RESUMO
Fanconi Anemia (FA) clinical phenotypes are heterogenous and rely on a mutation in one of the 22 FANC genes (FANCA-W) involved in a common interstrand DNA crosslink-repair pathway. A critical step in the activation of FA pathway is the monoubiquitination of FANCD2 and its binding partner FANCI. To better address the clinical phenotype associated with FANCI and the epistatic relationship with FANCD2, we created the first conditional inactivation model for FANCI in mouse. Fanci -/- mice displayed typical FA features such as delayed development in utero, microphtalmia, cellular sensitivity to mitomycin C, occasional limb abnormalities and hematological deficiencies. Interestingly, the deletion of Fanci leads to a strong meiotic phenotype and severe hypogonadism. FANCI was localized in spermatocytes and spermatids and in the nucleus of oocytes. Both FANCI and FANCD2 proteins co-localized with RPA along meiotic chromosomes, albeit at different levels. Consistent with a role in meiotic recombination, FANCI interacted with RAD51 and stimulated D-loop formation, unlike FANCD2. The double knockout Fanci-/- Fancd2-/- also showed epistatic relationship for hematological defects while being not epistatic with respect to generating viable mice in crosses of double heterozygotes. Collectively, this study highlights common and distinct functions of FANCI and FANCD2 during mouse development, meiotic recombination and hematopoiesis.
Assuntos
Reparo do DNA , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oócitos/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Espermatócitos/metabolismoRESUMO
The authors would like to make the following corrections to the published paper [...].
RESUMO
During the first wave of the COVID-19 pandemic, industries and academic institutes have collaborated to resolve the worldwide medical supply shortage issues. Innovative designs of 3D-printed items were proposed and developed by the maker community as a temporary solution to address the lack of personal protective equipment. An overview of global ongoing and past initiatives during the COVID-19 pandemic along with their challenges on retrofitting full-face snorkeling masks for healthcare applications such as splash-proof face shields, respirator masks and non-invasive ventilation systems are reported in this contribution. This study reviews these global initiatives and challenges. From our analysis, the present situation highlights the need to build solid networks between healthcare institutes and the different rapid prototyping initiatives. A clear feedback system needs to be implemented to facilitate effective collaboration between engineering (maker) and healthcare teams, to optimize the available human resources, and to achieve adequate product developments responding to the needs of healthcare workers.
RESUMO
The COVID-19 pandemic resulted in severe shortages of personal protection equipment and non-invasive ventilation devices. As traditional supply chains could not meet up with the demand, makeshift solutions were developed and locally manufactured by rapid prototyping networks. Among the different global initiatives, retrofitting of full-face snorkeling masks for Non-Invasive-Ventilation (NIV) applications seems the most challenging. This article provides a systematic overview of rapid prototyped - 3D printed - designs that enable attachment of medical equipment to snorkeling masks, highlighting potential and challenges in additive manufacturing. The different NIV connector designs are compared on low-cost 3D fabrication time and costs, which allows a rapid assessment of developed connectors for health care workers in urgent need of retrofitting snorkeling masks for NIV purposes. Challenges and safety issues of the rapid prototyping approach for healthcare applications during the pandemic are discussed as well. When critical parameters such as the final product cost, geographical availability of the feedstock and the 3D printers and the medical efficiency of the rapid prototyped products are well considered before deploying decentralized 3D printing as manufacturing method, this rapid prototyping strategy contributed to reduce personal protective equipment and NIV shortages during the first wave of the COVID-19 pandemic. It is also concluded that it is crucial to carefully optimize material and printer parameter settings to realize best fitting and airtight connector-mask connections, which is heavily depending on the chosen feedstock and type of printer.
RESUMO
Fanconi Anemia is a rare autosomal recessive genetic disease with heterogenous phenotypes including myelosuppression, congenital malformations and heightened cancer predisposition. FA cells are highly sensitive to cross-linking agents. Since the 90's, at least 19 FANC proteins (FANCA to FANCT) have been identified as working together in a unique pathway detecting and triggering the repair of DNA crosslinks. Since then, the creation of animal models in various species (nematode, fruit fly, zebrafish and mouse) contributed to a better understanding of the physiopathology of the disease. This review aims to summarize the main discoveries made in these in vivo models, as well as to discuss some controversies that arose from these studies.