Movement Disorders in Prionopathies: A Systematic Review

Background: Movement disorders are frequent features of prionopathies. However, their prevalence and onset remain poorly described. Methods: We performed a systematic review of case reports and case series of pathologically- and genetically confirmed prionopathies. Timing of symptom and movement disorder onset were documented. Continuous variables were compared between two groups using the Wilcoxon rank sum test and between multiple groups using Kruskal–Wallis test. Categorical variables were compared using Fisher’s exact test. Results: A total of 324 cases were included in this analysis. Movement disorders were a common feature at the onset of symptoms in most prionopathies. Gait ataxia was present in more than half of cases in all types of prionopathies. The prevalence of limb ataxia (20%) and myoclonus (24%) was lower in Gerstmann–Sträussler–Scheinker disease compared to other prionopathies (p ≤ 0.004). Myoclonus was common but often a later feature in sporadic Creutzfeldt–Jakob disease (2 months before death). Chorea was uncommon but disproportionately prevalent in variant Creutzfeldt–Jakob disease (30% of cases; p < 0.001). In genetic Creutzfeldt–Jakob disease, E200K PRNP carriers exhibited gait and limb ataxia more often when compared to other mutation carriers. Discussion: Movement disorders are differentially present in the course of the various prionopathies. The movement phenomenology and appearance are associated with the type of prion disease and the PRNP genotype and likely reflect the underlying pattern of neurodegeneration. Reliance on myoclonus as a diagnostic feature of sporadic Creutzfeldt–Jakob disease may delay its recognition given its relatively late appearance in the disease course

Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D

Ultrafine Particles of Diesel Exhaust Induces Cytochrome P450 1A1 Mediated Oxidative Stress and DNA Damage in Cultured Blood and Lung Cells

Attempts were made to investigate the role of cytochrome P450 1A1 (CYP1A1) on similarities in the generation of reactive oxygen species (ROS) and DNA damage in IM9, a human B lymphoblastic cell line with A549, the human lung adenocarcinoma epithelial cell line on exposure of diesel exhaust particles (DEP). A suspension of ultrafine particles (&lt; 0.2 μM) of DEP (1mg/ml) in DMEM-F12 medium, at a concentration range of 1-100 μg/ml, was added to the cells for 6-48h. Expression studies revealed that DEP induced similar increase in the expression of CYP1A1, generation of ROS and DNA damage in both the cells. Pre-incubation with 3-methylcholanthrene (MC), a CYP1A1 inducer resulted in higher magnitude of induction of CYP1A1, ROS and DNA damage. This synergistic effect was lowered when α-naphthoflavone (α-NF), an inhibitor of CYP1A1 catalysed reactions, was added to these cells. Though the magnitude of alterations was lower in IM9 cells when compared to A549 cells, similarities in the alterations in blood and lungs cells has further suggested that blood lymphocytes can be used as a surrogate to monitor toxicity of vehicular emissions

Aptamer-based search for correlates of plasma and serum water T2: implications for early metabolic dysregulation and metabolic syndrome

Abstract Background Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T2 from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T2 was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T2 and thus, metabolic health. Methods Water T2 measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of 1310 proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T2. The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking. Results The multi-step analysis unveiled five new proteins most predictive of water T2: hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T2 have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T2 that would not have been identified in a hypothesis-driven biomarker search. Conclusions The identification of new proteins associated with water T2 demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T2 and the pathophysiology of metabolic syndrome

Supplementary Information: Optimized evolution of networks for principal eigenvector localization

Supplementary information of "Optimized evolution of networks for principal eigenvector localization" article<br

Correction: Topical Application of Ochratoxin A Causes DNA Damage and Tumor Initiation in Mouse Skin.

[This corrects the article DOI: 10.1371/journal.pone.0047280.]

Topical application of ochratoxin A causes DNA damage and tumor initiation in mouse skin.

Skin cancer is one of the most common forms of cancer and 2-3 million new cases are being diagnosed globally each year. Along with UV rays, environmental pollutants/chemicals including mycotoxins, contaminants of various foods and feed stuffs, could be one of the aetiological factors of skin cancer. In the present study, we evaluated the DNA damaging potential and dermal carcinogenicity of a mycotoxin, ochratoxin A (OTA), with the rationale that dermal exposure to OTA in workers may occur during their involvement in pre and post harvest stages of agriculture. A single topical application of OTA (20-80 µg/mouse) resulted in significant DNA damage along with elevated γ-H2AX level in skin. Alteration in oxidative stress markers such as lipid peroxidation, protein carbonyl, glutathione content and antioxidant enzymes was observed in a dose (20-80 µg/mouse) and time-dependent (12-72 h) manner. The oxidative stress was further emphasized by the suppression of Nrf2 translocation to nucleus following a single topical application of OTA (80 µg/mouse) after 24 h. OTA (80 µg/mouse) application for 12-72 h caused significant enhancement in- (a) reactive oxygen species generation, (b) activation of ERK1/2, p38 and JNK MAPKs, (c) cell cycle arrest at G0/G1 phase (37-67%), (d) induction of apoptosis (2.0-11.0 fold), (e) expression of p53, p21/waf1, (f) Bax/Bcl-2 ratio, (g) cytochrome c level, (h) activities of caspase 9 (1.2-1.8 fold) and 3 (1.7-2.2 fold) as well as poly ADP ribose polymerase cleavage. In a two-stage mouse skin tumorigenesis protocol, it was observed that a single topical application of OTA (80 µg/mouse) followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 24 week leads to tumor formation. These results suggest that OTA has skin tumor initiating property which may be related to oxidative stress, MAPKs signaling and DNA damage