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1.
Nat Commun ; 15(1): 5616, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965253

RESUMEN

Patterns on polymers usually have different mechanical properties as those of the substrates, causing deformation or distortion and even detachment of the patterns from the polymer substrates. Herein, we present a wrinkling strategy, which utilizes photolithography to define the area of stress distribution by light-induced physical crosslinking of polymers and controls diffusion of residual solvent to redistribute the stress and then offers the same material for patterns as substrate by thermal polymerization, providing uniform wrinkles without worrying about force relaxation. The strategy allows the recording and hiding of up to eight switchable images in one place that can be read by the naked eye without crosstalk, applying the wrinkled polymer for optical anti-counterfeiting. The wrinkled polyimide film was also utilized to act as a substrate for the creation of fine copper circuit by a full-additive process. It generates flexible integrated circuit (IC) carrier board with copper wire density of 400% higher than that of the state-of-the-art in industry while fulfilling the standards for industrialization.

2.
Zool Res ; 45(2): 275-283, 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38485497

RESUMEN

Huntington's disease (HD) is a hereditary neurodegenerative disorder for which there is currently no effective treatment available. Consequently, the development of appropriate disease models is critical to thoroughly investigate disease progression. The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin ( HTT) gene, leading to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain, which precipitate selective neuronal loss in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets. Due to the marked species differences between rodents and larger animals, substantial efforts have been directed toward establishing large animal models for HD research. These models are pivotal for advancing the discovery of novel therapeutic targets, enhancing effective drug delivery methods, and improving treatment outcomes. We have explored the advantages of utilizing large animal models, particularly pigs, in previous reviews. Since then, however, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. In the current review, we provide a comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. We also explore the utilization of large animal models in HD research, with a focus on sheep, non-human primates (NHPs), and pigs. Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.


Asunto(s)
Enfermedad de Huntington , Enfermedades de las Ovejas , Enfermedades de los Porcinos , Animales , Ovinos , Porcinos , Enfermedad de Huntington/genética , Enfermedad de Huntington/terapia , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/veterinaria , Modelos Animales de Enfermedad , Primates/genética , Encéfalo/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedades de las Ovejas/metabolismo , Enfermedades de las Ovejas/patología , Enfermedades de los Porcinos/metabolismo , Enfermedades de los Porcinos/patología
3.
Signal Transduct Target Ther ; 8(1): 358, 2023 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-37735155

RESUMEN

Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aß oligomers, constitute the major pathological hallmarks of Alzheimer's disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aß accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aß oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aß oligomers in the monkey spinal cord. These Aß oligomers were recognized by several antibodies to Aß1-42 and contributed to neurodegeneration. However, the generation of Aß oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aß oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aß pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Animales , Ratones , Macaca fascicularis , Tauopatías/genética , Péptidos beta-Amiloides/genética , Enfermedad de Alzheimer/genética , Médula Espinal
4.
Signal Transduct Target Ther ; 8(1): 327, 2023 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-37661226

RESUMEN

Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.


Asunto(s)
Linfopenia , Inmunodeficiencia Combinada Grave , Animales , Ratones , Inmunodeficiencia Combinada Grave/genética , Haplorrinos , Edición Génica , Proteínas de Homeodominio/genética
5.
Nat Biomed Eng ; 7(5): 629-646, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36797418

RESUMEN

The monogenic nature of Huntington's disease (HD) and other neurodegenerative diseases caused by the expansion of glutamine-encoding CAG repeats makes them particularly amenable to gene therapy. Here we show the feasibility of replacing expanded CAG repeats in the mutant HTT allele with a normal CAG repeat in genetically engineered pigs mimicking the selective neurodegeneration seen in patients with HD. A single intracranial or intravenous injection of adeno-associated virus encoding for Cas9, a single-guide RNA targeting the HTT gene, and donor DNA containing the normal CAG repeat led to the depletion of mutant HTT in the animals and to substantial reductions in the dysregulated expression and neurotoxicity of mutant HTT and in neurological symptoms. Our findings support the further translational development of virally delivered Cas9-based gene therapies for the treatment of genetic neurodegenerative diseases.


Asunto(s)
Enfermedad de Huntington , Animales , Porcinos , Enfermedad de Huntington/genética , Enfermedad de Huntington/terapia , Enfermedad de Huntington/metabolismo , Expansión de Repetición de Trinucleótido , Sistemas CRISPR-Cas/genética , Ingeniería Genética
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