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Abstract The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

BackgroundISL LIM homeobox 2, also known as insulin gene enhancer protein ISL-2 (ISL2), is a transcription factor gene that participates in a wide range of developmental events. However, the role of ISL2 in the hypothalamus-pituitary-thyroid axis is largely unknown. In the present study, we characterized the expression patterns of ISL2 and revealed its regulative role during embryogenesis using zebrafish.MethodsWe used the CRISPR/Cas9 system to successfully establish homozygous ISL2-orthologue (isl2a and isl2b) knockout zebrafish. Moreover, we utilized these knockout zebrafish to analyze the pituitary and thyroid phenotypes in vivo. For further molecular characterization, in situ hybridization and immunofluorescence were performed.ResultsThe isl2a mutant zebrafish presented with thyroid hypoplasia, reduced whole-body levels of thyroid hormones, increased early mortality, gender imbalance, and morphological retardation during maturity. Additionally, thyrotropes, a pituitary cell type, was notably decreased during development. Importantly, the transcriptional levels of pituitary-thyroid axis hormones-encoding genes, such as tshba, cga, and tg, were significantly decreased in isl2a mutants. Finally, the thyroid dysplasia in isl2a mutant larvae may be attributed to a reduction in proliferation rather than changes in apoptosis.ConclusionsIn summary, isl2a regulates the transcriptional levels of marker genes in hypothalamus-pituitary-thyroid axis, and isl2a knockout causing low thyroid hormone levels in zebrafish. Thus, isl2a identified by the present study, is a novel regulator for pituitary cell differentiation in zebrafish, resulting in thyroid gland hypoplasia and phenotypes of hypothyroidism.

INTRODUCTION: Defects in the human solute carrier family 26 member 4 (SLC26A4) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC26A4 mutations in Chinese patients with CH and analyze the function of the mutations. METHODS: Patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of SLC26A4 were identified and analyzed. The function of six missense mutation in SLC26A4 were further investigated in vitro. RESULTS: Among 273 patients with CH, seven distinct SLC26A4 heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H, p.H723R affect the membrane location and ion transport of SLC26A4, while p.S49R did not. Mutation p.T485M and p.D661E only affected ion transport, but had no effect on the membrane location. DISCUSSION AND CONCLUSION: The prevalence of SLC26A4 mutations was 3.66% in Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of SLC26A4, suggesting important roles for Ile363, Arg409, Thr485, Asp661, and His723 residues in SLC26A4 function. As all variants identified were heterozygous, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study

A variety of 2-substituted 3-selanyl-chromenones are readily prepared through a cascade selanylation/cyclization of alkynyl aryl ketones with sulfonoselenoates. This transformation is performed under metal-free conditions and does not require an additional oxidant. It also has the advantage of broad functional group tolerance and scalability. [ABSTRACT FROM AUTHOR]

Abstract Background With several susceptibility single nucleotide polymorphisms identified by case–control association studies, Graves’ disease is one of the most common forms of autoimmune thyroid disease. In this study, we aimed to determine whether any observed differences in genetic associations are influenced by sex in Chinese Han populations. Methods A total of 8,835 patients with Graves’ disease and 9,936 sex‐matched healthy controls were enrolled in the study. Confirmed by a two‐staged association analysis, sex‐specific analyses among 20 Graves’ disease susceptibility loci were conducted. Results A significant sex‐gene interaction was detected primarily at rs5912838 on Xq21.1 between the GPR174 and ITM2A genes, whereby male Graves’ disease patients possessed a significantly higher frequency of risk alleles than their female counterparts. Interestingly, compared to women, male patients with Graves’ disease had a higher cumulative genetic risk and higher persistent thyroid stimulating hormone receptor antibody‐positive rate after receiving antithyroid drug therapy for at least 1 year. Conclusion The findings of this study suggest the existence of one potential sex‐specific Graves’ disease variant on Xq21.1. This could increase our understanding of the pivotal mechanism behind Graves’ disease and ultimately aid in identifying possible therapeutic targets.

Global epidemiological evidence indicates high rates of mental illness but low rates of diagnosis among older people. In China, service providers identify older adults with mental disorders in varied ways. Taking Shanghai as an example, this study revealed how the identification methods of geriatric mental health disorders in nonspecialized institutions diverge, providing a reference for the integration of services. A purposive sampling method was adopted to conduct semi-structured interviews with 24 service providers from various nonspecialized geriatric mental health care institutions. Interview audio was recorded with consent and converted into verbatim transcripts. The interview data were analysed thematically. Although service providers from the health care system tended to apply a biomedical-oriented assessment, those from the social care system typically identified mental disorders among older people based on selective attention and interpersonal relationships. Although there are stark differences, the various identification mechanisms implicitly converge—the relationship with clients has become an important consideration. Geriatric mental health issues urgently require the integration of formal and informal care resources. Referring to the idea of task transfer, social identification mechanisms are expected to be a useful supplement to traditional biomedical-oriented identification. [ABSTRACT FROM AUTHOR]