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1.
Nature ; 618(7965): 543-549, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37225983

RESUMEN

The development of paired appendages was a key innovation during evolution and facilitated the aquatic to terrestrial transition of vertebrates. Largely derived from the lateral plate mesoderm (LPM), one hypothesis for the evolution of paired fins invokes derivation from unpaired median fins via a pair of lateral fin folds located between pectoral and pelvic fin territories1. Whilst unpaired and paired fins exhibit similar structural and molecular characteristics, no definitive evidence exists for paired lateral fin folds in larvae or adults of any extant or extinct species. As unpaired fin core components are regarded as exclusively derived from paraxial mesoderm, any transition presumes both co-option of a fin developmental programme to the LPM and bilateral duplication2. Here, we identify that the larval zebrafish unpaired pre-anal fin fold (PAFF) is derived from the LPM and thus may represent a developmental intermediate between median and paired fins. We trace the contribution of LPM to the PAFF in both cyclostomes and gnathostomes, supporting the notion that this is an ancient trait of vertebrates. Finally, we observe that the PAFF can be bifurcated by increasing bone morphogenetic protein signalling, generating LPM-derived paired fin folds. Our work provides evidence that lateral fin folds may have existed as embryonic anlage for elaboration to paired fins.


Asunto(s)
Aletas de Animales , Evolución Biológica , Mesodermo , Pez Cebra , Animales , Aletas de Animales/anatomía & histología , Aletas de Animales/embriología , Aletas de Animales/crecimiento & desarrollo , Larva/anatomía & histología , Larva/crecimiento & desarrollo , Mesodermo/anatomía & histología , Mesodermo/embriología , Mesodermo/crecimiento & desarrollo , Pez Cebra/anatomía & histología , Pez Cebra/embriología , Pez Cebra/crecimiento & desarrollo , Proteínas Morfogenéticas Óseas/metabolismo
2.
Dis Model Mech ; 12(9)2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31383797

RESUMEN

Reduced bone quality or mineral density predict susceptibility to fracture and also attenuate subsequent repair. Bone regrowth is also compromised by bacterial infection, which exacerbates fracture site inflammation. Because of the cellular complexity of fracture repair, as well as genetic and environmental influences, there is a need for models that permit visualisation of the fracture repair process under clinically relevant conditions. To characterise the process of fracture repair in zebrafish, we employed a crush fracture of fin rays, coupled with histological and transgenic labelling of cellular responses; the results demonstrate a strong similarity to the phased response in humans. We applied our analysis to a zebrafish model of osteogenesis imperfecta (OI), which shows reduced bone quality, spontaneous fractures and propensity for non-unions. We found deficiencies in the formation of a bone callus during fracture repair in our OI model and showed that clinically employed antiresorptive bisphosphonates can reduce spontaneous fractures in OI fish and also measurably reduce fracture callus remodelling in wild-type fish. The csf1ra mutant, which has reduced osteoclast numbers, also showed reduced callus remodelling. Exposure to excessive bisphosphonate, however, disrupted callus repair. Intriguingly, neutrophils initially colonised the fracture site, but were later completely excluded. However, when fractures were infected with Staphylococcus aureus, neutrophils were retained and compromised repair. This work elevates the zebrafish bone fracture model and indicates its utility in assessing conditions of relevance to an orthopaedic setting with medium throughput.This article has an associated First Person interview with the first author of the paper.


Asunto(s)
Fracturas Óseas/patología , Pez Cebra/fisiología , Alendronato/farmacología , Alendronato/uso terapéutico , Aletas de Animales/patología , Animales , Callo Óseo/efectos de los fármacos , Callo Óseo/patología , Difosfonatos/farmacología , Difosfonatos/uso terapéutico , Modelos Animales de Enfermedad , Curación de Fractura/efectos de los fármacos , Fracturas Óseas/tratamiento farmacológico , Fracturas Óseas/microbiología , Fracturas no Consolidadas/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Osteogénesis Imperfecta/patología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología
3.
PLoS One ; 10(12): e0144982, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26689368

RESUMEN

Osteoblast differentiation from mesenchymal cells is regulated by multiple signalling pathways. Here we have analysed the roles of Fibroblast Growth Factor (FGF) and canonical Wingless-type MMTV integration site (Wnt/ß-Catenin) signalling pathways on zebrafish osteogenesis. We have used transgenic and chemical interference approaches to manipulate these pathways and have found that both pathways are required for osteoblast differentiation in vivo. Our analysis of bone markers suggests that these pathways act at the same stage of differentiation to initiate expression of the osteoblast master regulatory gene osterix (osx). We use two independent approaches that suggest that osx is a direct target of these pathways. Firstly, we manipulate signalling and show that osx gene expression responds with similar kinetics to that of known transcriptional targets of the FGF and Wnt pathways. Secondly, we have performed ChIP with transcription factors for both pathways and our data suggest that a genomic region in the first intron of osx mediates transcriptional activation. Based upon these data, we propose that FGF and Wnt/ß-Catenin pathways act in part by directing transcription of osx to promote osteoblast differentiation at sites of bone formation.


Asunto(s)
Diferenciación Celular/fisiología , Factores de Crecimiento de Fibroblastos/metabolismo , Osteoblastos/metabolismo , Factores de Transcripción/biosíntesis , Vía de Señalización Wnt/fisiología , Proteínas de Pez Cebra/biosíntesis , Pez Cebra/metabolismo , beta Catenina/metabolismo , Animales , Factores de Crecimiento de Fibroblastos/genética , Osteoblastos/citología , Osteogénesis/fisiología , Factor de Transcripción Sp7 , Factores de Transcripción/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genética , beta Catenina/genética
4.
PLoS One ; 7(1): e29734, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22253766

RESUMEN

Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2⁻/⁻ fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2⁻/⁻ fish. Histological analysis reveals that ext2⁻/⁻ fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2⁻/⁻ fish have a single tooth at the end of the 5(th) pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2⁻/⁻ teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2⁺/⁻ adults. The tooth morphology in ext2⁻/⁻ was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems.


Asunto(s)
Exostosis Múltiple Hereditaria/patología , Proteoglicanos de Heparán Sulfato/deficiencia , Enfermedades Dentales/patología , Pez Cebra/metabolismo , Adulto , Envejecimiento/patología , Animales , Biomarcadores/metabolismo , Exostosis Múltiple Hereditaria/genética , Regulación del Desarrollo de la Expresión Génica , Proteoglicanos de Heparán Sulfato/metabolismo , Humanos , Larva , Mutación/genética , N-Acetilglucosaminiltransferasas/deficiencia , N-Acetilglucosaminiltransferasas/metabolismo , Fenotipo , Transducción de Señal , Diente/crecimiento & desarrollo , Diente/metabolismo , Diente/patología , Enfermedades Dentales/genética , Pez Cebra/genética
5.
Eur J Med Chem ; 46(9): 4125-32, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21726921

RESUMEN

A series of highly potent indole-3-glyoxylamide based antiprion agents was previously characterized, focusing on optimization of structure-activity relationship (SAR) at positions 1-3 of the indole system. New libraries interrogating the SAR at indole C-4 to C-7 now demonstrate that introducing electron-withdrawing substituents at C-6 may improve biological activity by up to an order of magnitude, and additionally confer higher metabolic stability. For the present screening libraries, both the degree of potency and trends in SAR were consistent across two cell line models of prion disease, and the large majority of compounds showed no evidence of toxic effects in zebrafish. The foregoing observations thus make the indole-3-glyoxylamides an attractive lead series for continuing development as potential therapeutic agents against prion disease.


Asunto(s)
Indoles/química , Indoles/farmacología , Microsomas/efectos de los fármacos , Priones/efectos de los fármacos , Animales , Línea Celular , Descubrimiento de Drogas , Indoles/efectos adversos , Relación Estructura-Actividad , Pez Cebra
6.
Mech Dev ; 128(1-2): 141-52, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21126582

RESUMEN

In tetrapod long bones, Hedgehog signalling is required for osteoblast differentiation in the perichondrium. In this work we analyse skeletogenesis in zebrafish larvae treated with the Hedgehog signalling inhibitor cyclopamine. We show that cyclopamine treatment leads to the loss of perichondral ossification of two bones in the head. We find that the Hedgehog co-receptors patched1 and patched2 are expressed in regions of the perichondrium that will form bone before the onset of ossification. We also show that cyclopamine treatment strongly reduces the expression of osteoblast markers in the perichondrium and that perichondral ossification is enhanced in patched1 mutant fish. This data suggests a conserved role for Hedgehog signalling in promoting perichondral osteoblast differentiation during vertebrate skeletal development. However, unlike what is seen during long bone development, we did not observe ectopic chondrocytes in the perichondrium when Hedgehog signalling is blocked. This result may point to subtle differences between the development of the skeleton in the skull and limb.


Asunto(s)
Diferenciación Celular , Proteínas Hedgehog/metabolismo , Receptores de Superficie Celular/metabolismo , Transducción de Señal , Pez Cebra/metabolismo , Animales , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Condrocitos/citología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Colágeno Tipo X/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Embrión no Mamífero/citología , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Proteínas Hedgehog/genética , Proteínas de la Membrana , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Alcaloides de Veratrum/farmacología , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
7.
Dev Dyn ; 239(6): 1901-4, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20503385

RESUMEN

On October 29, 2009, researchers and physicians gathered at the Sheraton Four Points Hotel in Boston for 4 days to discuss a disease called multiple hereditary exostoses (MHE). MHE is an autosomal dominant disease that is associated with mutations in two enzymes that are required for heparan sulfate (HS) synthesis. Children with the disease form numerous benign bone tumors (osteochondromas) and have >2% chance of developing chondrosarcoma. The aim of the meeting was to generate new ideas for the diagnoses, treatment, and cure of this disease. Discussions ranged from orthopedic surgical treatment and patients' personal experiences to fundamental questions in skeletal biology and the precise molecular role that HS plays in developmental signaling pathways.


Asunto(s)
Huesos/patología , Exostosis Múltiple Hereditaria/genética , Exostosis Múltiple Hereditaria/cirugía , Neoplasias Óseas/genética , Neoplasias Óseas/cirugía , Boston , Carbohidratos/genética , Niño , Condrosarcoma/genética , Exostosis Múltiple Hereditaria/patología , Heparitina Sulfato/genética , Humanos , Mutación , Osteocondroma/genética
8.
Development ; 137(3): 389-94, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20081187

RESUMEN

Although the regulation of osteoblast and adipocyte differentiation from mesenchymal stem cells has been studied for some time, very little is known about what regulates their appearance in discrete regions of the embryo. Here we show that, as in other vertebrates, zebrafish osteoblasts and adipocytes originate in part from cephalic neural crest (CNC) precursors. We investigated the roles that the retinoic acid (RA) and Peroxisome proliferator-activated receptor gamma (Pparg) pathways play in vivo and found that both pathways act on CNC to direct adipocyte differentiation at the expense of osteoblast formation. In addition, we identify two distinct roles for RA in the osteoblast lineage: an early role in blocking the recruitment of osteoblasts and a later role in mature osteoblasts to promote bone matrix synthesis. These findings might help to increase our understanding of skeletal and obesity-related diseases and aid in the development of stem cell-based regenerative therapies.


Asunto(s)
Cresta Neural/citología , PPAR gamma/fisiología , Tretinoina/fisiología , Adipocitos/citología , Animales , Matriz Ósea/crecimiento & desarrollo , Diferenciación Celular , Linaje de la Célula , Osteoblastos/citología , Células Madre/citología , Pez Cebra
9.
Dev Dyn ; 238(2): 459-66, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19161246

RESUMEN

The transcription factors RUNX2 and OSX have been shown to act sequentially to direct mammalian osteoblast differentiation. RUNX2 is required during the early stages of commitment and acts in part to activate Osx transcription. OSX and RUNX2 then act to direct transcription of bone matrix proteins. Here, we investigate the expression of these genes and others during zebrafish osteoblastogenesis. Using whole-mount in situ hybridization, we find that, during the formation of a given bone, the zebrafish homologues of mouse Runx2 (runx2a and runx2b) are typically expressed before the onset of osx. osx expression is usually followed by up-regulation of the bone matrix proteins, col1a2 and osteonectin. These results suggest that the mammalian pathway is conserved during development of the head and shoulder skeleton of zebrafish. We also analyze the expression of three atypical bone markers (tcf7, cvl2, and col10a1) in an effort to place them within this canonical hierarchy.


Asunto(s)
Matriz Ósea/metabolismo , Diferenciación Celular/fisiología , Osteoblastos/citología , Pez Cebra/embriología , Animales , Biomarcadores/metabolismo , Tipificación del Cuerpo , Osteoblastos/metabolismo , Factor de Transcripción Sp7 , Factores de Transcripción/metabolismo , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo
10.
PLoS Genet ; 4(7): e1000136, 2008 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-18654627

RESUMEN

Mutations in human Exostosin genes (EXTs) confer a disease called Hereditary Multiple Exostoses (HME) that affects 1 in 50,000 among the general population. Patients with HME have a short stature and develop osteochondromas during childhood. Here we show that two zebrafish mutants, dackel (dak) and pinscher (pic), have cartilage defects that strongly resemble those seen in HME patients. We have previously determined that dak encodes zebrafish Ext2. Positional cloning of pic reveals that it encodes a sulphate transporter required for sulphation of glycans (Papst1). We show that although both dak and pic are required during cartilage morphogenesis, they are dispensable for chondrocyte and perichondral cell differentiation. They are also required for hypertrophic chondrocyte differentiation and osteoblast differentiation. Transplantation analysis indicates that dak(-/-) cells are usually rescued by neighbouring wild-type chondrocytes. In contrast, pic(-/-) chondrocytes always act autonomously and can disrupt the morphology of neighbouring wild-type cells. These findings lead to the development of a new model to explain the aetiology of HME.


Asunto(s)
Proteínas de Transporte de Anión/genética , Regulación del Desarrollo de la Expresión Génica , N-Acetilglucosaminiltransferasas/genética , Osteogénesis/genética , Proteínas de Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Animales , Proteínas de Transporte de Anión/fisiología , Clonación Molecular , Embrión no Mamífero , Marcadores Genéticos , Homocigoto , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Modelos Animales , Mutación , N-Acetilglucosaminiltransferasas/fisiología , Osteogénesis/fisiología , Mapeo Físico de Cromosoma , ARN Mensajero/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/fisiología
11.
Development ; 135(11): 1935-46, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18469222

RESUMEN

The Trithorax group (TrxG) is composed of diverse, evolutionary conserved proteins that form chromatin-associated complexes accounting for epigenetic transcriptional memory. However, the molecular mechanisms by which particular loci are marked for reactivation after mitosis are only partially understood. Here, based on genetic analyses in zebrafish, we identify the multidomain protein Brpf1 as a novel TrxG member with a central role during development. brpf1 mutants display anterior transformations of pharyngeal arches due to progressive loss of anterior Hox gene expression. Brpf1 functions in association with the histone acetyltransferase Moz (Myst3), an interaction mediated by the N-terminal domain of Brpf1, and promotes histone acetylation in vivo. Brpf1 recruits Moz to distinct sites of active chromatin and remains at chromosomes during mitosis, mediated by direct histone binding of its bromodomain, which has a preference for acetylated histones, and its PWWP domain, which binds histones independently of their acetylation status. This is the first demonstration of histone binding for PWWP domains. Mutant analyses further show that the PWWP domain is absolutely essential for Brpf1 function in vivo. We conclude that Brpf1, coordinated by its particular set of domains, acts by multiple mechanisms to mediate Moz-dependent histone acetylation and to mark Hox genes for maintained expression throughout vertebrate development.


Asunto(s)
Proteínas Portadoras/metabolismo , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Acetilación , Proteínas Adaptadoras Transductoras de Señales , Animales , Sitios de Unión/genética , Región Branquial/anatomía & histología , Región Branquial/crecimiento & desarrollo , Región Branquial/metabolismo , Proteínas Portadoras/genética , Línea Celular , Cromatina/metabolismo , Proteínas de Unión al ADN , Regulación del Desarrollo de la Expresión Génica , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Humanos , Inmunoprecipitación , Hibridación in Situ , Ratones , Proteínas Nucleares/genética , Unión Proteica , Proteínas Recombinantes/metabolismo , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/genética
12.
J Exp Zool B Mol Dev Evol ; 310(4): 355-69, 2008 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-18338789

RESUMEN

Vertebrate head muscles exhibit a highly conserved pattern of innervation and skeletal connectivity and yet it is unclear whether the molecular basis of their development is likewise conserved. Using the highly conserved expression of Engrailed 2 (En2) as a marker of identity in the dorsal mandibular muscles of zebrafish, we have investigated the molecular signals and tissues required for patterning these muscles. We show that muscle En2 expression is not dependent on signals from the adjacent neural tube, pharyngeal endoderm or axial mesoderm and that early identity of head muscles does not require bone morphogenetic pathway, Notch or Hedgehog (Hh) signalling. However, constrictor dorsalis En2 expression is completely lost after a loss of fibroblast growth factor (Fgf) signalling and we show that is true throughout head muscle development. These results suggest that head muscle identity is dependent on Fgf signalling. Data from experiments performed in chick suggest a similar regulation of En2 genes by Fgf signalling revealing a conserved mechanism for specifying head muscle identity. We present evidence that another key gene important in the development of mouse head muscles, Tbx1, is also critical for specification of mandibular arch muscle identity and that this is independent of Fgf signalling. These data imply that dorsal mandibular arch muscle identity in fish, chick and mouse is specified by a highly conserved molecular process despite differing functions of these muscles in different lineages.


Asunto(s)
Tipificación del Cuerpo/fisiología , Mandíbula/embriología , Músculo Esquelético/embriología , Pez Cebra/embriología , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas de Homeodominio/metabolismo , Inmunohistoquímica , Hibridación in Situ , Mutación/genética , Proteínas del Tejido Nervioso/metabolismo , Transducción de Señal/fisiología , Especificidad de la Especie , Pez Cebra/genética
13.
Development ; 131(15): 3681-92, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15229178

RESUMEN

The pituitary gland consists of two major parts: the neurohypophysis, which is of neural origin; and the adenohypophysis, which is of non-neural ectodermal origin. Development of the adenohypophysis is governed by signaling proteins from the infundibulum, a ventral structure of the diencephalon that gives rise to the neurohypophysis. In mouse, the fibroblast growth factors Fgf8, Fgf10 and Fgf18 are thought to affect multiple processes of pituitary development: morphogenesis and patterning of the adenohypophyseal anlage; and survival, proliferation and differential specification of adenohypophyseal progenitor cells. Here, we investigate the role of Fgf3 during pituitary development in the zebrafish, analyzing lia/fgf3 null mutants. We show that Fgf3 signaling from the ventral diencephalon is required in a non-cell autonomous fashion to induce the expression of lim3, pit1 and other pituitary-specific genes in the underlying adenohypophyseal progenitor cells. Despite the absence of such early specification steps, fgf3 mutants continue to form a distinct pituitary anlage of normal size and shape, until adenohypophyseal cells die by apoptosis. We further show that Sonic Hedgehog (Shh) cannot rescue pituitary development, although it is able to induce adenohypophyseal cells in ectopic placodal regions of fgf3 mutants, indicating that Fgf3 does not act via Shh, and that Shh can act independently of Fgf3. In sum, our data suggest that Fgf3 signaling primarily promotes the transcriptional activation of genes regulating early specification steps of adenohypophyseal progenitor cells. This early specification seems to be essential for the subsequent survival of pituitary cells, but not for pituitary morphogenesis or pituitary cell proliferation.


Asunto(s)
Supervivencia Celular/fisiología , Diencéfalo/embriología , Factores de Crecimiento de Fibroblastos/metabolismo , Morfogénesis/fisiología , Adenohipófisis/embriología , Transducción de Señal/fisiología , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Secuencia de Aminoácidos , Animales , Apoptosis , Tipificación del Cuerpo , Linaje de la Célula , Diencéfalo/metabolismo , Estructuras Embrionarias/anomalías , Estructuras Embrionarias/anatomía & histología , Factor 10 de Crecimiento de Fibroblastos , Factor 3 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas Hedgehog , Humanos , Hibridación in Situ , Ratones , Datos de Secuencia Molecular , Adenohipófisis/citología , Alineación de Secuencia , Transactivadores/genética , Transactivadores/metabolismo , Pez Cebra/anomalías , Pez Cebra/anatomía & histología , Proteínas de Pez Cebra/genética
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