氨基酸重復(fù)擴(kuò)增發(fā)生在 >20 種遺傳性人類疾病中，許多發(fā)生在轉(zhuǎn)錄因子 (TFs) 的固有無序結(jié)構(gòu)域 (IDRs)。此類疾病與蛋白質(zhì)聚集有關(guān)，但聚集物對病理的作用一直存在爭議。該研究報(bào)道了轉(zhuǎn)錄因子 HOXD13 (導(dǎo)致人類遺傳性多指癥) 中，丙氨酸的重復(fù)擴(kuò)增改變了其相分離能力及與轉(zhuǎn)錄共激活因子共凝聚的能力。在體外和體內(nèi)，HOXD13 重復(fù)擴(kuò)增擾亂了含 HOXD13 凝結(jié)物的成分，并且在小鼠多指模型中以細(xì)胞特異性方式改變了轉(zhuǎn)錄程序。同樣的，其他 TFs (HOXA13, RUNX2 和 TBP) 中與疾病相關(guān)的重復(fù)擴(kuò)增也改變了其相分離。這些結(jié)果表明，轉(zhuǎn)錄凝聚物的非融合可能是對應(yīng)疾病的病理基礎(chǔ)。研究人員提出了 TF IDRs 的分子分類，這為轉(zhuǎn)錄失調(diào)相關(guān)疾病中的 TF 功能的研究提供了架構(gòu)。

Distinct Processing of lncRNAs Contributes toNon-conserved Functions in Stem Cells

This study reports that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. The researchers envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

Y-27632 (dihydrochloride), AP20187 purchased from MCE.

結(jié)直腸癌 (CRCs) 由不同基因型和表型的細(xì)胞混合組成。該研究首次揭示了 CRC 細(xì)胞生物合成能力的異質(zhì)性。研究人員發(fā)現(xiàn) CRCs 中的大部分核糖體 DNA 轉(zhuǎn)錄和蛋白質(zhì)合成發(fā)生在特定的有限腫瘤細(xì)胞亞群中。其余的腫瘤細(xì)胞由于分化而發(fā)生了不可逆的生物合成能力喪失。生物合成區(qū)域內(nèi)的癌細(xì)胞的 RNA 聚合酶 I 亞基 A (POLR1A) 水平升高。POLR1A 高水平細(xì)胞群體的遺傳消融對 CRCs 造成不可逆的生長停滯。研究顯示，升高的生物合成決定了 LGR5⁺ 和 LGR5^- 腫瘤細(xì)胞的干細(xì)胞特性。因此，CRCs 是基于轉(zhuǎn)錄核糖體 DNA 和合成蛋白質(zhì)的差異能力的簡單的細(xì)胞層次結(jié)構(gòu)。

The study reveals a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. The researchers discovered that the majority of ribosomal DNA transcription and protein synthesis in CRCsoccurs in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RNA polymerase I subunit A (POLR1A). Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest on CRCs. This research shows that elevated biosynthesis defines stemness in both LGR5⁺ and LGR5^- tumor cells. Therefore, a common architecture in CRCs is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins.

Seliciclib, THZ531, LDC000067 purchased from MCE.

分子膠化合物能誘導(dǎo)蛋白質(zhì)-蛋白質(zhì)相互作用，在存在泛素連接酶的情況下導(dǎo)致蛋白質(zhì)降解。與傳統(tǒng)的酶抑制劑不同，這些分子膠降解劑在亞化學(xué)計(jì)量起催化作用，快速降解其靶標(biāo)。在該研究中，研究人員通過系統(tǒng)地挖掘數(shù)據(jù)庫以研究 4,518 種臨床和臨床前小分子的細(xì)胞毒性與數(shù)百種人類癌細(xì)胞系中 E3 連接酶成分表達(dá)水平的相關(guān)性，鑒定了一種 CDK 抑制劑 CR8 作為分子膠降解劑。該研究表明，暴露在表面的部分的化學(xué)變化使抑制劑獲得分子膠功能，因此，研究人員認(rèn)為這可以作為更廣泛的策略，將目標(biāo)結(jié)合分子轉(zhuǎn)化為分子膠。

Remdesivir purchased from MCE.

This study shows the full functionality of a yeast-based synthetic genomics platform to genetically reconstruct diverse RNA viruses, including members of the Coronaviridae, Flaviviridae and Paramyxoviridae families. Viral subgenomic fragments were generated using viral isolates, cloned viral DNA, clinical samples, or synthetic DNA, and reassembled in one step in Saccharomyces cerevisiae using transformation associated recombination (TAR) cloning to maintain the genome as a yeast artificial chromosome (YAC). T7-RNA polymerase has been used to generate infectious RNA to rescue viable virus. Based on this platform we have been able to engineer and resurrect chemically-synthetized clones of the recent epidemic SARS-CoV-2 in only a week after receipt of the synthetic DNA fragments. The technical advance we describe here allows a rapidly response to emerging viruses as it enables the generation and functional characterization of evolving RNA virus variants-in real-time-during an outbreak.

盡管有證據(jù)表明骨髓增生異常綜合癥 (MDS) 中存在慢性炎癥， MDS 造血干細(xì)胞和祖細(xì)胞 (HSPC) 中 Toll 樣受體 (TLR) 信號調(diào)節(jié)異常，但 MDS HSPC 在炎癥環(huán)境中比正常 HSPC 更具有競爭優(yōu)勢的機(jī)制尚不清楚。該研究發(fā)現(xiàn)，慢性炎癥是 MDS HSPC 競爭優(yōu)勢和疾病進(jìn)展的決定因素。與正常 HSPC 相比，涉及通過非經(jīng)典 NF-κB 途徑信號傳導(dǎo)的 MDS HSPC 細(xì)胞內(nèi)源性反應(yīng)，保護(hù)了這些細(xì)胞免于慢性炎癥。為了響應(yīng)炎癥，MDS HSPC 由經(jīng)典的 NF-κB 信號轉(zhuǎn)為非經(jīng)典的 NF-κB 信號，這一過程依賴于 TLR-TRAF6 介導(dǎo)的 A20 激活。通過敲除 A20 或抑制非經(jīng)典 NF-κB 途徑，TLR-TRAF6 誘導(dǎo)的 HSPC 的競爭優(yōu)勢消失。這些發(fā)現(xiàn)揭示了 MDS HSPCs 克隆優(yōu)勢的機(jī)制基礎(chǔ)，并表明干擾非經(jīng)典 NF-κB 信號傳導(dǎo)可以抑制 MDS 的進(jìn)展。

Remdesivir purchased from MCE.

由 SARS-CoV-2 引起的 COVID-19 大流行已成為全球性危機(jī)。SARS-CoV-2 的復(fù)制需要病毒 RNA 依賴性的 RNA 聚合酶 (RdRp)，它是抗病毒藥物 Remdesivir 的靶標(biāo)。該研究報(bào)道了 SARS-CoV-2 RdRp 的兩種冷凍電子顯微鏡結(jié)構(gòu): 2.8Å 的分辨率下呈 apo 形式 (apo form)，和 2.5Å 的分辨率下的 50 個(gè)堿基的模板引物 RNA 和 Remdesivir 形成的復(fù)合體。復(fù)雜的結(jié)構(gòu)揭示了部分雙鏈 RNA 模板插入了 RdRp 的中心通道，Remdesivir 在第一個(gè)復(fù)制的堿基對處共價(jià)摻入引物鏈，并終止了鏈延長。該研究為抗病毒感染的藥物研發(fā)提供了重要的理論機(jī)制和結(jié)構(gòu)基礎(chǔ)。

This study reports the cryo-EM structure of the SARS-CoV-2 RdRp either in the apo format 2.8 Å resolution or in complex with a 50-base template-primer RNA and Remdesivir at 2.5 Å resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is covalently incorporated into the primer strand at the first replicated base pair and terminates chain elongation. Our structures provide critical insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.