VEGAWES: variational segmentation on whole exome sequencing for copy number detection

Background Copy number variations are important in the detection and progression of significant tumors and diseases. Recently, Whole Exome Sequencing is gaining popularity with copy number variations detection due to low cost and better efficiency. In this work, we developed VEGAWES for accurate and robust detection of copy number variations on WES data. VEGAWES is an extension to a variational based segmentation algorithm, VEGA: Variational estimator for genomic aberrations, which has previously outperformed several algorithms on segmenting array comparative genomic hybridization data. Results We tested this algorithm on synthetic data and 100 Glioblastoma Multiforme primary tumor samples. The results on the real data were analyzed with segmentation obtained from Single-nucleotide polymorphism data as ground truth. We compared our results with two other segmentation algorithms and assessed the performance based on accuracy and time. Conclusions In terms of both accuracy and time, VEGAWES provided better results on the synthetic data and tumor samples demonstrating its potential in robust detection of aberrant regions in the genome

Chimica e Biochimica per le Scienze Motorie

Il volume, organizzato in tre parti (Chimica generale, Chimica organica e Biochimica) fornisce le conoscenze di base di chimica generale, chimica organica e biochimica utili a comprendere dal punto di vista molecolare i fenomeni biologici e ad affrontare materie che utilizzano tali nozion

3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice

3,5,3’-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e. low density lipoprotein receptor (LDLr)-knockout (Ldlr-/-) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB) production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr-/- mice treated with either T3 or T2 was performed. From a total proteome of 450 liver proteins, 25 identified proteins were affected by both T2 and T3, 18 only by T3 and 9 only by T2. Using in silico analyses, an overlap was observed with 11/14 pathways common to both iodothyronines, with T2 and T3 preferentially altering sub-networks centered around hepatocyte nuclear factor 4 α (HNF4α) and peroxisome proliferator-activated receptor α (PPARα), respectively. Both T2 and T3 administration significantly reduced nuclear HNF4α protein content, while T2, but not T3, decreased the expression levels of the HNFα transcriptional coactivator PGC-1α. Lower PPARα levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor α (LXRα) nuclear content. Overall, this study, although it was not meant to investigate the use of T2 and T3 as a therapeutic agent, provides novel insights into the regulation of hepatic metabolic pathways involved in T3- and T2-driven cholesterol reduction in Ldlr-/- mice

Lipoprotein(a) Serum Levels Predict Pulse Wave Velocity in Subjects in Primary Prevention for Cardiovascular Disease with Large Apo(a) Isoforms: Data from the Brisighella Heart Study

In the last decades, high serum levels of lipoprotein(a) (Lp(a)) have been associated with increased cardiovascular disease (CVD) risk, in particular among individuals with smaller apolipoprotein(a) (apo(a)) isoforms than those with larger sizes. The aim of our analysis was to evaluate whether Lp(a) levels could predict early vascular aging, and whether smaller apo(a) isoforms had a predictive value for vascular aging different than larger apo(a) isoforms in a cohort of subjects free from CVD. We considered the data of a subset of Brisighella Heart Study (BHS) participants free from CVD (462 men and 516 women) who were clinically evaluated during the 2012 BHS population survey. Predictors of arterial stiffness, measured as carotid-femoral pulse wave velocity (cfPWV) were estimated by the application of a step-wise linear regression model. In our cohort, there were 511 subjects with small apo(a) size and 467 subjects with large apo(a) isoforms. Subjects with larger apo(a) isoform sizes had significantly lower serum levels of Lp(a). In the BHS subpopulation sample, cfPWV was predicted by age, systolic blood pressure (SBP), serum levels of high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and sex, higher HDL-C serum levels and female sex associated with lower values of cfPWV. In subjects with smaller apo(a) isoform sizes, predictors of cfPWV were age, SBP, sex and serum levels of HDL-C, being higher HDL-C serum levels and female sex associated to lower values of cfPWV. In subjects with larger apo(a) isoform sizes, cfPWV was predicted by age, SBP, serum levels of Lp(a) and sex, with female sex associated with lower values of cfPWV. In our subpopulation sample, Lp(a) did not predict cfPWV. However, in subjects with large apo(a) isoform sizes, Lp(a) was a significant predictor of arterial stiffness

Lipoprotein(a) Serum Levels Predict Pulse Wave Velocity in Subjects in Primary Prevention for Cardiovascular Disease with Large Apo(a) Isoforms: Data from the Brisighella Heart Study

In the last decades, high serum levels of lipoprotein(a) (Lp(a)) have been associated with increased cardiovascular disease (CVD) risk, in particular among individuals with smaller apolipoprotein(a) (apo(a)) isoforms than those with larger sizes. The aim of our analysis was to evaluate whether Lp(a) levels could predict early vascular aging, and whether smaller apo(a) isoforms had a predictive value for vascular aging different than larger apo(a) isoforms in a cohort of subjects free from CVD. We considered the data of a subset of Brisighella Heart Study (BHS) participants free from CVD (462 men and 516 women) who were clinically evaluated during the 2012 BHS population survey. Predictors of arterial stiffness, measured as carotid-femoral pulse wave velocity (cfPWV) were estimated by the application of a step-wise linear regression model. In our cohort, there were 511 subjects with small apo(a) size and 467 subjects with large apo(a) isoforms. Subjects with larger apo(a) isoform sizes had significantly lower serum levels of Lp(a). In the BHS subpopulation sample, cfPWV was predicted by age, systolic blood pressure (SBP), serum levels of high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and sex, higher HDL-C serum levels and female sex associated with lower values of cfPWV. In subjects with smaller apo(a) isoform sizes, predictors of cfPWV were age, SBP, sex and serum levels of HDL-C, being higher HDL-C serum levels and female sex associated to lower values of cfPWV. In subjects with larger apo(a) isoform sizes, cfPWV was predicted by age, SBP, serum levels of Lp(a) and sex, with female sex associated with lower values of cfPWV. In our subpopulation sample, Lp(a) did not predict cfPWV. However, in subjects with large apo(a) isoform sizes, Lp(a) was a significant predictor of arterial stiffness

Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities

International audienceThe transcriptomic classification of glioblastoma (GBM) has failed to predict survival and therapeutic vulnerabilities. A computational approach for unbiased identification of core biological traits of single cells and bulk tumors uncovered four tumor cell states and GBM subtypes distributed along neurodevelopmental and metabolic axes, classified as proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic. Each subtype was enriched with biologically coherent multiomic features. Mitochondrial GBM was associated with the most favorable clinical outcome. It relied exclusively on oxidative phosphorylation for energy production, whereas the glycolytic/plurimetabolic subtype was sustained by aerobic glycolysis and amino acid and lipid metabolism. Deletion of the glucose-proton symporter SLC45A1 was the truncal alteration most significantly associated with mitochondrial GBM, and the reintroduction of SLC45A1 in mitochondrial glioma cells induced acidification and loss of fitness. Mitochondrial, but not glycolytic/plurimetabolic, GBM exhibited marked vulnerability to inhibitors of oxidative phosphorylation. The pathway-based classification of GBM informs survival and enables precision targeting of cancer metabolism

Exploring the Molecular Crosstalk between Pancreatic Bud and Mesenchyme in Embryogenesis: Novel Signals Involved

Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development; nevertheless, the precise space-temporal signaling activation still needs to be clarified. This study reports a dissection of the pancreatic embryogenesis, highlighting the molecular network surrounding the epithelium-mesenchyme interaction. To investigate this crosstalk, pancreatic epithelium and surrounding mesenchyme, at embryonic day 10.5, were collected through laser capture microdissection (LCM) and characterized based on their global gene expression. We performed a bioinformatic analysis to hypothesize crosstalk interactions, validating the most promising genes and verifying the precise localization of their expression in the compartments, by RNA in situ hybridization (ISH). Our analyses pointed out also the c-Met gene, a very well-known factor involved in stimulating motility, morphogenesis, and organ regeneration. We also highlighted the potential crosstalk between Versican (Vcan) and Syndecan4 (Sdc4) since these genes are involved in pancreatic tissue repair, strengthening the concept that the same signaling pathways required during pancreatic embryogenesis are also involved in tissue repair. This finding leads to novel strategies for obtaining functional pancreatic stem cells for cell replacement therapies

Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus

BACKGROUND: MicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression. METHODS: Selective ablation of Dicer in AQP2-expressing cells (Dicer(AQP2Cre+) mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice. RESULTS: The mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in Dicer(AQP2Cre+) mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in Dicer(AQP2Cre+) mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409–3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in Dicer(AQP2Cre+) mice, resulting in decreased RNA Pol II association. CONCLUSIONS: Novel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression