Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion

In the paper

“T4 and rT3 also inhibit DIO2 by promoting its ubiquitination, which inhibits DIO2 activity and targets it for proteasomal degradation (37–40), forming an incoherent feedforward motif with T3 as the output.”

What the sources say

• Partly supported

  The Introduction identifies T4 and rT3 as D2 substrates that decrease its activity. The Results and Discussion show that rT3 accelerates D2 degradation through a proteasome-dependent pathway. The paper proposes ubiquitin conjugation as a possible step but does not demonstrate that T4 or rT3 promotes D2 ubiquitination. (LLM, conf=0.86)

  cites [37] Steinsapir, 1998, Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes, J Clin Invest sourceExperimental — accuracy not yet measured
• Supported

  The Discussion states that T4 or rT3 accelerates D2 ubiquitination, shifting it toward an inactive form that can enter proteasomes for degradation. The cited mechanism supports the portion of the sentence attached to references 37–40; the feedforward-motif description is the citing authors’ framing. (LLM, conf=0.92)

  cites [38] Gereben, 2000, Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation, Mol Endocrinol source
• ?Not checked — no full text of the sourcecites [39] Steinsapir, 2000, Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme’s active center, Endocrinology source
• Partly supported

  The introductory passage (page not provided) says T4 accelerates D2 ubiquitination, which inactivates D2 and targets it to the proteasome; the Results also report T4-induced loss of D2 activity. Our copy does not establish the same effect for rT3 (searched: rT3, reverse T3). The incoherent feedforward motif is the citing authors’ framing, not a finding attributed to this source. (LLM, conf=0.86)

  cites [40] Sagar, 2007, Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity, Mol Cell Biol sourceExperimental — accuracy not yet measured

In the paper

“Uptake of circulating I- by thyroid follicles is mediated by the Na+/I- symporter (NIS), a glycoprotein located on the basolateral plasma membrane of the thyrocytes and encoded by the solute carrier family 5 member 5 (SLC5A5) gene (51).”

What the sources say

• Partly supported

  The Introduction states that NIS is a plasma-membrane glycoprotein that transports iodide into the thyroid. The Molecular Characterization and Iodide Transport Defect sections identify NIS as SLC5A5 and state that the SLC5A5 gene encodes it. Our copy does not specify that NIS is on the basolateral membrane of thyrocytes; its explicit basolateral examples concern other tissues. Page numbers are unavailable in the indexed copy. (LLM, conf=0.86)

  cites [51] Ravera, 2017, The Sodium/Iodide symporter (NIS): Molecular physiology and preclinical and clinical applications, Annu Rev Physiol sourceExperimental — accuracy not yet measured

In the paper

“abnormality in the abundances or binding affinities of THBPs only result in changes in the concentrations of total, not free, THs in the blood, and the patients are in most cases clinically euthyroid (28).”

What the sources say

• Supported

  The Introduction says TH-binding protein abnormalities alter serum hormone concentrations without causing thyroid dysfunction. The Summary says affected individuals remain clinically euthyroid and free T4 is normal when measured by equilibrium dialysis; the TBG section describes abnormal serum T4 with normal free T4. The paper cautions that some routine free-hormone assays can give spurious results. (LLM, conf=0.92)

  cites [28] Pappa, 2015, Inherited defects of thyroxine-binding proteins, Best Pract Res Clin Endocrinol Metab source

In the paper

“an increase in serum T3 could upregulate DIO3 expression in the brain, increasing local T3 clearance, forming another local feedback control of T3 (41–43).”

What the sources say

• Partly supported

  The Results (p. 555) report that T3 degradation in cerebral-cortex homogenates was greatest in hyperthyroid rats, and the Discussion suggests that this activity could provide intracellular T3 disposal. The study does not show that a rise in serum T3 upregulates DIO3 expression or establish an in vivo feedback mechanism; the hyperthyroid rats were given T4. (LLM, conf=0.86)

  cites [41] Kaplan, 1980, Phenolic and tyrosyl ring deiodination of iodothyronines in rat brain homogenates, J Clin Invest sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Esfandiari, 1992, Induction of type III deiodinase activity in astroglial cells by thyroid hormones, Endocrinology source
• ?Not checked — no full text of the sourcecites [43] Becker, 1997, The type 2 and type 3 iodothyronine deiodinases play important roles in coordinating development in rana catesbeiana tadpoles, Endocrinology source

In the paper

“more recently synthesized TG molecules, which are low or yet to be iodinated, tend to bind to membrane receptors including megalin and ASGPR and are internalized along with receptor recycling, while highly iodinated and sialylated TG molecules preferentially undergo nonspecific fluid pinocytosis (68).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [68] Ulianich, 1999, Follicular thyroglobulin (TG) suppression of thyroid-restricted genes involves the apical membrane asialoglycoprotein receptor and TG phosphorylation, J Biol Chem sourceExperimental — accuracy not yet measured

In the paper

“Compared to DUOX1/DUOXA1, DUOX2/DUOXA2 has higher enzymatic activities and is the predominant form in the thyroid (57, 59).”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Poncelet, 2019, The dual oxidase Duox2 stabilized with DuoxA2 in an enzymatic complex at the surface of the cell produces extracellular H(2)O(2) able to induce DNA damage in an inducible cellular model, Exp Cell Res source
• Partly supported

  The Discussion (page unavailable) proposes that Duox2 is the predominant thyroid enzyme, supporting that part of the claim. But the functional-assay section reports comparable specific activities for the two enzymes under one tested condition, while the Discussion reports greater Duox2 sensitivity to PMA—not generally higher enzymatic activity. (LLM, conf=0.89)

  cites [59] Rigutto, 2009, Activation of dual oxidases Duox1 and Duox2: differential regulation mediated by camp-dependent protein kinase and protein kinase c-dependent phosphorylation, J Biol Chem sourceExperimental — accuracy not yet measured

In the paper

“It can physically interact with endocytosed TG and mediate the negative feedback of TG on TTFs (90).”

What the sources say

• Partly supported

  The indexed Abstract reports that flotillins physically interact with endocytosed Tg and that disrupting flotillin-containing lipid rafts inhibits Tg’s negative-feedback effect on thyroid-specific gene expression. It does not specifically report an effect on TTFs (thyroid transcription factors), so that part of the claim is not established by the retrieved passage. (LLM, conf=0.85)

  cites [90] Luo, 2016, A novel role for flotillin-containing lipid rafts in negative-feedback regulation of thyroid-specific gene expression by thyroglobulin, Thyroid sourceExperimental — accuracy not yet measured

In the paper

“These MIT and DIT can be deiodinated by iodotyrosine dehalogenase (DEHAL), and the iodide released is recycled as a sustained source of intrathyroidal iodide for TH synthesis (98, 99).”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Gnidehou, 2004, Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site, FASEB J source
• Supported

  The Introduction (page unavailable) says that iodine is actively recycled within the thyrocyte for thyroid-hormone biosynthesis and that thyroid iodotyrosine dehalogenase catalyzes the deiodination of MIT and DIT. This supports the claim's description of released iodide as an ongoing intrathyroidal source for synthesis. (LLM, conf=0.89)

  cites [99] Solís, 2004, Comparative kinetic characterization of rat thyroid iodotyrosine dehalogenase and iodothyronine deiodinase type 1, J Endocrinol source

In the paper

“MCT10 seems to be dispensable as far as secreting TH is concerned since the thyroidal TH content is not elevated in MCT10 KO mice, whereas the thyroidal TH content accumulates to higher levels in MCT8 KO or MCT8/MCT10 double KO mice (101, 105).”

What the sources say

• ?Not checked — no full text of the sourcecites [101] Trajkovic-Arsic, 2010, Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice, Endocrinology source
• Supported

  Figure 3C, reproduced in the Discussion (page not provided), reports unchanged thyroidal TH content in Mct10 knockout mice, elevated content in Mct8 knockouts, and still higher content in double knockouts. The Discussion also suggests that both transporters contribute to thyroidal TH efflux when Mct8 is absent, consistent with the claim's qualified wording about Mct10 alone. (LLM, conf=0.93)

  cites [105] Müller, 2014, Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency, Endocrinology source

In the paper

“MCT10 has a similar effect on transporting T3 to MCT8 but is less active toward T4 than MCT8, as demonstrated in COS1 cells transfected with human MCT10 cDNA (103).”

What the sources say

• Supported

  The Discussion reports that transfected COS1 cells show hMCT10 transports T3 more effectively than hMCT8, but T4 less effectively. Thus the claimed comparison is supported, although “similar” understates hMCT10’s advantage for T3. (LLM, conf=0.92)

  cites [103] Friesema, 2008, Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10, Mol Endocrinol source

In the paper

“TPO then further catalyzes the coupling of MIT and DIT in the same TG molecule to produce intramolecular T3 and T4 (66).”

What the sources say

• ?Could not verify

  The indexed copy identifies the cited review in repository metadata, but the substantive text returned is from a different paper about TSH genetics (Results; no page given). Searches for TPO, MIT, DIT, and iodotyrosine coupling found no passage from the cited review addressing the claimed intramolecular formation of T3 and T4, so the attribution cannot be verified from this copy. (LLM, conf=0.73)

  cites [66] Citterio, 2019, The role of thyroglobulin in thyroid hormonogenesis, Nat Rev Endocrinol sourceExperimental — accuracy not yet measured

In the paper

“Low-concentration TSH binds to the high-affinity binding site on one of the protomers of the TSHR homodimer, and preferentially activates Gαs to stimulate cyclic adenosine monophosphate (cAMP) accumulation, which then activates protein kinase A (PKA) (120).”

What the sources say

• Partly supported

  The Discussion (page not available) says TSH binding at the high-affinity site on one TSHR homodimer protomer favors Gs activation and stimulates cAMP production; the Results also show cAMP signaling at lower TSH concentrations than phosphoinositide signaling. Our copy does not state that the resulting cAMP activates PKA, so that final step is not supported by this source. (LLM, conf=0.88)

  cites [120] Allen, 2011, Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling, FASEB J sourceExperimental — accuracy not yet measured

In the paper

“Binding of TSH to TSHR activates signal transduction pathways that regulate TTF activities, which in turn control the gene expression of many thyroid-specific functional proteins, including NIS, pendrin, TG, TPO, DUOX(A)1/2, DIO1 and DIO2, that participate in the synthesis and secretion of THs (158, 159).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [158] Kambe, 1997, Thyroid-specific transcription factors, Endocr J sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [159] Pellizzari, 2000, Expression and function of the homeodomain-containing protein hex in thyroid cells, Nucleic Acids Res sourceExperimental — accuracy not yet measured

In the paper

“The HHEX promoter activity could be increased by 3~4 fold by TTF1 in rat FRTL-5 thyroid cells (146) and by PAX8 in transfected Hela cells (147).”

What the sources say

• ?Could not verify

  Citation (147) is attached to the PAX8 effect in transfected HeLa cells; the TTF-1 clause has a separate citation. Our copy’s Introduction mentions Pax8, but its Results on Hex promoter activation in HeLa cells test TTF-1 and Hex protein, not PAX8. A search for PAX8-mediated Hex promoter activation found no passage establishing the attributed effect. (LLM, conf=0.75)

  cites [146] Puppin, 2003, Thyroid-specific transcription factors control hex promoter activity, Nucleic Acids Res sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [147] Puppin, 2004, Functional interaction among thyroid-specific transcription factors: Pax8 regulates the activity of hex promoter, Mol Cell Endocrinol source

In the paper

“PAX8 and TTF1 are able to interact directly in vitro and form a functional complex in vivo responsible for the synergistic transcriptional activation of the TG promoter (145).”

What the sources say

• Supported

  The Discussion (page not available in our copy) states that Pax8 and TTF-1 interact directly in vitro, form a complex in vivo, and synergistically activate the Tg promoter. The Tg-promoter transfection results also report marked synergistic activation when both factors are expressed. (LLM, conf=0.94)

  cites [145] Di Palma, 2003, The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription, J Biol Chem source

In the paper

“TTF1 and PAX8 can activate the transcription of TPO by binding to specific DNA binding sites that overlap each other in the promoter region ( Figure 3C ) (169).”

What the sources say

• Supported

  The paper states that Pax-8 binds the TPO promoter at a site overlapping the TTF-1 site and activates TPO transcription. The Discussion also reports that TTF-1 activates the TPO promoter, though less strongly than the Tg promoter. The TTF-2 statement in the supplied quote is not part of the verbatim citing sentence attached to this citation. (LLM, conf=0.90)

  cites [169] Zannini, 1992, Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters, Mol Cell Biol source

In the paper

“The inhibition is transient, lasting approximately 26-50 h in rats, followed by adaption and escape of the thyroid from the inhibition despite ongoing iodine excess – the organification of intrathyroidal iodide resumes and TH synthesis returns to near normal levels (207, 208).”

What the sources say

• ?Not checked — no full text of the sourcecites [207] Wolff, 1949, The temporary nature of the inhibitory action of excess iodine on organic iodine synthesis in the normal thyroid, Endocrinology source
• Partly supported

  The opening paragraph (page not provided) says that inhibition of organic binding abated and hormone formation resumed in rats despite maintained high plasma iodide; the Summary (page not provided) also describes escape during prolonged iodide administration. Our copy does not give the claimed 26–50-hour duration or say that thyroid-hormone synthesis returned to near-normal levels. (LLM, conf=0.88)

  cites [208] Braverman, 1963, Changes in thyroidal function during adaptation to large doses of iodide, J Clin Invest sourceExperimental — accuracy not yet measured

In the paper

“Abolishing PAX8 downregulated DIO1 expression in thyroid cells, suggesting that PAX8 activates DIO1 transcriptionally, which is likely mediated by the selenocystein insertion sequence in the 3’ untranslated region of the DIO1 gene (178).”

What the sources say

• Partly supported

  The Discussion ('Identification of biological processes controlled by Pax8 in thyroid cells'; page unavailable) reports DIO1 downregulation after Pax8 abolition and potential Pax8 binding near a region important for selenocysteine insertion. The Results describe Dio1 among validated targets with reduced expression after Pax8 silencing. But the paper does not establish that transcriptional activation is mediated by a sequence in the DIO1 3′ UTR; the Discussion instead cites preliminary evidence for Pax8-dependent DIO1 mRNA stabilization. (LLM, conf=0.88)

  cites [178] Ruiz-Llorente, 2012, Genome-wide analysis of Pax8 binding provides new insights into thyroid functions, BMC Genomics sourceExperimental — accuracy not yet measured

In the paper

“The two can form heterodimeric complex which directly modulates the selectivity of TSHR-mediated signal transduction pathways. MCT8 profoundly reduces the capacity of TSH to induce Gαq/11-mediated signaling at TSHR, without affecting Gαs-mediated cAMP accumulation (196).”

What the sources say

• Partly supported

  The Results (page not supplied) report a 60–70% reduction in the IP3 measure of Gq/11 signaling with MCT8 co-expression, while the slight reduction in TSH-induced cAMP accumulation was not statistically significant. The Discussion (page not supplied) says the TSHR/MCT8 complex *could* directly modulate pathway selectivity and leaves its exact heteromeric nature for future study; the claim presents direct modulation and a heterodimeric complex as established. (LLM, conf=0.86)

  cites [196] Fischer, 2018, Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level, Cell Mol Life Sci sourceExperimental — accuracy not yet measured

In the paper

“The promoter of the DIO2 gene contains both CREB-binding site and TTF1 binding site, and TSH and TTF1 were shown to upregulate DIO2 activity ( Figure 3F ) (176, 177).”

What the sources say

• ?Not checked — no full text of the sourcecites [176] Bartha, 2000, Characterization of the 5’-flanking and 5’-untranslated regions of the cyclic adenosine 3’,5’-monophosphate-responsive human type 2 iodothyronine deiodinase gene, Endocrinology source
• Partly supported

  The Discussion reports a functional CRE and TTF-1 binding sites in the human DIO2 promoter, and the promoter-response results show that TTF-1 increases its transcriptional activity. The paper does not show that TSH upregulates DIO2 activity; its rat-thyroid results instead report lower D2 mRNA after TSH stimulation. (LLM, conf=0.88)

  cites [177] Gereben, 2001, The human, but not rat, dio2 gene is stimulated by thyroid transcription factor-1 (TTF-1), Mol Endocrinol sourceExperimental — accuracy not yet measured

In the paper

“Iodine organification and TH secretion in response to TSH are severely reduced in thyrocyte-specific Gαq/11-deficient mice which often develop hypothyroidism after birth (131).”

What the sources say

• Supported

  The section on TSH-induced thyroid function (page not provided) reports that TSH-stimulated iodine incorporation into thyroid proteins was abrogated and TSH-induced thyroid hormone release was almost completely abrogated in the deficient mice. The hypothyroidism section (page not provided) reports that about half developed overt hypothyroidism at six months of age or older. (LLM, conf=0.94)

  cites [131] Kero, 2007, Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development, J Clin Invest source

In the paper

“Besides, MCT10 plays an important role in maintaining TSHR at the basolateral plasma membrane of the thyrocytes. In murine models lacking MCT10, the localization of TSHR is restricted to vesicles (197).”

What the sources say

• Partly supported

  Results §2.2 reports that Mct10−/− thyrocytes have TSH receptors exclusively in vesicles, supporting MCT10’s role in maintaining basolateral localization. But the claim is too broad for all murine models lacking MCT10: the same section reports that additional cathepsin K deficiency maintains basolateral TSH receptor localization. (LLM, conf=0.88)

  cites [197] Venugopalan, 2021, The amino acid transporter Mct10/Tat1 is important to maintain the TSH receptor at its canonical basolateral localization and assures regular turnover of thyroid follicle cells in Male mice, Int J Mol Sci sourceExperimental — accuracy not yet measured

In the paper

“It has been demonstrated that TSH can increase the half-life of NIS protein and plasma membrane translocation, which may be mediated by TSH-stimulated NIS phosphorylation (165).”

What the sources say

• Partly supported

  The Results report that NIS half-life was approximately 5 days with TSH versus 3 days without it, and that TSH regulates NIS distribution at the cell surface. The Discussion says TSH is required for targeting NIS to and/or retaining it at the plasma membrane, but explicitly leaves those possibilities unresolved. It also shows TSH-dependent phosphorylation changes while treating a role for phosphorylation in targeting as a question for future investigation, not an established mechanism. (LLM, conf=0.86)

  cites [165] Riedel, 2001, Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin, J Biol Chem sourceExperimental — accuracy not yet measured

In the paper

“In human thyroid tissues, the mRNAs of TTF1 and HHEX were found to be positively correlated (146) and so were the mRNAs of PAX8 and HHEX (147).”

What the sources say

• Supported

  This source supports the clause cited as (146), not the separate PAX8–HHEX clause cited as (147). In “Correlation between TTF-1 and HEX gene expression in human thyroid,” it reports a significant correlation between TTF-1 and HEX mRNA levels in both normal human thyroid tissue and differentiated thyroid neoplasms. (LLM, conf=0.94)

  cites [146] Puppin, 2003, Thyroid-specific transcription factors control hex promoter activity, Nucleic Acids Res source
• ?Not checked — no full text of the sourcecites [147] Puppin, 2004, Functional interaction among thyroid-specific transcription factors: Pax8 regulates the activity of hex promoter, Mol Cell Endocrinol source

In the paper

“HHEX can bind to the TG promoter and function as a repressor to abolish the activating effects of both TTF1 and PAX8 in FRTL-5 cells (159).”

What the sources say

• Partly supported

  The Results (p. 2506) report that Hex abolishes both TTF-1 and Pax8 activation of the Tg promoter, and the Discussion describes Hex as a Tg-promoter repressor. But the Methods place the TTF-1/Pax8 co-transfection experiments in HeLa cells; the FRTL-5 experiment tested Hex-mediated repression, not abolition of both factors’ activating effects. The binding assays used Tg-promoter sequences (Fig. 6, p. 2509). (LLM, conf=0.93)

  cites [159] Pellizzari, 2000, Expression and function of the homeodomain-containing protein hex in thyroid cells, Nucleic Acids Res sourceExperimental — accuracy not yet measured

In the paper

“TTF1 and Pax8 are able to interact directly, as demonstrated in rat PCCl3 thyrocytes in vitro, thus they may form a functional protein complex driving synergistic transcriptional activation of target genes such as TG (145).”

What the sources say

• Supported

  The section on Pax8 and TTF-1 interaction reports pull-down experiments using PC Cl3 thyroid-cell extracts and demonstrates direct binding with purified proteins; it also reports a complex in PC Cl3 cells by co-immunoprecipitation. The Tg-promoter section reports synergistic transcriptional activation when both factors were expressed together in HeLa cells. Thus, the interaction was tested using PC Cl3 extracts, while the synergistic activation assay used HeLa cells. (LLM, conf=0.92)

  cites [145] Di Palma, 2003, The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription, J Biol Chem source

In the paper

“PKC can phosphorylate DUOX2 and induce its H2O2-generating activity, while PKA-mediated phosphorylation of serine 955 of DUOX1 can stimulate its activity (59).”

What the sources say

• Supported

  The Duox2 activity section reports PMA-stimulated Duox2 phosphorylation and H2O2 production, with PKC inhibitors reducing the response; the authors conclude that PKC isoforms participate in Duox2 phosphorylation and activation. The Discussion identifies Ser 955 as crucial for positive regulation of Duox1 activity through PKA-mediated phosphorylation. Page numbers are not provided in our copy. (LLM, conf=0.91)

  cites [59] Rigutto, 2009, Activation of dual oxidases Duox1 and Duox2: differential regulation mediated by camp-dependent protein kinase and protein kinase c-dependent phosphorylation, J Biol Chem source

In the paper

“High-concentration TSH binds to both the high- and low-affinity protomers, activating both Gαs and Gαq/11 to increase cAMP production and activate PKC, respectively (120).”

What the sources say

• Partly supported

  The Discussion states that TSH occupancy of both the high- and low-affinity sites permits Gs and Gq/11 activation, increasing cAMP and IP1 production. The paper describes phosphoinositide signaling through Gq/11 but does not report PKC activation; that part of the attributed claim is unsupported. (LLM, conf=0.89)

  cites [120] Allen, 2011, Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling, FASEB J sourceExperimental — accuracy not yet measured

In the paper

“Lastly, positive autoregulatory loops also exist for TTF1 (152), PAX8 (150) and HHEX (146).”

What the sources say

• ?Not checked — no full text of the sourcecites [152] Oguchi, 1998, Multiple transcripts encoded by the thyroid-specific enhancer-binding protein (T/EBP)/thyroid-specific transcription factor-1 (TTF-1) gene: evidence of autoregulation, Endocrinology source
• ?Not checked — no full text of the sourcecites [150] D’Andrea, 2006, Functional inactivation of the transcription factor Pax8 through oligomerization chain reaction, Mol Endocrinol source
• Supported

  Citation (146) is attached to HHEX, not TTF1 or PAX8. In the section “Effect of Hex protein on the Hex promoter” (page not provided), the paper reports that Hex increased activity of its own promoter and proposes a positive regulatory loop; the Discussion calls it a positive feedback loop. (LLM, conf=0.93)

  cites [146] Puppin, 2003, Thyroid-specific transcription factors control hex promoter activity, Nucleic Acids Res source

In the paper

“The follicle heterogeneity may also result from the operation of the negative feedback of TG autoregulation, which may cause cyclic changes in each follicle’s function, termed as thyroid follicular cycle (257, 270).”

What the sources say

• ?Not checked — no full text of the sourcecites [257] Sellitti, 2014, Intrinsic regulation of thyroid function by thyroglobulin, Thyroid source
• Supported

  Section 2 (“Tg negative-feedback theory and follicular cycle model”) describes a repeating cycle in which follicular Tg suppresses its own synthesis, is reabsorbed, and then accumulates again as inhibition weakens. It says follicles at different stages of this cycle exhibit heterogeneity. The section identifies the model as a hypothesis, consistent with the citing sentence’s “may.” (LLM, conf=0.94)

  cites [270] Chen, 2019, Progress in the research of negative feedback effect of thyroglobulin, Nan Fang Yi Ke Da Xue Xue Bao source

In the paper

“Lastly, iodide overload decreased MCT8 mRNA and protein expression in rats, thus reducing T4 and T3 secretion into the blood stream (102, 215).”

What the sources say

• ?Not checked — no full text of the sourcecites [102] de Souza, 2015, MCT8 is downregulated by short time iodine overload in the thyroid gland of rats, Horm Metab Res source
• Partly supported

  The Discussion (p. 18) reports that MCT8 mRNA decreased one day after KI administration in rats, but attributes the MCT8 protein finding to de Souza et al. (2015), rather than measuring it in this study. The Discussion (p. 19) says thyroid hormone levels were unchanged, so this paper does not establish the claimed reduction of T4 and T3 in the bloodstream. (LLM, conf=0.88)

  cites [215] Lebsir, 2018, Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat, Mol Cell Endocrinol sourceExperimental — accuracy not yet measured

In the paper

“The intrathyroidal T4-to-T3 conversion driven by TSH-stimulated DIO2 induction was explored for its role in circadian secretion of T3 (180).”

What the sources say

• Partly supported

  The model description says it explores TSH-stimulated intrathyroidal T4-to-T3 conversion, and the Conclusion and Outlook links intrathyroidal T3 secretion to a circadian FT3 pattern. But the Dynamic Simulation section does not identify TSH-induced DIO2 as the driver: type 2 deiodination contributes only 0.002% of modeled thyroidal T3 secretion and is described as negligible. Page numbers are not available in our copy. (LLM, conf=0.88)

  cites [180] Berberich, 2018, Mathematical modeling of the pituitary-thyroid feedback loop: Role of a TSH-T(3)-Shunt and sensitivity analysis, Front Endocrinol (Lausanne) sourceExperimental — accuracy not yet measured

In the paper

“While there are many models focusing on various aspects of the HPT axis (180, 273–275), models that specifically simulate the molecular regulations in thyroid follicles are still uncommon.”

What the sources say

• Supported

  The citation is attached to the first clause, about the existence of many HPT-axis models. The Introduction (page unavailable) describes an increasing body of such models and points to surveys of existing approaches. The uncited statement about the rarity of thyroid-follicle models is not attributed to this source. (LLM, conf=0.90)

  cites [180] Berberich, 2018, Mathematical modeling of the pituitary-thyroid feedback loop: Role of a TSH-T(3)-Shunt and sensitivity analysis, Front Endocrinol (Lausanne) source
• ?Not checked — no full text of the sourcecites [273] Saratchandran, 1976, An improved mathematical model of human thyroid hormone regulation, Clin Endocrinol (Oxf) source
• ?Not checked — no full text of the sourcecites [274] Liu, 1994, A new mathematical model of hypothalamo-pituitary-thyroid axis, Math Comput Model source
• Supported

  The citation is attached to the statement that models address aspects of the HPT axis. The Introduction describes this paper’s whole-axis simulation model, and the Discussion describes earlier models of thyroid hormone regulation. The citing sentence does not attribute the claim about the rarity of follicular molecular models to this source. (LLM, conf=0.91)

  cites [275] Eisenberg, 2008, Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis, Thyroid source

In the paper

“More recently, Cohen et al. has used a bioinformatic approach to map out a regulatory network underpinning the Wolff-Chaikoff phenomena, with the goal of predicting the protective effect of repetitive dosing of iodide as a prophylactic measure (277).”

What the sources say

• Partly supported

  The Abstract and Materials and methods describe a systems-biology network used to investigate Wolff–Chaikoff regulation during repetitive potassium iodide administration. But the paper states its aim was to explain observed gene-expression changes and propose a mechanism of NIS regulation, not to predict the protective effect of repeated prophylactic dosing. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [277] Cohen, 2019, A systems biology approach to propose a new mechanism of regulation of repetitive prophylaxis of stable iodide on sodium/iodide symporter (NIS), Biochimie sourceExperimental — accuracy not yet measured

In the paper

“NIS is downregulated by high iodide through several mechanisms. First of all, high iodide inhibits the transcription of NIS (216, 234, 235).”

What the sources say

• ?Not checked — no full text of the sourcecites [216] Eng, 1999, Escape from the acute Wolff-chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein, Endocrinology source
• ?Not checked — no full text of the sourcecites [234] Eng, 2001, Regulation of the sodium iodide symporter by iodide in FRTL-5 cells, Eur J Endocrinol source
• Partly supported

  The Validation of SAGE data section reports that high iodide reduced Nis mRNA expression in PCCl3 cells, supporting NIS downregulation. The paper does not establish that inhibition of NIS transcription, rather than another mechanism affecting mRNA abundance, caused the reduction. The poly(A)-tail and protein-half-life mechanisms are not part of the quoted citing sentence assessed here. (LLM, conf=0.87)

  cites [235] Leoni, 2008, Differential gene expression analysis of iodide-treated rat thyroid follicular cell line PCCl3, Genomics sourceExperimental — accuracy not yet measured

In the paper

“many of the regulations reviewed here are based on in vitro and in vivo studies in a variety of species, particularly rat thyroid cell lines, thus caution should be exercised when generalization is made.”

In the paper

“The effects of TSH are mediated by the thyrotropin receptor (TSHR) which belongs to a family of GPCRs and is located at the basolateral plasma membrane of the thyrocytes (107).”

What the sources say

• ?Not checked — no full text of the sourcecites [107] Rapoport, 1998, The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies, Endocr Rev source

In the paper

“T3 can repress the gene transcription of DIO2, the primary activating enzyme that converts T4 into T3, therefore forming a negative feedback loop to keep intracellular T3 within a range (30–32).”

What the sources say

• ?Not checked — no full text of the sourcecites [30] Kim, 1998, Studies of the hormonal regulation of type 2 5’-iodothyronine deiodinase messenger ribonucleic acid in pituitary tumor cells using semiquantitative reverse transcription-polymerase chain reaction, Endocrinology source
• ?Not checked — no full text of the sourcecites [31] Hosoi, 1999, Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [32] Bianco, 2019, Paradigms of dynamic control of thyroid hormone signaling, Endocr Rev source

In the paper

“the THBPs serve as a reservoir to buffer free T4 and T3 concentrations against transient fluctuations and ensure steady delivery of THs through the target tissues (26, 27).”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Schussler, 2000, The thyroxine-binding proteins, Thyroid source
• ?Not checked — no full text of the sourcecites [27] Richardson, 2007, Cell and molecular biology of transthyretin and thyroid hormones, Int Rev Cytol. source

In the paper

“ANO1 is a calcium-activated chloride channel, which has been demonstrated to mediate I- efflux across the apical membrane of thyrocytes (54).”

What the sources say

• ?Not checked — no full text of the sourcecites [54] Twyffels, 2014, Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte, Am J Physiol Cell Physiol source

In the paper

“This unique storage mechanism makes TG highly enriched in the lumen, reaching a concentration as high as nearly 600 mg/ml in the human thyroid gland, and constituting >95% of the colloid protein content (67, 78–80).”

What the sources say

• ?Not checked — no full text of the sourcecites [67] Marinò, 2000, Role of thyroglobulin endocytic pathways in the control of thyroid hormone release, Am J Physiol Cell Physiol source
• ?Not checked — no full text of the sourcecites [78] Hayden, 1970, Micropuncture investigation of the anion content of colloid from single rat thyroid follicles. a micromethod for the simultaneous determination of iodide and chloride in nanomole quantities, Pflugers Arch source
• ?Not checked — no full text of the sourcecites [79] Smeds, 1972, A microgel electrophoretic analysis of the colloid proteins in single rat thyroid follicles. II. the protein concentration of the colloid single rat thyroid follicles, Endocrinology source
• ?Not checked — no full text of the sourcecites [80] Berndorfer, 1996, Multimerization of thyroglobulin (TG) during extracellular storage: isolation of highly cross-linked TG from human thyroids, J Clin Endocrinol Metab source

In the paper

“nearly 99.97% of T4 and 99.70% of T3 are bound to specific THBPs (22)”

What the sources say

• ?Not checked — no full text of the sourcecites [22] Mendel, 1989, The free hormone hypothesis: a physiologically based mathematical model, Endocr Rev source

In the paper

“Feedback and feedforward are key network motifs that underpin a variety of dynamic behaviors, including signal amplification, multistability, adaptation, homeostasis, oscillation, fold-change detection, signaling delay and acceleration, threshold and nonmonotonic effect etc. (48, 49).”

What the sources say

• ?Not checked — no full text of the sourcecites [48] Alon, 2007, Network motifs: theory and experimental approaches, Nat Rev Genet source
• ?Not checked — no full text of the sourcecites [49] El-Samad, 2021, Biological feedback control–respect the loops, Cell Syst source

In the paper

“MCT8 favors T4 secretion over T3 secretion, as demonstrated by the higher-than-normal T3/T4 ratio in MCT8 KO mice and in patients with MCT8 mutation (101, 102).”

What the sources say

• ?Not checked — no full text of the sourcecites [101] Trajkovic-Arsic, 2010, Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice, Endocrinology source
• ?Not checked — no full text of the sourcecites [102] de Souza, 2015, MCT8 is downregulated by short time iodine overload in the thyroid gland of rats, Horm Metab Res source

In the paper

“A human TG molecule contains on average 2.28 molecules of T4 and 0.29 molecules of T3 (67).”

What the sources say

• ?Not checked — no full text of the sourcecites [67] Marinò, 2000, Role of thyroglobulin endocytic pathways in the control of thyroid hormone release, Am J Physiol Cell Physiol source

In the paper

“Under circumstances such as iodine deprivation or TSH overstimulation, the colloid TG globule will be solubilized by proteinases and the solubilized TG will be taken up by thyrocytes (67).”

What the sources say

• ?Not checked — no full text of the sourcecites [67] Marinò, 2000, Role of thyroglobulin endocytic pathways in the control of thyroid hormone release, Am J Physiol Cell Physiol source

In the paper

“The close proximity between DUOX and TPO makes newly produced H2O2 readily captured by TPO and reduces potential oxidative damage by H2O2 that would otherwise diffuse afar (64, 65).”

What the sources say

• ?Not checked — no full text of the sourcecites [64] Fortunato, 2010, Functional consequences of dual oxidase-thyroperoxidase interaction at the plasma membrane”, J Clin Endocrinol Metab source
• ?Not checked — no full text of the sourcecites [65] Song, 2010, Association of duoxes with thyroid peroxidase and its regulation in thyrocytes, J Clin Endocrinol Metab source

In the paper

“TAAR1 can co-localize with cathepsins B and L and regulate the proteolytic action of these cysteine cathepsins and internalization of TG (77).”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Brix, 2020, Auto-regulation of the thyroid gland beyond classical pathways, Exp Clin Endocrinol Diabetes source

In the paper

“The active uptake of I- by NIS is Na+-dependent, which couples the energy released by the inward translocation of Na+ down its chemical gradient to the simultaneous inward translocation of I- against its electrochemical gradient (52).”

What the sources say

• Not checked yetcites [52] Rousset, 2000, Thyroid hormone synthesis and secretion

In the paper

“While likely important for TSHR homeostasis and receptor desensitization, the positive and negative regulations of TSHR by TSH and cAMP form an incoherent feedforward control.”

In the paper

“The Plummer effect is more prominent in hyperthyroid patients but also occurs, to a less degree, in euthyroid individuals (214).”

What the sources say

• ?Not checked — no full text of the sourcecites [214] Phillppou, 1992, The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement, Clin Endocrinol source

In the paper

“In FRTL-5 thyroid cells, TSH treatment first upregulated TSHR mRNA moderately in the initial 2 hours and then downregulated it by 75%, and the mRNA recovered in 6 days after TSH withdrawal (188, 189).”

What the sources say

• ?Not checked — no full text of the sourcecites [188] Akamizu, 1990, Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies, Proc Natl Acad Sci U.S.A. source
• ?Not checked — no full text of the sourcecites [189] Saji, 1992, Regulation of thyrotropin receptor gene expression in rat FRTL-5 thyroid cells, Endocrinology source

In the paper

“The inhibition involves blockade of multiple molecular events in the sequential processes of TH synthesis and secretion, including iodide organification, proteolysis of iodinated TG to liberate T4 and T3, and release of T4 and T3 into the blood stream ( Figure 4A ).”

In the paper

“These TTFs play critical roles in thyroid differentiation and also coordinately regulate the suite of functional genes involved in TH synthesis (142).”

What the sources say

• ?Not checked — no full text of the sourcecites [142] Suzuki, 1998, Autoregulation of thyroid-specific gene transcription by thyroglobulin, Proc Natl Acad Sci U.S.A. source

In the paper

“Thus, the physiological function of cAMP signaling activated via Gαs is to promote TH synthesis, thyrocyte growth and proliferation.”

In the paper

“Therefore, the incoherent feedforward motif formed by Gαs and Gαi/o ( Figure 1 ) is responsible for the biphasic cAMP response and, likely, similar downstream gene expression responses.”

In the paper

“These cross-regulations can be either stimulatory or inhibitory, forming tiered, coherent or incoherent feedforward motifs ( Figure 1 ).”

In the paper

“PAX8 can bind to the 5′-flanking region of the DUOX2 gene to activate its transcription ( Figure 3E ) (150).”

What the sources say

• ?Not checked — no full text of the sourcecites [150] D’Andrea, 2006, Functional inactivation of the transcription factor Pax8 through oligomerization chain reaction, Mol Endocrinol source

In the paper

“With CREB added to the top of the TTF network, more feedforward motifs are formed, including incoherent ones through the inhibition of TTF1 by CREB ( Figure 2 ).”

In the paper

“Since Gαq/11 is involved through calcium signaling in the cleavage of T3 and T4 from TG by cathepsins and their release as an acute effect (77, 130), MCT8, by heterodimerizing with TSHR and interfering with Gαq/11 signaling, may inhibit T3/T4 release, while the long-term stimulatory effect of TSH mediated by Gαs is spared.”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Brix, 2020, Auto-regulation of the thyroid gland beyond classical pathways, Exp Clin Endocrinol Diabetes source
• ?Not checked — no full text of the sourcecites [130] Linke, 2002, Thyroid stimulating hormone upregulates secretion of cathepsin b from thyroid epithelial cells, Biol Chem source

In the paper

“As revealed below, a number of negative feedback regulatory pathways also operate on top of the feedforward backbone, providing important functions to thyroid homeostasis.”

In the paper

“TTF1, TTF2, and PAX8 can bind to the upstream enhancer and promoter regions of NIS and stimulate its transcriptional activity ( Figure 3A ).”

In the paper

“Since iodide is required for TH synthesis and high iodide inhibits TH synthesis through the mechanisms detailed below, it follows that iodide regulates TH synthesis in an incoherent feedforward manner ( Figure 4B , top half involving red line).”

In the paper

“For instance, the multiple incoherent feedforward motifs formed by the signal transduction pathways, TTFs and thyroid functional genes may be responsible for the biphasic response of the thyroid to TSH.”

In the paper

“Iodolipid, such as 2-iodohexadecanal (2-IHDA), is believed to play a major role in mediating the Wolff-Chaikoff inhibitory effect.”

In the paper

“This is believed to result from reduction of the proteolytic cleavage of iodinated TG to liberate T4 and T3 and inhibition of TH secretion from the thyrocytes (226), which form another incoherent feedforward motif ( Figure 4B , top half involving blue line).”

What the sources say

• ?Not checked — no full text of the sourcecites [226] Koukkou, 2017, Effect of excess iodine intake on thyroid on human health, Minerva Med source

In the paper

“The incoherent feedforward motif driven by iodide is responsible for the TH synthesis at normal conditions and the Wolff-Chaikoff inhibition under high iodine load.”

In the paper

“Highly iodinated TG suppressed TTF1 and PAX8 expression at both mRNA and protein levels, which is likely mediated by augmented PKC and suppressed PKA activities (157).”

What the sources say

• ?Not checked — no full text of the sourcecites [157] Huang, 2017, Iodinated TG in thyroid follicular lumen regulates TTF-1 and PAX8 expression via TSH/TSHR signaling pathway, J Cell Biochem source

In the paper

“Therefore, the TG-mediated feedback may function to maintain the homeostasis of iodinated TG, rather than THs.”

In the paper

“A better understanding of complex pathways as such requires formulation of mathematical models to simulate the network as nonlinear dynamical systems (49).”

What the sources say

• ?Not checked — no full text of the sourcecites [49] El-Samad, 2021, Biological feedback control–respect the loops, Cell Syst source

In the paper

“Dysregulation of this network, either internally or externally by exogenous disruptors, can lead to pathological thyroid conditions, including goiter, hypothyroidism, hyperthyroidism, and thyroid cancers.”

In the paper

“A potential oscillatory behavior resulting from TG-mediated negative feedback regulation may lead to cyclic follicular function and underpin the observed follicular heterogeneity (257).”

What the sources say

• ?Not checked — no full text of the sourcecites [257] Sellitti, 2014, Intrinsic regulation of thyroid function by thyroglobulin, Thyroid source

In the paper

“Such systems biology models can incorporate genetic, epigenetic, environmental and nutritional status to better predict responses of individuals.”

In the paper

“Follicles in a thyroid gland are highly heterogeneous in morphology and functional states (261, 262).”

What the sources say

• ?Not checked — no full text of the sourcecites [261] Studer, 1989, Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth, Endocr Rev source
• ?Not checked — no full text of the sourcecites [262] Aeschimann, 1993, Morphological and functional polymorphism within clonal thyroid nodules, J Clin Endocrinol Metab source

In the paper

“Degon et al. constructed a complex model describing the intrafollicular iodine turnover in humans, including uptake, apical transport, organification, endocytosis, recycling, secretion of iodide, upregulation of TPO, TG, NIS and other proteins by TSH, feedback inhibition of H2O2 production and NIS by iodide, and of TG, NIS, and TPO by TG (276).”

What the sources say

• ?Not checked — no full text of the sourcecites [276] Degon, 2008, A computational model of the human thyroid, Math Biosci source

In the paper

“The escape phenomenon seems to be a result of adaptation in response to high intracellular iodide load, involving negative feedback regulation of multiple processes that participate in the intracellular iodide turnover ( Figure 4B , lower half).”