Lower Emsian biostratigraphy and event stratigraphy of Ha Giang Province,northern Vietnam

A new species of rugose coral, Sanidophyllum dubium n. sp., and the typical Emsian (Early Devonian) rugose coral Xystriphylloides nobilis are described from the Mia Le Formation in northern Vietnam. The lower Emsian index conodonts ranging from the Polygnathus excavatus zone to the P. nothoperbonus zone are illustrated. The biostratigraphic correlation between northern Vietnam and South China shows that the Mia Le Formation in northern Vietnam is early Emsian in age, and its upper part can be correlated with the lower part of the Shizhou Member of the Yukiang Formation in Liujing, Guangxi and its equivalents in South China. Based on the study of the lower Emsian biostratigraphic sequence, the disappearance of Xystriphylloides nobilis fauna in the overlying bed of the uppermost Mia Le Formation and the extinction of the “tonkinensis fauna” (sensu lato) in the interval between the basal Si Phai Formation and the uppermost Mia Le Formation demonstrate the influence of the Yujiang Event in northern Vietnam.     

Therapeutic efficacy of novel memantine nitrate MN‐08 in animal models of Alzheimer’s disease

Alzheimer''s disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over‐activation of N‐methyl‐D‐aspartate (NMDA) receptors, amyloid β (Aβ) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. In the present study, MN‐08, a novel memantine nitrate, was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and consequently attenuate cognitive deficits in 2‐month‐old APP/PS1 transgenic mice (for a 6‐month preventative course) and in the 8‐month‐old triple‐transgenic (3×Tg‐AD) mice (for a 4‐month therapeutic course). In vitro, MN‐08 could bind to and antagonize NMDA receptors, inhibit the calcium influx, and reverse the dysregulations of ERK and PI3K/Akt/GSK3β pathway, subsequently preventing glutamate‐induced neuronal loss. In addition, MN‐08 had favorable pharmacokinetics, blood‐brain barrier penetration, and safety profiles in rats and beagle dogs. These findings suggest that the novel memantine nitrate MN‐08 may be a useful therapeutic agent for AD.     

Mesenchymal stem cell‐conditioned medium attenuates the retinal pathology in amyloid‐β‐induced rat model of Alzheimer's disease: Underlying mechanisms

Amyloid‐beta (Aβ) oligomer is known to contribute to the pathophysiology of age‐related macular degeneration. Herein, we aimed to elucidate the in vivo and in vitro effects of Aβ_1‐42 application on retinal morphology in rats. Our in vivo studies revealed that intracerebroventricular administration of Aβ_1‐42 oligomer caused dysmorphological changes in both retinal ganglion cells and retinal pigment epithelium. In addition, in vitro studies revealed that ARPE‐19 cells following Aβ_1‐42 oligomer application had decreased viability along with apoptosis and decreased expression of the tight junction proteins, increased expression of both phosphor‐AKT and phosphor‐GSK3β and decreased expression of both SIRT1 and β‐catenin. Application of conditioned medium (CM) obtained from mesenchymal stem cells (MSC) protected against Aβ_1‐42 oligomer‐induced retinal pathology in both rats and ARPE‐19 cells. In order to explore the potential role of peptides secreted from the MSCs, we applied mass spectrometry to compare the peptidomics profiles of the MSC‐CM. Gene ontology enrichment analysis and String analysis were performed to explore the differentially expressed peptides by predicting the functions of their precursor proteins. Bioinformatics analysis showed that 3‐8 out of 155–163 proteins in the MSC‐CM maybe associated with SIRT1/pAKT/pGSK3β/β‐catenin, tight junction proteins, and apoptosis pathway. In particular, the secretomes information on the MSC‐CM may be helpful for the prevention and treatment of retinal pathology in age‐related macular degeneration.     

Effect of Non-Volatile Constituents of Elsholtzia ciliata (Thunb.) Hyl. from Southern Vietnam on Reactive Oxygen Species and Nitric Oxide Release in Macrophages

The extract of Elsholtzia ciliata aerial parts was subjected to bio-guided isolation using the intercellular ROS reduction in J774A.1 macrophages to monitor the anti-oxidative activity. Fifteen compounds were isolated from the active fractions including eleven flavonoids (vitexin, pedalin, luteolin-7-O-β-d -glucopyranoside, apigenin-5-O-β-d -glucopyranoside, apigenin-7-O-β-d -glucopyranoside, chrysoeriol-7-O-β-d -glucopyranoside, 7,3′-dimethoxyluteolin-6-O-β-d -glucopyranoside, luteolin, 5,6,4′-trihydroxy-7,3′-dimethoxyflavone, 5-hydroxy-6,7-dimethoxyflavone (compound 13 ), 5-hydroxy-7,8-dimethoxyflavone); three hydroxycinnamic acid derivatives (caffeic acid, 4-(E)-caffeoyl-l -threonic acid, 4-O-(E)-p-coumaroyl-l -threonic acid) and one fatty acid (α-linolenic acid). The biological evaluation of these compounds (10–2.5 μm ) indicated that all of them exerted good antioxidant and anti-inflammatory activities, in particular compound 13 .     

线粒体DNA靶向治疗

线粒体(mitochondrion)是真核生物细胞中的一种非常重要的细胞器,含有独立于细胞核染色体外的遗传物质,通过氧化磷酸化产生ATP,是细胞的能量工厂,与细胞分化、信号转导、代谢稳态等过程密切联系。线粒体功能的紊乱与癌症、神经退行性疾病、糖尿病等许多疾病的发生、发展及治疗息息相关。线粒体在细胞命运中扮演的关键角色,使对线粒体这一特殊细胞器的探索成为生命科学研究热点之一。人线粒体DNA(mitochondrial DNA, mtDNA)是一相对保守且仅16 kb的环状双链DNA分子,只含37个基因,但这些基因都是维持线粒体功能稳定必不可少的部分。随着对线粒体功能认识的不断深入,研究人员发现mtDNA突变,会导致活性氧自由基过量产生,从而引起细胞衰老,甚至引发诸多疾病,例如遗传性视神经病变、线粒体脑肌病伴高乳酸血症和卒中样发作综合征等。但是,目前针对这些线粒体基因疾病尚无非常有效的治疗手段。为了进一步了解这一关键细胞器,研究人员开发了一些有效的方法来突破线粒体的复杂屏障。本文将重点介绍并讨论近几年靶向mtDNA的研究进展,主要从药物修饰、材料递送、基因编辑等方面进行了总结,希望能为推动线粒体的研究提供一些新的思路。     

Concurrent exposure to a dectin-1 agonist suppresses the Th2 response to epicutaneously introduced antigen in mice

Background

Epicutaneous sensitization with protein allergen that induces predominant Th2 responses is an important sensitization route in atopic dermatitis. Fungal components have been shown to modulate Th cell differentiation. However, the effects of fungal components on epicutaneous sensitization are unclear.

Results

In this study, we showed that co-administration of curdlan, a dectin-1 agonist, during epicutaneous ovalbumin sensitization of BALB/c mice decreased the IL-5 and IL-13 levels in supernatants of lymph node cell ovalbumin reactivation cultures. Mechanistically, curdlan co-administration decreased IL-4 and IL-1β expressions in draining lymph nodes. Curdlan co-administration also lower the migration of langerin⁺ CD103^- epidermal Langerhans cells into draining lymph nodes at 96 hours post-sensitization which might be attributed to decreased expressions of IL-18 and IL-1β in patched skin. Moreover, adoptive transfer of CFSE-labeled transgenic CD4 T cells confirmed that curdlan co-administration decreased the proliferation and IL-4-production of ovalbumin -specific T cells primed by epidermal Langerhans cells.

Conclusions

These results indicated that concurrent exposure to a dectin-1 agonist suppresses the epicutaneously induced Th2 response by modulating the cytokine expression profiles in draining LNs and the migration of epidermal Langerhans cells. These results highlight the effects of fungal components on epicutaneous allergen sensitization in atopic diseases.     

Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers

The fibroblast growth factor receptors (FGFRs) regulate important biological processes including cell proliferation and differentiation during development and tissue repair. Over the past decades, numerous pathological conditions and developmental syndromes have emerged as a consequence of deregulation in the FGFRs signaling network. This review aims to provide an overview of FGFR family, their complex signaling pathways in tumorigenesis, and the current development and application of therapeutics targeting the FGFRs signaling for treatment of refractory human cancers.     

Optimization, validation, and application of a real-time PCR protocol for quantification of viable bacterial cells in municipal sewage sludge and biosolids using reporter genes and Escherichia coli

Biosolids result from treatment of sewage sludge to meet jurisdictional standards, including pathogen reduction. Once government regulations are met, materials can be applied to agricultural lands. Culture-based methods are used to enumerate pathogen indicator microorganisms but may underestimate cell densities, which is partly due to bacteria existing in a viable but non-culturable physiological state. Viable indicators can also be quantified by real-time polymerase chain reaction (qPCR) used with propidium monoazide (PMA), a dye that inhibits amplification of DNA found extracellularly or in dead cells. The objectives of this study were to test an optimized PMA-qPCR method for viable pathogen detection in wastewater solids and to validate it by comparing results to data obtained by conventional plating. Reporter genes from genetically marked Pseudomonas sp. UG14Lr and Agrobacterium tumefaciens 542 cells were spiked into samples of primary sludge, and anaerobically digested and Lystek-treated biosolids as cell-free DNA, dead cells, viable cells, and mixtures of live and dead cells, followed by DNA extraction with and without PMA, and qPCR. The protocol was then used for Escherichia coli quantification in the three matrices, and results compared to plate counts. PMA-qPCR selectively detected viable cells, while inhibiting signals from cell-free DNA and DNA found in membrane-compromised cells. PMA-qPCR detected 0.5–1 log unit more viable E. coli cells in both primary solids and dewatered biosolids than plate counts. No viable E. coli was found in Lystek-treated biosolids. These data suggest PMA-qPCR may more accurately estimate pathogen cell numbers than traditional culture methods.