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,Researchersshow that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.
Miglustat hydrochloride purchased from MCE.
代谢已被证明可以调控外周免疫，但对其在中枢神经系统 (CNS) 炎症中的作用知之甚少。通过结合蛋白质组,代谢组,转录组,和摄动研究, 研究者发现 cPLA2-MAVS 通过代谢调控星形胶质细胞的致病性。
A Translation-Activating Function of MIWI/piRNA during Mouse Spermiogenesis.
Cycloheximide purchased from MCE.
精子发生是一个高度协调发育过程，在此过程中染色质浓缩使转录与翻译解耦。生精 mRNAs 转录较早并以翻译惰性状态保存，直到翻译需要。然而，目前仍不清楚在精子发生过程中这种抑制的 mRNA 如何被激活。作者团队之前已报道过，在精子形成后期，MIWI/piRNA 机制负责 mRNA 的消除，为产生精子做准备。本次研究意外地发现同样的机制还负责激活部分生精 mRNA 的翻译，以协调向精子的形态转化。这种作用需要 piRNA 与 3'UTR 中靶标 mRNA 的特定碱基配对相互作用，与顺式作用 AU- 富含元件偶联来激活翻译，使 MIWI/piRNA/eIF3f/HuR 超复合体以发育阶段特异性方式成核。这些发现揭示了 piRNA 系统在翻译激活中的关键作用，这在精子细胞发育是必需的。
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.
The ADP/ATP translocase drives mitophagy independent of nucleotide exchange.
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 is the molecular switch for apoptosis, necroptosis and pyroptosis.
Emricasan (IDN-6556) purchased from MCE.
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 Casp8C362S/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Casp8c362/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Casp8C362S/C362SMlkl-/-Asc-/- 或 Casp8C362S/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, Casp8C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotypebut unexpectedly caused perinatal lethality in Casp8C362S/C362S mice, indicating that CASP8 (C362S) causes necroptosis-independent death at laterstages of embryonic development. Specific loss of the catalytic activity of caspase-8in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specificCasp8knockout mice. Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality inMlklknockout 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 inCasp8C362S/C362S Mlkl-/- Asc-/- or Casp8C362S/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.
Gemcitabine，Amphotericin B purchased from MCE.
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。
Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.
Forodesine hydrochloridepurchased 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。
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