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1. A Computational Approach: The Functional Effects of Thyroid Peroxidase Variants in Thyroid Cancer and Genetic Disorders

   https://doi.org/10.1200/CCI.23.00140  

   Sobitan, Adebiyi; Gebremedhin, Brhan; Yao, Qiaobin; Xie, Guiqin; Gu, Xinbin; Li, Jiang; Teng, Shaolei (March 2024, JCO Clinical Cancer Informatics)

   PURPOSEThyroid peroxidase (TPO) is essential for the synthesis of thyroid hormones. However, specific mutations render TPO antigenic and prone to autoimmune attacks leading to thyroid cancer, TPO deficiency, and congenital hypothyroidism (CH). Despite technological advancement, most experimental procedures cannot quickly identify the genetic causes of CH nor detect thyroid cancer in the early stages. METHODSWe performed saturated computational mutagenesis to calculate the folding energy changes (∆∆G) caused by missense mutations and analyzed the mutations involved in post-translational modifications (PTMs). RESULTSOur results showed that the functional important missense mutations occurred in the heme peroxidase domain. Through computational saturation mutagenesis, we identified the TPO mutations in G393 and G348 affecting protein stability and PTMs. Our folding energy calculations revealed that seven of nine somatic thyroid cancer mutations destabilized TPO. CONCLUSIONThese findings highlight the impact of these specific mutations on TPO stability, linking them to thyroid cancer and other genetic thyroid-related disorders. Our results show that computational mutagenesis of proteins provides a quick insight into rare mutations causing Mendelian disorders and cancers in humans. 

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2. Thyroid hormone regulates proximodistal patterning in fin rays

   https://doi.org/10.1073/pnas.2219770120  

   Harper, Melody; Hu, Yinan; Donahue, Joan; Acosta, Benjamin; Dievenich Braes, Flora; Nguyen, Stacy; Zeng, Jenny; Barbaro, Julianna; Lee, Hyungwoo; Bui, Hoa; et al (May 2023, Proceedings of the National Academy of Sciences)

   Processes that regulate size and patterning along an axis must be highly integrated to generate robust shapes; relative changes in these processes underlie both congenital disease and evolutionary change. Fin length mutants in zebrafish have provided considerable insight into the pathways regulating fin size, yet signals underlying patterning have remained less clear. The bony rays of the fins possess distinct patterning along the proximodistal axis, reflected in the location of ray bifurcations and the lengths of ray segments, which show progressive shortening along the axis. Here, we show that thyroid hormone (TH) regulates aspects of proximodistal patterning of the caudal fin rays, regardless of fin size. TH promotes distal gene expression patterns, coordinating ray bifurcations and segment shortening with skeletal outgrowth along the proximodistal axis. This distalizing role for TH is conserved between development and regeneration, in all fins (paired and medial), and between Danio species as well as distantly related medaka. During regenerative outgrowth, TH acutely induces Shh-mediated skeletal bifurcation. Zebrafish have multiple nuclear TH receptors, and we found that unliganded Thrab—but not Thraa or Thrb—inhibits the formation of distal features. Broadly, these results demonstrate that proximodistal morphology is regulated independently from size-instructive signals. Modulating proximodistal patterning relative to size—either through changes to TH metabolism or other hormone-independent pathways—can shift skeletal patterning in ways that recapitulate aspects of fin ray diversity found in nature. 

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3. SGUNet: Semantic Guided UNet for Thyroid Nodule Segmentation.

   Pan, Huitong; Zhou, Quan; Latecki, Longin Jan (April 2021, IEEE Int. Symposium on Biomedical Imaging (ISBI))

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4. Thyroid hormone shapes craniofacial bones during postembryonic zebrafish development

   https://doi.org/10.1111/ede.12399  

   Keer, Stephanie; Storch, Joshua D.; Nguyen, Stacy; Prado, Mia; Singh, Rajendra; Hernandez, Luz Patricia; McMenamin, Sarah K. (March 2022, Evolution & Development)

   Abstract Changing the shape of craniofacial bones can profoundly alter ecological function, and understanding how developmental conditions sculpt skeletal phenotypes can provide insight into evolutionary adaptations. Thyroid hormone (TH) stimulates metamorphosis and regulates skeletal morphogenesis across vertebrates. To assess the roles of this hormone in sculpting the craniofacial skeleton of a non‐metamorphic vertebrate, we tested zebrafish for developmental periods of TH‐induced craniofacial shape change. We analyzed shapes of specific bones that function in prey detection, capture and processing. We quantified these elements from late‐larval through adult stages under three developmental TH profiles. Under wild‐type conditions, each bone progressively grows allometrically into a mature morphology over the course of postembryonic development. In three of the four bones, TH was required to sculpt an adult shape: hypothyroidism inhibited aspects of shape change, and allowed some components of immature shape to be retained into adulthood. Excess developmental TH stimulated aspects of precocious shape change leading to abnormal morphologies in some bones. Skeletal features with functional importance showed high sensitivities to TH, including the transformator process of the tripus, the mandibular symphysis of the lower jaw, the scutiform lamina of the hyomandibula, and the anterior arm of the pharyngeal jaw. In all, we found that TH is necessary for shaping mature morphology of several essential skeletal elements; this requirement is particularly pronounced during larval development. Altered TH titer leads to abnormal morphologies with likely functional consequences, highlighting the potential of TH and downstream pathways as targets for evolutionary change. 

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5. Cadaver Microbial Signatures of the Submandibular Glands and Thyroid for Forensic Investigations

   Sheree Finley, PhD*; Matteo Moretti, MD; Silvia Visonà, PhD; Gulnaz Javan, PhD* (January 2023, Cadaver Microbial Signatures of the Submandibular Glands and Thyroid for Forensic Investigations)

   The study of the thyroid is an emerging topic, particularly in postmortem microbiome studies, due to the organ’s ability to affect the endocrine system. Also, the submandibular gland is a promising, emerging gland of study due to its position relative to the oral cavity. Previous thanatomicrobiome studies have demonstrated that bacteria belonging to the phyla Firmicutes, Proteobacteria, Bacteroides, and Pseudomonadota predominate internal organs and have been considered an important biomarker for postmortem interval. Further, Clostridium species that dominate in internal organs are linked to the hypoxic change that occurs after death, which leads to the switch of bacteria to become obligate anaerobes. Therefore, obligate anaerobes dominate the body after death due to their ability to thrive off fermentation products. 16S rRNA gene sequencing has been critical in thanatomicrobiome studies, which refers to the human microbiome (microorganisms within the body) after death. Currently, it has not been elucidated regarding the microorganisms that are associated with the decay of submandibular and thyroid glands. We hypothesized that through sequencing of the 16S rRNA gene of the submandibular and thyroid glands, the presence of Firmicutes and Proteobacteria will indicate potential biomarkers for postmortem interval. The present study revealed the postmortem microbial signatures of the submandibular and thyroid glands using the 16S rRNA gene, specifically the V3-V4 hypervariable regions, using universal primers 341F and 805R. We investigated a total of 37 cadavers obtained from ongoing criminal casework, 17 submandibular samples and 20 thyroid samples, and found that there is a correlation between microbial abundance in these postmortem glands. The predominating phyla of interest found in both glands were Firmicutes and Proteobacteria. The predominating genera were Paeniclostridium and Streptococcus in both glands, respectively. Further experimentation of the submandibular and thyroid glands will help to link oral thanatomicrobiome communities to “microbial clock” determinations, thus enhancing postmortem interval estimation. 

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