DH, and information useful for prediction is contained in the whole transcriptome rather than limited to a regulatory element’s neighboring genes. We show that the predicted DH predicts transcription factor binding sites (TFBSs), prediction models trained using ENCODE data can be applied to gene expression samples in Gene Expression Omnibus (GEO) to predict regulome, and one can use predictions as pseudo-replicates to improve the analysis of high-throughput regulome profiling data. Besides improving our understanding of the regulome-transcriptome relationship, this study suggests that transcriptome-based prediction can provide a useful new approach for regulome mapping.
Global Prediction of Chromatin Accessibility Using RNA-seq from Small Number of Cells
Authors: Zhou Weiqiang , Ji Zhicheng , Ji Hongkai 
Published: January 2016

ABSTRACTConventional high-throughput technologies for mapping regulatory element activities such as ChIP-seq, DNase-seq and FAIRE-seq cannot analyze samples with small number of cells. The recently developed ATAC-seq allows regulome mapping in small-cell-number samples, but its signal in single cell or samples with ≤500 cells remains discrete or noisy. Compared to these technologies, measuring transcriptome by RNA-seq in single-cell and small-cell-number samples is more mature. Here we show that one can globally predict chromatin accessibility and infer regulome using RNA-seq. Genome-wide chromatin accessibility predicted by RNA-seq from 30 cells is comparable with ATAC-seq from 500 cells. Predictions based on single-cell RNA-seq can more accurately reconstruct bulk chromatin accessibility than using single-cell ATAC-seq by pooling the same number of cells. Integrating ATAC-seq with predictions from RNA-seq increases power of both methods. Thus, transcriptome-based prediction can provide a new tool for decoding gene regulatory programs in small-cell-number samples.
The Maintenance of Sex and David Lack’s Principle
Authors: Dagg Joachim L. 
Published: January 2016

AbstractCombining George C. Williams’ idea that evolutionary constraints prevent asexual mutants from arising more frequently in low fecundity organisms, like mammals and birds, with an earlier one by David Lack that the brood size of these organisms has an optimum, and producing larger broods reduces their fitness, leads to a novel hypothesis about the maintenance of sex in them. All else equal, the eggs of an asexual mutant female should simply start developing without fertilisation, and there is no reason to assume that they would stop doing so after the optimal number of offspring has been produced. Without a way to control their reproductive output, asexual mutants should over-reproduce and suffer a cost of doing so. Experimental studies suggest that the cost of enlarged broods could limit the advantage of asexual mutants considerably. Moreover, research discovered that increased reproductive effort reduces immune functions of low fecundity organisms. This offers a surprising synthesis between Williams’ constraint and Hamilton’s parasite hypothesis on maintaining sex in low fecundity organisms: Compromised immune functions of asexual hosts may render them susceptible rather than adaptation on the side of parasites to overcome host resistance.
Restoration of sub‐alpine shrub‐encroached grasslands through pastoral practices: effects on vegetation structure and botanical composition
Authors: Pittarello Marco , Probo Massimiliano , Lonati Michele , Lombardi Giampiero 
Published: January 2016

AbstractAimsTo reverse shrub encroachment and restore grassland vegetation, two pastoral practices were implemented over shrub‐encroached areas: the arrangement of temporary night camp areas (TNCA) and the strategic placement of mineral mix supplements (MMS) for cattle. The aim was to assess the effects produced on (1) vegetation structure and (2) botanical composition of both pastoral practices in order to identify their potential to reverse shrub encroachment and restore semi‐natural grassland vegetation.LocationShrub‐encroached sites in Val Troncea Natural Park, southwest Italian Alps.MethodsWe measured the effects produced by both practices on vegetation cover and height, cover of species belonging to different vegetation units, biodiversity indices (species richness and Shannon diversity index), forage pastoral value, and average indicator value for soil nutrient content from 2011 to 2014 along permanent linear transects. Data were analysed with GLMMs, multiple response permutational procedure (MRPP) and principal response curve (PRC).ResultsBoth practices were effective in reducing shrub cover and increasing average height of the herbaceous layer, but within TNCA a marked increase in herbaceous cover was also evident. Moreover, the arrangement of TNCA increased the cover of meso‐eutrophic grassland and fringe and tall herb species and decreased the cover of boreal‐like shrubland and woodland species. The main effect produced by the placement of MMS on botanical composition was an increase in cover of fringe and tall herb species. Plant biodiversity was enhanced by the arrangement of TNCA but not by the placement of MMS, and the implementation of both practices increased forage pastoral value and average indicator value for soil nutrient content.ConclusionsThe arrangement of TNCA was the most effective pastoral practice to reverse shrub encroachment, restore semi‐natural meso‐eutrophic grassland vegetation and increase plant diversity, herbage mass and forage quality.
Downstream activation of NF-κB in the EDA-A1/EDAR signalling in Sjögren's syndrome and its regulation by the ubiquitin-editing enzyme A20
Authors: Sisto M , Barca A , Lofrumento D D , Lisi S 
Published: January 2016

SummarySjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1–3%, whereas secondary SS has been observed in 10–20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor-kappa B (NF-κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin-editing enzyme A20 (tumour necrosis factor-α-induced protein 3, TNFAIP3) serves as a critical inhibitor on NF-κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin-A1 (EDA-A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1-induced NF-κB signalling, this work investigates the expression levels of EDA-A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC-specific deregulation of A20 results in excessive EDA1-induced NF-κB signalling in SS. Our approach, which combines the use of siRNA-mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA-A1/EDAR/NF-κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.
Cognitive effects of adjunctive perampanel for partial‐onset seizures: A randomized trial
Authors: Meador Kimford J. , Yang Haichen , Piña‐Garza Jesus Eric , Laurenza Antonio , Kumar Dinesh , Wesnes Keith A. 
Published: January 2016

SummaryObjectiveAssess cognitive effects of adjunctive perampanel in adolescents.MethodsIn this double‐blind study (ClinicalTrials.gov identifier:NCT01161524), patients aged 12 to <18 years with partial‐onset seizures despite receiving 1–3 antiepileptic drugs were randomized (2:1) to perampanel or placebo. Perampanel was increased weekly in 2‐mg increments to 8–12 mg/day (6‐week titration; 13‐week maintenance). Changes in neuropsychological outcomes were assessed at end of maintenance: Cognitive Drug Research (CDR) System Global Cognition Score (primary end point), fiveCDRSystem domain T‐scores (secondary end points), letter fluency, category fluency, and Lafayette Grooved Pegboard Test (LGPT).ResultsOne hundred thirty‐three patients were randomized. In the full analysis set, there were no differences of perampanel (n = 79) vs. placebo (n = 44) inCDRSystem Global Cognition Score (least squares mean change, −0.6 vs. 1.6; p = 0.145), Quality of Working Memory (1.1 vs. 2.0; p = 0.579), or Power of Attention (−6.9 vs. −2.7; p = 0.219). There were small differences with perampanel vs. placebo in otherCDRSystem domains: improvements in Quality of Episodic Memory (3.0 vs. −1.2; p = 0.012), and worsening in Continuity of Attention (−3.3 vs. 1.6; p = 0.013) and Speed of Memory (0.3 vs. 7.0; p = 0.032). Letter fluency, category fluency, andLGPTwere not significantly different between groups. The most frequent adverse events with perampanel were dizziness (30.6%) and somnolence (15.3%).SignificancePerampanel did not differ from placebo in the global cognitive score, two of five subdomains, and four other cognitive measures. Perampanel was worse on two and better on one subdomain.
Functional polymer‐dependent 3D culture accelerates the differentiation of HepaRG cells into mature hepatocytes
Authors: Higuchi Yichiro , Kawai Kenji , Kanaki Tatsuro , Yamazaki Hiroshi , Chesné Christophe , Guguen‐Guillouzo Christiane , Suemizu Hiroshi 
Published: January 2016

AimThe hepatoma‐derived cell line HepaRG is regarded as an in vitro model of drug metabolism because fully differentiated HepaRG cells demonstrate functional metabolic responses comparable to those of primary human hepatocytes. Recently, it was demonstrated that the 3D culture of HepaRG cells enhanced their metabolic functions and toxicological responses. We approached the mechanisms underlying these enhancement effects.MethodsWe compared 2D‐cultured HepaRG cells with 3D‐cultured HepaRG spheroids in the gene expression patterns and the metabolic functions. In the present study, we performed 3D culture of HepaRG cells using functional polymers (FP). To reveal the in vivo differentiation ability, we transplanted the 3D‐cultured HepaRG spheroids into TK‐NOG mice.ResultsA comparison between 2D and 3D cultures revealed that 3D‐cultured HepaRG spheroids demonstrated reductions in bile duct marker expression, accelerated expression of cytochrome P450 3A4, and increases in the ratio of albumin‐expressing hepatocytes. Furthermore, catalytic activities of cytochrome P450 3A4 were modified by omeprazole and rifampicin in the 3D‐cultured HepaRG spheroids. Transplantation analysis revealed that 3D‐cultured HepaRG spheroids formed hepatocyte‐like colonies rather than cholangiocytes in vivo.ConclusionOur results indicated that the enhancement of hepatic functions in 3D‐cultured HepaRG cells was induced by selective hepatocyte differentiation and accelerated hepatocyte maturation. HepaRG spheroids reproduced the metabolic responses of human hepatocytes. Therefore, FP‐dependent 3D‐cultured HepaRG cells may serve as an excellent in vitro model for evaluating the hepatic metabolism and toxicity.
Study of Textural, Chemical, Color and Sensory Properties of Organic Blueberries Harvested in Two Distinct Years: A Chemometric Approach
Authors: Vilela Alice , Gonçalves Berta , Ribeiro Carlos , Fonseca Ana teresa , Correia Sofia , Fernandes Hortense , Ferreira Sónia , Bacelar Eunice , Silva Ana Paula 
Published: January 2016

AbstractIn Portugal, two groups of blueberry plants are of interest: the Northern and the Southern Highbush Blueberry. The short season and short shelf life of blueberries yields excess fruit, and those harvests not destined for the fresh market are frozen or processed, sometimes leading to economic losses for the producers. From a technological point of view, fruit characterization is performed on the basis of physical, chemical properties as well as organoleptic properties (texture, flavor, color/pigmentation). These properties are directly correlated with fruit utilization. Thus, in this work, chemometric tools, such as texture, soluble solids (SS), titratable acidity (TA), fruit surface color and a trained sensory panel, for the exploration of textural, chemical, color and sensory characteristics of four blueberry cultivars harvested in two different years were applied.Surface color, maximum force, SS, TA and SS/TA ratio varied among cultivars and years and, in general, all the fruits presented in 2013 had lower values for SS and TA when compared with those collected in 2011.After analyzing all the parameters and independently of their origin, Duke and Palmetto seem to be more suitable for fresh market consumption since the attribute crispness did not change significantly between the 2 years, while Camellia, a cultivar where the attribute crispness, seems to be weather dependent, and Legacy a cultivar with less odor and flavor, seems to be more suitable for processing into products such juice and jam.Practical ApplicationsBlueberry is a product of interest due to their nutritional and health benefits. Recently, scientists have determined that is the “blueberry‐like flavor intensity” the eating quality that has a much higher correlation to consumer acceptance than the traditional measures of sweetness, acidity or sugar/acid. Ripeness and maturity are the key factors that influence the taste of a fruit. Ripening processes play a key role in flavor development and can affect the chemical and sensory characteristics (acidity, sweetness) of fruits. Thus, with this study we can understand the influence of the harvest year in the textural and sensory attributes of blueberry fruits that can help to determine the optimal use of fruit.
Timing of extreme drought modifies reproductive output in semi‐natural grassland
Authors: Zeiter Michaela , Schärrer Sara , Zweifel Roman , Newbery David M. , Stampfli Andreas 
Published: January 2016

AbstractQuestionsDo extreme dry spells in late summer or in spring affect abundance and species composition of the reproductive shoots and the seed rain in the next annual crop? Are drought effects on reproductive shoots related to the rooting depths of species?LocationSpecies‐rich semi‐natural grassland at Negrentino, Switzerland.MethodsIn plots under automated rain‐out shelters, rainwater was added to simulate normal conditions and compare them with two experimentally effected long dry spells, in late summer (2004) and in the following spring (2005). For 28 plots, numbers of reproductive shoots per species were counted in 1‐m2 areas and seed rain was estimated using nine sticky traps of 102 cm2 after dry spells.ResultsThe two extreme dry spells in late summer and spring were similar in length and their probability of recurrence. They independently reduced the subsequent reproductive output of the community, while their seasonal timing modified its species composition. Compared to drought in spring, drought in late summer reduced soil moisture more and reduced the number of reproductive shoots of more species. The negative effects of summer drought decreased with species’ rooting depth. The shallow‐rooted graminoids showed a consistent susceptibility to summer drought, while legumes and other forbs showed more varied responses to both droughts. Spring drought strongly reduced density (–53%) and species richness (–43%) of the community seed rain, while summer drought had only a marginally significant impact on seed density of graminoids (–44%). Reductions in seed number per shoot vs reproductive shoot density distinguished the impacts of drought with respect to its seasonal timing.ConclusionThe essentially negative impact of drought in different seasons on reproductive output suggests that more frequent dry spells could contribute to local plant diversity loss by aggravating seed deficiency in species‐rich grassland.
Post‐translational methylations of the archaeal Mre11:Rad50 complex throughout the DNA damage response
Authors: Kish Adrienne , Gaillard Jean‐Charles , Armengaud Jean , Elie Christiane 
Published: January 2016

SummaryThe Mre11:Rad50 complex is central to DNA double strand break repair in the Archaea and Eukarya, and acts through mechanical and nuclease activities regulated by conformational changes induced by ATP binding and hydrolysis. Despite the widespread use of Mre11 and Rad50 from hyperthermophilic archaea for structural studies, little is known in the regulation of these proteins in the Archaea. Using purification and mass spectrometry approaches allowing nearly full sequence coverage of both proteins from the species Sulfolobus acidocaldarius, we show for the first time post‐translational methylation of the archaeal Mre11:Rad50 complex. Under basal growth conditions, extensive lysine methylations were identified in Mre11 and Rad50 dynamic domains, as well as methylation of a few aspartates and glutamates, including a key Mre11 aspartate involved in nuclease activity. Upon γ‐irradiation induced DNA damage, additional methylated residues were identified in Rad50, notably methylation of Walker B aspartate and glutamate residues involved in ATP hydrolysis. These findings strongly suggest a key role for post‐translational methylation in the regulation of the archaeal Mre11:Rad50 complex and in the DNA damage response.