Genome-Wide Linkage in a Highly Consanguineous Pedigree Reveals Two Novel Loci on Chromosome 7 for Non-Syndromic Familial Premature Ovarian Failure

BACKGROUND: The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10-15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients.¦METHODOLOGY/PRINCIPAL FINDINGS: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LOD(max) of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1) included within the largest region did not reveal any causal mutations.¦CONCLUSIONS/SIGNIFICANCE: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function

The Oncogenic EWS-FLI1 Protein Binds In Vivo GGAA Microsatellite Sequences with Potential Transcriptional Activation Function

The fusion between EWS and ETS family members is a key oncogenic event in Ewing tumors and important EWS-FLI1 target genes have been identified. However, until now, the search for EWS-FLI1 targets has been limited to promoter regions and no genome-wide comprehensive analysis of in vivo EWS-FLI1 binding sites has been undertaken. Using a ChIP-Seq approach to investigate EWS-FLI1-bound DNA sequences in two Ewing cell lines, we show that this chimeric transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences. Most bound sites are found outside promoter regions. Microsatellites containing more than 9 GGAA repeats are very significantly enriched in EWS-FLI1 immunoprecipitates. Moreover, in reporter gene experiments, the transcription activation is highly dependent upon the number of repeats that are included in the construct. Importantly, in vivo EWS-FLI1-bound microsatellites are significantly associated with EWS-FLI1-driven gene activation. Put together, these results point out the likely contribution of microsatellite elements to long-distance transcription regulation and to oncogenesis

Assessing motor-related phenotypes of Caenorhabditis elegans with the wide field-of-view nematode tracking platform

Caenorhabditis elegans is a valuable model organism in biomedical research that has led to major discoveries in the fields of neurodegeneration, cancer and aging. Because movement phenotypes are commonly used and represent strong indicators of C. elegans fitness, there is an increasing need to replace manual assessments of worm motility with automated measurements to increase throughput and minimize observer biases. Here, we provide a protocol for the implementation of the improved wide field-of-view nematode tracking platform (WF-NTP), which enables the simultaneous analysis of hundreds of worms with respect to multiple behavioral parameters. The protocol takes only a few hours to complete, excluding the time spent culturing C. elegans, and includes (i) experimental design and preparation of samples, (ii) data recording, (iii) software management with appropriate parameter choices and (iv) post-experimental data analysis. We compare the WF-NTP with other existing worm trackers, including those having high spatial resolution. The main benefits of WF-NTP relate to the high number of worms that can be assessed at the same time on a whole-plate basis and the number of phenotypes that can be screened for simultaneously

German translation, cross-cultural adaptation and validation of the Musculoskeletal Health Questionnaire: cohort study

BACKGROUND: The Musculoskeletal Health Questionnaire (MSK-HQ) was developed to measure the health status of patients with various musculoskeletal conditions across multiple settings including rehabilitation. AIM: Formal translation and cross-cultural adaptation of the MSK-HQ into German (MSK-HQG), to determine test-retest-reliability, standard error of measurement (SEM), smallest detectable change (SDC), construct validity, responsiveness, minimal important change (MIC), and to test for floor or ceiling effects. DESIGN: Cohort study with six weeks follow-up. SETTING: Seven physiotherapy clinics/rehabilitation centres. POPULATION: Patients with a referral for physiotherapy indicating musculoskeletal complaints of the spine or extremities. METHODS: Translation and cross-cultural adaptation were carried out in accordance with guidelines provided by the developers. As reference standards we used pain intensity (0-10 numeric rating scale), quality of life (EQ5D-5L) and disability measures (RMDQ, NDI, WOMAC and SPADI) that were combined using z-scores. RESULTS: On 100 patients (age 44.8±13.4 years, 66% female) the test-retest-reliability intraclass correlation coefficient was 0.87 (95% CI 0.72; 0.93) and for construct validity correlation with the combined disability measure was rs = -0.81 (95% CI -0.88, -0.72), the SEM was 3.4, the SDC (individual) 9.4, and the MIC 8.5. CONCLUSIONS: Overall, the study provides evidence for good reliability and validity for the MSK-HQG. Further studies in different settings and diagnostic subgroups should follow to better understand the psychometric properties of this measure in primary care, rehabilitation and specialist care settings. CLINICAL REHABILITATION IMPACT: The results demonstrate that the MSK-HQG has sufficient psychometric properties for use in musculoskeletal research and practice. However, the SDC should be kept in mind when using the tool for individual patients. The MSK-HQG has the advantage of being a single instrument that can measure musculoskeletal health status across different pain sites, reducing the burden from the use of multiple tools

Turbulent equipartition pinch of toroidal momentum in spherical torus

We present a new analytic expression for turbulent equipartition (TEP) pinch of toroidal angular momentum originating from magnetic field inhomogeneity of spherical torus (ST) plasmas. Starting from a conservative modern nonlinear gyrokinetic equation (Hahm et al 1988 Phys. Fluids 31 2670), we derive an expression for pinch to momentum diffusivity ratio without using a usual tokamak approximation of B∝1/R which has been previously employed for TEP momentum pinch derivation in tokamaks (Hahm et al 2007 Phys. Plasmas 14 072302). Our new formula is evaluated for model equilibria of National Spherical Torus eXperiment (NSTX) (Ono et al 2001 Nucl. Fusion 41 1435) and Versatile Experiment Spherical Torus (VEST) (Chung et al 2013 Plasma Sci. Technol. 15 244) plasmas. Our result predicts stronger inward pinch for both cases, as compared to the prediction based on the tokamak formula

E × B shear suppression of turbulence in diverted H-mode plasmas: Role of edge magnetic shear

We show that strong edge magnetic shear, which is generic to divertor plasmas, makes the E × B shearing of turbulence eddys in toroidal geometry more effective. From calculations of the E × B shearing rates for KSTAR edge parameters, we conclude that the enhanced magnetic shear at the diverted KSTAR plasma edge facilitates E × B shear suppression of turbulence and ensuing H-mode transition. © 2013 IAEA, Vienna

E × B shear suppression of turbulence in diverted H-mode plasmas: Role of edge magnetic shear

We show that strong edge magnetic shear, which is generic to divertor plasmas, makes the E × B shearing of turbulence eddys in toroidal geometry more effective. From calculations of the E × B shearing rates for KSTAR edge parameters, we conclude that the enhanced magnetic shear at the diverted KSTAR plasma edge facilitates E × B shear suppression of turbulence and ensuing H-mode transition. © 2013 IAEA, Vienna