다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

ROS Function in Redox Signaling and Oxidative Stress

Retrospective study: The diagnostic accuracy of conventional forceps biopsy of gastric epithelial compared to endoscopic submucosal dissection (STROBE compliant).

Loss of proteostasis induced by amyloid beta peptide in brain endothelial cells.

Amyloid beta-peptide (Abeta) is widely held to be associated with Alzheimer's disease, the insoluble aggregates of the peptide being the major constituents of senile plaques In this study, we evaluated the effect of Zn(2+) (5, 50 and 200 microM) on Abeta induced toxicity using the human teratocarcinome (NT2) cell line Our results proved that 50 and 200 microM Zn(2+) protected NT2 cells from Abeta 25-35 toxicity Zinc was also shown to be effective by preventing the loss of mitochondrial membrane potential (DeltaPsi(m)) induced by Abeta 25-35, not allowing cytochrome c release from mitochondria, and subsequently, caspase 3 activation However, when the cells were treated with Abeta 1-40, only Zn(2+) 5 microM had a protective effect We have further observed that 5 microM Zn(2+) prevented Abeta 1-40 aggregation into a beta-sheet structure Considering the results presented, we argue that Zn(2+) has a concentration-dependent protective effect

Protective effect of zinc on amyloid-beta 25-35 and 1-40 mediated toxicity.

Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the action of amyloid beta-peptide (A beta). We observed that A beta 25-35 induced an increase in reactive oxygen species (ROS) in NT2 rho+ cells, leading to protein and lipid oxidation. This oxidative status was partially prevented by the antioxidants, vitamin E, reduced glutathione, and by melatonin. However, NT2 rho0 cells (that lack mitochondrial DNA) in the absence of A beta showed an increase in ROS production, lipid and protein oxidation, as compared with parental rho+ cells. Upon A beta 25-35 treatment, in rho+ cells, a decrease in glutathione reductase activity and in GSH levels was observed, whereas glutathione peroxidase activity was shown to be increased. In NT2 rho0 cells, in the absence of A beta, GSH levels were maintained, whereas glutathione reductase and peroxidase activities were increased. The exposure of A beta to rho0 cells did not induce any change in these parameters. We observed that melatonin prevented caspase activation and DNA fragmentation in rho+ cells treated with A beta. Considering the evidence presented, we argue that the glutathione cycle impairment is a key event in A beta-induced cell toxicity.

Glutathione cycle impairment mediates A beta-induced cell toxicity.

The brain is an immunologically active organ where neurons and glia cells orchestrate complex innate immune responses against infections and injuries. Neuronal responses involve Toll-like or Nod-like receptors and the secretion of antimicrobial peptides and cytokines. The endosymbiotic theory for the evolutionary origin of mitochondria from primitive bacteria, suggests that they may have also retained the capacity to activate neuronal innate immunity. In fact, it was shown that mitochondrial damage-associated molecular patterns could signal and activate innate immunity and inflammation. Moreover, the mitochondrial cascade hypothesis for sporadic Parkinson’s disease (PD) argues that altered mitochondrial metabolism and function can drive neurodegeneration. Additionally, a neuroinflammatory signature with increased levels of pro-inflammatory mediators in PD affected brain areas was recently detected. Herein, we propose that a cascade of events initiating in a dysbiotic gut microbiome drive the production of toxins or antibiotics that target and damage mitochondria. This in turn activates neuronal innate immunity and triggers sterile inflammation phenomena that culminate in the neurodegenerative processes observed in the enteric and in the central nervous systems and that ultimately lead to Parkinson’s Disease.

The Microbiome-Mitochondria Dance in Prodromal Parkinson's Disease.

Mild cognitive impairment (MCI) is considered a nosological entity or a translational state between normal agingand sporadic Alzheimer´s disease (AD). From brain tissue to peripheral blood samples, it is evident that the earlymarkers of metabolic dysfunction observed in AD have also been found in MCI subjects. These observations obtainedfrom MCI and AD subjects leave open the possibility that mitochondrial dysfunction-induced oxidative damage happeninga priori of symptom onset, may trigger other pathological hallmarks, namely Aβ oligomerization.In this study, we used a citoplasmic hybrid (cybrid) model created by the repopulation of human teratocarcinoma (NT2)cells depleted of endogenous mitochondrial DNA (mtDNA) with platelets from age-matched controls, MCI and AD subjects.We found mitochondrial deficits in MCI and AD cybrids as compared with controls, such as a decrease in cytochromec oxidase (COX) activity, a decrease in mitochondrial membrane potential and in mitochondrial cytochrome ccontent. Consequently, we analyzed parameters of oxidative damage and found that AD and MCI cybrids exhibit an increasein lipid peroxides, higher production of superoxide radicals, and higher content in protein carbonyls. Since our dataclearly show alterations in mitochondrial-mediated oxidative damage in MCI cybrids we propose that mitochondrial dysfunctionis an early event in idiopathic AD. Moreover, we found that mitochondrial Aβ oligomeric content increases inAD, which may exacerbate initial mitochondrial damage. Altogether, our data strongly supports a key role for mitochondria/mtDNA in aged-driven AD pathology.

Sandra M. Cardoso

Papers

Loss of proteostasis induced by amyloid beta peptide in brain endothelial cells.

Protective effect of zinc on amyloid-beta 25-35 and 1-40 mediated toxicity.

Glutathione cycle impairment mediates A beta-induced cell toxicity.

The Microbiome-Mitochondria Dance in Prodromal Parkinson's Disease.

Prodromal Metabolic Phenotype in MCI Cybrids: Implications for Alzheimer’s Disease