Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease

The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD

Buckling Strength of Cold-Formed Circular Steel Column Subjected to Axial Load

In this study, the global buckling behavior of a cold-formed circular steel column was discussed with a focus on the effects of its mechanical properties and initial imperfections on the behavior. As the first step, the stress–strain curves of the column under tensile and compressive loads as well as its residual stresses were investigated. Subsequently, a finite element analysis was conducted to clarify if the analysis properly simulated the stub column behavior. The analysis results obtained using measured compressive stress–strain curves and residual stresses agreed well with experimental results. Finally, another finite element analysis was performed on the long column buckling to examine the effects of its mechanical properties and initial imperfections. It was shown that the global buckling strength was affected not only by imperfections such as residual stress and out-of-straightness but also by the anisotropic mechanical properties of the material

Stargazer: Long-Term and Multiregional Measurement of Timing/ Geolocation-Based Cloaking

Malicious hosts have come to play a significant and varied role in today's cyber attacks. Some of these hosts are equipped with a technique called cloaking, which discriminates between access from potential victims and others and then returns malicious content only to potential victims. This is a serious threat because it can evade detection by security vendors and researchers and cause serious damage. As such, cloaking is being extensively investigated, especially for phishing sites. We are currently engaged in a long-term cloaking study of a broader range of threats. In the present study, we implemented Stargazer, which actively monitors malicious hosts and detects geographic and temporal cloaking, and collected 30,359,410 observations between November 2019 and February 2022 for 18,397 targets from 13 sites where our sensors are installed. Our analysis confirmed that cloaking techniques are widely abused, i.e., not only in the context of specific threats such as phishing. This includes geographic and time-based cloaking, which is difficult to detect with single-site or one-shot observations. Furthermore, we found that malicious hosts that perform cloaking include those that survive for relatively long periods of time, and those whose contents are not present in VirusTotal. This suggests that it is not easy to observe and analyze the cloaking malicious hosts with existing technologies. The results of this study have deepened our understanding of various types of cloaking, including geographic and temporal ones, and will help in the development of future cloaking detection methods

Height Constitutes an Important Predictor of Mortality in End-Stage Renal Disease

Aim. Height is an important determinant of augmentation index (AI) that anticipates cardiovascular prognosis. There is a scanty of the data whether short height predicts survival in patients with end-stage renal diseases, a high risk population. Methods. Fifty two hypertensive patients with type 2 diabetic nephropathy receiving hemodialysis and 52 patients with nondiabetic nephropathy were enrolled. In addition to AI estimated with radial artery tonometry, classical cardiovascular risk factors were considered. Patients were followed for 2 years to assess cardiovascular prognosis. Results. Cox hazards regression revealed that both smoking and shortness in height independently contributed to total mortality and indicated that smoking as well as the presence of left ventricular hypertrophy predicted cardiovascular mortality. Our findings implicated that high AI, the presence of diabetes, and low high-density lipoprotein cholesterol were significant contributors to cardiovascular events. Conclusions. Our findings provide new evidence that shortness in height independently contributes to total mortality in hemodialysis patients

Expression of c-myc, c-fos and CA19-9 in Human Non-Malignant and Malignant Gallbladder Tissues

Immunohistochemical study was performed on expressions of c-myc, c-fos and CA19-9 in gallbladder tissue with or without malignant lesions. A total of 81 tissues were divided into four groups including 47 carcinomas, 3 dysplasias, 17 metaplasias and 14 normal lesions. After these tissues were routinely fixed in 10% formalin solution and embedded in paraffin, 4 micrometer-thick sections were made and stained with hematoxylin-eosin to classify the type of lesions. Immunohistochemical stains were carried out for c-myc and c-fos oncoproteins, and CA19-9. The percentages of positive reaction for c-myc oncoprotein were 77%, 67%, 88% and 36%, those for c-fos oncoprotein were 83%, 66%, 35% and 7%, and those for CA19-9 were 85%, 100%, 88% and 71% in carcinoma, dysplasia, metaplasia and normal tissues, respectively. These results suggest that c-myc and c-fos oncogenes play some kind of roles in malignant transformation of the gallbladder tissues and that abnormal expression of CA19-9 is the sign of antigen reversion of carcinoma cells toward embryonic cells of the gallbladder tissue

PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy

Defective mitochondrial quality control is shown to be a mechanism for neurodegeneration in some forms of Parkinson's disease

Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson’s disease

AbstractMutations in parkin gene are responsible for autosomal recessive Parkinson’s disease (ARPD) and its loss-of-function is assumed to affect parkin ubiquitin ligase activity. Accumulation of its substrate may induce dopaminergic neurodegeneration in the substantia nigra (SN) of ARPD. Here, we show that parkin interacts with programmed cell death-2 isoform 1 (PDCD2-1) and promotes its ubiquitination. Furthermore, accumulation of PDCD2-1 was found in the SN of ARPD as well as in sporadic PD, suggesting that common failure of the ubiquitin–proteasome system is associated with neuronal death in both ARPD and sporadic PD.Structured summary:MINT-6805975, MINT-6806032, MINT-6806051, MINT-6806070:PDCD2 (uniprotkb:Q16342) physically interacts (MI:0218) with Parkin (uniprotkb:O60260) by anti tag coimmunoprecipitation (MI:0007)MINT-6805947:Parkin (uniprotkb:O60260) physically interacts (MI:0218) with PDCD2 (uniprotkb:Q16342) by two hybrid (MI:0018)MINT-6806000: PDCD2 (uniprotkb:Q16342) physically interacts (MI:0218) with ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007)

Programs for calculating the statistical powers of detecting susceptibility genes in case–control studies based on multistage designs

Motivation: A two-stage association study is the most commonly used method among multistage designs to efficiently identify disease susceptibility genes. Recently, some SNP studies have utilized more than two stages to detect disease genes. However, there are few available programs for calculating statistical powers and positive predictive values (PPVs) of arbitrary n-stage designs

Case report: Transient lactate elevation by intravenous insulin infusion therapy for diabetic ketoacidosis in a patient with mitochondrial DNA 3243 A > G mutation: A glycolysis rebooting syndrome?

Mitochondrial disease, most cases of which are caused by mitochondrial DNA (mtDNA) mutation, is present with multiple phenotypes including diabetes mellitus, sensorineural hearing loss, cardiomyopathy, muscle weakness, renal dysfunction, and encephalopathy, depending on the degree of heteroplasmy. While mitochondria play an important role in intracellular glucose and lactate metabolism in insulin-sensitive tissues such as muscles, appropriate strategies for glycemic control have not yet been established in a patient with mitochondrial disease, which is often complicated by myopathy. Here, we describe the history of a 40-year-old man with mtDNA 3243A > G who had sensorineural hearing loss, cardiomyopathy, muscle wasting, and diabetes mellitus with stage 3 chronic kidney disease. He developed mild diabetic ketoacidosis (DKA) in the process of treatment for poor glycemic control with severe latent hypoglycemia. According to the standard therapy for DKA, he was treated with continuous intravenous insulin infusion therapy, which unexpectedly resulted in an abrupt and transient elevation in blood lactate levels without exacerbation of heart failure and kidney function. Since blood lactate levels are determined by the balance between lactate production and consumption, an abrupt and transient lactate elevation following intravenous insulin injection therapy may reflect not only enhanced glycolysis in insulin-sensitive tissues with mitochondrial dysfunction but also decreased lactate consumption in the sarcopenic skeletal muscle and failing heart. Intravenous insulin infusion therapy in patients with mitochondrial disease may unmask derangements of intracellular glucose metabolism in response to insulin signaling