The TSH Receptor Antibody Reactome Contributes to Retro-Orbital Inflammation.

The thyroid eye disease (TED) of Graves disease is associated with high titers of stimulating TSH receptor antibodies, retro-orbital inflammation, fibroblast release of cytokines and chemokines, and adipogenesis, which in turn leads to proptosis, muscle fibrosis, and dysfunction. Part of this scenario is the induction of fibroblast proliferation and autophagy secondary to synergism between the TSH receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R). While TED is well associated with thyroid-stimulating antibodies to the TSHR, which is also well expressed on fibroblasts, in fact the TSHR reactome has a variety of TSHR antibodies with varying biological activity.

TSH enhances neurite outgrowth.

Extra-thyroidal effects of TSH have been reported in various tissues expressing the TSH receptor (TSHR) including several areas of the brain. However, the influence of TSH on neuronal phenotypes has not been examined. Using a well-characterized human neuroblastoma cell line (SH-SY5Y), we have examined TSH signaling effects on the phenotype of these cells after their neuronal differentiation.

Hypothyroidism Induced by a TSH Receptor Peptide-Implications for Thyroid Autoimmunity.

The "neutral" thyrotropin receptor autoantibodies (N-TSHR-Ab) directed at the TSHR ectodomain's hinge region have been shown to induce thyroid cell damage . During these earlier studies, we developed a mouse monoclonal antibody (MC1) specific for a peptide (amino acid 322-340) in the region (MC1-Mab) which was able to induce thyroid cell stress and apoptosis when administered . In order to examine the effect of generated N-TSHR-Abs, rather than an acutely administered monoclonal antibody, we immunized Balb/c mice with the hinge region peptide over 18 weeks.

Harnessing urban analytics and machine learning for sustainable urban development: A multidimensional framework for modeling environmental impacts of urbanization in Saudi Arabia.

Sustainable urban development is crucial for managing natural resources and mitigating environmental impacts induced by rapid urbanization. This study demonstrates an integrated framework using machine learning-based urban analytics techniques to evaluate spatiotemporal urban expansion in Saudi Arabia (1987-2022) and quantify impacts on leading land, water, and air-related environmental parameters (EPs). Remote sensing and statistical techniques were applied to estimate vegetation health, built-up area, impervious surface, water bodies, soil characteristics, thermal comfort, air pollutants (PM, CH, CO, NO, SO), and nighttime light EPs.

Decoding seasonal variability of air pollutants with climate factors: A geostatistical approach using multimodal regression models for informed climate change mitigation.

In response to changes in climatic patterns, a profound comprehension of air pollutants (AP) variability is vital for enhancing climate models and facilitating informed decision-making in nations susceptible to climate change. Earlier research primarily depended on limited models, potentially neglecting intricate relationships and not fully encapsulating associations. This study, in contrast, probed the spatiotemporal variability of airborne particles (CO, CH, SO, and NO) under varying climatic conditions within a climate-sensitive nation, utilizing multiple regression models.

Spatiotemporal characterization of relative humidity trends and influence of climatic factors in Bangladesh.

The frequency and intensity of climate change and resulting impacts are more prevalent in South Asian countries, particularly in Bangladesh. Relative humidity (RH) is a crucial aspect of climate, and higher RH variability has far-reaching impacts on human health, agriculture, environment, and infrastructure. While temperature and rainfall have gained much research attention, RH studies have received scant attention in the research literature.

The role of the microbiome on fish mucosal immunity under changing environments.

The environment is crucial for fish as their mucosal surfaces face continuous challenges in the water. Fish mucosal surfaces harbor the microbiome and mucosal immunity. Changes in the environment could affect the microbiome, thus altering mucosal immunity.

Thyroid Stem Cell Speciation-a Major Role for PKC.

Instructive signals that delineate the formation of thyroid follicles by thyrotropin (TSH) in stem cells are complex. Here, we have examined the role of protein kinase C (PKC) by using a unique Gαq/11 biased small molecule (MSq1) to develop thyroid progenitor cells. Mouse embryonic stem cells (mESCs) were differentiated into anterior endoderm cells and treated with either TSH or MSq1 in the presence or absence of PKC inhibitors.

Freshwater transfer affected intestinal microbiota with correlation to cytokine gene expression in Asian sea bass.

As a catadromous fish, Asian sea bass () juveniles migrate from seawater (SW) to freshwater (FW) for growth and development. During migration, they undergo physiological changes to acclimate to environmental salinity. Thus, it is crucial to understand how SW-to-FW migration affects the gut microbiota of catadromous fish.

A GIS and remote sensing approach for measuring summer-winter variation of land use and land cover indices and surface temperature in Dhaka district, Bangladesh.

Rapid urbanization has induced land use and land cover change (LULC) that increases land surface temperature (LST). Analyzing seasonal variations of LULC and LST is a precondition for mitigating heat island effects and promoting a sustainable living environment. The objective of this study is to explore the association between the seasonal LST dynamics and LULC indices for the Dhaka district of Bangladesh.

Brief Report - Monoclonal Antibodies Illustrate the Difficulties in Measuring Blocking TSH Receptor Antibodies.

TSH receptor (TSHR) antibodies are the cause of Graves' disease and may also be found in patients with Hashimoto's thyroiditis. They come in at least three varieties: thyroid stimulating, thyroid blocking and neutral. The measurement of TSH receptor antibodies in Graves' disease and Hashimoto's thyroiditis is a common clinical activity and can be useful in diagnosis and prognosis.

Environmental benefits of blue ecosystem services and residents' willingness to pay in Khulna city, Bangladesh.

Nature-based solutions for urban problems gaining popularity globally. The well-functioning ecosystem could offer a nature-based solution to many urban problems including water, drainage and flooding problems. Therefore, conservation and restoration of urban blue ecosystem components such as pond scape are crucial.

Mechanisms in Graves Eye Disease: Apoptosis as the End Point of Insulin-Like Growth Factor 1 Receptor Inhibition.

Graves' eye disease, also called Graves' orbitopathy (GO), is a potentially debilitating autoimmune disease associated with retro-orbital inflammation and tissue expansion, involving both fibroblasts and adipocytes, resulting in periorbital edema, worsening proptosis, and muscle dysfunction with diplopia and may ultimately threaten sight. Accumulating evidence has indicated that autoantibodies to the thyrotropin receptor (TSHR), which induce the hyperthyroidism of Graves' disease, also help mediate the pathogenesis of the eye disease in susceptible individuals through TSHR expression on retro-orbital cells. Since it has long been known that the effects of insulin-like growth factor 1 (IGF-1) and thyrotropin are additive, recent clinical trials with a human monoclonal IGF-1 receptor blocking antibody (teprotumumab; IGF-1R-B-monoclonal antibody [mAb]) have demonstrated its ability to induce significant reductions in proptosis, diplopia, and clinical activity scores in patients with GO.

Rescue of thyroid cells from antibody induced cell death via induction of autophagy.

Background: Graves' disease (GD) is associated with thyroid stimulating hormone (TSH) receptor (TSHR) antibodies of variable bioactivity. We have previously characterized "neutral" TSHR antibodies (N-TSHR-Abs) that bind to the hinge region of the TSHR ectodomain. We showed that an N-TSHR monoclonal antibody (mAb) failed to induce any G proteins to sustain survival signaling and lead to excessive stress and apoptosis.

Long Term Rescue of the TSH Receptor Knock-Out Mouse - Thyroid Stem Cell Transplantation Restores Thyroid Function.

The synergistic activation of transcription factors can lead to thyroid progenitor cell speciation. We have previously shown that mouse or human stem cells, expressing the transcription factors NKx2-1 and Pax8, can differentiate into thyroid neo-follicular structures (TFS). We now show that syngeneic mouse TFS when implanted into hypothyroid TSH receptor knockout (TSHR-KO) mice can ameliorate the hypothyroid state for an extended period.

A Stem Cell Surge During Thyroid Regeneration.

Background: Many tissues, including the thyroid, contain resident (adult) stem cells that are responsible for regeneration and repair after injury. The mechanisms of thyroid regeneration and the role of thyroid stem cells and thyroid progenitor cells in this process are not well understood. We have now used a new mouse thyroid injury model to gain insight into this phenomenon.

Derivation and 97% Purification of Human Thyroid Cells From Dermal Fibroblasts.

The success in rescuing thyroid deficiency in mice using thyroid cells derived from embryonic stem (ES) cells, together with the discovery of human induced pluripotent stem cells (iPSCs) from somatic cells, has raised the possibility of patient-specific thyroid cell replacement. In this study we demonstrate that human thyroid follicular cells can be derived from human iPSCs and show the ability of highly purified and differentiated cells to secrete thyroid hormone. Human iPSCs were derived from adult skin fibroblasts using RNA reprogramming and differentiated into thyroid follicular cells by exposure to activin A, ethacridine and TSH as we have previously described for human ES cells.

A Gq Biased Small Molecule Active at the TSH Receptor.

G protein coupled receptors (GPCRs) can lead to G protein and non-G protein initiated signals. By virtue of its structural property, the TSH receptor (TSHR) has a unique ability to engage different G proteins making it highly amenable to selective signaling. In this study, we describe the identification and characterization of a novel small molecule agonist to the TSHR which induces primary engagement with G.

Epigenetic Changes During Human Thyroid Cell Differentiation.

It has been demonstrated that the transcription factors TAZ (transcriptional coactivator with PDZ-binding motif), paired box gene 8 (PAX8), and NK2 homeobox 1 (NKX2-1) are coexpressed in the nucleus of thyroid cells. Furthermore, TAZ is known to enhance the transcriptional activity of PAX8 and NKX2-1 as well as the key thyroid-specific gene, thyroglobulin (TG), suggesting a critical role for TAZ in the control of thyroid cell speciation. We previously reported that the small molecule ethacridine, identified as a TAZ activator, was able to induce thyroid-specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells using activin A.

Understanding Thyroid Cell Stress.

Understanding the regulatory mechanisms that control intracellular stress has fundamental importance since its failure results in cell death. Evidence has emerged indicating that the intracellular signals that are induced in response to diverse stresses include the deoxyribonucleic acid damage response, the unfolded protein response, the mitochondrial and/or endoplasmic reticulum stress responses, and the autophagy signals to degrade dangerous protein aggregates. These signals bring changes to the stressed cells that may support systemic homeostasis or contribute to disease pathology.

Cleavage Region Thyrotropin Receptor Antibodies Influence Thyroid Cell Survival .

Graves' disease is associated with thyrotropin receptor (TSHR) antibodies of variable bioactivity. Recently, antibodies have been characterized that bind to the cleavage region of the TSHR ectodomain (C-TSHR-Ab), and their ability to induce thyroid cell apoptosis via excessive cell stress involving multiple organelles was demonstrated. To investigate the effects of C-TSHR-Ab, first a murine monoclonal antibody (mAb) directed against residues 337 to 356 of the TSHR cleavage region was developed, and then it was injected into mice.

A Modifying Autoantigen in Graves' Disease.

The TSH receptor (TSHR) is the major autoantigen in Graves' disease (GD). Bioinformatic analyses predict the existence of several human TSHR isoforms from alternative splicing, which can lead to the coexpression of multiple receptor forms. The most abundant of these is TSHRv1.

Antigenic "Hot- Spots" on the TSH Receptor Hinge Region.

The TSH receptor (TSHR) hinge region was previously considered an inert scaffold connecting the leucine-rich ectodomain to the transmembrane region of the receptor. However, mutation studies have established the hinge region to be an extended hormone-binding site in addition to containing a region which is cleaved thus dividing the receptor into (A) and β (B) subunits. Furthermore, we have shown that monoclonal antibodies directed to the cleaved part of the hinge region (often termed "neutral" antibodies) can induce thyroid cell apoptosis in the absence of cyclic AMP signaling.

Biased signaling by thyroid-stimulating hormone receptor-specific antibodies determines thyrocyte survival in autoimmunity.

The thyroid-stimulating hormone receptor (TSHR) is a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR). Autoimmune hyperthyroidism, commonly known as Graves' disease (GD), is caused by stimulating autoantibodies to the TSHR. We previously described TSHR-specific antibodies (TSHR-Abs) in GD that recognize linear epitopes in the cleavage region of the TSHR ectodomain (C-TSHR-Abs) and induce thyroid cell apoptosis instead of stimulating the TSHR.