Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion

May combine two claims.

T4 and rT3 inhibit DIO2 by promoting its ubiquitination, which inhibits DIO2 activity and targets it for proteasomal degradation, forming an incoherent feedforward motif with T3 as the output.

“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.”

• cites [37] Steinsapir, 1998, Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes, J Clin Invest sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [38] Gereben, 2000, Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation, Mol Endocrinol sourceSupported
• cites [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 sourceNot checked — no full text of the source
• cites [40] Sagar, 2007, Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity, Mol Cell Biol sourcePartly 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)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Uptake of circulating I- by thyroid follicles is mediated by the Na+/I- symporter (NIS), a glycoprotein located on the basolateral plasma membrane of thyrocytes and encoded by SLC5A5.

“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).”

• cites [51] Ravera, 2017, The Sodium/Iodide symporter (NIS): Molecular physiology and preclinical and clinical applications, Annu Rev Physiol sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Abnormality in abundances or binding affinities of THBPs only results in changes in total, not free, THs in the blood, and patients are in most cases clinically euthyroid.

“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).”

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

May combine two claims.

An increase in serum T3 could upregulate DIO3 expression in the brain, increasing local T3 clearance, forming another local feedback control of T3.

“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).”

• cites [41] Kaplan, 1980, Phenolic and tyrosyl ring deiodination of iodothyronines in rat brain homogenates, J Clin Invest sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [42] Esfandiari, 1992, Induction of type III deiodinase activity in astroglial cells by thyroid hormones, Endocrinology sourceNot checked — no full text of the source
• cites [43] Becker, 1997, The type 2 and type 3 iodothyronine deiodinases play important roles in coordinating development in rana catesbeiana tadpoles, Endocrinology sourceNot checked — no full text of the source

May combine two claims.

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.

“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).”

• cites [68] Ulianich, 1999, Follicular thyroglobulin (TG) suppression of thyroid-restricted genes involves the apical membrane asialoglycoprotein receptor and TG phosphorylation, J Biol Chem sourcePartly supported

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

  Experimental — accuracy not yet measured

May combine two claims.

DUOX2/DUOXA2 has higher enzymatic activities and is the predominant form in the thyroid compared to DUOX1/DUOXA1.

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

• cites [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 sourceNot checked — no full text of the source
• 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 sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Flotillin can physically interact with endocytosed TG and mediate the negative feedback of TG on TTFs.

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

• cites [90] Luo, 2016, A novel role for flotillin-containing lipid rafts in negative-feedback regulation of thyroid-specific gene expression by thyroglobulin, Thyroid sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

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.

“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).”

• cites [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 sourceNot checked — no full text of the source
• cites [99] Solís, 2004, Comparative kinetic characterization of rat thyroid iodotyrosine dehalogenase and iodothyronine deiodinase type 1, J Endocrinol sourceSupported

May combine two claims.

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.

“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).”

• cites [101] Trajkovic-Arsic, 2010, Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice, Endocrinology sourceNot checked — no full text of the source
• cites [105] Müller, 2014, Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency, Endocrinology sourceSupported

May combine two claims.

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

“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).”

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

Probably not a substantial claim: may not pass S3 (load-bearing).

TPO catalyzes the coupling of MIT and DIT in the same TG molecule to produce intramolecular T3 and T4.

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

• cites [66] Citterio, 2019, The role of thyroglobulin in thyroid hormonogenesis, Nat Rev Endocrinol sourceCould 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)

  Experimental — accuracy not yet measured

May combine two claims.

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 cAMP accumulation, which then activates PKA.

“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).”

• cites [120] Allen, 2011, Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling, FASEB J sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

TSH binding to TSHR activates signal transduction pathways that regulate TTF activities, which in turn control expression of thyroid-specific functional proteins including NIS, pendrin, TG, TPO, DUOX(A)1/2, DIO1 and DIO2, participating in TH synthesis and secretion.

“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).”

• cites [158] Kambe, 1997, Thyroid-specific transcription factors, Endocr J sourcePartly supported

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

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

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

  Experimental — accuracy not yet measured

May combine two claims.

HHEX promoter activity could be increased by 3~4 fold by TTF1 in rat FRTL-5 thyroid cells and by PAX8 in transfected Hela cells.

“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).”

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

  Experimental — accuracy not yet measured
• cites [147] Puppin, 2004, Functional interaction among thyroid-specific transcription factors: Pax8 regulates the activity of hex promoter, Mol Cell Endocrinol sourceNot checked — no full text of the source

May combine two claims.

PAX8 and TTF1 activate the TG promoter and interact directly to form a functional complex responsible for synergistic transcriptional activation of the TG promoter.

“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).”

• 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 sourceSupported

May combine two claims.

TTF1 and PAX8 activate TPO transcription by binding to overlapping DNA sites in the promoter, and TTF2 may interfere with their binding to inhibit TPO transcriptional activation.

“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).”

• 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 sourceSupported

May combine two claims.

The Wolff-Chaikoff effect is a transient inhibition of iodide organification and TH synthesis caused by high iodide, lasting approximately 26-50 h in rats and followed by escape despite ongoing iodine excess.

“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).”

• cites [207] Wolff, 1949, The temporary nature of the inhibitory action of excess iodine on organic iodine synthesis in the normal thyroid, Endocrinology sourceNot checked — no full text of the source
• cites [208] Braverman, 1963, Changes in thyroidal function during adaptation to large doses of iodide, J Clin Invest sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Abolishing PAX8 downregulates DIO1 expression in thyroid cells, suggesting PAX8 activates DIO1 transcriptionally, likely mediated by the selenocysteine insertion sequence in the 3' UTR of DIO1.

“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).”

• cites [178] Ruiz-Llorente, 2012, Genome-wide analysis of Pax8 binding provides new insights into thyroid functions, BMC Genomics sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

MCT8 and TSHR form a heterodimeric complex that directly modulates the selectivity of TSHR-mediated signal transduction pathways, with MCT8 profoundly reducing TSH-induced Gαq/11 signaling without affecting Gαs-mediated cAMP accumulation.

“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).”

• cites [196] Fischer, 2018, Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level, Cell Mol Life Sci sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

The DIO2 promoter contains both a CREB-binding site and a TTF1 binding site, and TSH and TTF1 upregulate DIO2 activity.

“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).”

• cites [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 sourceNot checked — no full text of the source
• cites [177] Gereben, 2001, The human, but not rat, dio2 gene is stimulated by thyroid transcription factor-1 (TTF-1), Mol Endocrinol sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

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.

“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).”

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

May combine two claims.

MCT10 plays an important role in maintaining TSHR at the basolateral plasma membrane of thyrocytes; in murine models lacking MCT10, TSHR localization is restricted to vesicles.

“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).”

• 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 sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

TSH can increase the half-life of NIS protein and plasma membrane translocation, possibly mediated by TSH-stimulated NIS phosphorylation.

“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).”

• cites [165] Riedel, 2001, Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin, J Biol Chem sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

In human thyroid tissues, the mRNAs of TTF1 and HHEX were found to be positively correlated and so were the mRNAs of PAX8 and HHEX.

“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).”

• cites [146] Puppin, 2003, Thyroid-specific transcription factors control hex promoter activity, Nucleic Acids Res sourceSupported
• cites [147] Puppin, 2004, Functional interaction among thyroid-specific transcription factors: Pax8 regulates the activity of hex promoter, Mol Cell Endocrinol sourceNot checked — no full text of the source

May combine two claims.

HHEX binds to the TG promoter and functions as a repressor to abolish the activating effects of both TTF1 and PAX8 in FRTL-5 cells.

“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).”

• cites [159] Pellizzari, 2000, Expression and function of the homeodomain-containing protein hex in thyroid cells, Nucleic Acids Res sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

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.

“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).”

• 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 sourceSupported

May combine two claims.

PKC phosphorylates DUOX2 and induces its H2O2-generating activity, while PKA-mediated phosphorylation of serine 955 of DUOX1 stimulates its activity.

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

• 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 sourceSupported

May combine two claims.

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.

“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).”

• cites [120] Allen, 2011, Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling, FASEB J sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Positive autoregulatory loops exist for TTF1, PAX8 and HHEX.

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

• cites [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 sourceNot checked — no full text of the source
• cites [150] D’Andrea, 2006, Functional inactivation of the transcription factor Pax8 through oligomerization chain reaction, Mol Endocrinol sourceNot checked — no full text of the source
• cites [146] Puppin, 2003, Thyroid-specific transcription factors control hex promoter activity, Nucleic Acids Res sourceSupported

May combine two claims.

The negative feedback of TG autoregulation may act as an oscillator that drives cyclic follicular function and renders follicle heterogeneity.

“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).”

• cites [257] Sellitti, 2014, Intrinsic regulation of thyroid function by thyroglobulin, Thyroid sourceNot checked — no full text of the source
• cites [270] Chen, 2019, Progress in the research of negative feedback effect of thyroglobulin, Nan Fang Yi Ke Da Xue Xue Bao sourceSupported

May combine two claims.

Iodide overload decreases MCT8 mRNA and protein expression in rats, thus reducing T4 and T3 secretion into the blood stream.

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

• cites [102] de Souza, 2015, MCT8 is downregulated by short time iodine overload in the thyroid gland of rats, Horm Metab Res sourceNot checked — no full text of the source
• 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 sourcePartly 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)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

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

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

• 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) sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Many models focus on various aspects of the HPT axis, but models that specifically simulate the molecular regulations in thyroid follicles are still uncommon.

“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.”

• 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) sourceSupported
• cites [273] Saratchandran, 1976, An improved mathematical model of human thyroid hormone regulation, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [274] Liu, 1994, A new mathematical model of hypothalamo-pituitary-thyroid axis, Math Comput Model sourceNot checked — no full text of the source
• cites [275] Eisenberg, 2008, Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis, Thyroid sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Cohen et al. 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.

“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).”

• 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 sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

High iodide downregulates NIS through inhibition of NIS transcription, shortening of NIS mRNA poly(A) tail and destabilization, and shortening of NIS protein half-life.

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

• cites [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 sourceNot checked — no full text of the source
• cites [234] Eng, 2001, Regulation of the sodium iodide symporter by iodide in FRTL-5 cells, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [235] Leoni, 2008, Differential gene expression analysis of iodide-treated rat thyroid follicular cell line PCCl3, Genomics sourcePartly 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)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Many of the regulations reviewed 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.

“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.”

May combine two claims.

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.

“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).”

• cites [107] Rapoport, 1998, The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies, Endocr Rev sourceNot checked — no full text of the source

May combine two claims.

T3 represses gene transcription of DIO2, forming a negative feedback loop to keep intracellular T3 within a range.

“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).”

• cites [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 sourceNot checked — no full text of the source
• cites [31] Hosoi, 1999, Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [32] Bianco, 2019, Paradigms of dynamic control of thyroid hormone signaling, Endocr Rev sourceNot checked — no full text of the source

May combine two claims.

THBPs serve as a reservoir to buffer free T4 and T3 concentrations against transient fluctuations and ensure steady delivery of THs through target tissues.

“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).”

• cites [26] Schussler, 2000, The thyroxine-binding proteins, Thyroid sourceNot checked — no full text of the source
• cites [27] Richardson, 2007, Cell and molecular biology of transthyretin and thyroid hormones, Int Rev Cytol. sourceNot checked — no full text of the source

May combine two claims.

ANO1 is a calcium-activated chloride channel that mediates I- efflux across the apical membrane of thyrocytes.

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

• cites [54] Twyffels, 2014, Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte, Am J Physiol Cell Physiol sourceNot checked — no full text of the source

May combine two claims.

TG storage in the colloid 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.

“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).”

• cites [67] Marinò, 2000, Role of thyroglobulin endocytic pathways in the control of thyroid hormone release, Am J Physiol Cell Physiol sourceNot checked — no full text of the source
• cites [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 sourceNot checked — no full text of the source
• cites [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 sourceNot checked — no full text of the source
• cites [80] Berndorfer, 1996, Multimerization of thyroglobulin (TG) during extracellular storage: isolation of highly cross-linked TG from human thyroids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

May combine two claims.

In human blood, nearly 99.97% of T4 and 99.70% of T3 are bound to specific THBPs.

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

• cites [22] Mendel, 1989, The free hormone hypothesis: a physiologically based mathematical model, Endocr Rev sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Feedback and feedforward are key network motifs that underpin dynamic behaviors including signal amplification, multistability, adaptation, homeostasis, oscillation, fold-change detection, signaling delay and acceleration, threshold and nonmonotonic effect.

“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).”

• cites [48] Alon, 2007, Network motifs: theory and experimental approaches, Nat Rev Genet sourceNot checked — no full text of the source
• cites [49] El-Samad, 2021, Biological feedback control–respect the loops, Cell Syst sourceNot checked — no full text of the source

May combine two claims.

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.

“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).”

• cites [101] Trajkovic-Arsic, 2010, Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice, Endocrinology sourceNot checked — no full text of the source
• cites [102] de Souza, 2015, MCT8 is downregulated by short time iodine overload in the thyroid gland of rats, Horm Metab Res sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A human TG molecule contains on average 2.28 molecules of T4 and 0.29 molecules of T3.

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

• cites [67] Marinò, 2000, Role of thyroglobulin endocytic pathways in the control of thyroid hormone release, Am J Physiol Cell Physiol sourceNot checked — no full text of the source

May combine two claims.

Under circumstances such as iodine deprivation or TSH overstimulation, the colloid TG globule is solubilized by proteinases and the solubilized TG is taken up by thyrocytes.

“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).”

• cites [67] Marinò, 2000, Role of thyroglobulin endocytic pathways in the control of thyroid hormone release, Am J Physiol Cell Physiol sourceNot checked — no full text of the source

May combine two claims.

The close proximity between DUOX and TPO makes newly produced H2O2 readily captured by TPO and reduces potential oxidative damage by H2O2.

“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).”

• cites [64] Fortunato, 2010, Functional consequences of dual oxidase-thyroperoxidase interaction at the plasma membrane”, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [65] Song, 2010, Association of duoxes with thyroid peroxidase and its regulation in thyrocytes, J Clin Endocrinol Metab sourceNot checked — no full text of the source

May combine two claims.

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

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

• cites [77] Brix, 2020, Auto-regulation of the thyroid gland beyond classical pathways, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The active uptake of I- by NIS is Na+-dependent, coupling energy from inward Na+ translocation to inward I- translocation against its electrochemical gradient.

“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).”

• cites [52] Rousset, 2000, Thyroid hormone synthesis and secretionNot checked yet

  Not checked in the free run.

May combine two claims.

The positive and negative regulations of TSHR by TSH and cAMP form an incoherent feedforward control that is likely important for TSHR homeostasis and receptor desensitization.

“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.”

May combine two claims.

The Plummer effect is more prominent in hyperthyroid patients but also occurs, to a lesser degree, in euthyroid individuals.

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

• cites [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 sourceNot checked — no full text of the source

May combine two claims.

In FRTL-5 thyroid cells, TSH treatment first upregulates TSHR mRNA moderately in the initial 2 hours and then downregulates it by 75%, with mRNA recovering in 6 days after TSH withdrawal.

“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).”

• cites [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. sourceNot checked — no full text of the source
• cites [189] Saji, 1992, Regulation of thyrotropin receptor gene expression in rat FRTL-5 thyroid cells, Endocrinology sourceNot checked — no full text of the source

May combine two claims.

The inhibitory effect of high iodine involves blockade of multiple molecular events in 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.

“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 ).”

May combine two claims.

These TTFs play critical roles in thyroid differentiation and coordinately regulate the suite of functional genes involved in TH synthesis.

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

• cites [142] Suzuki, 1998, Autoregulation of thyroid-specific gene transcription by thyroglobulin, Proc Natl Acad Sci U.S.A. sourceNot checked — no full text of the source

May combine two claims.

The physiological function of cAMP signaling activated via Gαs is to promote TH synthesis, thyrocyte growth and proliferation.

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

May combine two claims.

The incoherent feedforward motif formed by Gαs and Gαi/o is responsible for the biphasic cAMP response and likely for similar downstream gene expression responses.

“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.”

May combine two claims.

These cross-regulations can be either stimulatory or inhibitory, forming tiered, coherent or incoherent feedforward motifs.

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

May combine two claims.

PAX8 binds to the 5'-flanking region of DUOX2 to activate its transcription, while TTF2 binds to the DUOX2 promoter but represses its transcription.

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

• cites [150] D’Andrea, 2006, Functional inactivation of the transcription factor Pax8 through oligomerization chain reaction, Mol Endocrinol sourceNot checked — no full text of the source

May combine two claims.

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.

“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 ).”

May combine two claims.

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.

“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.”

• cites [77] Brix, 2020, Auto-regulation of the thyroid gland beyond classical pathways, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source
• cites [130] Linke, 2002, Thyroid stimulating hormone upregulates secretion of cathepsin b from thyroid epithelial cells, Biol Chem sourceNot checked — no full text of the source

May combine two claims.

Negative feedback regulatory pathways operate on top of the feedforward backbone and provide important functions to thyroid homeostasis.

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

May combine two claims.

TTF1, TTF2, and PAX8 can bind to upstream enhancer and promoter regions of NIS and stimulate its transcriptional activity.

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

May combine two claims.

Iodide regulates TH synthesis in an incoherent feedforward manner because iodide is required for TH synthesis and high iodide inhibits TH synthesis.

“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).”

Probably not a substantial claim: may not pass S4 (based).

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

“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.”

May combine two claims. The quote only partly states this claim.

Iodolipid 2-IHDA is believed to play a major role in mediating the Wolff-Chaikoff inhibitory effect by inhibiting H2O2 production and TPO/TG expression.

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

May combine two claims.

The Plummer effect is believed to result from reduced proteolytic cleavage of iodinated TG to liberate T4 and T3 and inhibition of TH secretion from thyrocytes, forming another incoherent feedforward motif.

“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).”

• cites [226] Koukkou, 2017, Effect of excess iodine intake on thyroid on human health, Minerva Med sourceNot checked — no full text of the source

May combine two claims.

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

“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.”

May combine two claims.

Highly iodinated TG suppresses TTF1 and PAX8 expression at both mRNA and protein levels, likely mediated by augmented PKC and suppressed PKA activities.

“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).”

• cites [157] Huang, 2017, Iodinated TG in thyroid follicular lumen regulates TTF-1 and PAX8 expression via TSH/TSHR signaling pathway, J Cell Biochem sourceNot checked — no full text of the source

May combine two claims. The quote only partly states this claim.

TG-mediated feedback appears to inhibit processes leading to accumulation of iodinated TG and promote TG lysosomal degradation and TH release, and may function to maintain homeostasis of iodinated TG rather than THs.

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

Probably not a substantial claim: may not pass S2 (checkable).

A better understanding of complex pathways requires formulation of mathematical models to simulate the network as nonlinear dynamical systems.

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

• cites [49] El-Samad, 2021, Biological feedback control–respect the loops, Cell Syst sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S4 (based).

Dysregulation of the intrathyroidal molecular network, internally or externally by exogenous disruptors, can lead to pathological thyroid conditions including goiter, hypothyroidism, hyperthyroidism, and thyroid cancers.

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

• AssumptionRests on an assumption: The intrathyroidal molecular network described is sufficient to explain thyroid hormone homeostasis under physiological and pathological conditions.

May combine two claims.

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

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

• cites [257] Sellitti, 2014, Intrinsic regulation of thyroid function by thyroglobulin, Thyroid sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Systems biology models can incorporate genetic, epigenetic, environmental and nutritional status to better predict responses of individuals.

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

May combine two claims.

Follicles in a thyroid gland are highly heterogeneous in morphology and functional states, with variation in follicular size, TG content, colloid density, epithelial morphology, and iodide uptake and distribution.

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

• cites [261] Studer, 1989, Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth, Endocr Rev sourceNot checked — no full text of the source
• cites [262] Aeschimann, 1993, Morphological and functional polymorphism within clonal thyroid nodules, J Clin Endocrinol Metab sourceNot checked — no full text of the source

May combine two claims.

Degon et al. constructed a complex model describing 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.

“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).”

• cites [276] Degon, 2008, A computational model of the human thyroid, Math Biosci sourceNot checked — no full text of the source

May combine two claims. The quote only partly states this claim.

Wolff-Chaikoff escape involves negative feedback regulation of multiple processes, mainly NIS downregulation, PDS upregulation, and DEHAL/DIO1 downregulation, to normalize intracellular iodide and TH synthesis and release.

“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).”