Project description:The Migraine Disability Assessment (MIDAS) is a brief questionnaire and measures headache-related disability. This study aimed to translate and cross-culturally adapt the original English version of the MIDAS to German and to test its reliability.The standardized translation process followed international guidelines. The pre-final version was tested for clarity and comprehensibility by 34 headache sufferers. Test-retest reliability of the final version was quantified by 36 headache patients completing the MIDAS twice with an interval of 48 h. Reliability was determined by intraclass correlation coefficients and internal consistency by Cronbach's ?.All steps of the translation process were followed, documented and approved by the developer of the MIDAS. The expert committee discussed in detail the complex phrasing of the questions that refer to one to another, especially exclusion of headache-days from one item to the next. The German version contains more active verb sentences and prefers the perfect to the imperfect tense. The MIDAS scales intraclass correlation coefficients ranged from 0.884 to 0.994 and was 0.991 (95% CI: 0.982-0.995) for the MIDAS total score. Cronbach's ? for the MIDAS as a whole was 0.69 at test and 0.67 at retest.The translation process was challenged by the comprehensibility of the questionnaire. The German version of the MIDAS is a highly reliable instrument for assessing headache related disability with moderate internal consistency. Provided validity testing of the German MIDAS is successful, it can be recommended for use in clinical practice as well as in research.
Project description:BACKGROUND:The Migraine Disability Assessment (MIDAS) questionnaire is widely used to determine the degree of migraine-related disability of subjects. So far, and to the best of our knowledge, no Spanish version of this tool has been validated. The questionnaire comprises seven items, with the first five constituting the main scale while the sixth and seventh items referring, respectively, to the frequency and intensity of headache. The present study aims to analyze the clinimetric properties of the Spanish version of the MIDAS questionnaire in a population of university students. METHODS:We performed a cross-sectional study of validation for this measuring instrument. A total of 153 subjects participated in the study. We analyzed construct validity using factor analysis, test-retest reliability by the Intraclass Correlation Coeficient (ICC), internal consistency, and concurrent validity with respect to the 12-Item Short Form Health Survey (SF-12). RESULTS:Factor analysis revealed a two-factor structure. The questionnaire has good reliability for the MIDAS main-scale score ([ICC?=?0.81; 95% CI: 0.63-0.90]), excellent reliability for headache frequency (ICC?=?0.90; 95%; CI: [0.79-0.95]), and moderately good reliability for headache intensity (ICC?=?0.63; 95% CI: [0.34-0.80]). The analysis also yielded good internal consistency results (? Cronbach?=?0.797) and a moderate correlation between MIDAS-main scale and the physical component summary of SF-12 (Rho?=?-?0.326; p?<? 0.001). CONCLUSIONS:The Spanish version of the MIDAS questionnaire is a valid and reliable tool to measure migraine-related disability in university subjects. The two additional items provide information that could help clinicians in making decisions.
Project description:The Rea1 AAA+-ATPase dislodges assembly factors from pre-60S ribosomes upon ATP hydrolysis, thereby driving ribosome biogenesis. Here, we present crystal structures of Rea1-MIDAS, the conserved domain at the tip of the flexible Rea1 tail, alone and in complex with its substrate ligands, the UBL domains of Rsa4 or Ytm1. These complexes have structural similarity to integrin ?-subunit domains when bound to extracellular matrix ligands, which for integrin biology is a key determinant for force-bearing cell-cell adhesion. However, the presence of additional motifs equips Rea1-MIDAS for its tasks in ribosome maturation. One loop insert cofunctions as an NLS and to activate the mechanochemical Rea1 cycle, whereas an additional ?-hairpin provides an anchor to hold the ligand UBL domains in place. Our data show the versatility of the MIDAS fold for mechanical force transmission in processes as varied as integrin-mediated cell adhesion and mechanochemical removal of assembly factors from pre-ribosomes.
Project description:Statistical parametric maps formed via voxel-wise mass-univariate tests, such as the general linear model, are commonly used to test hypotheses about regionally specific effects in neuroimaging cross-sectional studies where each subject is represented by a single image. Despite being informative, these techniques remain limited as they ignore multivariate relationships in the data. Most importantly, the commonly employed local Gaussian smoothing, which is important for accounting for registration errors and making the data follow Gaussian distributions, is usually chosen in an ad hoc fashion. Thus, it is often suboptimal for the task of detecting group differences and correlations with non-imaging variables. Information mapping techniques, such as searchlight, which use pattern classifiers to exploit multivariate information and obtain more powerful statistical maps, have become increasingly popular in recent years. However, existing methods may lead to important interpretation errors in practice (i.e., misidentifying a cluster as informative, or failing to detect truly informative voxels), while often being computationally expensive. To address these issues, we introduce a novel efficient multivariate statistical framework for cross-sectional studies, termed MIDAS, seeking highly sensitive and specific voxel-wise brain maps, while leveraging the power of regional discriminant analysis. In MIDAS, locally linear discriminative learning is applied to estimate the pattern that best discriminates between two groups, or predicts a variable of interest. This pattern is equivalent to local filtering by an optimal kernel whose coefficients are the weights of the linear discriminant. By composing information from all neighborhoods that contain a given voxel, MIDAS produces a statistic that collectively reflects the contribution of the voxel to the regional classifiers as well as the discriminative power of the classifiers. Critically, MIDAS efficiently assesses the statistical significance of the derived statistic by analytically approximating its null distribution without the need for computationally expensive permutation tests. The proposed framework was extensively validated using simulated atrophy in structural magnetic resonance imaging (MRI) and further tested using data from a task-based functional MRI study as well as a structural MRI study of cognitive performance. The performance of the proposed framework was evaluated against standard voxel-wise general linear models and other information mapping methods. The experimental results showed that MIDAS achieves relatively higher sensitivity and specificity in detecting group differences. Together, our results demonstrate the potential of the proposed approach to efficiently map effects of interest in both structural and functional data.
Project description:The Microbial Database for Activated Sludge (MiDAS) field guide is a freely available online resource linking the identity of abundant and process critical microorganisms in activated sludge wastewater treatment systems to available data related to their functional importance. Phenotypic properties of some of these genera are described, but most are known only from sequence data. The MiDAS taxonomy is a manual curation of the SILVA taxonomy that proposes a name for all genus-level taxa observed to be abundant by large-scale 16?S rRNA gene amplicon sequencing of full-scale activated sludge communities. The taxonomy can be used to classify unknown sequences, and the online MiDAS field guide links the identity to the available information about their morphology, diversity, physiology and distribution. The use of a common taxonomy across the field will provide a solid foundation for the study of microbial ecology of the activated sludge process and related treatment processes. The online MiDAS field guide is a collaborative workspace intended to facilitate a better understanding of the ecology of activated sludge and related treatment processes--knowledge that will be an invaluable resource for the optimal design and operation of these systems.
Project description:BACKGROUND: Animal pigmentation has received much attention in evolutionary biology research due to its strong implications for adaptation and speciation. However, apart from a few cases the genetic changes associated with these evolutionary processes remain largely unknown. The Midas cichlid fish from Central America are an ideal model system for investigating pigmentation traits that may also play a role in speciation. Most Midas cichlids maintain their melanophores and exhibit a grayish (normal) color pattern throughout their lives. A minority of individuals, however, undergo color change and exhibit a distinctive gold or even white coloration in adulthood. The ontogenetic color change in the Midas cichlids may also shed light on the molecular mechanisms underlying pigmentation disorders in humans. RESULTS: Here we use next-generation sequencing (Illumina) RNAseq analyses to compare skin transcriptome-wide expression levels in three distinct stages of color transformation in Midas cichlids. cDNA libraries of scale tissue, for six biological replicates of each group, were generated and sequenced using Illumina technology. Using a combination of three differential expression (DE) analyses we identified 46 candidate genes that showed DE between the color morphs. We find evidence for two key DE patterns: a) genes involved in melanosomal pathways are up-regulated in normally pigmented fish; and b) immediate early and inflammatory response genes were up-regulated in transitional fish, a response that parallels some human skin disorders such as melanoma formation and psoriasis. One of the DE genes segregates with the gold phenotype in a genetic cross and might be associated with incipient speciation in this highly "species-rich" lineage of cichlids. CONCLUSIONS: Using transcriptomic analyses we successfully identified key expression differences between different color morphs of Midas cichlid fish. These differentially expressed genes have important implications for our understanding of the molecular mechanisms underlying speciation in this lineage of extremely young species since they mate strongly assortatively, and new species may arise by sexual selection due to this color polymorphism. Some of the human orthologues of the genes identified here may also be involved in pigmentation differences and diseases and therefore provide genetic markers for the detection of human pigmentation disorders.
Project description:<h4>Background</h4>Cerebral microbleeds, visible on gradient-recalled echo (GRE) T2* MRI, have generated increasing interest as an imaging marker of small vessel diseases, with relevance for intracerebral bleeding risk or brain dysfunction.<h4>Methodology/principal findings</h4>Manual rating methods have limited reliability and are time-consuming. We developed a new method for microbleed detection using automated segmentation (MIDAS) and compared it with a validated visual rating system. In thirty consecutive stroke service patients, standard GRE T2* images were acquired and manually rated for microbleeds by a trained observer. After spatially normalizing each patient's GRE T2* images into a standard stereotaxic space, the automated microbleed detection algorithm (MIDAS) identified cerebral microbleeds by explicitly incorporating an "extra" tissue class for abnormal voxels within a unified segmentation-normalization model. The agreement between manual and automated methods was assessed using the intraclass correlation coefficient (ICC) and Kappa statistic. We found that MIDAS had generally moderate to good agreement with the manual reference method for the presence of lobar microbleeds (Kappa?=?0.43, improved to 0.65 after manual exclusion of obvious artefacts). Agreement for the number of microbleeds was very good for lobar regions: (ICC?=?0.71, improved to ICC?=?0.87). MIDAS successfully detected all patients with multiple (?2) lobar microbleeds.<h4>Conclusions/significance</h4>MIDAS can identify microbleeds on standard MR datasets, and with an additional rapid editing step shows good agreement with a validated visual rating system. MIDAS may be useful in screening for multiple lobar microbleeds.
Project description:Cichlid fishes are an ideal model system for studying biological diversification because they provide textbook examples of rapid speciation. To date, there has been little focus on the role of gene regulation during cichlid speciation. However, in recent years, gene regulation has been recognized as a powerful force linking diversification in gene function to speciation. Here, we investigated the potential role of miRNA regulation in the diversification of six cichlid species of the Midas cichlid lineage (Amphilophus spp.) inhabiting the Nicaraguan crater lakes. Using several genomic resources, we inferred 236 Midas miRNA genes that were used to predict the miRNA target sites on 8,232 Midas 3'-UTRs. Using population genomic calculations of SNP diversity, we found the miRNA genes to be more conserved than protein coding genes. In contrast to what has been observed in other cichlid fish, but similar to what has been typically found in other groups, we observed genomic signatures of purifying selection on the miRNA targets by comparing these sites with the less conserved nontarget portion of the 3'-UTRs. However, in one species pair that has putatively speciated sympatrically in crater Lake Apoyo, we recovered a different pattern of relaxed purifying selection and high genetic divergence at miRNA targets. Our results suggest that sequence evolution at miRNA binding sites could be a critical genomic mechanism contributing to the rapid phenotypic evolution of Midas cichlids.
Project description:An integrin found on platelets, ?(IIb)?(3) mediates platelet aggregation, and ?(IIb)?(3) antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg(2+)) located in the ? subunit metal ion-dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the ?(IIb) subunit and a carboxyl group that coordinates the MIDAS Mg(2+) in the ?(3) subunits. They induce conformational changes in the ?(3) subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of ?(IIb)?(3) (RUC-1) that binds exclusively to the ?(IIb) subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a ~100-fold higher affinity. RUC-2 does not induce major conformational changes in ?(3) as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2-?(IIb)?(3) headpiece complex in 1 mM calcium ion (Ca(2+))/5 mM Mg(2+) at 2.6 Å revealed that RUC-2 binds to ?(IIb) the way RUC-1 does, but in addition, it binds to the ?(3) MIDAS residue glutamic acid 220, thus displacing Mg(2+) from the MIDAS. When the Mg(2+) concentration was increased to 20 mM, however, Mg(2+) was identified in the MIDAS and RUC-2 was absent. RUC-2's ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg(2+) concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other ?(IIb)?(3) antagonists and may offer advantages as a therapeutic agent.