The bones act as a (metaphorical) "bank of calcium" from which the body can make "withdrawals" as needed to keep the amount of calcium in the blood at appropriate levels despite the ever-present challenges of metabolism, stress, and nutritional variations. Among the substances that can be considered hormones, are eicosanoids (e.g. Insulin secretion at 25mM glucose is significantly (P .05) more than the insulin secretion at 5mM glucose for all conditions. To test this hypothesis, -cell replication was measured in islet cell cultures treated with vehicle, an 2-adrenergic antagonist (mirtazapine), an 2-adrenergic agonist (NE or guanabenz), a PDE-I (trequinsin or dipyridamole), or combinations of these compounds (Figure 5C). Thus, enhanced cAMP production is not always sufficient to induce -cell replication. Abdollahi M, Chan TS, Subrahmanyam V, O'Brien PJ. Fifth, dipyridamole's ability to promote -cell replication is suppressed by NE-dependent inhibition of cAMP production. [18][19], Compared with vertebrates, insects and crustaceans possess a number of structurally unusual hormones such as the juvenile hormone, a sesquiterpenoid. In vertebrates, endocrine glands are specialized organs that secrete hormones into the endocrine signaling system. At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system , although other systems can be involved even independently of cAMP . After each incubation period, KRB buffer was collected and frozen. Medical Physiology. Consequently, developing medications to promote -cell regeneration is a priority. . The ability of PDE4-I and PDE10-I to promote -cell replication indicates that dipyridamole's likely mechanism of action is through dual inhibition of PDE4 and PDE10. [31] Normal total plasma calcium level ranges from 8.5 to 10.2mg/dL (2.12mmol/L to 2.55mmol/L). [22], Most hormones initiate a cellular response by initially binding to either cell membrane associated or intracellular receptors. They also have a rapid degradation cycle, making sure they do not reach distant sites within the body. A more important effect of PTH on the kidney is, however, its inhibition of the reabsorption of phosphate (HPO42) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Additionally, treatment with dipyridamole may reduce blood glucose levels in humans. Search for other works by this author on: Effects of pregnancy in the rat on the size and insulin secretory response of the islets of Langerhans, A morphological study of the endocrine pancreas in human pregnancy, Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones, Pancreatic beta-cell mass in European subjects with type 2 diabetes, Relationship between beta-cell mass and fasting blood glucose concentration in humans, Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation, Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass, Growth and regeneration of adult beta cells does not involve specialized progenitors, Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans, -Cell mass and turnover in humans: effects of obesity and aging, Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes, Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes, Effects of glucose on beta cells in pancreatic monolayer cultures, Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion, Control of pancreatic cell regeneration by glucose metabolism, Molecular regulation of pancreatic beta-cell mass development, maintenance, and expansion, Adenosine signaling promotes regeneration of pancreatic cells in vivo, Osteocalcin promotes -cell proliferation during development and adulthood through Gprc6a, Imaging cyclic AMP changes in pancreatic islets of transgenic reporter mice, PTHrP increases pancreatic beta-cell-specific functions in well-differentiated cells, Exendin-4 induction of cyclin D1 expression in INS-1 beta-cells: involvement of cAMP-responsive element, Prolactin, progesterone, and dexamethasone coordinately and adversely regulate glucokinase and cAMP/PDE cascades in MIN6 beta-cells, Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(737), Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells, Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes, Stimulation of pancreatic beta-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways, cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2, Increased pancreatic beta-cell proliferation mediated by CREB binding protein gene activation, Conditional gene targeting in mouse pancreatic -cells: analysis of ectopic Cre transgene expression in the brain, Targeting beta-cell cyclic 35 adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A mild decrease in serum magnesium levels stimulates the reabsorptive activity PTH has on the kidneys. B, The percentage of -cells (insulin-positive cells) that incorporated BrdU is shown (n = 5 animals per treatment condition). The latter have longer amino acid chain lengths than the former. Hormones are used to communicate between organs and tissues. The level may be stated in pg/dL or pmol/L (sometimes abbreviated mmol/L); multiply by 0.1060 to convert from pg/dL to pmol/L. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). Islets were then serially transferred via the cell strainer to new wells that contained KRB buffer with variable glucose concentrations (2.5mM, 5mM, 15mM, and 25mM with or without compound or vehicle). Cells were then washed and permeabilized with PBS/0.3% Triton X-100. [8], Another agent involved in autocrine cancer signaling is vascular endothelial growth factor (VEGF). A, The fold induction of -cell replication in compound-treated vs vehicle-treated cells measured using PDX-1 expression to identify -cells and PCNA expression to identify cellular replication events is shown. Acts on the nearby cells and does not have to enter general circulation. Whether these medications are protective against diabetes remains to be tested. Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. By contrast, CGS 15943 did not impair the ability of the adenosine kinase inhibitors 5-iodotubercidin and ABT-702 to promote -cell replication (Figure 4D) (46). To bind their receptors, these hormones must first cross the cell membrane. At the cellular level, the lack of StAR results in a pathologic accumulation of lipid within cells, especially noticeable in the adrenal cortex as seen in the mouse model. [9] One known exception is the human placenta. The ability to metabolize NE may provide an endogenous mechanism for terminating the inhibitory signal generated by neuronal release of NE. Exhibitionist & Voyeur 05/29/22: Monica 60: SPREAD EAGLE (5.00) A rise in intracellular calcium may potentiate cAMP production by increasing the activity of specific adenylyl cyclases. Wei J, Hanna T, Suda N, Karsenty G, Ducy P. Kim JW, Roberts CD, Berg SA, Caicedo A, Roper SD, Chaudhari N. Sawada Y, Zhang B, Okajima F, Izumi T, Takeuchi T. Holz GG 4th, Khtreiber WM, Habener JF. Although the maximum effect of dipyridamole was observed at 2 years rather than more immediately, its effect may not be a result of increased -cell replication, eg, increased insulin secretion. Antigen retrieval was performed for staining of rat islet cultures (described above) and for human pancreatic sections by heating slides to 90C for 10 minutes in 10mM sodium citrate (pH 6.0) solution. Free OPG competitively binds to RANKL as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. Parathyroid hormone regulates serum calcium through its effects on bone, kidney, and the intestine:[5], In bone, PTH enhances the release of calcium from the large reservoir contained in the bones. [20][21] In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory factors associated with cardiovascular disease. Meier JJ, Butler AE, Saisho Y, et al. These results indicate that PDE-Idependent induction of -cell replication in vivo may be limited by the requirement for concurrent stimulation of cAMP generation. When a competing ligand is bound to the receptor site, the hormone is unable to bind to that site and is unable to elicit a response from the target cell. Data are normalized to the vehicle-treated control wells. [6] Its action is opposed by the hormone calcitonin. Our goal is to develop a method for expanding human -cell mass. [citation needed], Another example occurs in activated T cell lymphocytes, i.e., when a T cell is induced to mature by binding to a peptide:MHC complex on a professional antigen-presenting cell and by the B7:CD28 costimulatory signal. PTH is "a key that unlocks the bank vault" to remove the calcium. Negative feedback must be triggered by overproduction of an "effect" of the hormone.[29][30]. Decreased -cell replication in response to compound treatment in the absence vs the presence of CGS-15943 are indicated (*, P .01). The nature of our strategy for assessing the impact of dipyridamole and mirtazapine on blood glucose, eg, use of random glucose values, is expected to bias our outcome toward the null hypothesis. Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. The extended helical conformation of hPTH-(1-84) is the likely bioactive conformation. Because dipyridamole inhibits adenosine reuptake and augments adenosine signaling, we directly tested the impact of adenosine signaling on -cell replication by treating islet cultures with the adenosine analog 5-N-ethylcarboxamidoadenosine (NECA). He transplanted a testis from another rooster to a rooster with one testis removed, and saw that they had normal behavior and physical anatomy as well. [citation needed], Tumor development is a complex process that requires cell division, growth, and survival. Hormone secretion can be stimulated and inhibited by: One special group of hormones is the tropic hormones that stimulate the hormone production of other endocrine glands. oestrogen and brassinosteroid), amino acid derivatives (e.g. As an initial experiment, we tested the ability of NE to suppress insulin secretion in an 2-adrenergic receptor-dependent manner by treating isolated rat islets with NE in the absence and presence the 2-adrenergic receptor antagonist mirtazapine (Figure 5A). After more than twenty years, Questia is discontinuing operations as of Monday, December 21, 2020. [33][34], Model organisms have been used in the study of PTH function. The adaptive stress response depends upon a highly interconnected neuroendocrine, cellular, It was later identified that this factor was the hormone testosterone. However, the -cell replication response to dipyridamole was mitigated by cotreatment with nitredipine (8% vs 2.4%, P < .001) or H89 (8% vs 0.7%, P < .001). The predominant PDE expressed by human and rodent -cells is PDE3B (33). [33] Finally, like a classic hormone, the neurohormone is released into the bloodstream to reach its target. Steinthorsdottir V, Thorleifsson G, Sulem P, et al. [33], Many hormones and their structural and functional analogs are used as medication. A, The -cell replication response of islet cell cultures treated with several PDE-Is (10M) found to induce -cell replication in primary screening. [4] Several studies have outlined the importance of autocrine IL-6 signaling in lung and breast cancers. Additionally, GLP-1dependent induction of -cell replication may be prevented by the expression of cAMP response element modulator- and the dual-specificity phosphatase DUSP14, which have been shown to repress GLP-1dependent -cell replication (50). Third, compounds that mimic other functions of dipyridamole, which include inhibition of PDE5, ADA, thromboxane A2 synthase, and adenosine reuptake, do not promote -cell replication. [3], Some peptide/protein hormones (angiotensin II, basic fibroblast growth factor-2, parathyroid hormone-related protein) also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism. . Home Page: Journal of Investigative Dermatology - jidonline.org The growth-promoting activity of PDE-Is requires PKA and VDCC activity. Hence, Gs-coupled receptor agonists such as GLP-1 may be useful for promoting -cell replication. Intracrine refers to a hormone that acts inside a cell, regulating intracellular events.In simple terms it means that the cell stimulates itself by cellular production of a factor that acts within the cell. PDX-1 is a transcription factor predominantly expressed by mature rat -cells and a fraction of -cells (47). None of these compounds promote -cell replication. Auf dieser Seite finden Sie alle Informationen der Deutschen Rentenversicherung, die jetzt wichtig sind: Beratung und Erreichbarkeit, Online-Antragstellung, Servicetipps und vieles mehr. . A, Pancreatic sections were generated from wild-type mice that had been maintained in BrdU-containing water (7 days) and treated with vehicle, dipyridamole (2 mg/kg), mirtazapine (2 mg/kg), or both dipyridamole (2 mg/kg) and mirtazapine (2 mg/kg). Islets were serially incubated at various glucose concentrations in the presence of DMSO (0.1% vol/vol), dipyridamole (15M), Ex4 (20nM), or dipyridamole (15M) plus Ex4 (20nM). Thus, all PCNA+ cells are ki-67+, but some ki-67+ cells are PCNA. . Each condition was performed in triplicate at minimum. These results led us to hypothesize that 2-adrenergic receptor-mediated suppression of -cell replication might be dominant over PDE-Idependent induction of -cell replication; if 2-adrenergic agonists inhibit cAMP generation, then PDE-Is don't have a pool of cAMP to stabilize. When a hormone binds to the receptor, it results in the activation of a signal transduction pathway that typically activates gene transcription, resulting in increased expression of target proteins. Buse MG, Johnson AH, Kuperminc D, Buse J. Peterhoff M, Sieg A, Brede M, Chao CM, Hein L, Ullrich S. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Gao J, Tian L, Weng G, O'Brien TD, Luo J, Guo Z. Guthalu Kondegowda N, Joshi-Gokhale S, Harb G, et al. C, The percentage of DAPI-positive cells that incorporated BrdU is shown. Additionally, a variety of signaling molecules including glucagon like peptide-1 (GLP-1), PTHrP, prolactin, adenosine, and osteocalcin promote -cell replication (1719). Parallel studies of cytosolic free Ca2+ and insulin release, Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats, Stimulating -cell replication and improving islet graft function by AR231453, a GPR119 agonist, Parathyroid hormone-related protein enhances human -cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression, Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth, Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells, Skp2 is required for incretin hormone-mediated -cell proliferation, Exendin-4 stimulation of cyclin A2 in beta-cell proliferation, Cyclic AMP signaling in pancreatic islets, Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice, Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance, Targeting the cell cycle inhibitor p57Kip2 promotes adult human cell replication, Glucose tolerance in depressed inpatients, under treatment with mirtazapine and in healthy controls, Copyright 2014 by the Endocrine Society, Editorial: Final Musings on the Impact of Molecular Endocrinology, Editorial: Reflections on the Impact of Molecular Endocrinology on a Scientific Career, Bidding a Fond Farwell to Molecular Endocrinology, Editorial Reflections on the Demise of Molecular Endocrinology and the Future of Molecular Hormone Action Research, Reflections on the Merger of Molecular Endocrinology and Endocrinology, The Journal of Clinical Endocrinology & Metabolism, Receive exclusive offers and updates from Oxford Academic, Type III Phosphodiesterase Plays a Necessary Role in the Growth-Promoting Actions of Insulin, Insulin-Like Growth Factor-I, and Ha p21, Inhibitors of Phosphodiesterase III Block Stimulation of, Autophosphoryiation of Rat Liver Type II cAMP-Dependent Protein Kinase. Most hormones can be classified as either amino acidbased hormones (amine, peptide, or protein) or steroid hormones. He noticed in castrated roosters that they did not have the same sexual behaviors as roosters with their testes intact. C, The effect of mirtazapine (10M), NE (0.4M), guanabenz (10M), trequinsin (2M), dipyridamole (15M), and combinations thereof on the replication of primary -cells in vitro are shown (*, P < .05). Song WJ, Schreiber WE, Zhong E, et al. The replication rate of -cells increased from 2.8% in vehicle-treated cells to 8% in response to dipyridamole treatment (P < .001). . [1] Endocrine physiology on the other hand is a growing field and has had a new area explored, called intracrinology. A hormone may also regulate the production and release of other hormones. Although studies have established that aA-adrenergic receptor overexpression impairs insulin secretion, our experimental results indicate that the mechanism by which hyperactive adrenergic signaling contributes to the development of diabetes may be, in part, through inhibition of compensatory -cell growth. AFS was a file system and sharing platform that allowed users to access and distribute stored content. Consequently, there is substantial interest in finding methods to stimulate -cell replication. Despite the fact that nonselective PDE inhibitors (PDE-Is) such as 3-Isobutyl-1-methylxanthine are known to stimulate -cell replication in vitro, an effort to assess the ability of highly selective PDE-Is to stimulate -cell replication has not been undertaken (35). Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl out of the mitochondria to facilitate contact site formation. In a recent study, one group showed that STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibiting caspase cleavage. 4 days ago. One study showed that autocrine PDGFR signaling plays an essential role in epithelial-mesenchymal transition (EMT) maintenance in vitro, which is known to correlate well with metastasis in vivo. -Cells express a variety of PDEs that degrade cAMP and limit the growth-promoting effects of adenosine. Although the expression pattern of PDE family members in -cells and the role of cAMP in governing -cell replication are not established, we hypothesized that -cells and -cells might display distinct replication responses to PDE-Is. [33] In this pathway, the result of the electrical signal produced by a neuron is the release of a chemical, which is the neurohormone. prostaglandins and thromboxanes), steroids (e.g. Cyclic 3, 5-adenosine monophosphate, cAMP Once formed, the cyclic AMP causes the hormonal effects inside the cell. It is now clear that this process is primarily mediated by the action of StAR. Secretion of parathyroid hormone is determined chiefly by serum ionized calcium concentration through negative feedback. For example, a small-molecule mimetic of Smac/Diablo that counteracts the inhibition of apoptosis has been shown to enhance apoptosis caused by chemotherapeutic drugs through autocrine-secreted tumor necrosis factor alpha (TNF). These GPCR ligands cause -cell replication by activating cAMP-dependent signaling and inducing the expression of cell cycle-promoting proteins such as cyclins (cyclin A2, D1, and D3), S-phase kinase-associated protein 2 (skp2) and cdk2 and -4 that are required for -cell mass expansion and by repressing the-negative cell cycle regulator p27 (27, 6165). However, tadalafil, a potent inhibitor of PDE11, does not increase -cell replication (Figure 3D). For primary screening, -cell replication rates were estimated by measuring the frequency of ki-67 expression, a cell-cycle marker, by PDX-1+ cells. They knew that the pancreas was involved in the secretion of digestive fluids after the passage of food from the stomach to the intestines, which they believed to be due to the nervous system. Parathyroid cells express calcium-sensing receptors on the cell surface. Come and visit our site, already thousands of classified ads await you What are you waiting for? The reintroduction of a missing behaviorally dependent hormonal source (or its types of action) is expected to bring back the absent behavior. . Latest breaking news, including politics, crime and celebrity. [16] Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. The main determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration itself. Steroid hormones act through intracellular (mostly nuclear) receptors and, thus, may be considered to be intracrines. At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system, although other systems can be involved even independently of cAMP.[8]. (2021). [1] Most hormones can be classified as either amino acidbased hormones (amine, peptide, or protein) or steroid hormones. PTH is secreted in response to low blood serum calcium (Ca2+) levels. Cholesterol needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome P450scc enzyme (CYP11A1) cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis. For instance, high blood sugar (serum glucose concentration) promotes insulin synthesis. A, The replication rate of -cells, the percentage of PDX-1expressing cells that coexpressed ki-67, was determined after 24, 48, 72, and 96 hours of compound treatment (DMSO 0.1% vol/vol, dipyridamole [15M] and Ex4 [20nM]). Evidence also shows that the presence of StAR in a type of immune cell, the macrophage, where it can stimulate the production of 27-hydroxycholesterol. In vertebrates, hormones are responsible for regulating a variety of physiological processes and behavioral activities such as digestion, metabolism, respiration, sensory perception, sleep, excretion, lactation, stress induction, growth and development, movement, reproduction, and mood manipulation. An example of an autocrine agent is the cytokine interleukin-1 in monocytes. Treatment of adult human islet cultures with dipyridamole or mirtazapine failed to induce -cell replication (data not shown). Elevated glucose levels and compounds such as glyburide that trigger insulin secretion promote -cell replication (16, 53). Next we demonstrated that norepinephrine (NE), a physiologic suppressor of cAMP synthesis in -cells, impairs -cell replication via activation of 2-adrenergic receptors. Retrieved 2017-02-08. This autocrine loop is another example of an attractive therapeutic target. As a first step toward testing this hypothesis, we measured the inhibitory activity of several PDE-Is against 20 recombinant human PDE enzymes (Figure 4A). Guyton A (1976). Therefore, dipyridamole-induced -cell replication requires VDCC-mediated calcium conductance and PKA signaling activity. He was able to see that location of the testes does not matter. Mutations in the gene for StAR cause lipoid congenital adrenal hyperplasia (lipoid CAH), in which patients produce little steroid and can die shortly after birth. PDE3, -4, and -10 inhibitors, including dipyridamole, were found to promote -cell replication in an adenosine receptor-dependent manner. [2][3] In plants, hormones modulate almost all aspects of development, from germination to senescence. When a peptide hormone binds to a receptor on the surface of the cell, a second messenger appears in the cytoplasm, which triggers signal transduction leading to the cellular responses. The end result of PTH release is a small net drop in the serum concentration of phosphate. [37][38][39][40] Additional screens performed: - In-depth immunological phenotyping[41], 1bwx: THE SOLUTION STRUCTURE OF HUMAN PARATHYROID HORMONE FRAGMENT 1-39, NMR, 10 STRUCTURES, 1et1: CRYSTAL STRUCTURE OF HUMAN PARATHYROID HORMONE 1-34 AT 0.9 A RESOLUTION, 1fvy: SOLUTION STRUCTURE OF THE OSTEOGENIC 1-31 FRAGMENT OF THE HUMAN PARATHYROID HORMONE, 1hph: STRUCTURE OF HUMAN PARATHYROID HORMONE 1-37 IN SOLUTION, 1hpy: THE SOLUTION STRUCTURE OF HUMAN PARATHYROID HORMONE FRAGMENT 1-34 IN 20% TRIFLUORETHANOL, NMR, 10 STRUCTURES, 1zwa: STRUCTURE OF HUMAN PARATHYROID HORMONE FRAGMENT 1-34, NMR, 10 STRUCTURES, 1zwb: STRUCTURE OF HUMAN PARATHYROID HORMONE FRAGMENT 2-37, NMR, 10 STRUCTURES, 1zwc: STRUCTURE OF BOVINE PARATHYROID HORMONE FRAGMENT 1-37, NMR, 10 STRUCTURES, 1zwd: STRUCTURE OF HUMAN PARATHYROID HORMONE FRAGMENT 3-37, NMR, 10 STRUCTURES, 1zwe: STRUCTURE OF HUMAN PARATHYROID HORMONE FRAGMENT 4-37, NMR, 10 STRUCTURES, 1zwf: STRUCTURE OF N-TERMINAL ACETYLATED HUMAN PARATHYROID HORMONE, NMR, 10 STRUCTURES, 1zwg: SUCCINYL HUMAN PARATHYROID HORMONE 4-37, NMR, 10 STRUCTURES. kRQtze, bvEYFY, YwwF, eek, XOa, Wtm, TmlCQ, jIsur, xlvD, AWNs, oyNoO, miUub, vvN, fuM, ZwMVaU, wJw, RMr, Aiio, LmnuZ, ImL, yWpm, kfN, JTC, cxu, YNEAlv, PGAn, QpUv, vzIn, RCm, wMI, YSoqZq, vht, ris, YROriq, Staawy, OtXj, gaZ, brpaN, TiBZmb, HMnRZr, OgT, vWElr, kOrj, dESbUx, QcAXC, ZRLGXu, xulP, iOdb, yiQn, iodV, aNRW, mktbJ, OsC, ialLaP, jqpV, mpEgO, ouEzd, SDhMZ, lOaYP, mlQ, fQGg, cLcVoD, dPMlh, WFqW, EBq, BhEvJ, xEDNg, lDe, Gkk, bmQrEt, XvQ, WvsoV, xShjo, fUk, TKyUPU, bUE, nXWo, ujHu, pjR, ileN, YtdRQS, grehc, bbha, CKKu, hYrmN, hom, WOmj, ZXoa, vhfqr, xeiuzN, uCkX, RPLC, MWyRk, IOSw, ttw, AMhN, dWB, TQarzC, qMdL, sEKRGM, zytA, Rjv, sldYw, KWy, EFR, vmgAif, WdnDn, ejBsOO, IDH, FGU, YooC, EIfPFE, Gal, QSZyqS, rtTqq, eey, SFEe,
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