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1.
Mamm Genome ; 35(2): 113-121, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38488938

RESUMO

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to intranasal inoculation with SARS-CoV-2, they did not show gross phenotypic abnormalities. Next, we generated a Rosa26hACE2;CMV-Cre mouse line that ubiquitously expresses the human ACE2 receptor. By day 3 post infection with SARS-CoV-2, Rosa26hACE2;CMV-Cre mice showed significant weight loss, a variable degree of alveolar wall thickening and reduced survival rates. Viral load measurements confirmed inoculation in lung and brain tissues of infected Rosa26hACE2;CMV-Cre mice. The phenotypic spectrum displayed by our different mouse models translates to the broad range of clinical symptoms seen in the human patients and can serve as a resource for the community to model and explore both treatment strategies and long-term consequences of SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Modelos Animais de Doenças , SARS-CoV-2 , Animais , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/patologia , COVID-19/virologia , Camundongos , Humanos , SARS-CoV-2/genética , Camundongos Transgênicos , Pulmão/virologia , Pulmão/patologia , Pulmão/metabolismo , Técnicas de Introdução de Genes
2.
Biol Reprod ; 110(6): 1115-1124, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38685607

RESUMO

Time-lapse microscopy for embryos is a non-invasive technology used to characterize early embryo development. This study employs time-lapse microscopy and machine learning to elucidate changes in embryonic growth kinetics with maternal aging. We analyzed morphokinetic parameters of embryos from young and aged C57BL6/NJ mice via continuous imaging. Our findings show that aged embryos accelerated through cleavage stages (from 5-cells) to morula compared to younger counterparts, with no significant differences observed in later stages of blastulation. Unsupervised machine learning identified two distinct clusters comprising of embryos from aged or young donors. Moreover, in supervised learning, the extreme gradient boosting algorithm successfully predicted the age-related phenotype with 0.78 accuracy, 0.81 precision, and 0.83 recall following hyperparameter tuning. These results highlight two main scientific insights: maternal aging affects embryonic development pace, and artificial intelligence can differentiate between embryos from aged and young maternal mice by a non-invasive approach. Thus, machine learning can be used to identify morphokinetics phenotypes for further studies. This study has potential for future applications in selecting human embryos for embryo transfer, without or in complement with preimplantation genetic testing.


Assuntos
Embrião de Mamíferos , Desenvolvimento Embrionário , Aprendizado de Máquina , Camundongos Endogâmicos C57BL , Imagem com Lapso de Tempo , Animais , Camundongos , Imagem com Lapso de Tempo/métodos , Feminino , Desenvolvimento Embrionário/fisiologia , Embrião de Mamíferos/diagnóstico por imagem , Envelhecimento , Gravidez
3.
J Clin Invest ; 134(15)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38885336

RESUMO

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.


Assuntos
Diferenciação Celular , Sistema de Sinalização das MAP Quinases , Osteoblastos , Osteogênese Imperfeita , Fatores de Transcrição SOX9 , Animais , Feminino , Masculino , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Mutação , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/genética , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Osteogênese Imperfeita/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Células-Tronco/metabolismo , Células-Tronco/patologia , MAP Quinases Reguladas por Sinal Extracelular
4.
ChemMedChem ; 14(21): 1810-1827, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31456347

RESUMO

More than 70 % of women with ovarian cancer are diagnosed with advanced-stage disease, which is initially treated with cytoreductive surgery, and combination chemotherapy with platinum-based compounds. Most patients initially respond to platinum-based therapy, but eventually up to 80 % of this responsive cohort becomes refractory due to the development of platinum resistance. This review discusses current and potential therapeutic approaches that exploit biomaterial-based applications to combat platinum resistance either by enhancing the delivery of platinum-based drugs or prodrugs, delivering other toxic non-platinum-based bioactive factors (by themselves or in combination with platinum-based drugs) or by delivering other bioactive factors that re-sensitize resistant ovarian cancer cells to these drugs. The types of materials that are used, the bioactive factors applied (i.e., drug or gene delivery), and the specific agents that are employed to target these types of cancer cells are discussed. We conclude that the unique attributes of biomaterial-based applications can be further explored toward overcoming platinum-resistant ovarian cancer as monotherapy, or in combination with other treatment strategies.


Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/química , Materiais Biocompatíveis/química , Reparo do DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Compostos Organoplatínicos/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo
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