bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional, socioeconomic and occupational groups and risk of hospital admission for multiple sclerosis: a cohort study in Sweden
Authors: Li X , Hemminki K , Sundquist K 
Published: June 2008

Objective The aim of this study was to investigate possible associations between hospitalization for multiple sclerosis (MS) and region, socioeconomic status and occupation. Methods A nationwide database was constructed by linking Swedish Census data to the Hospital Discharge Register (1987–2001). The hospital diagnoses of MS were based on the International Classification of Diseases. Standardized incidence ratios (SIRs) with 95% confidence intervals were calculated. Results Significantly increased or decreased risks of hospitalization for MS were found for individuals living in some counties. The overall SIRs for hospitalizations for MS were close to unity between different socioeconomic groups. Male religious workers, male postal workers and female administrators who had the same occupational title in two consecutive censuses had substantially higher risks of hospitalization for MS than the reference group. However, no increased risks were found for most occupational groups. Conclusions The present study suggests that region, socioeconomic status and occupation have a minor effect on the population’s risk of hospitalization for MS.
Pain in multiple sclerosis: a clinical and instrumental approach
Authors: Grasso MG , Clemenzi A , Tonini A , Pace L , Casillo P , Cuccaro A , Pompa A , Troisi E 
Published: June 2008

Background Pain is a frequent and disabling symptom in multiple sclerosis (MS) patients. In this study we assess the frequency and intensity of pain, as well as its impact on the quality of life and activities of daily living, in a sample of MS patients. Methods One hundred and twenty eight MS patients underwent a neurological examination, a structured interview designed to assess pain, and a Medical Outcome 36-item Short Form Health Survey. Functional status was assessed by means of the Barthel Index (BI) and Rivermead Mobility Index. We also assessed the presence of depression, by means of the Montgomery and Asberg Depression Rating Scale, and fatigue, by means of the Fatigue Severity Scale. An algometer was used to measure thermal and discomfort thresholds in all of the patients and a group of 61 age- and sex-matched healthy subjects. Results Pain was present in 61 patients. No differences were found between patients with and those without pain in disease duration, disease form or Expanded Disability Status Scale and its functional systems. Patients with pain had a lower vitality score ( p = 0.008), mental health score ( p = 0.03) and physical ( p < 0.001) and mental composite scores ( p = 0.01) than patients without pain. Furthermore, there was a significant difference between patients with and those without pain in the BI ( p = 0.04). Both thermal and discomfort thresholds, as assessed by means of the algometer, were statistically lower in MS patients than in controls, whereas no difference was observed between patients with and those without pain. There was a statistically significant improvement in the thermal threshold in patients with pain who were treated pharmacologically when compared with those who were not treated ( p = 0.049). Conclusion The results of this study provide further evidence of the negative impact that the presence of pain has on both the quality of life and activities of daily living in MS patients. The lower thermal and discomfort thresholds observed in our MS patients, compared with controls, may represent a predisposition to develop pain during the course of the disease.
Relationship between MRI lesion activity and response to IFN-β in relapsing–remitting multiple sclerosis patients
Authors: Río J , Rovira À , Tintoré M , Huerga E , Nos C , Tellez N , Tur C , Comabella M , Montalban X 
Published: June 2008

Objective Our objective in this study is to evaluate whether brain magnetic resonance imaging (MRI) performed at interferon-beta (IFN-β) onset and after 12 months allow us to identify relapsing–remitting multiple sclerosis (RRMS) patients with a disability increase in the first 2 years of therapy. Methods This is a prospective and longitudinal study of patients with RRMS treated with IFN-β. All patients included underwent brain MRI before the onset of therapy with IFN-β and 12 months after. MRI measures (T2, unenhanced T1-weighted and gadolinium-enhancing T1-weighted brain lesion load, brain parenchymal fraction) were undertaken at baseline and after 12 months. The number of active lesions (new or enlarging T2 plus gadolinium-enhancing brain lesions) was also assessed on the 12 months MRI scan. Expanded Disability Status Scale (EDSS) was scored every 3 months. We defined an increase in disability as an increase of at least 1 EDSS point confirmed and sustained during the first 2 years of therapy with IFN-β. Regression analysis was performed in order to identify MRI variables of response. Results We included 152 patients who were followed-up for at least 2 years. After 2 years of therapy, 24 patients (16%) had an increase in disability. The logistic regression model showed that active lesions in the scan performed at 12 months were the most important factor related with the increase of disability after 2 years of therapy (odds ratio 8.3, 95% confidence interval 3.1–21.9; p < 0.0001). Conclusions In RRMS patients treated with IFN-β the MRI changes occurring during the first year may have a prognostic value for identifying patients with a confirmed increase of disability after 2 years of therapy.
Review: Atrial fibrillation and renin-angiotensin system
Authors: Serra José Luis , Bendersky Mario 
Published: June 2008

Atrial Fibrillation (AF) is one of the most frequent arrhythmias, especially in elderly patients. Cardiac overload increases the incidence of AF. Clinical presentation of atrial fibrillation can occur as nonsustained paroxysms, persistent episodes and in chronic-permanent form. The physio-pathological mechanisms are: • Circuit of multiple and anarchic re-entries • Atrial fibrillatory conduction • Re-entry circuit with fibrillatory conduction. Remodeling (electrical or structural) facilitates the appearance and persistence of AF: Neurovegetative changes and cytosolic Ca overload facilitate AF. Interstitial atrial fibrosis, in which Renin-Angiotensin System (RAS) hyperactivity is a main aspect of remodeling. There is clinical evidence that supports the antiatrial fibrillatory actions of RAS blockade. Potential mechanisms are: (a) direct modulation of ionic channels, (b) hemodynamic improvement, (c) reduction of atrial stretching, (d) antifibrotic effects. There is less clinical evidence with antialdosterone drugs, but theoretically these might also be useful.
Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos
Authors: Trindade Alexandre , Ram Kumar S. , Scehnet Jeffrey S. , Lopes-da-Costa Luis , Becker Jorg , Jiang Weidong , Liu Ren , Gill Parkash S. , Duarte Antonio 
Published: June 2008

AbstractThe importance of Notch signaling pathway in the regulation of vascular development and angiogenesis is suggested by the expression of Notch receptors and ligands in vascular endothelial cells (ECs) and the observed vascular phenotypes in mutants of Notch receptors or ligands, especially Dll4. DLL4 is specifically expressed in arterial ECs during development, and haplo-insufficiency is embryonically lethal in mice. To address the role of Dll4 in vascular development, we produced mDll4 conditionally overexpressed transgenic mice that were crossed with constitutive recombinase cre lines. Double transgenic embryos displayed grossly enlarged dorsal aortae (DA) and died before embryonic day 10.5 (E10.5), showing a variable degree of premature arteriovenous fusion. Veins displayed ectopic expression of arterial markers. Other defects included reduced vascular sprouting, EC proliferation, and migration. mDll4 overexpression also inhibited VEGF signaling and increased fibronectin accumulation around the vessels. In vitro and in vivo studies of DLL4-FL (Dll4–full-length) in ECs recapitulate many of the mDll4 transgenics findings, including decreased tube formation, reduced vascular branching, fewer vessels, increased pericyte recruitment, and increased fibronectin expression. These results establish the role of Dll4 in arterial identity determination, and regulation of angiogenesis subject to dose and location.
Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study
Authors: Young Ken H. , Leroy Karen , Møller Michael B. , Colleoni Gisele W. B. , Sánchez-Beato Margarita , Kerbauy Fábio R. , Haioun Corinne , Eickhoff Jens C. , Young Allen H. , Gaulard Philippe , Piris Miguel A. , Oberley Terry D. , Rehrauer William M. , Kahl Brad S. , Malter James S. , Campo Elias , Delabie Jan , Gascoyne Randy D. , Rosenwald Andreas , Rimsza Lisa , Huang James , Braziel Rita M. , Jaffe Elaine S. , Wilson Wyndham H. , Staudt Louis M. , Vose Julie M. , Chan Wing C. , Weisenburger Dennis D. , Greiner Timothy C. 
Published: June 2008

AbstractThe purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.
Crystal structures of TAFI elucidate the inactivation mechanism of activated TAFI: a novel mechanism for enzyme autoregulation
Authors: Marx Pauline F. , Brondijk T. Harma C. , Plug Tom , Romijn Roland A. , Hemrika Wieger , Meijers Joost C. M. , Huizinga Eric G. 
Published: June 2008

AbstractThrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-metallocarboxypeptidase that can be proteolytically activated (TAFIa). TAFIa is unique among carboxypeptidases in that it spontaneously inactivates with a short half-life, a property that is crucial for its role in controlling blood clot lysis. We studied the intrinsic instability of TAFIa by solving crystal structures of TAFI, a TAFI inhibitor (GEMSA) complex and a quadruple TAFI mutant (70-fold more stable active enzyme). The crystal structures show that TAFIa stability is directly related to the dynamics of a 55-residue segment (residues 296-350) that includes residues of the active site wall. Dynamics of this flap are markedly reduced by the inhibitor GEMSA, a known stabilizer of TAFIa, and stabilizing mutations. Our data provide the structural basis for a model of TAFI auto-regulation: in zymogen TAFI the dynamic flap is stabilized by interactions with the activation peptide. Release of the activation peptide increases dynamic flap mobility and in time this leads to conformational changes that disrupt the catalytic site and expose a cryptic thrombin-cleavage site present at Arg302. This represents a novel mechanism of enzyme control that enables TAFI to regulate its activity in plasma in the absence of specific inhibitors.
A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function
Authors: Lasry Inbal , Berman Bluma , Straussberg Rachel , Sofer Yael , Bessler Hanna , Sharkia Mohamad , Glaser Fabian , Jansen Gerrit , Drori Stavit , Assaraf Yehuda G. 
Published: June 2008

AbstractHereditary folate malabsorption (HFM) patients harbor inactivating mutations including R113S in the proton-coupled folate transporter (PCFT), an intestinal folate transporter with optimal activity at acidic pH. Here we identified and characterized a novel R113C mutation residing in the highly conserved first intracellular loop of PCFT. Stable transfectants overexpressing a Myc-tagged wild-type (WT) and mutant R113C PCFT displayed similar transporter targeting to the plasma membrane. However, whereas WT PCFT transfectants showed a 22-fold increase in [3H]folic acid influx at pH 5.5, R113C or mock transfectants showed no increase. Moreover, WT PCFT transfectants displayed a 50% folic acid growth requirement concentration of 7 nM, whereas mock and R113C transfectants revealed 24- to 27-fold higher values. Consistently, upon fluorescein-methotrexate labeling, WT PCFT transfectants displayed a 50% methotrexate displacement concentration of 50 nM, whereas mock and R113C transfectants exhibited 12- to 14-fold higher values. Based on the crystal structure of the homologous Escherichia coli glycerol-3-phosphate transporter, we propose that the cationic R113 residue of PCFT is embedded in a hydrophobic pocket formed by several transmembrane helices that may be part of a folate translocation pore. These findings establish a novel loss of function mutation in HFM residing in an intracellular loop of PCFT crucial for folate transport.
Inferring modules of functionally interacting proteins using the Bond Energy Algorithm
Authors: Watanabe Ryosuke LA , Morett Enrique , Vallejo Edgar E 
Published: June 2008

Abstract

Background
Non-homology based methods such as phylogenetic profiles are effective for predicting functional relationships between proteins with no considerable sequence or structure similarity. Those methods rely heavily on traditional similarity metrics defined on pairs of phylogenetic patterns. Proteins do not exclusively interact in pairs as the final biological function of a protein in the cellular context is often hold by a group of proteins. In order to accurately infer modules of functionally interacting proteins, the consideration of not only direct but also indirect relationships is required.
In this paper, we used the Bond Energy Algorithm (BEA) to predict functionally related groups of proteins. With BEA we create clusters of phylogenetic profiles based on the associations of the surrounding elements of the analyzed data using a metric that considers linked relationships among elements in the data set.

Results
Using phylogenetic profiles obtained from the Cluster of Orthologous Groups of Proteins (COG) database, we conducted a series of clustering experiments using BEA to predict (upper level) relationships between profiles. We evaluated our results by comparing with COG's functional categories, And even more, with the experimentally determined functional relationships between proteins provided by the DIP and ECOCYC databases. Our results demonstrate that BEA is capable of predicting meaningful modules of functionally related proteins. BEA outperforms traditionally used clustering methods, such as k-means and hierarchical clustering by predicting functional relationships between proteins with higher accuracy.

Conclusion
This study shows that the linked relationships of phylogenetic profiles obtained by BEA is useful for detecting functional associations between profiles and extending functional modules not found by traditional methods. BEA is capable of detecting relationship among phylogenetic patterns by linking them through a common element shared in a group. Additionally, we discuss how the proposed method may become more powerful if other criteria to classify different levels of protein functional interactions, as gene neighborhood or protein fusion information, is provided.
Partial mixture model for tight clustering of gene expression time-course
Authors: Yuan Yinyin , Li Chang-Tsun , Wilson Roland 
Published: June 2008

AbstractBackgroundTight clustering arose recently from a desire to obtain tighter and potentially more informative clusters in gene expression studies. Scattered genes with relatively loose correlations should be excluded from the clusters. However, in the literature there is little work dedicated to this area of research. On the other hand, there has been extensive use of maximum likelihood techniques for model parameter estimation. By contrast, the minimum distance estimator has been largely ignored.ResultsIn this paper we show the inherent robustness of the minimum distance estimator that makes it a powerful tool for parameter estimation in model-based time-course clustering. To apply minimum distance estimation, a partial mixture model that can naturally incorporate replicate information and allow scattered genes is formulated. We provide experimental results of simulated data fitting, where the minimum distance estimator demonstrates superior performance to the maximum likelihood estimator. Both biological and statistical validations are conducted on a simulated dataset and two real gene expression datasets. Our proposed partial regression clustering algorithm scores top in Gene Ontology driven evaluation, in comparison with four other popular clustering algorithms.ConclusionFor the first time partial mixture model is successfully extended to time-course data analysis. The robustness of our partial regression clustering algorithm proves the suitability of the combination of both partial mixture model and minimum distance estimator in this field. We show that tight clustering not only is capable to generate more profound understanding of the dataset under study well in accordance to established biological knowledge, but also presents interesting new hypotheses during interpretation of clustering results. In particular, we provide biological evidences that scattered genes can be relevant and are interesting subjects for study, in contrast to prevailing opinion.
Genome-scale cluster analysis of replicated microarrays using shrinkage correlation coefficient
Authors: Yao Jianchao , Chang Chunqi , Salmi Mari L , Hung Yeung Sam , Loraine Ann , Roux Stanley J 
Published: June 2008

AbstractBackgroundCurrently, clustering with some form of correlation coefficient as the gene similarity metric has become a popular method for profiling genomic data. The Pearson correlation coefficient and the standard deviation (SD)-weighted correlation coefficient are the two most widely-used correlations as the similarity metrics in clustering microarray data. However, these two correlations are not optimal for analyzing replicated microarray data generated by most laboratories. An effective correlation coefficient is needed to provide statistically sufficient analysis of replicated microarray data.ResultsIn this study, we describe a novel correlation coefficient, shrinkage correlation coefficient (SCC), that fully exploits the similarity between the replicated microarray experimental samples. The methodology considers both the number of replicates and the variance within each experimental group in clustering expression data, and provides a robust statistical estimation of the error of replicated microarray data. The value of SCC is revealed by its comparison with two other correlation coefficients that are currently the most widely-used (Pearson correlation coefficient and SD-weighted correlation coefficient) using statistical measures on both synthetic expression data as well as real gene expression data fromSaccharomyces cerevisiae. Two leading clustering methods, hierarchical and k-means clustering were applied for the comparison. The comparison indicated that using SCC achieves better clustering performance. Applying SCC-based hierarchical clustering to the replicated microarray data obtained from germinating spores of the fernCeratopteris richardii, we discovered two clusters of genes with shared expression patterns during spore germination. Functional analysis suggested that some of the genetic mechanisms that control germination in such diverse plant lineages as mosses and angiosperms are also conserved among ferns.ConclusionThis study shows that SCC is an alternative to the Pearson correlation coefficient and the SD-weighted correlation coefficient, and is particularly useful for clustering replicated microarray data. This computational approach should be generally useful for proteomic data or other high-throughput analysis methodology.
Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains
Authors: Tadepally Hamsa D , Burger Gertraud , Aubry Muriel 
Published: June 2008

AbstractBackgroundC2H2 zinc finger genes (C2H2-ZNF) constitute the largest class of transcription factors in humans and one of the largest gene families in mammals. Often arranged in clusters in the genome, these genes are thought to have undergone a massive expansion in vertebrates, primarily by tandem duplication. However, this view is based on limited datasets restricted to a single chromosome or a specific subset of genes belonging to the large KRAB domain-containing C2H2-ZNF subfamily.ResultsHere, we present the first comprehensive study of the evolution of the C2H2-ZNF family in mammals. We assembled the complete repertoire of human C2H2-ZNF genes (718 in total), about 70% of which are organized into 81 clusters across all chromosomes. Based on an analysis of their N-terminal effector domains, we identified two new C2H2-ZNF subfamilies encoding genes with a SET or a HOMEO domain. We searched for the syntenic counterparts of the human clusters in other mammals for which complete gene data are available: chimpanzee, mouse, rat and dog. Cross-species comparisons show a large variation in the numbers of C2H2-ZNF genes within homologous mammalian clusters, suggesting differential patterns of evolution. Phylogenetic analysis of selected clusters reveals that the disparity in C2H2-ZNF gene repertoires across mammals not only originates from differential gene duplication but also from gene loss. Further, we discovered variations among orthologs in the number of zinc finger motifs and association of the effector domains, the latter often undergoing sequence degeneration. Combined with phylogenetic studies, physical maps and an analysis of the exon-intron organization of genes from the SCAN and KRAB domains-containing subfamilies, this result suggests that the SCAN subfamily emerged first, followed by the SCAN-KRAB and finally by the KRAB subfamily.ConclusionOur results are in agreement with the "birth and death hypothesis" for the evolution of C2H2-ZNF genes, but also show that this hypothesis alone cannot explain the considerable evolutionary variation within the subfamilies of these genes in mammals. We, therefore, propose a new model involving the interdependent evolution of C2H2-ZNF gene subfamilies.