Ep 838 - Google Drive

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After 2000, the WP warms accompanied by EP cooling. This could be due to the recent rapid Indian Ocean and warm pool warming (Cravatte et al. 2009; Rao et al. 2012; Luo et al. 2012) or the recent negative phase of the Pacific decadal oscillation (England et al. 2014; Lyon et al. 2014). This facilitates the strengthening of the easterly trade winds, Walker circulation, subtropical highs, and Hadley cell (England et al. 2014). Cai et al. (2015) also found that under global warming, the Indonesian Maritime Continent is warming faster than the equatorial CP to EP region. The increasing zonal temperature gradient between the two can drive stronger anomalous zonal easterly winds. In addition, the recent North Atlantic warming potentially contributed to the intensification of the Walker circulation through upward motion and lower SLP over the Atlantic and an enhanced descending air motion and higher pressure in the eastern Pacific, which in turn strengthened the trade winds over the central tropical Pacific (McGregor et al. 2014; Li et al. 2015; Zanchettin et al. 2016). This is consistent with Fig. 9a. Strong 200-mb divergence (convergence) is observed over the eastern Atlantic (western Atlantic and EP) in Fig. 11. The latter is indicative of a remote forcing from the Atlantic basin as discussed in the introduction (e.g., Kucharski et al. 2011, 2016; Zhang and Karnauskas 2017).

Tumors boast many mechanisms to evade efficacy immunosurveillance by upregulating immunosuppressive molecules and corresponding cells under the antitumor pressure of immunotherapy, resulting in the induction of peripheral tolerance and central tolerance and significantly impairing immunotherapy efficacy.374 The treatment strategies of ICBs are widely exploited to break immune tolerance, including anti-PD-1 antibodies,366 anti-CTLA-4 antibodies,375 and PD-L1 siRNA.376 Unlike ICBs, natural killer (NK) cells may be favorable for overcoming the tolerance mechanism, which is related to NK cells eliminating tumor cells without the presentation of MHC I molecules.366,377 TAAs, as self-antigens, have central tolerance due to the clonal deletion of autoreactive lymph cells during ontogenesis.378 Neoepitopes can bypass central tolerance with high immunogenicity because they are never present in normal tissues and generate the accumulation of gene mutations in cancer cells (including driver mutations and passenger mutations).379 Therefore, neoepitopes were applied to overcome the central tolerance of cancer vaccines and address the issue of tumor heterogeneity. The personal mRNA vaccine has shown relatively favorable clinical efficacy, but some patients were unavailable for vaccination due to disease progression, and merely a portion of neoepitopes successfully induced a specific immune response in patients.366 Recently, several clinical trials have been launched to further evaluate the antitumor efficacy of personal mRNA vaccines (NCT03313778, NCT02316457, and NCT03468244, relevant results have not yet been announced).380,381 Collectively, based on the complexity of tumor pathogenesis, codelivery of multiple therapeutic mRNAs has great potential to defeat cancer.

Gene editing has a torn pace of application in various fields driven by the rapid development of programmable nucleases,423,424 especially for cancer, infectious diseases, primary defects of the immune system, muscular dystrophy, and hematological disease.455 mRNA is widely used to deliver programmable nucleases.456 The three most important programmable nucleases, zinc finger nucleases (ZFNs),457 transcription activator-like effector nucleases (TALENs),458,459 and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein (CRISPR/Cas) nuclease system,460 have all achieved efficient transfection and manipulated insertions/deletions mutations in the form of mRNA. mRNA is an attractive approach in gene editing therapy due to its transient expression without mutant risk, and currently, several clinical trials based on mRNA genetic editing are in progress.461 Here, we discuss the application of mRNA-based gene editing, as well as its future prospects and challenges. 781b155fdc