RESUMEN
Duchenne muscular dystrophy (DMD) is the most prevalent herediatry disease in men, characterized by dystrophin deficiency, progressive muscle wasting, cardiac insufficiency, and premature mortality, with no effective therapeutic options. Here, we investigated whether adenine base editing can correct pathological nonsense point mutations leading to premature stop codons in the dystrophin gene. We identified 27 causative nonsense mutations in our DMD patient cohort. Treatment with adenine base editor (ABE) could restore dystrophin expression by direct A-to-G editing of pathological nonsense mutations in cardiomyocytes generated from DMD patient-derived induced pluripotent stem cells. We also generated two humanized mouse models of DMD expressing mutation-bearing exons 23 or 30 of human dystrophin gene. Intramuscular administration of ABE, driven by ubiquitous or muscle-specific promoters could correct these nonsense mutations in vivo, albeit with higher efficiency in exon 30, restoring dystrophin expression in skeletal fibers of humanized DMD mice. Moreover, a single systemic delivery of ABE with human single guide RNA (sgRNA) could induce body-wide dystrophin expression and improve muscle function in rotarod tests of humanized DMD mice. These findings demonstrate that ABE with human sgRNAs can confer therapeutic alleviation of DMD in mice, providing a basis for development of adenine base editing therapies in monogenic diseases.
RESUMEN
Telomeres are DNA-protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors.
RESUMEN
Climate warming greatly affects the frequency and intensity of flash droughts, which can cause huge damage to agriculture. It is important to understand the changing rules of future flash droughts and take precautionary measures in advance. Thus, we focused on the flash drought characteristic of the Jinghe River basin using variable infiltration capacity (VIC) model and four-model ensemble in the two representative concentration pathway scenarios. Four-model ensemble mean can well capture hydrological changes in the reference period. The heat wave flash drought (HWFD) and the precipitation deficit flash drought (PDFD) mainly occur in the northern during reference period. The HWFD and PDFD have shown a linear growth trend in the future and both shown higher growth rates in the RCP8.5 scenario. The frequency of occurrence (FOC) increments of flash droughts were relatively high in the southern Jinghe River basin. And the HWFD and the PDFD mainly occurred in May-September. Further results indicate that the contribution of the maximum temperature to HWFD was the biggest (greater than 0.7), followed by evapotranspiration (ET) and soil moisture (SM). The contribution of maximum temperature to PDFD was the biggest (greater than 0.5), followed by precipitation and ET. Global warming in the twenty-first century is likely to lead to intensification of flash droughts. Therefore, measures and suggestions were proposed to effectively respond to flash droughts in our study.
