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Chemosphere ; 242: 125285, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896209


The aim of this study was to assess the long-term effects of synthetic progestin norethindrone (NET) on the growth, reproductive histology, and transcriptional expression profiles of genes associated with the hypothalamic-pituitary-gonadal (HPG) axis and germ cells in adult zebrafish. Adult zebrafish were exposed to 7, 84 and 810 ng/L NET for 90 days. The results showed that exposure to 810 ng/L NET caused a significant decrease in growth of females and males. The ovary weight and GSI was significantly reduced by NET at concentrations of 84 or 810 ng/L, which came along with the delay of ovary maturation in females. However, NET at all treatments resulted in acceleration of sperm maturation in males. In the ovaries of females, a strong inhibition of cyp19a1a gene was observed following exposure to NET at 810 ng/L. Similarly, NET at the highest treatment led to a significant down-regulation of cyp17, cyp19a1a, vasa, nanos1, dazl and dmc1 genes in the testes of males. Taken together, the overall results demonstrated that NET could impact growth and gonadal maturation, with significant alterations of transcriptional expression genes along HPG axis and germ cells.

Expressão Gênica/efeitos dos fármacos , Noretindrona/toxicidade , Progestinas/toxicidade , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Animais , Regulação para Baixo , Feminino , Células Germinativas/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Masculino , Ovário/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Peixe-Zebra/genética
Cell Mol Life Sci ; 77(2): 323-330, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31203379


Zygosis is the generation of new biological individuals by the sexual fusion of gamete cells. Our current understanding of eukaryotic phylogeny indicates that sex is ancestral to all extant eukaryotes. Although sexual development is extremely diverse, common molecular elements have been retained. HAP2-GCS1, a protein that promotes the fusion of gamete cell membranes that is related in structure to certain viral fusogens, is conserved in many eukaryotic lineages, even though gametes vary considerably in form and behaviour between species. Similarly, although zygotes have dramatically different forms and fates in different organisms, diverse eukaryotes share a common developmental programme in which homeodomain-containing transcription factors play a central role. These common mechanistic elements suggest possible common evolutionary histories that, if correct, would have profound implications for our understanding of eukaryogenesis.

Zigoto/fisiologia , Animais , Evolução Biológica , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Eucariotos/metabolismo , Eucariotos/fisiologia , Células Germinativas/metabolismo , Filogenia , Fatores de Transcrição/metabolismo , Zigoto/metabolismo
Urologiia ; (5): 79-85, 2019 Dec.
Artigo em Russo | MEDLINE | ID: mdl-31808637


INTRODUCTION: as shown in previous studies, mutations in the BRCA1/2 and CHEK2 genes are associated with worsened long-term results of the definitive treatment for localized prostate cancer (PCa). AIM: to evaluate the prognostic value of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with metastatic PCa (mPCa), receiving hormonal therapy in the first-line systemic treatment. MATERIALS AND METHODS: A total of 76 patients with mPCa receiving hormonal therapy with luteinizing hormone-releasing hormone analogue (LHRHa) in N.N. Blokhin National Medical Research Center of Oncology were recruited in our prospective study. All patients were genotyped for germline mutations in the BRCA1/2 and CHEK2 genes by real-time polymerase chain reaction using a set "OncoGenetics" (LLC "Research and Production Company DNA-Technology", Russia, registration certificate No 2010/08415) and the Sanger sequencing using a set "Beckman Coulter enomeLab GeXP". In addition, a histologic grade and volume of metastatic disease were evaluated. RESULTS: Pathogenic and possibly pathogenic mutations in the BRCA2 and CHEK2 gene were identified in 19 (25%) patients. No cases of BRCA1 mutations were detected. Median time to castration resistance was significantly lower in BRCA2 and CHEK2 mutation carriers (7.93 mo, 95% confidence interval (CI) 2.62-13.25), than in non-carriers (48,66 mo, 95% CI 31.05-68.26, p<0,001). Cox analysis confirmed three independent unfavorable prognostic factors. DISCUSSION: The results of our study and other publications have confirmed limited efficacy of standard approach to treatment hormone-sensitive mPCa in germline mutation BRCA2 and CHEK2 carriers. However, the main objective of studies was to assess the survival rates in these patients at the stage of castration-resistant mPCa. CONCLUSION: Our results demonstrated that germline BRCA2 and CHEK2 mutations are independent unfavorable predictors in patients with mPCa which are associated with decreased time to castration resistance (HR 3.04, 95% CI 1.63-5.66, p<0.001), particularly in subgroup with low volume metastatic disease (HR 4.59, 95% CI 2.06-10.22, p<0,001). An evaluation of a prognostic value of mutations in other DNA repair genes requires additional research.

Castração , Quinase do Ponto de Checagem 2 , Genes BRCA2 , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias da Próstata/cirurgia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteína BRCA2 , Células Germinativas , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Federação Russa
Soins Pediatr Pueric ; 40(311): 30-34, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31757273


Today many heterosexual couples, as well as single women and lesbian couples, use gamete donation in France or abroad in order to fulfil their desire for a child. The construction of parenthood in these conditions raises many questions and requires specific psychological work in order to reflect on issues surrounding genetic transmission, the establishment of the bond and the appropriation of parenthood. Furthermore, what is the future of the children conceived by donation?

Células Germinativas , Obtenção de Tecidos e Órgãos , Feminino , França , Humanos
Nature ; 575(7783): 415-416, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31748735
Rev. bioét. derecho ; (47): 17-31, nov. 2019.
Artigo em Espanhol | IBECS | ID: ibc-184863


La tecnología de la edición genética por CRISPR ha revolucionado tanto la investigación en biotecnología como en biomedicina. Esta técnica tan poderosa y versátil permite editar los genes de cualquier especie a la carta. A pesar de su potencia y efectividad, quedan muchas cuestiones para resolver y controlar su resultado final, particularmente en las aplicaciones sobre el genoma de los seres humanos. En este artículo se plantean tanto los puntos fuertes y puntos débiles de la técnica, como otras cuestiones abiertas sobre la edición génica, sobre si debe dirigirse a la terapia o a la mejora, si la modificación debe constreñirse a células somáticas o también a editar a embriones, modificando el genoma de los seres humanos del futuro

La tecnologia de l'edició gènica mitjançant CRISPR ha revolucionat tant la recerca en biotecnologia com en biomedicina. Aquesta tècnica tan poderosa i versàtil permet editar els gens de qualsevol espècie a la carta. Malgrat la seva potència i efectivitat, queden moltes qüestions per resoldre i controlar el seu resultat final, particularment en les aplicacions sobre el genoma dels éssers humans. En aquest article es plantegen els punts forts i els punts febles de la tècnica, així com altres qüestions obertes sobre l'edició gènica, si ha de dirigir-se a la teràpia o a la millora, si la modificació ha de constrènyer-se a cèl•lules somàtiques o també es poden editar en embrions, modificant el genoma dels éssers humans del futur

Gene using CRISPR has completely revolutionized the research in biotechnology and biomedicine. This powerful and versatile technique enables the precise edition of genes from any organism. Even though the technique is so effective and amenable, many questions remain to be solved before the final genetic outcome can be fully controlled, particularly in its uses on the human genome. In this article, I discuss the current strengths and weaknesses of the technique. I also pose other open questions on gene editing, such as whether it should be used for either therapy or genetic enhancement, and whether it should be used only on somatic cells or also for embryo gene editing, the latter resulting in the modification of future human beings

Humanos , Edição de Genes/tendências , Sistemas CRISPR-Cas , Terapia Genética/legislação & jurisprudência , Tecnologia de Impulso Genético/legislação & jurisprudência , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Células Germinativas
Rev. bioét. derecho ; (47): 43-54, nov. 2019.
Artigo em Espanhol | IBECS | ID: ibc-184865


En este trabajo se plantean algunas reflexiones respecto de la edición genética y su impacto en la responsabilidad. Me centraré en la investigación y en las prácticas que se realizan en línea germinal, ya que son las que más preocupan a nuestra sociedad. Aunque estas tecnologías no generan problemas realmente novedosos, cuestionan el alcance de nuestra noción tradicional de responsabilidad y nos plantean nuevos desafíos respecto de cómo afrontarlas. Podemos pensar la responsabilidad de manera individual, en tanto progenitores, a la hora de decidir respecto de nuestra descendencia. Pero también se puede plantear una responsabilidad colectiva: por ejemplo, en tanto científicos a la hora de regular la ciencia, o en tanto sociedad. En este último sentido pareciera que deberíamos considerar cómo estas tecnologías puedan afectar el sistema público de acceso al cuidado de la salud así como también tener en cuenta si determinados grupos de pacientes corren el riesgo de ser postergados sin olvidar cuál pueda ser el impacto en las futuras generaciones

En aquest treball es plantegen algunes reflexions respecte de l'edició genètica i el seu impacte en la responsabilitat. Em centraré en la recerca i en les pràctiques que es realitzen en la línia germinal, ja que són les que més preocupen la nostra societat. Encara que aquestes tecnologies no generen problemes realment nous, qüestionen l'abast de la nostra noció tradicional de responsabilitat i ens plantegen nous desafiaments respecte de com afrontar-les. Podem pensar la responsabilitat de manera individual, en tant progenitors, a l'hora de decidir respecte de la nostra descendència. Però també es pot plantejar una responsabilitat col•lectiva: per exemple, en tant que científics a l'hora de regular la ciència, o en tant que societat. En aquest últim sentit hauríem de considerar com aquestes tecnologies poden afectar el sistema públic d'accés a la salut així com també tenir en compte si determinats grups de pacients corren el risc de ser postergats sense oblidar quin pugui ser l'impacte en les futures generacions

In this article I would like to examine gene editing and its impact on responsibility. I will focus on germ line’ research and practice. Though these technologies do not raise novel issues, they make us re-think the scope of traditional responsibility. I will examine responsibility from an individual perspective: for example our role as parents and the impact of our decisions on our descendants. I will also examine responsibility from a collective perspective: scientists should examine how to regulate these technologies. In addition, as a society we should address how these technologies may affect public access to health care, or if groups of patients might be overlooked. We should also think the impact gene editing may have on future generations

Humanos , Edição de Genes/ética , Responsabilidade Social , Células Germinativas , Sistemas de Saúde/legislação & jurisprudência , Sistemas de Saúde/organização & administração , Tecnologia/legislação & jurisprudência , Direitos Humanos/legislação & jurisprudência
Endocrinology ; 160(12): 2981-2989, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31617897


Testicular germ cell cancer (TGCC) is the most frequent cancer of the young male, with an increasing incidence worldwide. The pathogenesis and reasons for this increase remain unknown. However, epidemiological and experimental data have suggested that, similar to genital malformations and sperm impairment, it could result from the interaction of genetic and environmental factors including fetal exposure to endocrine-disrupting chemicals (EDCs) with estrogenic effects. In this review, we analyze the expression of classic and nonclassic estrogen receptors by TGCC cells, the way they may influence germ cell proliferation induced by EDCs, and discuss how this estrogen dependency supports the developmental and environmental hypothesis.

Disruptores Endócrinos/efeitos adversos , Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/etiologia , Receptores Estrogênicos/metabolismo , Neoplasias Testiculares/etiologia , Androgênios/metabolismo , Animais , Epigênese Genética , Humanos
Immunity ; 51(5): 813-825.e4, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31628053


Butyrophilin (BTN) and butyrophilin-like (BTNL/Btnl) heteromers are major regulators of human and mouse γδ T cell subsets, but considerable contention surrounds whether they represent direct γδ T cell receptor (TCR) ligands. We demonstrate that the BTNL3 IgV domain binds directly and specifically to a human Vγ4+ TCR, "LES" with an affinity (∼15-25 µM) comparable to many αß TCR-peptide major histocompatibility complex interactions. Mutations in germline-encoded Vγ4 CDR2 and HV4 loops, but not in somatically recombined CDR3 loops, drastically diminished binding and T cell responsiveness to BTNL3-BTNL8-expressing cells. Conversely, CDR3γ and CDR3δ loops mediated LES TCR binding to endothelial protein C receptor, a clonally restricted autoantigen, with minimal CDR1, CDR2, or HV4 contributions. Thus, the γδ TCR can employ two discrete binding modalities: a non-clonotypic, superantigen-like interaction mediating subset-specific regulation by BTNL/BTN molecules and CDR3-dependent, antibody-like interactions mediating adaptive γδ T cell biology. How these findings might broadly apply to γδ T cell regulation is also examined.

Antígenos/imunologia , Butirofilinas/metabolismo , Seleção Clonal Mediada por Antígeno/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Sequência de Aminoácidos , Animais , Antígenos/química , Butirofilinas/química , Linhagem Celular , Epitopos/imunologia , Células Germinativas/metabolismo , Humanos , Região Variável de Imunoglobulina/química , Região Variável de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/metabolismo , Ligantes , Camundongos , Ligação Proteica/imunologia , Domínios e Motivos de Interação entre Proteínas , Receptores de Antígenos de Linfócitos T gama-delta/química , Relação Estrutura-Atividade
Results Probl Cell Differ ; 68: 321-353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598863


When shifting research focus from model to non-model species, many differences in the working approach should be taken into account and usually methodological modifications are required because of the lack of genetics/genomics and developmental information for the vast majority of organisms. This lack of data accounts for the largely incomplete understanding of how the two components-genes and developmental programs-are intermingled in the process of evolution. A deeper level of knowledge was reached for a few model animals, making it possible to understand some of the processes that guide developmental changes during evolutionary time. However, it is often difficult to transfer the obtained information to other, even closely related, animals. In this chapter, we present and discuss some examples, such as the choice of molecular markers to be used to characterize differentiation and developmental processes. The chosen examples pertain to the study of germline in molluscs, reptiles, and other non-model animals.

Biomarcadores/metabolismo , Diferenciação Celular , Células Germinativas/citologia , Células Germinativas/metabolismo , Moluscos/citologia , Répteis , Animais , Biomarcadores/análise , Répteis/embriologia
Results Probl Cell Differ ; 68: 515-551, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31598870


Animal female and male germ-line cells often form syncytial units termed cysts, clusters, or clones. Within these cysts, the cells remain interconnected by specific cell junctions known as intercellular bridges or ring canals, which enable cytoplasm to be shared and macromolecules and organelles to be exchanged between cells. Numerous analyses have shown that the spatial organization of cysts and their functioning may differ between the sexes and taxa. The vast majority of our knowledge about the formation and functioning of germ-line cysts comes from studies of model species (mainly Drosophila melanogaster); the other systems of the cyst organization and functioning are much less known and are sometimes overlooked. Here, we present the current state of the knowledge of female germ-line cysts in clitellate annelids (Clitellata), which is a monophyletic taxon of segmented worms (Annelida). The organization of germ-line cysts in clitellates differs markedly from that of the fruit fly and vertebrates. In Clitellata, germ cells are not directly connected one to another, but, as a rule, each cell has one ring canal that connects it to an anuclear central cytoplasmic core, a cytophore. Thus, this pattern of cell distribution is similar to the germ-line cysts of Caenorhabditis elegans. The last decade of studies has revealed that although clitellate female germ-line cysts have a strong morphological plasticity, e.g., cysts may contain from 16 to as many as 2500 cells, the oogenesis always shows a meroistic mode, i.e., the interconnected cells take on different fates; a few (sometimes only one) become oocytes, whereas the rest play the role of supporting (nurse) cells and do not continue oogenesis.This is the first comprehensive summary of the current knowledge on the organization and functioning of female germ-line cysts in clitellate annelids.

Anelídeos/citologia , Células Germinativas/citologia , Células Gigantes/citologia , Células Gigantes/fisiologia , Animais , Feminino , Oócitos/citologia , Oócitos/crescimento & desenvolvimento , Oogênese
Immunity ; 51(4): 601-603, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618651


Using a transgenic mouse strain expressing the human VH1-69 germline gene used by many broadly neutralizing antibodies to influenza A virus, Sangesland et al. show that the VH1-69 gene segment provides the essentials for mounting antibody responses against the conserved hemagglutinin stem epitope.

Administração Financeira , Orthomyxoviridae , Vacinas , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Linfócitos B/imunologia , Células Germinativas , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Humanos , Camundongos
Nat Commun ; 10(1): 4310, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541084


Meiotic crossovers (COs) ensure proper chromosome segregation and redistribute the genetic variation that is transmitted to the next generation. Large populations and the demand for genome-wide, fine-scale resolution challenge existing methods for CO identification. Taking advantage of linked-read sequencing, we develop a highly efficient method for genome-wide identification of COs at kilobase resolution in pooled recombinants. We first test this method using a pool of Arabidopsis F2 recombinants, and recapitulate results obtained from the same plants using individual whole-genome sequencing. By applying this method to a pool of pollen DNA from an F1 plant, we establish a highly accurate CO landscape without generating or sequencing a single recombinant plant. The simplicity of this approach enables the simultaneous generation and analysis of multiple CO landscapes, accelerating the pace at which mechanisms for the regulation of recombination can be elucidated through efficient comparisons of genotypic and environmental effects on recombination.

Genoma de Planta/genética , Técnicas de Genotipagem/métodos , Células Germinativas , Recombinação Homóloga/genética , Recombinação Genética , Arabidopsis/genética , Pontos de Quebra do Cromossomo , Biologia Computacional/métodos , Troca Genética , Metilação de DNA , Genômica , Genótipo , Haplótipos , Pólen/genética , Análise de Sequência de DNA , Sequenciamento Completo do Genoma/métodos