Feasibility of identifying families for genetic studies of birth defects using the National Health Interview Survey

BACKGROUND: The purpose of this study was to determine whether the National Health Interview Survey is a useful source to identify informative families for genetic studies of birth defects. METHODS: The 1994/1995 National Health Interview Survey (NHIS) was used to identify households where individuals with two or more birth defects reside. Four groups of households were identified: 1) single non-familial (one individual with one birth defect); 2) single familial (more than one individual with one birth defect); 3) multiple non-familial (one individual with more than one birth defect), and 4) multiple familial (more than one individual with more than one birth defect). The March 2000 U.S. Census on households was used to estimate the total number of households in which there are individuals with birth defects. RESULTS: Of a total of 28,094 households and surveyed about birth defects and impairments, 1,083 single non-familial, 55 multiple non-familial, 54 single familial, and 8 multiple familial households were identified. Based on the 2000 U.S. census, it is estimated that there are 4,472,385 households where at least one person has one birth defect in the United States and in 234,846 of them there are at least two affected individuals. Western states had the highest prevalence rates. CONCLUSIONS: Population-based methods, such as the NHIS, are modestly useful to identify the number and the regions where candidate families for genetic studies of birth defects reside. Clinic based studies and birth defects surveillance systems that collect family history offer better probability of ascertainment

Evaluating LINE-1 methylation in cleft lip tissues and its association with early pregnancy exposures

Aim: To pilot investigation of methylation of long interspersed nucleotide element-1 in lip tissues from infants with nonsyndromic cleft lip, and its association with maternal periconceptional exposures. Methods: The lateral and medial sides of the cleft lips of 23 affected infants were analyzed for long interspersed nucleotide element-1 methylation by bisulfite conversion and pyrosequencing. Results: The medial side showed 1.8% higher methylation compared with the lateral side; p = 0.031, particularly in male infants (2.7% difference; p = 0.011) or when the mothers did not take folic acid during periconceptional period (2.4% difference; p = 0.011). These results were not statistically significant when Bonferroni adjustment was used. Conclusion: The observed differences in DNA methylation, although nonsignificant after correction for multiple comparisons, suggest that differential regulation of the two sides may impact lip fusion and warrant larger-scale replication

Resilin and chitinous cuticle form a composite structure for energy storage in jumping by froghopper insects

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Many insects jump by storing and releasing energy in elastic structures within their bodies. This allows them to release large amounts of energy in a very short time to jump at very high speeds. The fastest of the insect jumpers, the froghopper, uses a catapult-like elastic mechanism to achieve their jumping prowess in which energy, generated by the slow contraction of muscles, is released suddenly to power rapid and synchronous movements of the hind legs. How is this energy stored? Results The hind coxae of the froghopper are linked to the hinges of the ipsilateral hind wings by pleural arches, complex bow-shaped internal skeletal structures. They are built of chitinous cuticle and the rubber-like protein, resilin, which fluoresces bright blue when illuminated with ultra-violet light. The ventral and posterior end of this fluorescent region forms the thoracic part of the pivot with a hind coxa. No other structures in the thorax or hind legs show this blue fluorescence and it is not found in larvae which do not jump. Stimulating one trochanteral depressor muscle in a pattern that simulates its normal action, results in a distortion and forward movement of the posterior part of a pleural arch by 40 μm, but in natural jumping, the movement is at least 100 μm. Conclusion Calculations showed that the resilin itself could only store 1% to 2% of the energy required for jumping. The stiffer cuticular parts of the pleural arches could, however, easily meet all the energy storage needs. The composite structure therefore, combines the stiffness of the chitinous cuticle with the elasticity of resilin. Muscle contractions bend the chitinous cuticle with little deformation and therefore, store the energy needed for jumping, while the resilin rapidly returns its stored energy and thus restores the body to its original shape after a jump and allows repeated jumping

The Distribution of GYR- and YLP-Like Motifs in Drosophila Suggests a General Role in Cuticle Assembly and Other Protein-Protein Interactions

Background: Arthropod cuticle is composed predominantly of a self-assembling matrix of chitin and protein. Genes encoding structural cuticular proteins are remarkably abundant in arthropod genomes, yet there has been no systematic survey of conserved motifs across cuticular protein families. Methodology/Principal Findings: Two short sequence motifs with conserved tyrosines were identified in Drosophila cuticular proteins that were similar to the GYR and YLP Interpro domains. These motifs were found in members of the CPR, Tweedle, CPF/CPFL, and (in Anopheles gambiae) CPLCG cuticular protein families, and the Dusky/Miniature family of cuticleassociated proteins. Tweedle proteins have a characteristic motif architecture that is shared with the Drosophila protein GCR1 and its orthologs in other species, suggesting that GCR1 is also cuticular. A resilin repeat, which has been shown to confer elasticity, matched one of the motifs; a number of other Drosophila proteins of unknown function exhibit a motif architecture similar to that of resilin. The motifs were also present in some proteins of the peritrophic matrix and the eggshell, suggesting molecular convergence among distinct extracellular matrices. More surprisingly, gene regulation, development, and proteolysis were statistically over-represented ontology terms for all non-cuticular matches in Drosophila. Searches against other arthropod genomes indicate that the motifs are taxonomically widespread. Conclusions: This survey suggests a more general definition for GYR and YLP motifs and reveals their contribution to severa

NT-proBNP and Circulating Inflammation Markers in Prediction of a Normal Myocardial Scintigraphy in Patients with Symptoms of Coronary Artery Disease

Myocardial perfusion imaging (MPI) can detect myocardial perfusion abnormalities but many examinations are without pathological findings. This study examines whether circulating biomarkers can be used as screening modality prior to MPI.243 patients with an intermediate risk of CAD or with known CAD with renewed suspicion of ischemia were referred to MPI. Blood samples were analyzed for N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), YKL-40, IL-6, matrix metalloproteinase 9 (MMP-9) and high sensitive C-reactive protein (hsCRP). Patients with myocardial perfusion defects had elevated levels of NT-proBNP (p<0.0001), YKL-40 (p = 0.03) and IL-6 (p = 0.03) but not of hsCRP (p = 0.58) nor of MMP-9 (p = 0.14). The NT-proBNP increase was observed in both genders (p<0.0001), whereas YKL-40 (p = 0.005) and IL-6 (p = 0.02) were elevated only in men. A NT-proBNP cut off-concentration at 25 ng/l predicted a normal MPI with a negative predictive value >95% regardless of existing CAD.20-25% of patients suspected of CAD could have been spared a MPI by using a NT-proBNP cut-off concentration at 25 ng/l with a negative predictive value >95%. NT-proBNP has the potential use of being a screening marker of CAD before referral of the patient to MPI

ZEB2 Mediates Multiple Pathways Regulating Cell Proliferation, Migration, Invasion, and Apoptosis in Glioma

BACKGROUND: The aim of the present study was to analyze the expression of Zinc finger E-box Binding homeobox 2 (ZEB2) in glioma and to explore the molecular mechanisms of ZEB2 that regulate cell proliferation, migration, invasion, and apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: Expression of ZEB2 in 90 clinicopathologically characterized glioma patients was analyzed by immunohistochemistry. Furthermore, siRNA targeting ZEB2 was transfected into U251 and U87 glioma cell lines in vitro and proliferation, migration, invasion, and apoptosis were examined separately by MTT assay, Transwell chamber assay, flow cytometry, and western blot. RESULTS: The expression level of ZEB2 protein was significantly increased in glioma tissues compared to normal brain tissues (P<0.001). In addition, high levels of ZEB2 protein were positively correlated with pathology grade classification (P = 0.024) of glioma patients. Knockdown of ZEB2 by siRNA suppressed cell proliferation, migration and invasion, as well as induced cell apoptosis in glioma cells. Furthermore, ZEB2 downregulation was accompanied by decreased expression of CDK4/6, Cyclin D1, Cyclin E, E2F1, and c-myc, while p15 and p21 were upregulated. Lowered expression of ZEB2 enhanced E-cadherin levels but also inhibited β-Catenin, Vimentin, N-cadherin, and Snail expression. Several apoptosis-related regulators such as Caspase-3, Caspase-6, Caspase-9, and Cleaved-PARP were activated while PARP was inhibited after ZEB2 siRNA treatment. CONCLUSION: Overexpression of ZEB2 is an unfavorable factor that may facilitate glioma progression. Knockdown ZEB2 expression by siRNA suppressed cell proliferation, migration, invasion and promoted cell apoptosis in glioma cells

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion

Prediction of metabolic clusters in early lactation dairy cows using models based on 2 milk biomarkers

The aim of this study was to describe metabolism of early-lactation dairy cows by clustering cows based on glucose, insulin-like growth factor I (IGF-I), free fatty acid, and beta-hydroxybutyrate (BHB) using the k-means method. Predictive models for metabolic clusters were created and validated using 3 sets of milk biomarkers (milk metabolites and enzymes, glycans on the immuno-gamma globulin fraction of milk, and Fourier-transform mid-infrared spectra of milk). Metabolic clusters are used to identify dairy cows with a balanced or imbalanced metabolic profile. Around 14 and 35 d in milk, serum or plasma concentrations of BHB, free fatty acids, glucose, and IGF-I were determined. Cows with a favorable metabolic profile were grouped together in what was referred to as the "balanced" group (n = 43) and were compared with cows in what was referred to as the "other balanced" group (n = 64). Cows with an unfavorable metabolic profile were grouped in what was referred to as the "imbalanced" group (n = 19) and compared with cows in what was referred to as the "other imbalanced" group (n = 88). Glucose and IGF-I were higher in balanced compared with other balanced cows. Free fatty acids and BHB were lower in balanced compared with other balanced cows. Glucose and IGF-I were lower in imbalanced compared with other imbalanced cows. Free fatty acids arid BHB were higher in imbalanced cows. Metabolic clusters were related to production parameters. There was a trend for a higher daily increase in fat- and protein-corrected milk yield in balanced cows, whereas that of imbalanced cows was higher. Dry matter intake and the daily increase in dry matter intake were higher in balanced cows and lower in imbalanced cows. Energy balance was continuously higher in balanced cows and lower in imbalanced cows. Weekly or twice-weekly milk samples were taken and milk metabolites and enzymes (milk glucose, glucose-6-phosphate, BHB, lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, isocitrate), immunogamma globulin glycans (19 peaks), and Fourier-transform mid-infrared spectra (1,060 wavelengths reduced to 15 principal components) were determined. Milk biomarkers with or without additional cow information (days in milk, parity, milk yield featurs) were used to create predictive models for the metabolic clusters. Accuracy for prediction of balanced (80%) and imbalanced (88%) cows was highest using milk metabolites and enzymes combined with days in milk and parity. The results and models of the present study are part of the GplusE project and identify novel milk-based phenotypes that may be used as predictors for metabolic and performance traits in early-lactation dairy cows

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons