Miracle-dz/UniFAR-FTUs huggingface dataset:
Contributions of the Individual Domains in Human La Protein to Its RNA 3′-End Binding Activity*

The autoantigen La regulates the maturation of RNA polymerase III transcripts by binding to their poly(U) termination signal. The modular protein harbors a N-terminal RNA recognition motif (RRM), RRM1, and in the C-terminal domain, a second, atypical RRM2, in addition to a phosphorylation site, and a putative nucleotide binding site. This study presents a detailed investigation into the RNA 3′-end binding properties of La by using binding titration and competition assays with subsequent gel mobility shift analysis. Two truncation mutants containing one (La-RRM1) or both (La-RRM1-RRM2) RNA-binding domains were constructed, overexpressed, and purified. AK d value of 25 ± 10 nm for La binding to a nonameric RNA ligand with the oligouridylate recognition sequence was obtained, discriminating with a specificity ratio of ∼100 for this probe over a RNA ligand with a 3′-poly(A) stretch. The N-terminal La-RRM1 region was identified as the major contributor of these properties to La, manifested in a 5-fold lowerK d of 5 ± 3 nm and a slightly increased specificity ratio of 120 for the RNA ligand. The atypical RRM2 in the C-terminal domain of La has an unprecedented negative effect on 3′-end RNA recognition, as indicated by a higherK d value of 90 ± 10 nm for the La-RRM1-RRM2 mutant but comparable specificity. Thus the C-terminal regions beyond RRM2 positively modulate the RNA binding affinity of La. Negative regulation, however, occurs through Ser366phosphorylation decreasing the binding affinity by 2-fold. ATP had no influence on RNA complex formation. The functional implications of these findings for the mechanism of action of La are discussed.
The expanding range of parvoviruses which infect humans

The first human parvoviruses to be described (1960s) were the adeno‐associated viruses (AAVs, now classed as dependoviruses), originally identified as contaminants of cell cultures, followed by parvovirus B19 (B19V) in 1974, the first parvovirus to be definitively shown to be pathogenic. More recently two new groups of parvoviruses, the human bocaviruses (HuBoV) and the Parv4 viruses have been identified. These four groups of human viruses are all members of different genera within the Parvovirus family, and have very different biology, epidemiology and disease associations from each other. This review will provide an overview of the virological, pathogenic and clinical features of the different human paroviruses, and how these new viruses and their variants fit into the current understanding of parvovirus infection. Copyright © 2010 John Wiley & Sons, Ltd.
Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute of Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. OBJECTIVES To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Last search: 13 January 2014.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 28 November 2013. SELECTION CRITERIA Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS Two authors independently assessed for inclusion in the review the eligibility of 43 studies (61 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.
Generation of a Danish TTO value set for EQ-5D health states

Aims: Health policy decisions should be based on national social preferences. In the absence of a set of Danish health preferences, patient outcome studies using the EQ-5D instrument have typically used UK health state valuations. This article describes the development of a Danish EQ-5D value set. Methods: Regression modelling was based on Time Trade-Off (TTO) data derived from computer-assisted interviews conducted with 1,332 respondents from the Danish general population. Using a split-sample technique, 46 health states were directly valued by the respondents. Five different model types were tested and compared on statistical and theoretical grounds. Eleven different specifications were then tested for the chosen model type to identify the most appropriate model that had high explanatory power and parameters that were both consistent (positively signed) and statistically significant. Results: An additive random effects model was found to be superior to ordinary least squares, fixed effects, random coefficient and censored Tobit modelling approaches. From the 11 model specifications tested, the TTO3 model (main effects model, without an N3 factor) performed best and was used to generate a Danish set of health state preferences. Conclusions: An additive random effects model appears to adequately generate a Danish set of EQ-5D health state preferences. The model has high explanatory power and produces consistent and significant parameters for EQ-5D dimensions and levels. It is recommended that this value set be used in Danish cost-utility studies using EQ-5D.
Molecular Screening for P53 Mutations among Tobacco Smokers in a Survey of Awareness of Links between Tobacco, Alcohol Use and Cancer in Saudi Arabia.

BACKGROUND Roles of tobacco and alcohol use in etiology of cancer are well established. Alterationin in P53 have essential roles neoplastic change by preventing genome mutation; the aim of this study was to assess the association between P53 mutation and tobacco and alcohol consumption, as well as to assess the epidemiology of tobacco and alcohol use as risk factors for cancer in the adult population of northern Saudi civilians. MATERIALS AND METHODS A cross-sectional survey from October 2014 to January 2015, covering 3,398 adults, was performed. P53 mutation molecular detection was performed for 100 tobacco and alcohol users, using DNA extracted from buccal cells. RESULTS Of the 3,398 participants 3,253/3398(95.7%) responded, with a male female ratio of 1.10: 1.00. Out of these, 24.8% had smoked tobacco in their lifetime and 2.7% were consumers of alcoholic beverages. None was identified with any P53 mutation. CONCLUSIONS The prevalence of tobacco smoking among the northern Saudi civilians was relatively high. Females' attitudes in tobacco and alcohol related issues were found to be affected by social stigma. Tobacco and alcohol use has no link to P53 gene mutations.
A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study.

CONTEXT Optimal levels of vitamin D have been a topic of heavy debate, and the correlation between 25-hydroxyvitamin D [25(OH)D] levels and mortality still remains to be established. OBJECTIVE The aim of the study was to determine the association between all-cause mortality and serum levels of 25(OH)D, calcium, and PTH. DESIGN AND SETTING We conducted a retrospective, observational cohort study, the CopD Study, in a single laboratory center in Copenhagen, Denmark. PARTICIPANTS Serum 25(OH)D was analyzed from 247,574 subjects from the Copenhagen general practice sector. In addition, serum levels of calcium, albumin-adjusted calcium, PTH, and creatinine were measured in 111,536; 20,512; 34,996; and 189,496 of the subjects, respectively. MAIN OUTCOME MEASURES Multivariate Cox regression analysis was used to compute hazard ratios for all-cause mortality. RESULTS During follow-up (median, 3.07 yr), 15,198 (6.1%) subjects died. A reverse J-shaped association between serum level of 25(OH)D and mortality was observed. A serum 25(OH)D level of 50-60 nmol/liter was associated with the lowest mortality risk. Compared to 50 nmol/liter, the hazard ratios (95% confidence intervals) of all-cause mortality at very low (10 nmol/liter) and high (140 nmol/liter) serum levels of 25(OH)D were 2.13 (2.02-2.24) and 1.42 (1.31-1.53), respectively. Similarly, both high and low levels of albumin-adjusted serum calcium and serum PTH were associated with an increased mortality, and secondary hyperparathyroidism was associated with higher mortality (P < 0.0001). CONCLUSION In this study from the general practice sector, a reverse J-shaped relation between the serum level of 25(OH)D and all-cause mortality was observed, indicating not only a lower limit but also an upper limit. The lowest mortality risk was at 50-60 nmol/liter. The study did not allow inference of causality, and further studies are needed to elucidate a possible causal relationship between 25(OH)D levels, especially higher levels, and mortality.
Chronic dizziness and anxiety: effect of course of illness on treatment outcome.

OBJECTIVE To investigate the hypothesis that the efficacy of selective serotonin reuptake inhibitors (SSRIs) for chronic subjective dizziness (CSD) and anxiety depends on the longitudinal pattern of the patients' symptoms. DESIGN Prospective cohort study. SETTING Tertiary care, multidisciplinary, balance center. PATIENTS Eighty-eight consecutive patients treated with an SSRI for CSD and anxiety between 1998 and 2003. All patients were referred for evaluation of unremitting dizziness. They entered SSRI treatment after comprehensive neurotologic and psychiatric evaluations revealed a syndrome of CSD with accompanying anxiety. Patients were separated into 3 groups according to their longitudinal patterns of illness: (1) otogenic, defined as primary neurotologic conditions triggering secondary anxiety disorders; (2) psychogenic, defined as anxiety disorders alone causing dizziness; and (3) interactive, defined neurotologic conditions exacerbating preexisting anxiety. INTERVENTIONS Patients with CSD were treated with an SSRI according to an established protocol for at least 8 weeks or until they proved intolerant to medication. MAIN OUTCOME MEASURES Changes in dizziness and anxiety as measured by the Clinical Global Impressions-Improvement scale. RESULTS Patients with the otogenic and psychogenic patterns of illness had a more complete response to SSRI treatment than did patients in the interactive group (P<.01). Rates of SSRI intolerance were similar for all 3 groups. CONCLUSIONS Selective serotonin reuptake inhibitors are effective for patients with CSD and anxiety. However, patients with clinically significant anxiety predating neurotologic illness may require more intensive interventions.
Risk factors for postoperative anxiety in children

Background: Anxiety is defined as a set of behavioural manifestations that can be divided into state‐ and trait‐anxiety. State‐anxiety is a transitory emotional condition that varies in intensity and fluctuates over time. Trait‐anxiety is a personality trait which remains relatively stable over time. The objective of this study was to identify and quantify perioperative risk factors for immediate postoperative anxiety in children.
MicroRNAs and phylogenomics resolve the relationships of Tardigrada and suggest that velvet worms are the sister group of Arthropoda

Morphological data traditionally group Tardigrada (water bears), Onychophora (velvet worms), and Arthropoda (e.g., spiders, insects, and their allies) into a monophyletic group of invertebrates with walking appendages known as the Panarthropoda. However, molecular data generally do not support the inclusion of tardigrades within the Panarthropoda, but instead place them closer to Nematoda (roundworms). Here we present results from the analyses of two independent genomic datasets, expressed sequence tags (ESTs) and microRNAs (miRNAs), which congruently resolve the phylogenetic relationships of Tardigrada. Our EST analyses, based on 49,023 amino acid sites from 255 proteins, significantly support a monophyletic Panarthropoda including Tardigrada and suggest a sister group relationship between Arthropoda and Onychophora. Using careful experimental manipulations—comparisons of model fit, signal dissection, and taxonomic pruning—we show that support for a Tardigrada + Nematoda group derives from the phylogenetic artifact of long-branch attraction. Our small RNA libraries fully support our EST results; no miRNAs were found to link Tardigrada and Nematoda, whereas all panarthropods were found to share one unique miRNA (miR-276). In addition, Onychophora and Arthropoda were found to share a second miRNA (miR-305). Our study confirms the monophyly of the legged ecdysozoans, shows that past support for a Tardigrada + Nematoda group was due to long-branch attraction, and suggests that the velvet worms are the sister group to the arthropods.
Influence des conditions trophiques sur le développement larvaire de l'espèce invasive Crepidula fornicata : conséquences sur ses capacités de dispersion

Les introductions d’especes exotiques constituent l’une des causes majeures d’alteration des ecosystemes marins cotiers. La phase larvaire pelagique des invertebres a cycle bentho-pelagique joue un role majeur a toutes les etapes du processus d'introduction et peut contribuer au succes ou a l'echec d'une introduction. L'etude des mecanismes modulant les traits d'histoire de vie larvaires est donc primordiale pour la comprehension des processus d'introduction. L'objectif general de mon travail de these est de determiner quelle est l'influence de la disponibilite en nourriture (en termes de quantite et de qualite) sur les capacites de developpement des larves de Crepidula fornicata, gasteropode emblematique des introductions biologiques sur les cotes europeennes. Cette problematique est complexe car dans son aire d’introduction, C. Fornicata presente une periode de reproduction longue (de fevrier a novembre) qui implique (1) que l’investissement maternel pour la descendance peut varier tout au long de cette periode et (2) que les larves emises se trouvent en presence de sources de nourriture variables. Les resultats obtenus ont mis en evidence, grâce au tracage isotopique enrichi (13C), que les embryons encapsules dependaient majoritairement de l’investissement maternel pour leur developpement. L'etude de la composition en acides gras (source energetique essentielle pour les descendants et biomarqueurs de la qualite) des femelles, des embryons et des larves a mis en evidence une meilleure qualite des femelles et des embryons en milieu de periode de reproduction. L'etude de la nutrition larvaire, a l’aide du double marquage isotopique (13C, 15N) et d'experiences de broutage sur des communautes planctoniques naturelles, a montre que les larves de C. Fornicata (1) utilisent preferentiellement le nanoplancton (dont les diatomees), et (2) ont la capacite de se nourrir a partir du compartiment bacterien. Ces resultats, combines aux donnees de suivi in situ et aux resultats issus de l'utilisation des biomarqueurs lipidiques, temoignent de la capacite des larves de C. Fornicata a se nourrir sur une large gamme de sources nutritives, tant sur le plan qualitatif que quantitatif. Il est propose que ces capacites trophiques aient contribue a favoriser l’expansion de cette espece sur les cotes europeennes.
A physical and functional link between cholesterol and tetraspanins

By interacting with each others, the tetraspanins are thought to assemble a network of molecular interactions, the tetraspanin web. These tetraspanin/tetraspanin interactions involve in part the palmitoylation of the proteins. We show that tetraspanins interact with cholesterol as indicated by the precipitation of tetraspanin/tetraspanin complexes by digitonin, a cholesterol‐precipitating reagent, and the labeling of the tetraspanins CD9, CD81 and CD82 with a photoactivatable cholesterol in vivo. Cholesterol may participate to the interaction of tetraspanins with each other since digitonin‐precipitation of tetraspanins was correlated with their mutual interaction, and because these interactions were disrupted following cholesterol depletion by methyl‐β‐cyclodextrin (MβCD) treatment, or cholesterol sequestration by saponin. A mutant CD9 molecule lacking all palmitoylation sites was not precipitated by digitonin under conditions in which wild‐type CD9 was precipitated, indicating a role of palmitoylation for the interaction with cholesterol. Finally, upon ligation of tetraspanins on the surface of a lymphoid B cell line, the tyrosine phosphorylation of several proteins, including the vav nucleotide exchange factor, was inhibited when cells were pretreated with MβCD, and increased when they were treated with MβCD/cholesterol complexes. Thus, there is a physical and functional link between tetraspanins and cholesterol.
Regulation of growth and metabolism by imprinted genes

A small sub-set of mammalian genes are subject to regulation by genomic imprinting such that only one parental allele is active in at least some sites of expression. Imprinted genes have diverse functions, notably including the regulation of growth. Much attention has been devoted to the insulin-like growth factor signalling pathway that has a major influence on fetal size and contains two components encoded by the oppositely imprinted genes, Igf2 (a growth promoting factor expressed from the paternal allele) and Igf2r (a growth inhibitory factor expressed from the maternal allele). These genes fit the parent-offspring conflict hypothesis for the evolution of genomic imprinting. Accumulated evidence indicates that at least one other fetal growth pathway exists that has also fallen under the influence of imprinting. It is clear that not all components of growth regulatory pathways are encoded by imprinted genes and instead it may be that within a pathway the influence of a single gene by each of the parental genomes may be sufficient for parent-offspring conflict to be enacted. A number of imprinted genes have been found to influence energy homeostasis and some, including Igf2 and Grb10, may coordinate growth with glucose-regulated metabolism. Since perturbation of fetal growth can be correlated with metabolic disorders in adulthood these imprinted genes are considered as candidates for involvement in this phenomenon of fetal programming.
Marine‐derived Nutrients from Green Turtle Nests Subsidize Terrestrial Beach Ecosystems

Spatially separated ecosystems are often linked by nutrient fluxes. Nutrient inputs may be transferred by physical vectors (i.e., wind and water) or by biotic vectors. In this study, we examine the role of green turtles (Chelonia mydas) as biotic transporters of nutrients from marine to terrestrial ecosystems, where they deposit eggs. We compare low and high nest density sites at Tortuguero, Costa Rica, the largest green turtle rookery in the western hemisphere. Four plant species (Costus woodsonii, Hibiscus pernanbucensis, Hymenocallis littoralis, Ipomoea pes‐caprae) were analyzed at both nest density sites for 15N, total carbon, nitrogen, and phosphorus, and vegetation cover. Sand was analyzed for 15N and total nitrogen. Vegetation at high nest density sites had higher total nitrogen, which was correlated with higher δ15N values, suggesting nutrient input from a marine source. The dominant plant species changed between low and high nest density sites, indicating that turtle‐derived nutrients may alter the plant community composition. The trend in δ15N values of sand was similar, although less pronounced than that of the vegetation. Sand may be a poor integrator of nutrient input due to low nutrient adsorption and high rate of leaching. Sea turtles have previously been shown to deposit considerable amounts of nutrients and energy on nesting beaches. In this study, we estimate annual nitrogen and phosphorus contributions at Tortuguero are 507 and 45 kg/km, respectively, and we demonstrate that beach vegetation likely assimilates a portion of these marine‐derived nutrients.
Fine-resolution analysis of products of intrachromosomal homeologous recombination in mammalian cells

Mouse Ltk- cell lines that contained a herpes simplex virus type 1 (HSV-1) thymidine kinase (tk) gene with a 16-bp insertion mutation linked to either a defective HSV-2 tk gene or a hybrid tk sequence comprised of HSV-1 and HSV-2 tk sequences were constructed. HSV-1 and HSV-2 tk genes have 81% nucleotide identity and hence are homeologous. Correction of the insertion mutant HSV-1 tk gene via recombination with the hybrid tk sequence required an exchange between homeologous tk sequences, although recombination could initiate within a region of significant sequence identity. Seven cell lines containing linked HSV-1 and HSV-1-HSV-2 hybrid tk sequences gave rise to tk+ segregants at an average rate of 10(-8) events per cell division. DNA sequencing revealed that each recombinant from these lines displayed an apparent gene conversion which involved an accurate transfer of an uninterrupted block of information between homeologous tk sequences. Conversion tract lengths ranged from 35 to >330 bp. In contrast, cell lines containing linked HSV-1 and HSV-2 tk sequences with no significant stretches of sequence identity had an overall rate of homeologous recombination of <10(-9). One such cell line produced homeologous recombinants at a rate of 10(-8). Strikingly, all homeologous recombinants from this latter cell line were due to crossovers between the HSV-1 and HSV-2 tk genes. Our results, which provide the first detailed analysis of homeologous recombination within a mammalian genome, suggest that rearrangements in mammalian genomes are regulated by the degree of sequence divergence located at the site of recombination initiation.