Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

Post-translational protein modifications play an important role in generating the large diversity of the proteome in comparison to the relatively small number of genes; phosphorylation being the most widespread. Phosphorylation of proteins regulates important molecular-switches for several cellular events and abnormal phosphorylation events are associated in many neurodegenerative diseases. In Parkinson’s disease (PD) the main hallmark is the accumulation of cytoplasmic inclusions, Lewy bodies (LBs), consisting of α-synuclein (α-Syn) and ubiquitin. There’s another key observation which is increasingly gaining prominence is a modified-form of α-Syn; the phospho α-Syn serine129 (pSyn). The significance of pSyn has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition. The revelation of the involvement of pSyn on α-Syn aggregation, LB formation and neurotoxicity is crucial to understanding the pathogenesis and progression of PD. Since some in vitro and in vivo studies have indicated that pSyn is an early event preceding apoptosis, some important questions now needs to be explored in reference to the physiological functions regulated by phosphorylation, such as dopamine synthesis, vesicle mobilization, regulation of synaptic proteins, and synaptic plasticity. An investigation of the role of enzymes on the phosphorylation and clearance of α-Syn and region-specific susceptibility is required to be determined; to identify viable targets for new therapeutics

Expression and regulatory roles of lncRNAs in G-CIMP-low vs G-CIMP-high Glioma: an in-silico analysis

BACKGROUND: Clinically relevant glioma subtypes, such as the glioma-CpG island methylator phenotype (G-CIMP), have been defined by epigenetics. In this study, the role of long non-coding RNAs in association with the poor-prognosis G-CMIP-low phenotype and the good-prognosis G-CMIP-high phenotype was investigated. Functional associations of lncRNAs with mRNAs and miRNAs were examined to hypothesize influencing factors of the aggressive phenotype. METHODS: RNA-seq data on 250 samples from TCGA\u27s Pan-Glioma study, quantified for lncRNA and mRNAs (GENCODE v28), were analyzed for differential expression between G-CIMP-low and G-CIMP-high phenotypes. Functional interpretation of the differential lncRNAs was performed by Ingenuity Pathway Analysis. Spearman rank order correlation estimates between lncRNA, miRNA, and mRNA nominated differential lncRNA with a likely miRNA sponge function. RESULTS: We identified 4371 differentially expressed features (mRNA = 3705; lncRNA = 666; FDR ≤ 5%). From these, the protein-coding gene TP53 was identified as an upstream regulator of differential lncRNAs PANDAR and PVT1 (p = 0.0237) and enrichment was detected in the development of carcinoma (p = 0.0176). Two lncRNAs (HCG11, PART1) were positively correlated with 342 mRNAs, and their correlation estimates diminish after adjusting for either of the target miRNAs: hsa-miR-490-3p, hsa-miR-129-5p. This suggests a likely sponge function for HCG11 and PART1. CONCLUSIONS: These findings identify differential lncRNAs with oncogenic features that are associated with G-CIMP phenotypes. Further investigation with controlled experiments is needed to confirm the molecular relationships

Mate Replacement and Alloparental Care in Ferruginous Hawk (Buteo regalis)

Alloparental care (i.e., care for unrelated offspring) has been documented in various avian species (Maxson 1978, Smith et al. 1996, Te Ila et al. 1997, Lislevand et al. 2001, Literak and Mraz 2011). A male replacement mate that encounters existing broods has options, which include alloparental care or infanticide. Infanticide may be beneficial in some species (Rohwer 1986, Kermott et al. 1990), but in long-lived avian species, like the ferruginous hawk (Buteo regalis) that do not renest within a season, infanticide might be detrimental. Adoption and rearing success likely provide direct evidence of competence of replacement mates as potential parents for future seasons, a benefit that might outweigh the investment of time and effort associated with adoption and rearing (after Rohwer 1986). Anticipated mating opportunity at the cost of adoption (Gori et al. 1996, Rohwer et al. 1999) may explain step-parental benevolence and therefore, in such a scenario would enhance individual fitness through subsequent recruitment of related young

Proteomic Profiles of Exosomes of Septic Patients Presenting to the Emergency Department Compared to Healthy Controls

BACKGROUND: Septic Emergency Department (ED) patients provide a unique opportunity to investigate early sepsis. Recent work focuses on exosomes, nanoparticle-sized lipid vesicles (30-130 nm) that are released into the bloodstream to transfer its contents (RNA, miRNA, DNA, protein) to other cells. Little is known about how early changes related to exosomes may contribute to the dysregulated inflammatory septic response that leads to multi-organ dysfunction. We aimed to evaluate proteomic profiles of plasma derived exosomes obtained from septic ED patients and healthy controls. METHODS: This is a prospective observational pilot study evaluating a plasma proteomic exosome profile at an urban tertiary care hospital ED using a single venipuncture blood draw, collecting 40 cc Ethylenediaminetetraacetic acid (EDTA) blood. MEASUREMENTS: We recruited seven patients in the ED within 6 h of their presentation and five healthy controls. Plasma exosomes were isolated using the Invitrogen Total Exosome Isolation Kit. Exosome proteomic profiles were analyzed using fusion mass spectroscopy and Proteome Discoverer. Principal component analysis (PCA) and differential expression analysis (DEA) for sepsis versus control was performed. RESULTS: PCA of 261 proteins demonstrated septic patients and healthy controls were distributed in two groups. DEA revealed that 62 (23.8%) proteins differed between the exosomes of septic patients and healthy controls, CONCLUSION: Exosome proteomic profiles of septic ED patients differ from their healthy counterparts with regard to acute phase response and inflammation

Mate Replacement and Alloparental Care in Ferruginous Hawk

Alloparental care (i.e., care for unrelated offspring) has been documented in various avian species (Maxson 1978, Smith et al. 1996, Tella et al. 1997, Lislevand et al. 2001, Literak and Mraz 2011). A male replacement mate that encounters existing broods has options, which include alloparental care or infanticide. Infanticide may be beneficial in some species (Rohwer 1986, Kermott et al. 1990), but in long-lived avian species, like the ferruginous hawk (Buteo regalis) that do not renest within a season, infanticide might be detrimental. Adoption and rearing success likely provide direct evidence of competence of replacement mates as potential parents for future seasons, a benefit that might outweigh the investment of time and effort associated with adoption and rearing (after Rohwer 1986). Anticipated mating opportunity at the cost of adoption (Gori et al. 1996, Rohwer et al. 1999) may explain step-parental benevolence and therefore, in such a scenario would enhance individual fitness through subsequent recruitment of related young

Efficient Generalized Least Squares Method for Mixed Population and Family‐based Samples in Genome‐wide Association Studies

Genome‐wide association studies (GWAS) that draw samples from multiple studies with a mixture of relationship structures are becoming more common. Analytical methods exist for using mixed‐sample data, but few methods have been proposed for the analysis of genotype‐by‐environment (G×E) interactions. Using GWAS data from a study of sarcoidosis susceptibility genes in related and unrelated African Americans, we explored the current analytic options for genotype association testing in studies using both unrelated and family‐based designs. We propose a novel method—generalized least squares (GLX)—to estimate both SNP and G×E interaction effects for categorical environmental covariates and compared this method to generalized estimating equations (GEE), logistic regression, the Cochran–Armitage trend test, and the W QLS and M QLS methods. We used simulation to demonstrate that the GLX method reduces type I error under a variety of pedigree structures. We also demonstrate its superior power to detect SNP effects while offering computational advantages and comparable power to detect G×E interactions versus GEE. Using this method, we found two novel SNPs that demonstrate a significant genome‐wide interaction with insecticide exposure—rs10499003 and rs7745248, located in the intronic and 3' UTR regions of the FUT9 gene on chromosome 6q16.1.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107571/1/gepi21811.pd

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin\u27s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers