The molecular landscape of ETMR at diagnosis and relapse.

Pamiparib purchased from MCE.

多层菊形团样胚胎性肿瘤 (ETMR) 是一种预后普遍较差的侵袭性儿科胚胎性脑肿瘤。研究团队收集了 193 个原发性 ETMR 和 23 个匹配复发样本，以研究其基因组图谱。研究发现，驱动器 C19MC 未被频繁扩增的肿瘤患者中，存在 DICER1 或者其他 microRNA 相关的胚系突变。全基因组测序表明，肿瘤的单核苷酸变异 (SNV) 总体复发率较低，但 R-loop 结构的广泛存在，导致普遍的基因组不稳定。研究表明，R-loop 相关的染色体不稳定可由 DICER1 功能缺失引起。原发肿瘤与匹配的复发样本的比较显示，结构变异的保守性很强，而 SNV 的保守性却很低。此外，许多新获得的 SNV 与顺铂治疗相关的突变信号有关。最后，研究证明了用拓扑异构酶和 PARP 抑制剂靶向 R-loop 可能是 ETMR 的有效治疗对策。

Researchers found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (alsoknown as MIR17HG). Whole-genome sequencing revealed that tumours had an overalllow recurrence of single-nucleotide variants (SNVs), but showed prevalentgenomic instability caused by widespread occurrence of R-loop structures. Weshow that R-loop-associated chromosomal instability can be induced by the lossof DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation ofSNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, Researchers show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

A Translation-Activating Function of MIWI/piRNA during Mouse Spermiogenesis.

Cycloheximide purchased from MCE.

Researchers unexpectedly discover that the MIWI/piRNA machinery is responsible for activating translation of a subset of spermiogenic mRNAs to coordinate with morphological transformation into spermatozoa. Such action requires specific base-pairing interactions of piRNAs with target mRNAs in their 3' UTRs, which activates translation through coupling with cis-acting AU-rich elements to nucleate the formation of a MIWI/piRNA/eIF3f/HuR super-complex in a developmental stage-specific manner. These findings reveal acritical role of the piRNA system in translation activation, and that is functionally required for spermatid development.

CCCP purchased from MCE.

线粒体稳态取决于线粒体，线粒体的程序性降解。已知只有少数蛋白质参与线粒体吞噬。该文章首次阐述了腺苷转运蛋白 ANT (Adenine Nucleotide Translocator) 对线粒体自噬的重要作用。

caspase-8 是外源性凋亡的启动半胱天冬酶，并抑制由 RIPK3 和 MLKL 介导的坏死性凋亡。该研究表明，酶活失效的 CASP8 (C362S) 的表达通过诱导坏死性凋亡和细胞焦亡诱导小鼠胚胎致死。与 Casp8^-/-小鼠类似，在内皮细胞坏死性凋亡导致心血管缺陷后 Casp8^C362S/C362S小鼠胚胎死亡。缺乏 MLKL 挽救了心血管疾病表型，但意外地导致了 Casp8^c362/c362 小鼠围产期死亡率升高，这表明 CASP8 (C362S) 在胚胎发育的后期引起坏死性凋亡非依赖性死亡。肠上皮细胞中 caspase-8 催化活性特异性缺失引起肠道炎症与小鼠 Casp8 敲除结果相似。肠道细胞 caspase-8 特异性缺失小鼠中，敲除 Mlk1 抑制坏死性凋亡会严重加重肠道炎症，并且引起过早的致死性。CASP8 (C362S) 的表达触发了 ASC 斑点的形成，caspase-1 的活化和 IL-1β 的分泌。在Casp8^C362S/C362SMlkl^-/-Asc^-/- 或 Casp8^C362S/C362SMlkl^-/-Casp1^-/- 小鼠中，胚胎致死率和过早死亡都完全得到挽救，表明当坏死性凋亡被阻断时，炎性小体的活化促进CASP8 (C362S) 介导的组织病理。因此，caspase-8 是控制细胞凋亡、坏死性凋亡和细胞焦亡的分子开关，在胚胎发育和成人时期防止组织损伤。

Researchers show that the expression ofenzymatically inactive CASP8 (C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8^-/- mice, Casp8^C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotypebut unexpectedly caused perinatal lethality in Casp8^C362S/C362S mice, indicating that CASP8 (C362S) causes necroptosis-independent death at laterstages of embryonic development. Specific loss of the catalytic activity of caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice. Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8 (C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1β. Both embryonic lethality and premature death were completely rescued in Casp8^C362S/C362S Mlkl^-/- Asc^-/- or Casp8^C362S/C362SMlkl^-/-Casp1^-/- mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when necroptosis is blocked. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood.

The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL.

细菌性营养不良伴随着结肠癌和肝癌等恶性肿瘤的癌变，并且最近与胰腺导管腺癌 (PDA) 的发病机理有关。该文章证明了真菌从肠腔迁移到胰腺与胰腺导管腺癌 (Pancreatic ductal adenocarcinoma, PDA) 的发病机制有关。

Forodesine hydrochloride purchased from MCE.

身体或精神上的压力会导致大脑神经可塑性，并增加患抑郁症和焦虑症的风险。应激暴露导致外周T淋巴细胞功能障碍。然而，尚未充分建立在情绪障碍中外周T淋巴细胞的病理作用和潜在的调节机制。文章表明，频繁应激通过扰乱外周 CD4+ T 细胞代谢导致焦虑、抑郁样行为，增加患焦虑症、抑郁症的风险。