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1.
J Biol Chem ; 294(31): 11829-11839, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31201268

RESUMO

Angiotensinogen (AGT) is the precursor of one of the most potent vasoconstrictors, peptide angiotensin II. Genome-wide association studies have shown that two A/G polymorphisms (rs2493134 and rs2004776), located at +507 and +1164 in intron I of the human AGT (hAGT) gene, are associated with hypertension. Polymorphisms of the AGT gene result in two main haplotypes. Hap-I contains the variants -217A, -6A, +507G, and +1164A and is pro-hypertensive, whereas Hap-II contains the variants -217G, -6G, +507A, and +1164G and does not affect blood pressure. The nucleotide sequence of intron I of the hAGT gene containing the +1164A variant has a stronger homology with the hepatocyte nuclear factor 3 (HNF3)-binding site than +1164G. Here we found that an oligonucleotide containing +1164A binds HNF3ß more strongly than +1164G and that Hap-I-containing reporter gene constructs have increased basal and HNF3- and glucocorticoid-induced promoter activity in transiently transfected liver and kidney cells. Using a knock-in approach at the hypoxanthine-guanine phosphoribosyltransferase locus, we generated a transgenic mouse model containing the human renin (hREN) gene and either Hap-I or Hap-II. We show that transgenic animals containing Hap-I have increased blood pressure compared with those containing Hap-II. Moreover, the transcription factors glucocorticoid receptor, CCAAT enhancer-binding protein ß, and HNF3ß bound more strongly to chromatin obtained from the liver of transgenic animals containing Hap-I than to liver chromatin from Hap-II-containing animals. These findings suggest that, unlike Hap-II variants, Hap-I variants of the hAGT gene have increased transcription rates, resulting in elevated blood pressure.


Assuntos
Angiotensinogênio/metabolismo , Pressão Sanguínea , Fator 3-beta Nuclear de Hepatócito/metabolismo , Angiotensinogênio/sangue , Angiotensinogênio/genética , Animais , Sítios de Ligação , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Cromatina/metabolismo , Células Hep G2 , Humanos , Íntrons , Desequilíbrio de Ligação , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Polimorfismo de Nucleotídeo Único , Ligação Proteica , RNA Mensageiro/metabolismo , Receptores de Glucocorticoides/metabolismo , Renina/genética
2.
Am J Physiol Endocrinol Metab ; 305(4): E519-29, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23800882

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance and endothelial survival. However, its role in the morphology of macrovessels remains unknown. Mice lacking Ceacam1 (Cc1-/-) exhibit hyperinsulinemia, which causes insulin resistance and fatty liver. With increasing evidence of an association among hyperinsulinemia, fatty liver disease, and atherosclerosis, we investigated whether Cc1-/- exhibited vascular lesions in atherogenic-prone aortae. Histological analysis revealed impaired endothelial integrity with restricted fat deposition and aortic plaque-like lesions in Cc1-/- aortae, likely owing to their limited lipidemia. Immunohistochemical analysis indicated macrophage deposition, and in vitro studies showed increased leukocyte adhesion to aortic wall, mediated in part by elevation in vascular cell adhesion molecule 1 levels. Basal aortic eNOS protein and NO content were reduced, in parallel with reduced Akt/eNOS and Akt/Foxo1 phosphorylation. Ligand-induced vasorelaxation was compromised in aortic rings. Increased NADPH oxidase activity and plasma 8-isoprostane levels revealed oxidative stress and lipid peroxidation in Cc1-/- aortae. siRNA-mediated CEACAM1 knockdown in bovine aortic endothelial cells adversely affected insulin's stimulation of IRS-1/PI 3-kinase/Akt/eNOS activation by increasing IRS-1 binding to SHP2 phosphatase. This demonstrates that CEACAM1 regulates both endothelial cell autonomous and nonautonomous mechanisms involved in vascular morphology and NO production in aortae. Systemic factors such as hyperinsulinemia could contribute to the pathogenesis of these vascular abnormalities. Cc1-/- mice provide a first in vivo demonstration of distinct CEACAM1-dependent hepatic insulin clearance linking hepatic to macrovascular abnormalities.


Assuntos
Antígenos CD/metabolismo , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Antígeno Carcinoembrionário/metabolismo , Moléculas de Adesão Celular/metabolismo , Endotélio Vascular/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Animais , Antígenos CD/genética , Aorta Torácica/imunologia , Antígeno Carcinoembrionário/química , Antígeno Carcinoembrionário/genética , Bovinos , Adesão Celular , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Células Cultivadas , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Peroxidação de Lipídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Placa Aterosclerótica/imunologia , Interferência de RNA , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
3.
J Biol Chem ; 286(50): 42911-22, 2011 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-21994940

RESUMO

Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) regulate adipogenesis by controlling the balance between lipolysis and lipogenesis. Here, we show that protein phosphatase 5 (PP5), a nuclear receptor co-chaperone, reciprocally modulates the lipometabolic activities of GRα and PPARγ. Wild-type and PP5-deficient (KO) mouse embryonic fibroblast cells were used to show binding of PP5 to both GRα and PPARγ. In response to adipogenic stimuli, PP5-KO mouse embryonic fibroblast cells showed almost no lipid accumulation with reduced expression of adipogenic markers (aP2, CD36, and perilipin) and low fatty-acid synthase enzymatic activity. This was completely reversed following reintroduction of PP5. Loss of PP5 increased phosphorylation of GRα at serines 212 and 234 and elevated dexamethasone-induced activity at prolipolytic genes. In contrast, PPARγ in PP5-KO cells was hyperphosphorylated at serine 112 but had reduced rosiglitazone-induced activity at lipogenic genes. Expression of the S112A mutant rescued PPARγ transcriptional activity and lipid accumulation in PP5-KO cells pointing to Ser-112 as an important residue of PP5 action. This work identifies PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium and as a potential target in the treatment of obesity.


Assuntos
Proteínas Nucleares/metabolismo , PPAR gama/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Receptores de Glucocorticoides/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Western Blotting , Células Cultivadas , Dexametasona/farmacologia , Eletroforese , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Camundongos , Proteínas Nucleares/genética , PPAR gama/genética , Fosfoproteínas Fosfatases/genética , Ligação Proteica , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Glucocorticoides/genética
4.
BMC Mol Biol ; 11: 87, 2010 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-21092102

RESUMO

BACKGROUND: Most type II restriction-modification (RM) systems have two independent enzymes that act on the same DNA sequence: a modification methyltransferase that protects target sites, and a restriction endonuclease that cleaves unmethylated target sites. When RM genes enter a new cell, methylation must occur before restriction activity appears, or the host's chromosome is digested. Transcriptional mechanisms that delay endonuclease expression have been identified in some RM systems. A substantial subset of those systems is controlled by a family of small transcription activators called C proteins. In the PvuII system, C.PvuII activates transcription of its own gene, along with that of the downstream endonuclease gene. This regulation results in very low R.PvuII mRNA levels early after gene entry, followed by rapid increase due to positive feedback. However, given the lethal consequences of premature REase accumulation, transcriptional control alone might be insufficient. In C-controlled RM systems, there is a ± 20 nt overlap between the C termination codon and the R (endonuclease) initiation codon, suggesting possible translational coupling, and in many cases predicted RNA hairpins could occlude the ribosome binding site for the endonuclease gene. RESULTS: Expression levels of lacZ translational fusions to pvuIIR or pvuIIC were determined, with the native pvuII promoter having been replaced by one not controlled by C.PvuII. In-frame pvuIIC insertions did not substantially decrease either pvuIIC-lacZ or pvuIIR-lacZ expression (with or without C.PvuII provided in trans). In contrast, a frameshift mutation in pvuIIC decreased expression markedly in both fusions, but mRNA measurements indicated that this decrease could be explained by transcriptional polarity. Expression of pvuIIR-lacZ was unaffected when the pvuIIC stop codon was moved 21 nt downstream from its WT location, or 25 or 40 bp upstream of the pvuIIR initiation codon. Disrupting the putative hairpins had no significant effects. CONCLUSIONS: The initiation of translation of pvuIIR appears to be independent of that for pvuIIC. Direct tests failed to detect regulatory rules for either gene overlap or the putative hairpins. Thus, at least during balanced growth, transcriptional control appears to be sufficiently robust for proper regulation of this RM system.


Assuntos
Enzimas de Restrição do DNA/genética , Regulação Bacteriana da Expressão Gênica , Homologia de Genes , Proteus vulgaris/enzimologia , Proteus vulgaris/genética , Transcrição Gênica , Sequência de Bases , Enzimas de Restrição do DNA/metabolismo , Óperon Lac , Dados de Sequência Molecular , Biossíntese de Proteínas
5.
Metabolism ; 107: 154215, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32209360

RESUMO

OBJECTIVE: PTEN haploinsufficiency plays an important role in prostate cancer development in men. However, monoallelic deletion of Pten gene failed to induce high prostate intraepithelial neoplasia (PIN) until Pten+/- mice aged or fed a high-calorie diet. Because CEACAM1, a cell adhesion molecule with a potential tumor suppression activity, is induced in Pten+/- prostates, the study aimed at examining whether the rise of CEACAM1 limited neoplastic progression in Pten+/- prostates. METHODS: Pten+/- were crossbred with Cc1-/- mice harboring a null deletion of Ceacam1 gene to produce Pten+/-/Cc1-/- double mutants. Prostates from 7-month old male mice were analyzed histologically and biochemically for PIN progression. RESULTS: Deleting Ceacam1 in Pten+/- mice caused an early development of high-grade PIN in parallel to hyperactivation of PI3 kinase/Akt and Ras/MAP kinase pathways, with an increase in cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and inflammation relative to Pten+/- and Cc1-/- individual mutants. It also caused a remarkable increase in lipogenesis in prostate despite maintaining insulin sensitivity. Concomitant Ceacam1 deletion with Pten+/- activated the IL-6/STAT3 signaling pathways to suppress Irf-8 transcription that in turn, led to a decrease in the expression level of promyelocytic leukemia gene, a well characterized tumor suppressor in prostate. CONCLUSIONS: Ceacam1 deletion accelerated high-grade prostate intraepithelial neoplasia in Pten haploinsufficient mice while preserving insulin sensitivity. This demonstrated that the combined loss of Ceacam1 and Pten advanced prostate cancer by increasing lipogenesis and modifying the STAT3-dependent inflammatory microenvironment of prostate.


Assuntos
Antígeno Carcinoembrionário/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/genética , Animais , Progressão da Doença , Haploinsuficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Neoplasias da Próstata/patologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
6.
Nat Struct Mol Biol ; 11(12): 1206-14, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15531892

RESUMO

The bacterial Sm-like protein Hfq facilitates RNA-RNA interactions involved in post-transcriptional regulation of the stress response. Specifically, Hfq helps pair noncoding RNAs (ncRNAs) with complementary regions of target mRNAs. To probe the mechanism of this pairing, we generated a series of Hfq mutants and measured their affinity for RNAs like those with which Hfq must associate in vivo. We tested the mutants' DsrA-dependent activation of rpoS, and their ability to stabilize DsrA ncRNA against degradation in vivo. Our results suggest that Hfq has two independent RNA-binding surfaces. In addition to a well-known site around the core of the Hfq hexamer, we observe interactions with the distal face of Hfq, a new locus with which mRNAs and poly(A) sequences associate. Our model explains how Hfq can simultaneously bind a ncRNA and its mRNA target to facilitate the strand displacement reaction required for Hfq-dependent translational regulation.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Escherichia coli/química , Escherichia coli/metabolismo , Fator Proteico 1 do Hospedeiro/química , Fator Proteico 1 do Hospedeiro/metabolismo , Poli A/metabolismo , Fator sigma/metabolismo , Sequência de Aminoácidos , Ligação Competitiva , Calorimetria , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Fator Proteico 1 do Hospedeiro/genética , Modelos Moleculares , Dados de Sequência Molecular , Mutação/genética , Poli A/química , Desnaturação Proteica , Estrutura Terciária de Proteína , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência , Titulometria
7.
J Mol Biol ; 339(3): 505-14, 2004 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-15147838

RESUMO

H-NS is an abundant prokaryotic transcription factor that preferentially binds to intrinsically bent DNA. Although H-NS has been shown to reduce the transcription of over 100 genes, evidence suggests that H-NS can also affect the translation of some genes. One such gene, rpoS, specifies a sigma factor, RpoS. The ability of H-NS to bind to the rpoS mRNA and the non-coding RNA regulator, DsrA, was tested. Electrophoretic mobility-shift assays yielded an apparent binding affinity of H-NS binding to curved DNA of approximately 1 microM, whereas binding to rpoS mRNA or DsrA RNA was approximately 3 microM. This RNA binding was not prevented by an excess of competitor yeast RNA, suggesting that H-NS specifically bound these RNAs. Footprint analysis with a single strand-specific ribonuclease was used to identify the H-NS binding site(s) on DsrA and rpoS mRNA. Surprisingly, H-NS appeared to enhance the cleavage of DsrA and rpoS mRNA. The enhanced cleavage was at sites that were predicted to be single-stranded and did not result from contaminating nucleases in the H-NS protein preparation or non-specific effects of the nuclease. Quantitative RT-PCR of RNA isolated from wild-type and hns- strains revealed that H-NS also affects the stability of DsrA in vivo. Thus H-NS appears to modulate RNA stability in vivo and in vitro.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Ligação a DNA/metabolismo , RNA Bacteriano/química , Sequência de Bases , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Escherichia coli/genética , Escherichia coli/metabolismo , Conformação de Ácido Nucleico , Ligação Proteica , RNA Bacteriano/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Circ Cardiovasc Genet ; 8(1): 30-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25504670

RESUMO

BACKGROUND: Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension. Various investigators, using genomic DNA analyses, have linked -344T polymorphism in the human CYP11B2 (hCYP11B2) gene to human hypertension. hCYP11B2 gene promoter has 3 single-nucleotide polymorphisms in linkage disequilibrium: T/A at -663, T/C at -470, and C/T at -344. Variants ACT occur together and form the haplotype-I (Hap-I), whereas variants TTC constitute Hap-II. We hypothesize that these single-nucleotide polymorphisms, when present together, will lead to haplotype-dependent differences in the transcriptional regulation of the hCYP11B2 gene and affect blood pressure regulation. METHODS AND RESULTS: We evaluated differences in tissue expression in vivo and consequential effects on blood pressure stemming from the 2 haplotypes. Novel transgenic mice with the hCYP11B2 gene, targeted to the mouse HPRT locus, with either Hap-II or Hap-I variant are used in this study. Our results show increased adrenal and renal expression of hCYP11B2 in transgenic mice with Hap-I when compared with mice with Hap-II. Importantly, we observed increased baseline blood pressure in Hap-I transgenic mice, an effect accentuated by a high-salt diet. Pathophysiological effects of elevated aldosterone were corroborated by our results showing upregulation of proinflammatory markers in renal tissues from the transgenic mice with Hap-I. CONCLUSIONS: These findings characterize the haplotype-dependent regulation of the hCYP11B2 gene where -344T serves as a reporter polymorphism and show that Hap-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu.


Assuntos
Citocromo P-450 CYP11B2 , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipertensão , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Citocromo P-450 CYP11B2/biossíntese , Citocromo P-450 CYP11B2/genética , Humanos , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Hipertensão/genética , Hipertensão/fisiopatologia , Camundongos , Cloreto de Sódio na Dieta/farmacologia
9.
Mol Metab ; 4(3): 186-98, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25737954

RESUMO

OBJECTIVE: Association between prostate cancer and obesity remains controversial. Allelic deletions of PTEN, a tumor suppressor gene, are common in prostate cancer in men. Monoallelic Pten deletion in mice causes low prostatic intraepithelial neoplasia (mPIN). This study tested the effect of a hypercaloric diet on prostate cancer in Pten (+/-) mice. METHODS: 1-month old mice were fed a high-calorie diet deriving 45% calories from fat for 3 and 6 months before prostate was analyzed histologically and biochemically for mPIN progression. Because Pten (+/-) mice are protected against diet-induced insulin resistance, we tested the role of insulin on cell growth in RWPE-1 normal human prostatic epithelial cells with siRNA knockdown of PTEN. RESULTS: In addition to activating PI3 kinase/Akt and Ras/MAPkinase pathways, high-calorie diet causes neoplastic progression, angiogenesis, inflammation and epithelial-mesenchymal transition. It also elevates the expression of fatty acid synthase (FAS), a lipogenic gene commonly elevated in progressive cancer. SiRNA-mediated downregulation of PTEN demonstrates increased cell growth and motility, and soft agar clonicity in addition to elevation in FAS in response to insulin in RWPE-1 normal human prostatic cells. Downregulating FAS in addition to PTEN, blunted the proliferative effect of insulin (and IL-6) in RWPE-1 cells. CONCLUSION: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

10.
Diabetes ; 64(8): 2780-90, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25972571

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic ß-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance.


Assuntos
Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Dieta Hiperlipídica , Resistência à Insulina/genética , Fígado/metabolismo , Animais , Antígenos CD/genética , Moléculas de Adesão Celular/genética , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Insulina/sangue , Camundongos , Camundongos Transgênicos
11.
J Clin Invest ; 121(8): 3331-42, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21747171

RESUMO

The failure of pancreatic ß cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from ß cell failure. We previously found that the hormone 17ß-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against ß cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERß in a rat ß cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα-/-) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα-/- mice were predisposed to islet lipid accumulation and ß cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited ß cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent ß cell failure in T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Lipídeos/química , Receptores de Estrogênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Modelos Animais de Doenças , Ácido Graxo Sintases/metabolismo , Deleção de Genes , Humanos , Masculino , Camundongos , Ratos , Ratos Zucker
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