Oxidative damage in Parkinson disease: Measurement using accurate biomarkers

Oxidative damage has been implicated in the pathogenesis of Parkinson disease (PD) but the literature data are confusing. Using products of lipid and DNA oxidation measured by accurate methods, we assessed the extent of oxidative damage in PD patients. The levels of plasma F₂-isoprostanes (F₂-IsoPs), hydroxyeicosatetraenoic acid products (HETEs), cholesterol oxidation products, neuroprostanes (F₄-NPs), phospholipase A₂ (PLA₂) and platelet activating factor–acetylhydrolase (PAF-AH) activities, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), and serum high-sensitivity C-reactive protein were compared in 61 PD patients and 61 age-matched controls. The levels of plasma F₂-IsoPs, HETEs, 7β-and 27-hydroxycholesterol, 7-ketocholesterol, F₄-NPs, and urinary 8-OHdG were elevated, whereas the levels of plasma PLA₂ and PAF-AH activities were lower, in PD patients compared to controls (p <  0.05). The levels of plasma F₂-IsoPs, HETEs, and urinary 8-OHdG were higher in the early stages of PD (p trend <  0.05). There was a significant negative correlation between the cumulative intake of levodopa and urinary 8-OHdG (r =  ?0.305, p =  0.023) and plasma total HETEs (r =  ?0.285, p =  0.043). Oxidative damage markers are systemically elevated in PD, which may give clues about the relation of oxidative damage to the onset and progression of PD.     

腾冲嗜热菌单链 DNA 结合蛋白 SSB2 和 SSB3 新的单链 DNA 结合特性

摘要：【目的】揭示腾冲嗜热菌中两个单链DNA结合蛋白SSB2和SSB3的全新的底物结合功能及其不同的体内表达模式。【方法】利用腾冲嗜热菌复制起始位点附近的长度较短的单链DNA为底物,采用非变性聚丙烯酰胺凝胶电泳及western blot方法,研究SSB2和SSB3体外单链DNA结合特征和体内表达模式。【结果】SSB2 与35nt的复制起始区单链DNA（ssDNA）结合, 形成单个SSB2-DNA复合物;当与59 nt ssDNA结合时,可以随着蛋白浓度的递增形成一个或两个SSB2-DNA复合物;而与70n     

Ligand activation domain of human orphan growth hormone (GH) secretagogue receptor (GHS-R) conserved from Pufferfish to humans

Synthetic ligands have been identified that reset and amplify the cycle of pulsatile GH secretion by interacting with the orphan GH-secretagogue receptor (GHS-R). The GHS-R is rhodopsin like, but does not obviously belong to any of the established G protein-coupled receptor (GPCR) subfamilies. We recently characterized the closely related orphan family member, GPR38, as the motilin receptor. A common property of both receptors is that they amplify and sustain pulsatile biological responses in the continued presence of their respective ligands. To efficiently identify additional members of this new GPCR family, we explored a vertebrate species having a compact genome, that was evolutionary distant from human, but where functionally important genes were likely to be conserved. Accordingly, three distinct full-length clones, encoding proteins of significant identity to the human GHS-R, were isolated from the Pufferfish (Spheroides nephelus). Southern analyses showed that the three cloned Pufferfish genes are highly conserved across species. The gene with closest identity (58%) was activated by three synthetic ligands that were chosen for their very high selectivity on the GHS-R as illustrated by their specificity in activating the wild-type human GHS-R but not the E124Q mutant. These results indicate that the ligand activation domain of the GHS-R has been evolutionary conserved from Pufferfish to human (400 million years), supporting the notion that the GHS-R and its natural ligand play a fundamentally important role in biology. Furthermore, they illustrate the power of exploiting the compact Pufferfish genome for simplifying the isolation of endocrinologically important receptor families.     

The interspecific competition presents greater nutrient facilitation compared with intraspecific competition through AM fungi interacting with litter for two host plants in karst soil

AM 真菌和枯落物互作下两种喀斯特植物种间竞争较种内竞争更能促进植物养分利用枯落物是植物养分获取和土壤养分转化的关键载体。丛枝菌根(Arbuscular mycorrhizae, AM)对植物养分摄取的影响已被广泛认知。然而,在养分亏缺的喀斯特生境中,不同竞争方式的植物如何通过AM真菌和枯落物利用养分尚不清楚。本研究对两种喀斯特适生植物构树(Broussonetia papyrifera)和云贵鹅耳枥(Carpinus pubescens)进行种内竞争和种  间竞争种植处理,并通过幼套球 囊霉(Glomus etunicatum)接种或不接种处理,以及土壤中添加或不添加两物种叶片混合枯落物处理,测定了植物生物量以及氮、磷、钾浓度等指标,研究植物的生长和养分利用。研究结果表明,AM真菌对两种植物养分摄取影响不同,AM真菌显著提高了种内和种间竞争下构树的养分摄取量,但降低了云贵鹅耳枥的养分摄取量。种间竞争下接种AM真菌,枯落物添加促进了云贵鹅耳枥对氮的摄取,抑制了构树对氮的摄取。接种AM真菌和添加枯落物条件下,种间竞争的构树对氮、磷和钾的摄取量及云贵鹅耳枥对氮的摄取量均高于种内竞争;种间竞争下两物种养分竞争力呈现明显差异,即构树对磷和钾养分竞争力显著提高,对氮则不显著;云贵鹅耳枥仅对钾的养分竞争力显著降低,对氮和磷则无显著影响。这些结果说明,在AM真菌与枯落物相互作用下,两种喀斯特植物种间竞争较种内竞争更能促进植物养分利用。     

Cryo-EM reveals a previously unrecognized structural protein of a dsRNA virus implicated in its extracellular transmission

Mosquito viruses cause unpredictable outbreaks of disease. Recently, several unassigned viruses isolated from mosquitoes, including the Omono River virus (OmRV), were identified as totivirus-like viruses, with features similar to those of the Totiviridae family. Most reported members of this family infect fungi or protozoans and lack an extracellular life cycle stage. Here, we identified a new strain of OmRV and determined high-resolution structures for this virus using single-particle cryo-electron microscopy. The structures feature an unexpected protrusion at the five-fold vertex of the capsid. Disassociation of the protrusion could result in several conformational changes in the major capsid. All these structures, together with some biological results, suggest the protrusions’ associations with the extracellular transmission of OmRV.     

Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.     

T and B cell Epitope analysis of SARS-CoV-2 S protein based on immunoinformatics and experimental research

COVID-19 caused by SARS-CoV-2 is pandemic with a severe morbidity and mortality rate across the world. Despite the race for effective vaccine and drug against further expansion and fatality rate of this novel coronavirus, there is still lack of effective antiviral therapy. To this effect, we deemed it necessary to identify potential B and T cell epitopes from the envelope S protein. This can be used as potential targets to develop anti-SARS-CoV-2 vaccine preparations. In this study, we used immunoinformatics to identify conservative B and T cell epitopes for S proteins of SARS-CoV-2, which might play roles in the initiation of SARS-CoV-2 infection. We identified the B cell and T cell peptide epitopes of S protein and their antigenicity, as well as the interaction between the peptide epitopes and human leucocyte antigen (HLA). Among the B cell epitopes, ‘EILDITPCSFGGVS’ has the highest score of antigenicity and great immunogenicity. In T cell epitopes, MHC-I peptide ‘KIADYNYKL’ and MHC-II peptide ‘LEILDITPC’ were identified as high antigens. Besides, docking analysis showed that the predicted peptide ‘KIADYNYKL’ was closely bound to the HLA-A*0201. The results of molecular dynamics simulation through GROMACS software showed that ‘HLA-A*0201~peptide’ complex was very stable. And the peptide we selected could induce the T cell response similar to that of SARS-CoV-2 infection. Moreover, the predicted peptides were highly conserved in different isolates from different countries. The antigenic epitopes presumed in this study were effective new vaccine targets to prevent SARS-CoV-2 infection.