Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy

Mitophagy is one of the processes that cells use to maintain overall health. An E3 ligase, parkin, ubiquitinates mitochondrial proteins prior to their degradation by autophagasomes. USP30 is an enzyme that de-ubiquitinates mitochondrial proteins; therefore, inhibiting this enzyme could foster mitophagy. Herein, we disclose the structure–activity relationships (SAR) within a novel series of highly selective USP30 inhibitors. Two structurally similar compounds, MF-094 (a potent and selective USP30 inhibitor) and MF-095 (a significantly less potent USP30 inhibitor), serve as useful controls for biological evaluation. We show that MF-094 increases protein ubiquitination and accelerates mitophagy.     

Discrete-time host–parasitoid models with pest control

We propose a simple discrete-time host–parasitoid model to investigate the impact of external input of parasitoids upon the host–parasitoid interactions. It is proved that the input of the external parasitoids can eventually eliminate the host population if it is above a threshold and it also decreases the host population level in the unique interior equilibrium. It can simplify the host–parasitoid dynamics when the host population practices contest competition. We then consider a corresponding optimal control problem over a finite time period. We also derive an optimal control model using a chemical as a control for the hosts. Applying the forward–backward sweep method, we solve the optimal control problems numerically and compare the optimal host populations with the host populations when no control is applied. Our study concludes that applying a chemical to eliminate the hosts directly may be a more effective control strategy than using the parasitoids to indirectly suppress the hosts.     

Isolation of dihydroxylupene and dihydroxylupane from the bark of Lawsonia inermis

Two pentacyclic triterpenes isolated from the bark of henna were identified as 3β, 30-dihydroxylup- 20(29)-ene (hennadiol), and (20S)-3β, 30-dihydroxylupane. The assignment of the C-20 configuration in the latter compound was supported by the analysis of Eu(fod)₃-induced ¹H NMR chemical shifts in the two C-20 epimers synthesized from lupeol.     

Isolation of virus-like (VL30) elements from theQ10 andD regions of the major histocompatibility complex

Previous studies from our laboratory have described two endogenous provirus-like sequences in a series of cosmids spanning theTL region of the major histocompatibility complex (MHC) of normal C57BL/10 mice. At least one of these viruses shares similarities withVL30 elements. To determine if additionalVL30-like retroviral elements are integrated in the MHC, we constructed a cosmid library using DNA from a radiation leukemia virus (RadLV)-transformed cell line derived from C57BL/6 mice. The library was first screened using theH-2III (5) probe, which detects Class I genes of theH-2 complex. In the primary screening 163H-2III positives were isolated. TheH-2III-positive isolates were then hybridized with an AKR-derived virus probe,EcoB/S, which contains sequences from both thepol and theenv genes of the virus. Nine virus-positive isolates were detected. Localization of these cosmid isolates containing viral sequences within theH-2 complex was done utilizing low-copy probes and confirmed using previously mapped cosmid isolates from other laboratories. We report here the isolation and characterization ofVL30-like elements from theQa andD regions of theMHC of several inbred mouse strains.     

MicroRNA‐30c suppresses the pro‐fibrogenic effects of cardiac fibroblasts induced by TGF‐β1 and prevents atrial fibrosis by targeting TGFβRII

Atrial fibrosis serves as an important contributor to atrial fibrillation (AF). Recent data have suggested that microRNA‐30c (miR‐30c) is involved in fibrotic remodelling and cancer development, but the specific role of miR‐30c in atrial fibrosis remains unclear. The purpose of this study was to investigate the role of miR‐30c in atrial fibrosis and its underlying mechanisms through in vivo and in vitro experiments. Our results indicate that miR‐30c is significantly down‐regulated in the rat abdominal aortic constriction (AAC) model and in the cellular model of fibrosis induced by transforming growth factor‐β1 (TGF‐β1). Overexpression of miR‐30c in cardiac fibroblasts (CFs) markedly inhibits CF proliferation, differentiation, migration and collagen production, whereas decrease in miR‐30c leads to the opposite results. Moreover, we identified TGFβRII as a target of miR‐30c. Finally, transferring adeno‐associated virus 9 (AAV9)‐miR‐30c into the inferior vena cava of rats attenuated fibrosis in the left atrium following AAC. These data indicate that miR‐30c attenuates atrial fibrosis via inhibition of CF proliferation, differentiation, migration and collagen production by targeting TGFβRII, suggesting that miR‐30c might be a novel potential therapeutic target for preventing atrial fibrosis.     

Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition

Endothelial-mesenchymal transition (EndoMT) is associated with damage to blood-brain barrier (BBB) integrity. Circular RNAs (circRNAs) are highly expressed in the brain and are involved in brain diseases; however, whether circRNAs regulate the EndoMT in the brain remains unknown. Our study demonstrated that circHECW2 regulated the EndoMT by directly binding to MIR30D, a significantly downregulated miRNA from miRNA profiling, which subsequently caused an increased expression of ATG5. These findings shed new light on the understanding of the noncanonical role of ATG5 in the EndoMT induced by methamphetamine (Meth) or lipopolysaccharide (LPS). The in vivo relevance was confirmed as microinjection of circHecw2 siRNA lentivirus into the mouse hippocampus suppressed the EndoMT induced by LPS. These findings provide novel insights regarding the contribution of circHECW2 to the nonautophagic role of ATG5 in the EndoMT process in the context of drug abuse and the broad range of neuroinflammatory disorders.     

Molecular replacement studies on crystal structure of DesBl-B2 Despentapeptide (B26-B30) insulin

Using the crystal structure of Despentapeptide (B26-B30) insulin (DPI) as the search model, the crystal structure of DesBl-B2 Despentapeptide (B26-B30) insulin (DesBl-2 DPI) has been studied by the molecular replacement method. There is one DesBl-2 DPI molecule in each crystallographic asymmetric unit. The cross rotation function search and the translation function search show apparent peaks and thus determine the orientation and position of DesBl-2 DPI molecule in the cell respectively. The subsequent three-dimensional structural rebuilding and refine-ment of DesBl-2 DPI molecule confirm the results by molecular replacement method.     

萝卜-芥蓝异源四倍体植物SR30基因转录本的选择性剪接分析

为了解异源多倍体形成后,其剪接因子基因SR30在各组织器官间的表达量以及选择性剪接模式与亲本的差异,选取萝卜-芥蓝异源四倍体(Raphanobrassica)及其亲本萝卜(Raphanus sativus)、芥蓝(Brassica oleracea var.alboglabra)为材料,运用RACE-PCR方法克隆到全长的编码序列(CDS)和3非编码区(3 UTR),运用q RT-PCR和半定量RT-PCR检测其在各组织器官中的表达量和各转录本表达量间的差异。结果表明,四倍体中萝卜同源的Rs SR30基因有5种转录本,芥蓝同源的Bo SR30基因有4种转录本。同时,SR30在3物种中的表达具有组织器官的差异,且在四倍体中的总体表达量显著低于亲本。根据克隆到的转录本,预测Rs SR30编码3种蛋白,Bo SR30编码2种,不同蛋白异构体的区别体现在C末端的丝氨酸-精氨酸富集(RS)结构域。因此,萝卜-芥蓝异源多倍体形成后,SR30基因在表达量和转录本选择性剪接方面都发生了改变。