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2.
J Mol Graph Model ; 129: 108725, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38373379

RESUMEN

The receptor for thyroid stimulating hormone (TSHR), a GPCR, is the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating TSHR antibodies. While we have previously published a full length model of the TSHR, including its leucine rich domain (LRD), linker region (LR) and transmembrane domain (TMD), to date, only a partial LRD (aa 21-261) stabilized with TSHR autoantibodies has been crystallized. Recently, however, cryo-EM structures of the full-length TSHR have been published but they include only an incomplete LR. We have now utilized the cryo-EM models, added disulfide bonds to the LR and performed longer (3000 ns) molecular dynamic (MD) simulations to update our previous model of the entire full-length TSHR, with and without the presence of TSH ligand. As in our earlier work, the new model was embedded in a lipid membrane and was solvated with water and counterions. We found that the 3000 ns Molecular Dynamic simulations showed that the structure of the LRD and TMD were remarkably constant while the LR, known more commonly as the "hinge region", again showed significant flexibility, forming several transient secondary structural elements. Analysis of the new simulations permitted a detailed examination of the effect of TSH binding on the structure of the TSHR. We found a structure-stabilizing effect of TSH, including increased stability of the LR, which was clearly demonstrated by analyzing several intrinsic receptor properties including hydrogen bonding, fluctuation of the LRD orientation, and radius of gyration. In conclusion, we were able to quantify the flexibility of the TSHR and show its increased stability after TSH binding. These data indicated the important role of ligands in directing the signaling structure of a receptor.


Asunto(s)
Receptores de Tirotropina , Tirotropina , Receptores de Tirotropina/química , Receptores de Tirotropina/metabolismo , Ligandos , Tirotropina/química , Tirotropina/metabolismo , Leucina
3.
Thyroid ; 34(3): 281-287, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38047527
4.
Endocrinology ; 164(11)2023 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-37767722

RESUMEN

The thyroid-stimulating hormone receptor (TSHR) transmembrane domain (TMD) is found in the plasma membrane and consists of lipids and water molecules. To understand the role of TSHR-associated water molecules, we used molecular dynamic simulations of the TMD and identified a network of putative receptor-associated transmembrane water channels. This result was confirmed with extended simulations of the full-length TSHR with and without TSH ligand binding. While the transport time observed in the simulations via the TSHR protein was slower than via the lipid bilayer itself, we found that significantly more water traversed via the TSHR than via the lipid bilayer, which more than doubled with the binding of TSH. Using rat thyroid cells (FRTL-5) and a calcein fluorescence technique, we measured cell volumes after blockade of aquaporins 1 and 4, the major thyroid cell water transporters. TSH showed a dose-dependent ability to influence water transport, and similar effects were observed with stimulating TSHR autoantibodies. Small molecule TSHR agonists, which are allosteric activators of the TMD, also enhanced water transport, illustrating the role of the TMD in this phenomenon. Furthermore, the water channel pathway was also mapped across 2 activation motifs within the TSHR TMD, suggesting how water movement may influence activation of the receptor. In pathophysiological conditions such as hypothyroidism and hyperthyroidism where TSH concentrations are highly variable, this action of TSH may greatly influence water movement in thyroid cells and many other extrathyroidal sites where the TSHR is expressed, thus affecting normal cellular function.

6.
Ann N Y Acad Sci ; 1525(1): 61-69, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37199228

RESUMEN

Seasonal changes in food intake and adiposity in many animal species are triggered by changes in the photoperiod. These latter changes are faithfully transduced into a biochemical signal by melatonin secreted by the pineal gland. Seasonal variations, encoded by melatonin, are integrated by third ventricular tanycytes of the mediobasal hypothalamus through the detection of the thyroid-stimulating hormone (TSH) released from the pars tuberalis. The mediobasal hypothalamus is a critical brain region that maintains energy homeostasis by acting as an interface between the neural networks of the central nervous system and the periphery to control metabolic functions, including ingestive behavior, energy homeostasis, and reproduction. Among the cells involved in the regulation of energy balance and the blood-hypothalamus barrier (BHB) plasticity are tanycytes. Increasing evidence suggests that anterior pituitary hormones, specifically TSH, traditionally considered to have unitary functions in targeting single endocrine sites, display actions on multiple somatic tissues and central neurons. Notably, modulation of tanycytic TSH receptors seems critical for BHB plasticity in relation to energy homeostasis, but this needs to be proven.


Asunto(s)
Melatonina , Animales , Melatonina/fisiología , Células Ependimogliales/metabolismo , Hipotálamo/fisiología , Encéfalo/metabolismo , Tirotropina/metabolismo , Estaciones del Año , Homeostasis
7.
Endocrinology ; 164(6)2023 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-37120783

RESUMEN

Instructive signals that delineate the formation of thyroid follicles by thyrotropin (TSH) in stem cells are complex. Here, we have examined the role of protein kinase C (PKC) by using a unique Gαq/11 biased small molecule (MSq1) to develop thyroid progenitor cells. Mouse embryonic stem cells (mESCs) were differentiated into anterior endoderm cells and treated with either TSH or MSq1 in the presence or absence of PKC inhibitors. The transcriptional and translational response of key thyroid markers-sodium iodide symporter (NIS), thyroglobulin (TG), and thyrotropin receptor (TSHR) as well as potential signaling molecules-were then analyzed. The data confirmed that MSq1 is a potent Gαq/11 activator with a major increase in Gαq/11 signaling when compared to TSH. MSq1 activation resulted in an increase in thyroid-specific genes, demonstrating that enhanced PKC signaling was able to induce their expression. The specificity of the PKC signals over the protein kinase A (PKA) pathway in regulating thyroid gene expression was shown by using a specific PKC enzyme inhibitor. The data revealed that TG and NIS expression were suppressed in the presence of the PKC inhibition but, in contrast, were not influenced by PKA inhibition. This indicated that PKC activation was the dominant pathway in the inductive process for thyroid hormone production. Furthermore, by examining PKC isoforms we found that PKCξ was the predominant form in the ES cells that mediated the effects. Since PKCξ can lead to activation of transforming growth factor-ß-activated kinase (pTAK1), and its downstream effector nuclear factor κB (NFκB) complex, this demonstrated the involvement of the TAK1/NFκB pathway in thyroid speciation.


Asunto(s)
Proteína Quinasa C , Glándula Tiroides , Animales , Ratones , Glándula Tiroides/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Tirotropina/farmacología , Tirotropina/metabolismo , Receptores de Tirotropina/genética , Receptores de Tirotropina/metabolismo , Células Madre/metabolismo
8.
Thyroid ; 33(4): 532, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36961419
9.
J Autoimmun ; 136: 103012, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36898184

RESUMEN

BACKGROUND: Graves' disease is associated with TSH receptor (TSHR) antibodies of variable bioactivity including "neutral" antibodies (N-TSHR-Ab) that bind to the hinge region of the TSHR ectodomain. We have previously found that such antibodies induced thyroid cell apoptosis via excessive mitochondrial and ER stress with elevated reactive oxygen species (ROS). However, the detailed mechanisms by which excess ROS was induced remained unclear. OBJECTIVES: To determine how ROS is induced by N-TSHR-monoclonal antibodies (mAb, MC1) mediated signaling and to measure stress in polyorganelles. METHODS: Total ROS and mitochondrial ROS was measured by fluorometry of live rat thyrocytes. Live-cell imaging of labelled organelles was carried out using red or green fluorescent dyes. Proteins were detected by Li-Cor Western immunoblots and immunocytochemistry. RESULTS: Endocytosis of N-TSHR-mAb induced ROS, disturbed vesicular trafficking, damaged organelles and failed to induce lysosomal degradation and autophagy. We found that the endocytosis triggered signaling cascades involving Gα13 and PKC-δ leading to intrinsic thyroid cell apoptosis. CONCLUSIONS: These studies define the mechanism of ROS induction in thyroid cells following the endocytosis of N-TSHR-Ab/TSHR complexes. We suggest that a viscous cycle of stress initiated by cellular ROS and induced by N-TSHR-mAbs may orchestrate overt intra-thyroidal, retro-orbital, and intra-dermal inflammatory autoimmune reactions in patients with Graves' disease.


Asunto(s)
Enfermedad de Graves , Ratas , Animales , Especies Reactivas de Oxígeno/metabolismo , Inmunoglobulinas Estimulantes de la Tiroides , Receptores de Tirotropina , Anticuerpos Monoclonales/farmacología
10.
Elife ; 122023 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-36656634

RESUMEN

The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.


Asunto(s)
Huesos , Osteoblastos , Humanos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteocitos/metabolismo , Hormonas Hipofisarias/metabolismo
12.
Endocrinology ; 163(12)2022 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-36223484

RESUMEN

Biophysical studies have established that the thyrotropin (TSH) receptor (TSHR) undergoes posttranslational modifications including dimerization. Following our earlier simulation of a TSHR-transmembrane domain (TMD) monomer (called TSHR-TMD-TRIO) we have now proceeded with a molecular dynamics simulation (MD) of TSHR-TMD dimerization using this improved membrane-embedded model. The starting structure was the TMD protein with all extracellular and intracellular loops and internal waters, which was placed in the relative orientation of the model originally generated with Brownian dynamics. Furthermore, this model was embedded in a DPPC lipid bilayer further solvated with water and added salt. Data from the MD simulation studies showed that the dimeric subunits stayed in the same relative orientation and distance during the 1000 ns of study. Comparison of representative conformations of the individual monomers when dimerized with the conformations from the monomer simulation showed subtle differences as represented by the backbone root mean square deviations. Differences in the conformations of the ligand-binding sites, suggesting variable affinities for these "hot spots," were also revealed by comparing the docking scores of 46 small-molecule ligands that included known TSHR agonists and antagonists as well as their derivatives. These data add further insight into the tendency of the TSHR-TMD to form dimeric and oligomeric structures and show that the differing conformations influence small-molecule binding sites within the TMD.


Asunto(s)
Receptores de Tirotropina , Tirotropina , Receptores de Tirotropina/metabolismo , Dimerización , Dominios Proteicos , Tirotropina/metabolismo , Ligandos
13.
Elife ; 112022 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-36305581

RESUMEN

(GPCR)The receptor for TSH receptor (TSHR), a G protein coupled receptor (GPCR), is of particular interest as the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating TSHR antibodies. To date, only one domain of the extracellular region of the TSHR has been crystallized. We have run a 1000 ns molecular dynamic simulation on a model of the entire TSHR generated by merging the extracellular region of the receptor, obtained using artificial intelligence, with our recent homology model of the transmembrane domain, embedded it in a lipid membrane and solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linker region (LR), known more commonly as the 'hinge region,' showed significant flexibility, forming several transient secondary structural elements. Furthermore, the relative orientation of the leucine-rich domain with the rest of the receptor was also seen to be variable. These data suggest that this LR is an intrinsically disordered protein. Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the LR and TSH ligand and (b) the association of the LR and the TSH ligand reduces the structural fluctuations in the LR. This full-length model illustrates the importance of the LR in responding to ligand binding and lays the foundation for studies of pathologic TSHR autoantibodies complexed with the TSHR to give further insight into their interaction with the flexible LR.


Asunto(s)
Inteligencia Artificial , Receptores de Tirotropina , Receptores de Tirotropina/química , Receptores de Tirotropina/metabolismo , Ligandos , Leucina/metabolismo , Autoanticuerpos , Receptores Acoplados a Proteínas G , Tirotropina/química , Tirotropina/metabolismo
14.
Elife ; 112022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-36052994

RESUMEN

There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHR, LHCGR, and FSHR. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and subnuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and subnuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHR in human brain samples, where transcripts were co-localized in MALAT1-positive neurons. In addition, we show high expression for all three receptors in the ventricular region-with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. In contrast, Fshr was localized to NeuN-positive neurons in the granular layer of the dentate gyrus in murine and human brain-both are Alzheimer's disease-vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.


Asunto(s)
Glicoproteínas , Células de Sertoli , Animales , Encéfalo , Hormonas , Humanos , Masculino , Ratones , Testículo/fisiología
15.
Front Endocrinol (Lausanne) ; 13: 943459, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35909553

RESUMEN

TSH receptor (TSHR) antibodies are the cause of Graves' disease and may also be found in patients with Hashimoto's thyroiditis. They come in at least three varieties: thyroid stimulating, thyroid blocking and neutral. The measurement of TSH receptor antibodies in Graves' disease and Hashimoto's thyroiditis is a common clinical activity and can be useful in diagnosis and prognosis. We show that it is not possible to detect the blocking variety of TSHR antibody in patients with Graves' disease because the stimulating antibody may overwhelm the measurement of blocking in the bioassays available for their measurement and may blind the valid interpretation of the results. To help explain this in more detail we show a series of studies with monoclonal TSHR antibodies which support this conclusion.


Asunto(s)
Anticuerpos Monoclonales , Enfermedad de Graves , Enfermedad de Hashimoto , Receptores de Tirotropina , Anticuerpos Monoclonales/análisis , Autoanticuerpos/análisis , Enfermedad de Graves/diagnóstico , Enfermedad de Hashimoto/diagnóstico , Humanos , Receptores de Tirotropina/análisis
17.
J Autoimmun ; 126: 102746, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34801870

RESUMEN

BACKGROUND: Graves' disease (GD) is associated with thyroid stimulating hormone (TSH) receptor (TSHR) antibodies of variable bioactivity. We have previously characterized "neutral" TSHR antibodies (N-TSHR-Abs) that bind to the hinge region of the TSHR ectodomain. We showed that an N-TSHR monoclonal antibody (mAb) failed to induce any G proteins to sustain survival signaling and lead to excessive stress and apoptosis. Furthermore, the addition of TSH, or the antioxidant N-acetyl-l-cysteine (NAC), rescued N-TSHR-mAb-induced apoptotic death. However, the detailed mechanisms of this rescue remained unclear. METHODS: Autophagy is activated in response to diverse stress related stimuli so we have, therefore, studied the autophagy response in rat thyroid cells (FRTL-5) during N-TSHR-mAb induced thyrocyte stress and apoptosis using the In Cell Western technique for quantitation along with immunocytochemistry. RESULTS: Under starvation conditions with N-TSHR-mAb the addition of TSH or NAC prevented thyroid cell death by enhancing autophagy. This was evidenced by elevated levels of autophagy related proteins including beclin 1, LC3A, LC3B, ULK1, p62, and also activated pink and perkin mitophagy related proteins. The phenomenon was further confirmed by image analyses using Cyto-ID and Mito-ID autophagy detection systems. We also found that either TSH or NAC enhanced PKA, Akt, mTORC, AMPK, Sirtuins, PGC1α, NRF-2, mitofusin-2, TFAM and catalase in the N-TSHR-mAb stressed cells. Thus TSH or NAC restored cell survival signaling which reduced cell stress and enhanced mitochondrial biogenesis. The N-TSHR-mAb also activated cytochrome-C, Bax, caspase-9, caspase-3A, and had less effect on FADD or caspase-8 indicating activation of the intrinsic pathway for apoptosis. CONCLUSIONS: These findings indicated that TSH or antioxidant can rescue thyroid cells from N-TSHR-mAb induced apoptosis via enhanced autophagy. These observations signify that N-TSHR-mAb in GD under low TSH conditions caused by the hyperthyroidism could be detrimental for thyrocyte survival which would be another factor able to precipitate ongoing autoinflammation.


Asunto(s)
Receptores de Tirotropina , Glándula Tiroides , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacología , Apoptosis , Autofagia , Ratas
18.
Am J Ind Med ; 65(2): 117-131, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34825393

RESUMEN

BACKGROUND: The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions. OBJECTIVES: Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC. METHODS: Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases. RESULTS: Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's. CONCLUSIONS: The study found no statistically significant increased risk of autoimmune conditions with WTC exposures.


Asunto(s)
Enfermedades Autoinmunes , Socorristas , Exposición Profesional , Ataques Terroristas del 11 de Septiembre , Enfermedades Autoinmunes/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Incidencia , Masculino , Ciudad de Nueva York , Exposición Profesional/efectos adversos
19.
Thyroid ; 32(4): 429-439, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34927457

RESUMEN

Background: Graves' eye disease, also called Graves' orbitopathy (GO), is a potentially debilitating autoimmune disease associated with retro-orbital inflammation and tissue expansion, involving both fibroblasts and adipocytes, resulting in periorbital edema, worsening proptosis, and muscle dysfunction with diplopia and may ultimately threaten sight. Accumulating evidence has indicated that autoantibodies to the thyrotropin receptor (TSHR), which induce the hyperthyroidism of Graves' disease, also help mediate the pathogenesis of the eye disease in susceptible individuals through TSHR expression on retro-orbital cells. Since it has long been known that the effects of insulin-like growth factor 1 (IGF-1) and thyrotropin are additive, recent clinical trials with a human monoclonal IGF-1 receptor blocking antibody (teprotumumab; IGF-1R-B-monoclonal antibody [mAb]) have demonstrated its ability to induce significant reductions in proptosis, diplopia, and clinical activity scores in patients with GO. However, the molecular mechanisms by which such an antibody achieves this result is unclear. Methods: We have used Li-Cor In-Cell Western, Western blot, and immunohistochemistry to define levels of different proteins in mouse and human fibroblast cells. Proteomic array was also used to define pathway signaling molecules. Using CCK-8 and BrdU cell proliferation ELISA, we have analyzed proliferative response of these cells to different antibodies. Results: We now show that a stimulating TSHR antibody was able to induce phosphorylation of the IGF-1R and initiate both TSHR and IGF-1R signaling in mouse and human fibroblasts. IGF-1R-B-mAb (1H7) inhibited all major IGF-1R signaling cascades and also reduced TSHR signaling. This resulted in the antibody-induced suppression of autophagy as shown by inhibition of multiple autophagy-related proteins (Beclin1, LC3a, LC3b, p62, and ULK1) and the induction of cell death by apoptosis as evidenced by activation of cleaved caspase 3, FADD, and caspase 8. Furthermore, this IGF-1R-blocking mAb suppressed serum-induced perkin and pink mitophagic proteins. Conclusions: Our observations clearly indicated that stimulating TSHR antibodies were able to enhance IGF-1R activity and contribute to retro-orbital cellular proliferation and inflammation. In contrast, an IGF-1R-B-mAb was capable of suppressing IGF-1R signaling leading to retro-orbital fibroblast/adipocyte death through the cell-extrinsic pathway of apoptosis. This is likely the major mechanism involved in proptosis reduction in patients with Graves' eye disease treated by IGF-1R inhibition.


Asunto(s)
Enfermedad de Graves , Oftalmopatía de Graves , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Apoptosis , Diplopía , Fibroblastos , Oftalmopatía de Graves/metabolismo , Humanos , Inmunoglobulinas Estimulantes de la Tiroides/metabolismo , Inflamación/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones , Proteómica , Receptor IGF Tipo 1/metabolismo , Receptores de Tirotropina , Tirotropina/metabolismo
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