A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents

<div><p>Background</p><p>Hypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.</p><p>Objective</p><p>This study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.</p><p>Methods</p><p>Genome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5−24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2−22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.</p><p>Results</p><p>No novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (<i>PDE10A</i> (rs2983511: <i>β</i> = 0.112<i>SD</i>, <i>p</i> = 4.8 ∙ 10⁻¹⁶), <i>FOXE1</i> (rs7847663: <i>β</i> = 0.223<i>SD</i>, <i>p</i> = 1.5 ∙ 10⁻²⁰), <i>NR3C2</i> (rs9968300: <i>β</i> = 0.194<i>SD</i>), <i>p</i> = 2.4 ∙ 10⁻¹¹), <i>VEGFA (</i>rs2396083: <i>β</i> = 0.088<i>SD</i>, <i>p</i> = 2.2 ∙ 10⁻¹⁰)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (<i>p</i><0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.</p><p>Conclusion</p><p>In a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.</p></div

Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

The tissue-specific translation elongation factor eEF1A2 is a potential oncogene that is overexpressed in human ovarian cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-α) making analysis with commercial antibodies difficult. We wanted to establish the expression pattern of eEF1A2 in ovarian cancer of defined histological subtypes at both the RNA and protein level, and to establish the mechanism for the overexpression of eEF1A2 in tumours. We show that while overexpression of eEF1A2 is seen at both the RNA and protein level in up to 75% of clear cell carcinomas, it occurs at a lower frequency in other histological subtypes. The copy number at the EEF1A2 locus does not correlate with expression level of the gene, no functional mutations were found, and the gene is unmethylated in both normal and tumour DNA, showing that overexpression is not dependent on genetic or epigenetic modifications at the EEF1A2 locus. We suggest that the cause of overexpression of eEF1A2 may be the inappropriate expression of a trans-acting factor. The oncogenicity of eEF1A2 may be related either to its role in protein synthesis or to potential non-canonical functions

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Estimating Sensitivity of Laboratory Testing for Influenza in Canada through Modelling

Background: The weekly proportion of laboratory tests that are positive for influenza is used in public health surveillance systems to identify periods of influenza activity. We aimed to estimate the sensitivity of influenza testing in Canada based on results of a national respiratory virus surveillance system. Methods and Findings: The weekly number of influenza-negative tests from 1999 to 2006 was modelled as a function of laboratory-confirmed positive tests for influenza, respiratory syncytial virus (RSV), adenovirus and parainfluenza viruses, seasonality, and trend using Poisson regression. Sensitivity was calculated as the number of influenza positive tests divided by the number of influenza positive tests plus the model-estimated number of false negative tests. The sensitivity of influenza testing was estimated to be 33 % (95%CI 32–34%), varying from 30–40 % depending on the season and region. Conclusions: The estimated sensitivity of influenza tests reported to this national laboratory surveillance system is considerably less than reported test characteristics for most laboratory tests. A number of factors may explain this difference, including sample quality and specimen procurement issues as well as test characteristics. Improved diagnosis would permit better estimation of the burden of influenza

Genetic Polymorphisms and Drug Susceptibility in Four Isolates of Leishmania tropica Obtained from Canadian Soldiers Returning from Afghanistan

Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease transmitted by the bite of sandflies, resulting in sores on the skin. No vaccines are available, and treatment relies on chemotherapy. CL has been frequently diagnosed in military personnel deployed to Afghanistan and returning from duty. The parasites isolated from Canadian soldiers were characterized by pulsed field gels and by sequencing conserved genes and were identified as Leishmania tropica. In contrast to other Leishmania species, high allelic polymorphisms were observed at several genetic loci for the L. tropica isolates that were characterized. In vitro susceptibility testing in macrophages showed that all isolates, despite their genetic heterogeneity, were sensitive to most antileishmanial drugs (antimonials, miltefosine, amphotericin B, paromomycin) but were insensitive to fluconazole. This study suggests a number of therapeutic regimens for treating cutaneous leishmaniasis caused by L. tropica among patients and soldiers returning from Afghanistan. Canadian soldiers from this study were successfully treated with miltefosine

Eef1a2 Promotes Cell Growth, Inhibits Apoptosis and Activates JAK/STAT and AKT Signaling in Mouse Plasmacytomas

The canonical function of EEF1A2, normally expressed only in muscle, brain, and heart, is in translational elongation, but recent studies suggest a non-canonical function as a proto-oncogene that is overexpressed in a variety of solid tumors including breast and ovary. Transcriptional profiling of a spectrum of primary mouse B cell lineage neoplasms showed that transcripts encoding EEF1A2 were uniquely overexpressed in plasmacytomas (PCT), tumors of mature plasma cells. Cases of human multiple myeloma expressed significantly higher levels of EEF1A2 transcripts than normal bone marrow plasma cells. High-level expression was also a feature of a subset of cell lines developed from mouse PCT and from the human MM.Heightened expression of EEF1A2 was not associated with increased copy number or coding sequence mutations. shRNA-mediated knockdown of Eef1a2 transcripts and protein was associated with growth inhibition due to delayed G1-S progression, and effects on apoptosis that were seen only under serum-starved conditions. Transcriptional profiles and western blot analyses of knockdown cells revealed impaired JAK/STAT and PI3K/AKT signaling suggesting their contributions to EEF1A2-mediated effects on PCT induction or progression.EEF1A2 may play contribute to the induction or progression of some PCT and a small percentage of MM. Eef1a2 could also prove to be a useful new marker for a subset of MM and, ultimately, a possible target for therapy

Molecular characterization and expression analysis of five different elongation factor 1 alpha genes in the flatfish Senegalese sole (Solea senegalensis Kaup): Differential gene expression and thyroid hormones dependence during metamorphosis

<p>Abstract</p> <p>Background</p> <p>Eukaryotic elongation factor 1 alpha (eEF1A) is one of the four subunits composing eukaryotic translation elongation factor 1. It catalyzes the binding of aminoacyl-tRNA to the A-site of the ribosome in a GTP-dependent manner during protein synthesis, although it also seems to play a role in other non-translational processes. Currently, little information is still available about its expression profile and regulation during flatfish metamorphosis. With regard to this, Senegalese sole (<it>Solea senegalensis</it>) is a commercially important flatfish in which <it>eEF1A </it>gene remains to be characterized.</p> <p>Results</p> <p>The development of large-scale genomics of Senegalese sole has facilitated the identification of five different <it>eEF1A </it>genes, referred to as <it>SseEF1A1</it>, <it>SseEF1A2</it>, <it>SseEF1A3</it>, <it>SseEF1A4</it>, and <it>Sse42Sp50</it>. Main characteristics and sequence identities with other fish and mammalian eEF1As are described. Phylogenetic and tissue expression analyses allowed for the identification of <it>SseEF1A1 </it>and <it>SseEF1A2 </it>as the Senegalese sole counterparts of mammalian <it>eEF1A1 </it>and <it>eEF1A2</it>, respectively, and of <it>Sse42Sp50 </it>as the ortholog of <it>Xenopus laevis </it>and teleost <it>42Sp50 </it>gene. The other two elongation factors, <it>SseEF1A3 </it>and <it>SseEF1A4</it>, represent novel genes that are mainly expressed in gills and skin. The expression profile of the five genes was also studied during larval development, revealing different behaviours. To study the possible regulation of <it>SseEF1A </it>gene expressions by thyroid hormones (THs), larvae were exposed to the goitrogen thiourea (TU). TU-treated larvae exhibited lower <it>SseEF1A4 </it>mRNA levels than untreated controls at both 11 and 15 days after treatment, whereas transcripts of the other four genes remained relatively unchanged. Moreover, addition of exogenous T4 hormone to TU-treated larvae increased significantly the steady-state levels of <it>SseEF1A4 </it>with respect to untreated controls, demonstrating that its expression is up-regulated by THs.</p> <p>Conclusion</p> <p>We have identified five different <it>eEF1A </it>genes in the Senegalese sole, referred to as <it>SseEF1A1</it>, <it>SseEF1A2</it>, <it>SseEF1A3</it>, <it>SseEF1A4</it>, and <it>Sse42Sp50</it>. The five genes exhibit different expression patterns in tissues and during larval development. TU and T4 treatments demonstrate that <it>SseEF1A4 </it>is up-regulated by THs, suggesting a role in the translational regulation of the factors involved in the dramatic changes that occurs during Senegalese sole metamorphosis.</p

What’s retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151310/1/dvg23308.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151310/2/dvg23308_am.pd