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1.
Eur J Endocrinol ; 183(3): 285-295, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32567559

RESUMO

Objective: Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease. Design: To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort). Methods: A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed. Results: People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D. Conclusions: The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.

2.
Biomarkers ; 25(2): 201-211, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32063068

RESUMO

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes.Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression.Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism.Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Fenótipo , Idoso , Biomarcadores/análise , Análise por Conglomerados , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Proteômica , Volume Sistólico
3.
Molecules ; 25(4)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32093126

RESUMO

By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected-thanks to the molecular docking results-were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC 50 of 7.2 µ M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development.

4.
Clin Res Cardiol ; 109(1): 22-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31062082

RESUMO

BACKGROUND: Hypertension, obesity and diabetes are major and potentially modifiable "risk factors" for cardiovascular diseases. Identification of biomarkers specific to these risk factors may help understanding the underlying pathophysiological pathways, and developing individual treatment. METHODS: The FIBRO-TARGETS (targeting cardiac fibrosis for heart failure treatment) consortium has merged data from 12 patient cohorts in 1 common database of > 12,000 patients. Three mutually exclusive main phenotypic groups were identified ("cases"): (1) "hypertensive"; (2) "obese"; and (3) "diabetic"; age-sex matched in a 1:2 proportion with "healthy controls" without any of these phenotypes. Proteomic associations were studied using a biostatistical method based on LASSO and confronted with machine-learning and complex network approaches. RESULTS: The case:control distribution by each cardiovascular phenotype was hypertension (50:100), obesity (50:98), and diabetes (36:72). Of the 86 studied proteins, 4 were found to be independently associated with hypertension: GDF-15, LEP, SORT-1 and FABP-2; 3 with obesity: CEACAM-8, LEP and PRELP; and 4 with diabetes: GDF-15, REN, CXCL-1 and SCF. GDF-15 (hypertension + diabetes) and LEP (hypertension + obesity) are shared by 2 different phenotypes. A machine-learning approach confirmed GDF-15, LEP and SORT-1 as discriminant biomarkers for the hypertension group, and LEP plus PRELP for the obesity group. Complex network analyses provided insight on the mechanisms underlying these disease phenotypes where fibrosis may play a central role. CONCLUSION: Patients with "mutually exclusive" phenotypes display distinct bioprofiles that might underpin different biological pathways, potentially leading to fibrosis. Plasma protein biomarkers and their association with mutually exclusive cardiovascular phenotypes: the FIBRO-TARGETS case-control analyses. Patients with "mutually exclusive" phenotypes (blue: obesity, hypertension and diabetes) display distinct protein bioprofiles (green: decreased expression; red: increased expression) that might underpin different biological pathways (orange arrow), potentially leading to fibrosis.

6.
Clin Res Cardiol ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784904

RESUMO

INTRODUCTION: The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research. METHODS: Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent. RESULTS: The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34-0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09-1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers. CONCLUSION: We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF. SUMMARY OF THE FINDINGS: PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.

7.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652525

RESUMO

Root-knot nematodes (RKN), from the Meloidogyne genus, have a worldwide distribution and cause severe economic damage to many life-sustaining crops. Because of their lack of specificity and danger to the environment, most chemical nematicides have been banned from use. Thus, there is a great need for new and safe compounds to control RKN. Such research involves identifying beforehand the nematode proteins essential to the invasion. Since G protein-coupled receptors GPCRs are the target of a large number of drugs, we have focused our research on the identification of putative nematode GPCRs such as those capable of controlling the movement of the parasite towards (or within) its host. A datamining procedure applied to the genome of Meloidogyne incognita allowed us to identify a GPCR, belonging to the neuropeptide GPCR family that can serve as a target to carry out a virtual screening campaign. We reconstructed a 3D model of this receptor by homology modeling and validated it through extensive molecular dynamics simulations. This model was used for large scale molecular dockings which produced a filtered limited set of putative antagonists for this GPCR. Preliminary experiments using these selected molecules allowed the identification of an active compound, namely C260-2124, from the ChemDiv provider, which can serve as a starting point for further investigations.


Assuntos
Antinematódeos/química , Proteínas de Helminto/química , Proteínas de Helminto/genética , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/genética , Tylenchoidea/genética , Animais , Antinematódeos/metabolismo , Antinematódeos/farmacologia , Genoma Helmíntico , Proteínas de Helminto/antagonistas & inibidores , Interações Hospedeiro-Parasita/genética , Lycopersicon esculentum/parasitologia , Simulação de Dinâmica Molecular , Filogenia , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Raízes de Plantas/parasitologia , Estrutura Secundária de Proteína , Receptores Acoplados a Proteínas-G/antagonistas & inibidores
8.
Front Plant Sci ; 9: 904, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29997646

RESUMO

The pathogenicity of phytonematodes relies on secreted virulence factors to rewire host cellular pathways for the benefits of the nematode. In the root-knot nematode (RKN) Meloidogyne incognita, thousands of predicted secreted proteins have been identified and are expected to interact with host proteins at different developmental stages of the parasite. Identifying the host targets will provide compelling evidence about the biological significance and molecular function of the predicted proteins. Here, we have focused on the hub protein CSN5, the fifth subunit of the pleiotropic and eukaryotic conserved COP9 signalosome (CSN), which is a regulatory component of the ubiquitin/proteasome system. We used affinity purification-mass spectrometry (AP-MS) to generate the interaction network of CSN5 in M. incognita-infected roots. We identified the complete CSN complex and other known CSN5 interaction partners in addition to unknown plant and M. incognita proteins. Among these, we described M. incognita PASSE-MURAILLE (MiPM), a small pioneer protein predicted to contain a secretory peptide that is up-regulated mostly in the J2 parasitic stage. We confirmed the CSN5-MiPM interaction, which occurs in the nucleus, by bimolecular fluorescence complementation (BiFC). Using MiPM as bait, a GST pull-down assay coupled with MS revealed some common protein partners between CSN5 and MiPM. We further showed by in silico and microscopic analyses that the recombinant purified MiPM protein enters the cells of Arabidopsis root tips in a non-infectious context. In further detail, the supercharged N-terminal tail of MiPM (NTT-MiPM) triggers an unknown host endocytosis pathway to penetrate the cell. The functional meaning of the CSN5-MiPM interaction in the M. incognita parasitism is discussed. Moreover, we propose that the cell-penetrating properties of some M. incognita secreted proteins might be a non-negligible mechanism for cell uptake, especially during the steps preceding the sedentary parasitic phase.

9.
Artigo em Inglês | MEDLINE | ID: mdl-29109696

RESUMO

Fetal and neonatal exposure to long-chain alkylphenols has been suspected to promote breast developmental disorders and consequently to increase breast cancer risk. However, disease predisposition from developmental exposures remains unclear. In this work, human MCF-10A mammary epithelial cells were exposed in vitro to a low dose of a realistic (4-nonylphenol + 4-tert-octylphenol) mixture. Transcriptome and cell-phenotype analyses combined to functional and signaling network modeling indicated that long-chain alkylphenols triggered enhanced proliferation, migration ability, and apoptosis resistance and shed light on the underlying molecular mechanisms which involved the human estrogen receptor alpha 36 (ERα36) variant. A male mouse-inherited transgenerational model of exposure to three environmentally relevant doses of the alkylphenol mix was set up in order to determine whether and how it would impact on mammary gland architecture. Mammary glands from F3 progeny obtained after intrabuccal chronic exposure of C57BL/6J P0 pregnant mice followed by F1-F3 male inheritance displayed an altered histology which correlated with the phenotypes observed in vitro in human mammary epithelial cells. Since cellular phenotypes are similar in vivo and in vitro and involve the unique ERα36 human variant, such consequences of alkylphenol exposure could be extrapolated from mouse model to human. However, transient alkylphenol treatments combined to ERα36 overexpression in mammary epithelial cells were not sufficient to trigger tumorigenesis in xenografted Nude mice. Therefore, it remains to be determined if low-dose alkylphenol transgenerational exposure and subsequent abnormal mammary gland development could account for an increased breast cancer susceptibility.

10.
J Biomed Semantics ; 8(1): 29, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28830518

RESUMO

BACKGROUND: Patient data, such as electronic health records or adverse event reporting systems, constitute an essential resource for studying Adverse Drug Events (ADEs). We explore an original approach to identify frequently associated ADEs in subgroups of patients. RESULTS: Because ADEs have complex manifestations, we use formal concept analysis and its pattern structures, a mathematical framework that allows generalization using domain knowledge formalized in medical ontologies. Results obtained with three different settings and two different datasets show that this approach is flexible and allows extraction of association rules at various levels of generalization. CONCLUSIONS: The chosen approach permits an expressive representation of a patient ADEs. Extracted association rules point to distinct ADEs that occur in a same group of patients, and could serve as a basis for a recommandation system. The proposed representation is flexible and can be extended to make use of additional ontologies and various patient records.


Assuntos
Ontologias Biológicas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Reconhecimento Automatizado de Padrão , Registros Eletrônicos de Saúde , Humanos , Fenótipo
11.
Peptides ; 79: 75-82, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26996966

RESUMO

The osmotin proteins of several plants display antifungal activity, which can play an important role in plant defense against diseases. Thus, this protein can be useful as a source for biotechnological strategies aiming to combat fungal diseases. In this work, we analyzed the antifungal activity of a cacao osmotin-like protein (TcOsm1) and of two osmotin-derived synthetic peptides with antimicrobial features, differing by five amino acids residues at the N-terminus. Antimicrobial tests showed that TcOsm1 expressed in Escherichia coli inhibits the growth of Moniliophthora perniciosa mycelium and Pichia pastoris X-33 in vitro. The TcOsm1-derived peptides, named Osm-pepA (H-RRLDRGGVWNLNVNPGTTGARVWARTK-NH2), located at R23-K49, and Osm-pepB (H-GGVWNLNVNPGTTGARVWARTK-NH2), located at G28-K49, inhibited growth of yeasts (Saccharomyces cerevisiae S288C and Pichia pastoris X-33) and spore germination of the phytopathogenic fungi Fusarium f. sp. glycines and Colletotrichum gossypi. Osm-pepA was more efficient than Osm-pepB for S. cerevisiae (MIC=40µM and MIC=127µM, respectively), as well as for P. pastoris (MIC=20µM and MIC=127µM, respectively). Furthermore, the peptides presented a biphasic performance, promoting S. cerevisiae growth in doses around 5µM and inhibiting it at higher doses. The structural model for these peptides showed that the five amino acids residues, RRLDR at Osm-pepA N-terminus, significantly affect the tertiary structure, indicating that this structure is important for the peptide antimicrobial potency. This is the first report of development of antimicrobial peptides from T. cacao. Taken together, the results indicate that the cacao osmotin and its derived peptides, herein studied, are good candidates for developing biotechnological tools aiming to control phytopathogenic fungi.


Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Cacau/química , Proteínas de Plantas/farmacologia , Sequência de Aminoácidos , Antifúngicos/química , Basidiomycota/efeitos dos fármacos , Colletotrichum/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Micélio/efeitos dos fármacos , Pichia/efeitos dos fármacos , Proteínas de Plantas/química , Domínios Proteicos , Saccharomyces cerevisiae/efeitos dos fármacos
12.
BMC Bioinformatics ; 17(Suppl 18): 463, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28105916

RESUMO

BACKGOUND: Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. RESULTS: In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds blocking this particular target requires the knowledge of its 3D-structure. As no experimental X-Ray structure of the selected protein was available, a 3D model was built by homology modeling. The model quality and stability was checked by 100 ns of molecular dynamics simulations. Two stable conformations representative of the conformational families of the protein were extracted from the 100 ns simulation and were used for an ensemble docking campaign. The model quality and stability was checked by 100 ns of molecular dynamics simulations previously to the virtual screening step. The virtual screening step comprised the exploration of a chemical library with 11,000 compounds that were docked to the GPCR model. Among these compounds, we selected the ten top-ranked nontoxic molecules proposed to be experimentally tested to validate the in silico simulation. CONCLUSIONS: This study provides an integrated process merging genomics, structural bioinformatics and drug design for proposing innovative solutions to a world wide threat to grain producers and consumers.


Assuntos
Proteínas Fúngicas/química , Fusarium/metabolismo , Doenças das Plantas/microbiologia , Receptores Acoplados a Proteínas-G/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fusarium/química , Fusarium/genética , Simulação de Dinâmica Molecular , Doenças das Plantas/prevenção & controle , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais
13.
BMC Bioinformatics ; 14: 207, 2013 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-23802887

RESUMO

BACKGROUND: Drug side effects represent a common reason for stopping drug development during clinical trials. Improving our ability to understand drug side effects is necessary to reduce attrition rates during drug development as well as the risk of discovering novel side effects in available drugs. Today, most investigations deal with isolated side effects and overlook possible redundancy and their frequent co-occurrence. RESULTS: In this work, drug annotations are collected from SIDER and DrugBank databases. Terms describing individual side effects reported in SIDER are clustered with a semantic similarity measure into term clusters (TCs). Maximal frequent itemsets are extracted from the resulting drug x TC binary table, leading to the identification of what we call side-effect profiles (SEPs). A SEP is defined as the longest combination of TCs which are shared by a significant number of drugs. Frequent SEPs are explored on the basis of integrated drug and target descriptors using two machine learning methods: decision-trees and inductive-logic programming. Although both methods yield explicit models, inductive-logic programming method performs relational learning and is able to exploit not only drug properties but also background knowledge. Learning efficiency is evaluated by cross-validation and direct testing with new molecules. Comparison of the two machine-learning methods shows that the inductive-logic-programming method displays a greater sensitivity than decision trees and successfully exploit background knowledge such as functional annotations and pathways of drug targets, thereby producing rich and expressive rules. All models and theories are available on a dedicated web site. CONCLUSIONS: Side effect profiles covering significant number of drugs have been extracted from a drug ×side-effect association table. Integration of background knowledge concerning both chemical and biological spaces has been combined with a relational learning method for discovering rules which explicitly characterize drug-SEP associations. These rules are successfully used for predicting SEPs associated with new drugs.


Assuntos
Inteligência Artificial , Biologia Computacional/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Bases de Dados de Produtos Farmacêuticos , Árvores de Decisões , Reprodutibilidade dos Testes
14.
Eur J Hum Genet ; 21(12): 1457-61, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23422940

RESUMO

Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.


Assuntos
Códon sem Sentido/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/genética , Criança , Pré-Escolar , Feminino , Genes Duplicados/genética , Humanos , Masculino
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