bluuebunny/crossref_metadata_2025_split huggingface dataset:
A systematic study of genome context methods: calibration, normalization and combination
Authors: Ferrer Luciana , Dale Joseph M , Karp Peter D 
Published: October 2010

AbstractBackgroundGenome context methods have been introduced in the last decade as automatic methods to predict functional relatedness between genes in a target genome using the patterns of existence and relative locations of the homologs of those genes in a set of reference genomes. Much work has been done in the application of these methods to different bioinformatics tasks, but few papers present a systematic study of the methods and their combination necessary for their optimal use.ResultsWe present a thorough study of the four main families of genome context methods found in the literature: phylogenetic profile, gene fusion, gene cluster, and gene neighbor. We find that for most organisms the gene neighbor method outperforms the phylogenetic profile method by as much as 40% in sensitivity, being competitive with the gene cluster method at low sensitivities. Gene fusion is generally the worst performing of the four methods. A thorough exploration of the parameter space for each method is performed and results across different target organisms are presented.We propose the use of normalization procedures as those used on microarray data for the genome context scores. We show that substantial gains can be achieved from the use of a simple normalization technique. In particular, the sensitivity of the phylogenetic profile method is improved by around 25% after normalization, resulting, to our knowledge, on the best-performing phylogenetic profile system in the literature.Finally, we show results from combining the various genome context methods into a single score. When using a cross-validation procedure to train the combiners, with both original and normalized scores as input, a decision tree combiner results in gains of up to 20% with respect to the gene neighbor method. Overall, this represents a gain of around 15% over what can be considered the state of the art in this area: the four original genome context methods combined using a procedure like that used in the STRING database. Unfortunately, we find that these gains disappear when the combiner is trained only with organisms that are phylogenetically distant from the target organism.ConclusionsOur experiments indicate that gene neighbor is the best individual genome context method and that gains from the combination of individual methods are very sensitive to the training data used to obtain the combiner's parameters. If adequate training data is not available, using the gene neighbor score by itself instead of a combined score might be the best choice.
Data-driven assessment of eQTL mapping methods
Authors: Michaelson Jacob J , Alberts Rudi , Schughart Klaus , Beyer Andreas 
Published: October 2010

AbstractBackgroundThe analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis.ResultsHere we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods.ConclusionsBenchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods.
Carbohydrate antigens in nipple aspirate fluid predict the presence of atypia and cancer in women requiring diagnostic breast biopsy
Authors: Deutscher Susan L , Dickerson Marie , Gui Gerald , Newton Jessica , Holm Jeffrey E , Vogeltanz-Holm Nancy , Kliethermes Beth , Hewett John E , Kumar Senthil R , Quinn Thomas P , Sauter Edward R 
Published: October 2010

AbstractBackgroundThe goal of this prospective study was to determine (a) concentrations of the carbohydrate biomarkers Thomsen Friedenreich (TF) antigen and its precursor, Tn antigen, in nipple discharge (ND) collected from women requiring biopsy because of a suspicious breast lesion; and (b) if concentration levels predicted pathologic diagnosis.MethodsAdult women requiring biopsy to exclude breast cancer were enrolled and ND obtained. The samples from 124 women were analyzed using an anti-TF and anti-Tn monoclonal antibodies in direct immunoassay.ResultsThe highest median concentration in ND for TF and Tn was in women with ductal carcinomain situ(DCIS). TF was higher in women with 1) cancer (DCIS or invasive) vs. either no cancer (atypia or benign pathology, p = .048), or benign pathology (p = .018); and 2) abnormal (atypia or cancer) versus benign pathology (p = .016); and was more predictive of atypia or cancer in post- compared to premenopausal women. Tn was not predictive of disease. High TF concentration and age were independent predictors of disease, correctly classifying either cancer or abnormal vs. benign pathology 83% of the time in postmenopausal women.ConclusionsTF concentrations in ND were higher in women with precancer and cancer compared to women with benign disease, and TF was an independent predictor of breast atypia and cancer. TF may prove useful in early breast cancer detection.
Molecular determinants of improved cathepsin B inhibition by new cystatins obtained by DNA shuffling
Authors: Valadares Napoleão F , Dellamano Márcia , Soares-Costa Andrea , Henrique-Silva Flávio , Garratt Richard C 
Published: October 2010

Abstract

Background
Cystatins are inhibitors of cysteine proteases. The majority are only weak inhibitors of human cathepsin B, which has been associated with cancer, Alzheimer's disease and arthritis.

Results
Starting from the sequences of oryzacystatin-1 and canecystatin-1, a shuffling library was designed and a hybrid clone obtained, which presented higher inhibitory activity towards cathepsin B. This clone presented two unanticipated point mutations as well as an N-terminal deletion. Reversing each point mutation independently or both simultaneously abolishes the inhibitory activity towards cathepsin B. Homology modeling together with experimental studies of the reverse mutants revealed the likely molecular determinants of the improved inhibitory activity to be related to decreased protein stability.

Conclusion
A combination of experimental approaches including gene shuffling, enzyme assays and reverse mutation allied to molecular modeling has shed light upon the unexpected inhibitory properties of certain cystatin mutants against Cathepsin B. We conclude that mutations disrupting the hydrophobic core of phytocystatins increase the flexibility of the N-terminus, leading to an increase in inhibitory activity. Such mutations need not affect the inhibitory site directly but may be observed distant from it and manifest their effects via an uncoupling of its three components as a result of increased protein flexibility.
Anti-inflammatory properties of the PI3K pathway are mediated by IL-10/DUSP regulation
Authors: Günzl Philipp , Bauer Kathrin , Hainzl Eva , Matt Ulrich , Dillinger Barbara , Mahr Benedikt , Knapp Sylvia , Binder Bernd R , Schabbauer Gernot 
Published: October 2010

Abstract
Activation of the PI3K/PTEN signaling pathway down-regulates pro-inflammatory gene expression via up-regulation of DUSP1.
Resolution of inflammation is an important hallmark in the course of infectious diseases. Dysregulated inflammatory responses may have detrimental consequences for the affected organism. Therefore, tight regulation of inflammation is indispensable. Among numerous modulatory signaling pathways, the PI3K/PTEN signaling pathway has been proposed recently to be involved in the regulation of innate immune reactions. Here, we attempted to elucidate molecular mechanisms that contribute to the modulatory properties of the PI3K signaling pathway in inflammation. PTEN-deficient macrophages, which harbor constitutively active PI3Ks, were analyzed in response to gram-negative bacteria and PAMPs such as LPS. PTEN-deficient cells showed reduced inflammatory cytokine production, which was accompanied by reduced MAPK signaling activation in early- as well as late-phase activation. Simultaneously, we found increased levels of the MKP DUSP1, as well as the anti-inflammatory cytokine IL-10. Our data suggest that differential DUSP1 regulation coupled with enhanced IL-10 production contributes to the anti-inflammatory properties of the PI3K pathway.
Regulatory T cells suppress antigen-driven CD4 T cell reactivity following injury
Authors: MacConmara Malcolm P , Tajima Goro , O'Leary Fionnuala , Delisle Adam J , McKenna Ann M , Stallwood Christopher G , Mannick John A , Lederer James A 
Published: October 2010

ABSTRACTInjury initiates local and systemic host responses and is known to increase CD4 Treg activity in mice and humans. This study uses a TCR transgenic T cell adoptive transfer approach and in vivo Treg depletion to determine specifically the in vivo influence of Tregs on antigen-driven CD4 T cell reactivity following burn injury in mice. We report here that injury in the absence of recipient and donor Tregs promotes high antigen-driven CD4 T cell expansion and increases the level of CD4 T cell reactivity. In contrast, CD4 T cell expansion and reactivity were suppressed significantly in injured Treg-replete mice. In additional experiments, we found that APCs prepared from burn- or sham-injured, Treg-depleted mice displayed significantly higher antigen-presenting activity than APCs prepared from normal mice, suggesting that Tregs may suppress injury responses by controlling the intensity of APC activity. Taken together, these findings demonstrate that Tregs can actively control the in vivo expansion and reactivity of antigen-stimulated, naïve CD4 T cells following severe injury.
Suppressing LPS-induced early signal transduction in macrophages by a polyphenol degradation product: a critical role of MKP-1
Authors: Tucsek Zsuzsanna , Radnai Balazs , Racz Boglarka , Debreceni Balazs , Priber Janos K , Dolowschiak Tamas , Palkovics Tamas , Gallyas Ferenc , Sumegi Balazs , Veres Balazs 
Published: October 2010

ABSTRACTMacrophages represent the first defense line against bacterial infection and therefore, play a crucial role in early inflammatory response. In this study, we investigated the role of MAPKs and MKP-1 activation in regulation of an early inflammatory response in RAW 264.7 macrophage cells. We induced the inflammatory response by treating the macrophages with LPS and inhibited an early inflammatory response by using ferulaldehyde, a water-soluble end-product of dietary polyphenol degradation that we found previously to exert its beneficial anti-inflammatory effects during the early phase of in vivo inflammation. We found that LPS-induced ROS and nitrogen species formations were reduced by ferulaldehyde in a concentration-dependent manner, and ferulaldehyde protected mitochondria against LPS-induced rapid and massive membrane depolarization. LPS induced early suppression of MKP-1, which was accompanied by activation of JNK, ERK, and p38 MAPK. By reversing LPS-induced early suppression of MKP-1, ferulaldehyde diminished MAPK activation, thereby inhibiting NF-κB activation, mitochondrial depolarization, and ROS production. Taken together, our data suggest that ferulaldehyde exerts its early anti-inflammatory effect by preserving the mitochondrial membrane integrity and shifting the expression of MKP-1 forward in time in macrophages.
HIV inhibits early signal transduction events triggered by CD16 cross-linking on NK cells, which are important for antibody-dependent cellular cytotoxicity
Authors: Lichtfuss Gregor F , Meehan Aislin C , Cheng Wan-Jung , Cameron Paul U , Lewin Sharon R , Crowe Suzanne M , Jaworowski Anthony 
Published: October 2010

ABSTRACTMeasurement of NK cell cytolytic activity in the setting of chronic viral infection is important for determining viral pathogenicity. Mobilization of LAMP-1 (CD107a) to the NK cell surface is a surrogate marker for cytotoxic granule release and hence, NK cell cytotoxicity. We have developed a convenient, rapid, whole blood flow cytometric assay for measuring CD107a mobilization in response to CD16 cross-linking, a surrogate for NK cell ADCC activity ex vivo, which can be performed using small volumes of patient whole blood. Using this assay, we show that CD107a mobilization, in response to CD16 cross-linking, is triggered in CD56dim but not CD56bright NK cells, requiring Syk/Zap70 tyrosine kinase activity, and that there is a significant correlation between CD107a mobilization and pSyk/Zap70 in response to CD16 cross-linking. We compared whole blood from treatment-naïve, HIV-infected patients with age- and sex-matched HIV-uninfected control subjects and found a significant reduction in CD16-dependent pSyk/Zap70 (median=32.7% compared with 67.8%; P=0.0002) and CD107a mobilization (median=9.72% compared with 32.9%; P=0.046) in NK cells. Reduction of both correlated strongly with reduced CD16 surface expression on NK cells of HIV-infected individuals (P&lt;0.01). These data suggest that ADCC is inhibited in NK cells from therapy-naïve, HIV-infected individuals at the level of early events in CD16 signal transduction, associated with low CD16R expression, and our method is a useful and reliable tool to detect pathological defects in NK cell degranulation.
Always on the bright side of life: anti-adhesive properties of insect ommatidia grating
Authors: Peisker Henrik , Gorb Stanislav N. 
Published: October 2010

SUMMARYThe surface of some insect eyes consists of arrays of cuticular protuberances, which are 50–300 nm in diameter, and are termed corneal nipples or ommatidia gratings. They were widely reported to reduce the reflectance for normally incident light, contributing to camouflage by reducing glare to predators, while furthermore enhancing the intake of light, which is especially important for nocturnal insects. Our preliminary observations suggest a third function: in contrast to the rest of the body, ommatidia of various insects remain clean, even in a heavy contaminated environment. In order to prove such an anti-contamination hypothesis of these structures, we measured the adhesive properties of polymer moulds of insect ommatidia, and compared these data with control surfaces having the same curvature radii but lacking such a nanostructure. A scanning electron microscope (SEM) study and force measurements using an atomic force microscope (AFM) on the eye surfaces of three different insect species, dragonfly Aeshna mixta (Odonata), moth Laothoe populi (Lepidoptera) and fly Volucella pellucens (Diptera), were undertaken. We revealed that adhesion is greatly reduced by corneal grating in L. populi and V. pellucens when compared with their smooth controls. The smooth cornea of A. mixta showed no statistically significant difference to its control. We assume that this anti-adhesive phenomenon is due to a decrease in the real contact area between contaminating particles and the eye's surface. Such a combination of three functions in one nanostructure can be interesting for the development of industrial multifunctional surfaces capable of enhancing light harvesting while reducing light reflection and adhesion.
Lifespan and oxidative stress show a non-linear response to atmospheric oxygen inDrosophila
Authors: Rascón Brenda , Harrison Jon F. 
Published: October 2010

SUMMARYOxygen provides the substrate for most ATP production, but also serves as a source of reactive oxygen species (ROS), which can induce cumulative macromolecular oxidative damage and cause aging. Pure oxygen atmospheres (100 kPa) are known to strongly reduce invertebrate lifespan and induce aging-related physiological changes. However, the nature of the relationship between atmospheric oxygen, oxidative stress, and lifespan across a range of oxygen levels is poorly known. Developmental responses are likely to play a strong role, as prior research has shown strong effects of rearing oxygen level on growth, size and respiratory system morphology. In this study, we examined (1) the effect of oxygen on adult longevity and (2) the effect of the oxygen concentration experienced by larvae on adult lifespan by rearing Drosophila melanogaster in three oxygen atmospheres throughout larval development (10, 21 and 40 kPa), then measuring the lifespan of adults in five oxygen tensions (2, 10, 21, 40, 100 kPa). We also assessed the rate of protein carbonyl production for flies kept at 2, 10, 21, 40 and 100 kPa as adults (all larvae reared in normoxia). The rearing of juveniles in varying oxygen treatments affected lifespan in a complex manner, and the effect of different oxygen tensions on adult lifespan was non-linear, with reduced longevity and heightened oxidative stress at extreme high and low atmospheric oxygen levels. Moderate hypoxia (10 kPa) extended maximum, but not mean lifespan.
Multi‐level aspects of social cohesion of secondary schools and pupils' feelings of safety
Authors: Mooij Ton , Smeets Ed , de Wit Wouter 
Published: October 2010

Background. School safety and corresponding feelings of both pupils and school staff are beginning to receive more and more attention. The social cohesion characteristics of a school may be useful in promoting feelings of safety, particularly in pupils. Aims. To conceptualize theoretically, and check empirically a two‐level model of social cohesion between and within schools, in order to explain a pupil's feelings of safety at school. Samples. Data were collected aided by a national Dutch survey in secondary education carried out via the Internet. In 2008, digital questionnaires were completed by about 78,800 pupils, 6,200 teachers and educational support staff, and 600 school managers. Methods. Data were checked for reliability and representativity. Social cohesion was indicated by self‐reported measures of individual pupils and by aggregating scale and item scores of school managers, teachers, and other support staff within schools. Multi‐level analysis using individual pupil data and school‐level data was performed using MLwiN. Results. A pupil's age, educational attainment level, experience of mild physical violence, prosocial rules of conduct and joint control of these rules, and school measures against playing truant, show positive influences on a pupil's feelings of safety at school. Negative influences are exerted by not feeling most at home in The Netherlands, peers taking drugs and weapons into school, and by experiencing social violence, severe physical violence, and sexual violence. Negative school effects exist simultaneously in severe physical violence experienced by teachers and other staff, and in curriculum differentiation applied by teachers and other staff; a positive school effect is school size. Some interaction effects between pupil and school‐level variables were explored. Conclusions. The variance at school level is relatively low compared with the variance at pupil level. However, a much higher percentage of variance at school level than at pupil level is explained with respect to the pupils' feelings of safety at school. The resulting two‐level model also reflects the streaming of pupils in Dutch secondary schools. To improve school safety, the national results emphasize the need to enhance prosocial behaviour rules and to enhance the shared control of these rules between teachers and pupils. They also emphasize the need for the school to take measures that prevent truancy and redefine curriculum differentiation procedures. National educational policy and research can combine efforts to assist schools in developing reliable and valid procedures to increase effectively safety in and around schools.
Parameters in minimalist theory: The case of Scandinavian
Authors: Holmberg Anders 
Published: October 2010

Abstract
The P&P theory of UG has come under heavy criticism, lately, from outside but also from inside generative grammar. The claim is that the search for ‘deep parameters’ underlying clusters of properties across languages has led nowhere, and should be given up. I have revisited a theory, now two decades old, which explained ten syntactic differences between Insular and Mainland Scandinavian as the effects of a single parametric difference (in a series of works by C. Platzack and A. Holmberg). The theory is shown to be fundamentally right, descriptively and theoretically. Later developments in generative theory only serve to sharpen the formulations, adding another layer of explanatory depth to the earlier theory. The conclusion is that there are parameters of the traditional kind. The problems encountered when the theory is tested on more distantly related languages is discussed on the basis of facts from Finnish. P&P theory is perfectly consistent with the minimalist approach to UG and variation when parameters are seen as points of under-specification in UG, and restrictions on variation are seen as, in part, third factor effects, in the sense of Chomsky (Linguistic Inquiry 36: 1–22, 2005).
Radiation exposure during cardiac catheterization: Implications for the transradial approach
Authors: Komócsi András , Kónyi A. , Kovács E. , Ungi I. 
Published: October 2010

Abstract
Coronary angiography and intervention became an integral part of the modern cardiology. These invasive procedures beside their firmly established benefits also expose the patient to a hazard for access site complication, contrast material and radiation exposure. Transradial access significantly reduces the risk associated with the arterial puncture; however its effect regarding the radiation exposure is debated. Our aim was to review the aspects of transradial coronary intervention in the context of the radiation exposure. This review focuses on key aspects of feasibility and safety related to the access site choice and the learning curve.