The molecular landscape of ETMR at diagnosis and relapse.

Pamiparib purchased from MCE.

多層菊形團(tuán)樣胚胎性腫瘤 (ETMR) 是一種預(yù)后普遍較差的侵襲性兒科胚胎性腦腫瘤。研究團(tuán)隊(duì)收集了 193 個原發(fā)性 ETMR 和 23 個匹配復(fù)發(fā)樣本，以研究其基因組圖譜。研究發(fā)現(xiàn)，驅(qū)動器 C19MC 未被頻繁擴(kuò)增的腫瘤患者中，存在 DICER1 或者其他 microRNA 相關(guān)的胚系突變。全基因組測序表明，腫瘤的單核苷酸變異 (SNV) 總體復(fù)發(fā)率較低，但 R-loop 結(jié)構(gòu)的廣泛存在，導(dǎo)致普遍的基因組不穩(wěn)定。研究表明，R-loop 相關(guān)的染色體不穩(wěn)定可由 DICER1 功能缺失引起。原發(fā)腫瘤與匹配的復(fù)發(fā)樣本的比較顯示，結(jié)構(gòu)變異的保守性很強(qiáng)，而 SNV 的保守性卻很低。此外，許多新獲得的 SNV 與順鉑治療相關(guān)的突變信號有關(guān)。最后，研究證明了用拓?fù)洚悩?gòu)酶和 PARP 抑制劑靶向 R-loop 可能是 ETMR 的有效治療對策。

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.

線粒體穩(wěn)態(tài)取決于線粒體，線粒體的程序性降解。已知只有少數(shù)蛋白質(zhì)參與線粒體吞噬。該文章首次闡述了腺苷轉(zhuǎn)運(yùn)蛋白 ANT (Adenine Nucleotide Translocator) 對線粒體自噬的重要作用。

caspase-8 是外源性凋亡的啟動半胱天冬酶，并抑制由 RIPK3 和 MLKL 介導(dǎo)的壞死性凋亡。該研究表明，酶活失效的 CASP8 (C362S) 的表達(dá)通過誘導(dǎo)壞死性凋亡和細(xì)胞焦亡誘導(dǎo)小鼠胚胎致死。與 Casp8^-/-小鼠類似，在內(nèi)皮細(xì)胞壞死性凋亡導(dǎo)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，但意外地導(dǎo)致了 Casp8^c362/c362 小鼠圍產(chǎn)期死亡率升高，這表明 CASP8 (C362S) 在胚胎發(fā)育的后期引起壞死性凋亡非依賴性死亡。腸上皮細(xì)胞中 caspase-8 催化活性特異性缺失引起腸道炎癥與小鼠 Casp8 敲除結(jié)果相似。腸道細(xì)胞 caspase-8 特異性缺失小鼠中，敲除 Mlk1 抑制壞死性凋亡會嚴(yán)重加重腸道炎癥，并且引起過早的致死性。CASP8 (C362S) 的表達(dá)觸發(fā)了 ASC 斑點(diǎn)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，胚胎致死率和過早死亡都完全得到挽救，表明當(dāng)壞死性凋亡被阻斷時，炎性小體的活化促進(jìn)CASP8 (C362S) 介導(dǎo)的組織病理。因此，caspase-8 是控制細(xì)胞凋亡、壞死性凋亡和細(xì)胞焦亡的分子開關(guān)，在胚胎發(fā)育和成人時期防止組織損傷。

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.

細(xì)菌性營養(yǎng)不良伴隨著結(jié)腸癌和肝癌等惡性腫瘤的癌變，并且最近與胰腺導(dǎo)管腺癌 (PDA) 的發(fā)病機(jī)理有關(guān)。該文章證明了真菌從腸腔遷移到胰腺與胰腺導(dǎo)管腺癌 (Pancreatic ductal adenocarcinoma, PDA) 的發(fā)病機(jī)制有關(guān)。

Forodesine hydrochloride purchased from MCE.

身體或精神上的壓力會導(dǎo)致大腦神經(jīng)可塑性，并增加患抑郁癥和焦慮癥的風(fēng)險。應(yīng)激暴露導(dǎo)致外周T淋巴細(xì)胞功能障礙。然而，尚未充分建立在情緒障礙中外周T淋巴細(xì)胞的病理作用和潛在的調(diào)節(jié)機(jī)制。文章表明，頻繁應(yīng)激通過擾亂外周 CD4+ T 細(xì)胞代謝導(dǎo)致焦慮、抑郁樣行為，增加患焦慮癥、抑郁癥的風(fēng)險。