Colocalised Genetic Associations Reveal Alternative Splicing Variants as Candidate Causal Links for Breast Cancer Risk in 10 Loci.

Genome-wide association studies (GWASs) have revealed numerous loci associated with breast cancer risk, yet the precise causal variants, their impact on molecular mechanisms, and the affected genes often remain elusive. We hypothesised that specific variants exert their influence by affecting cis-regulatory alternative splice elements. An analysis of splicing quantitative trait loci (sQTL) in healthy breast tissue from female individuals identified multiple variants linked to alterations in splicing ratios.

Germline allelic expression of genes at 17q22 locus associates with risk of breast cancer.

Introduction: Translation of genome-wide association study (GWAS) findings into preventive approaches is challenged by the identification of the causal risk variants and the understanding of the biological mechanisms by which they act. We present using allelic expression (AE) ratios to perform quantitative case-control analysis as a novel approach to identify risk associations, causal regulatory variants, and target genes.

Methods: Using the breast cancer (BC) risk locus 17q22 to validate this approach, we measured AE ratios in normal breast tissue samples from controls and cases, as well as from unmatched blood samples.

Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk.

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to -regulate the expression of genes. We hypothesise that -regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( ) raSNPs, plus proxies.

Mitochondrial genome association study with peripheral arterial disease and venous thromboembolism.

Background And Aims: Peripheral arterial disease (PAD) and venous thromboembolism (VTE) are vascular traits sharing common modifiable and non-modifiable risk factors. These vascular pathologies have known nuclear-encoded genetic risk factors and the mitochondrial DNA may account for part of the missing heritability. To determine if PAD and VTE have a dual genetic control (mitochondrial and nuclear), we hereby investigated the association of mitochondrial DNA polymorphisms and haplogroups with these vascular traits.

Ulcerative Colitis Is Under Dual (Mitochondrial and Nuclear) Genetic Control.

Background: Cellular oxidative stress and genetic susceptibility have been implicated in the multifactorial etiology of ulcerative colitis (UC). The nuclear genome association with UC has been intensely investigated, but the role of the mitochondrial DNA (mtDNA) has received far less attention and may account for part of the missing heritability. This study is a comprehensive analysis of the mtDNA contribution to UC susceptibility.

Genetic Variants Underlying Risk of Intracranial Aneurysms: Insights from a GWAS in Portugal.

Subarachnoid hemorrhage (SAH) is a life-threatening event that most frequently leads to severe disability and death. Its most frequent cause is the rupture of a saccular intracranial aneurysm (IA), which is a blood vessel dilation caused by disease or weakening of the vessel wall. Although the genetic contribution to IA is well established, to date no single gene has been unequivocally identified as responsible for IA formation or rupture.

Brief report: association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 With Behçet's disease in Iranians.

Objective: To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behçet's disease (BD).

Methods: We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R-IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers.

Results: Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.

Mitochondria: Major Regulators of Neural Development.

Mitochondria are organelles derived from primitive symbiosis between archeon ancestors and prokaryotic α-proteobacteria species, which lost the capacity of synthetizing most proteins encoded the bacterial DNA, along the evolutionary process of eukaryotes. Nowadays, mitochondria are constituted by small circular mitochondrial DNA of 16 kb, responsible for the control of several proteins, including polypeptides of the electron transport chain. Throughout evolution, these organelles acquired the capacity of regulating energy production and metabolism, thus becoming central modulators of cell fate.

Characterization of the major histocompatibility complex locus association with Behçet's disease in Iran.

Introduction: The aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) in an Iranian dataset.

Methods: The association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case-control study on 973 BD patients and 825 controls from Iran, and the association of HLA-B alleles was tested in a subset of 681 patients and 414 controls.

Results: We found that HLA-B*51 (P = 4.

Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling.

The low survival and differentiation rates of stem cells after either transplantation or neural injury have been a major concern of stem cell-based therapy. Thus, further understanding long-term survival and differentiation of stem cells may uncover new targets for discovery and development of novel therapeutic approaches. We have previously described the impact of mitochondrial apoptosis-related events in modulating neural stem cell (NSC) fate.

MicroRNA-34a Modulates Neural Stem Cell Differentiation by Regulating Expression of Synaptic and Autophagic Proteins.

We have previously demonstrated the involvement of specific apoptosis-associated microRNAs (miRNAs), including miR-34a, in mouse neural stem cell (NSC) differentiation. In addition, a growing body of evidence points to a critical role for autophagy during neuronal differentiation, as a response-survival mechanism to limit oxidative stress and regulate synaptogenesis associated with this process. The aim of this study was to further investigate the precise role of miR-34a during NSC differentiation.

Targeting molecular networks for drug research.

The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks.

StemCellNet: an interactive platform for network-oriented investigations in stem cell biology.

Stem cells are characterized by their potential for self-renewal and their capacity to differentiate into mature cells. These two key features emerge through the interplay of various factors within complex molecular networks. To provide researchers with a dedicated tool to investigate these networks, we have developed StemCellNet, a versatile web server for interactive network analysis and visualization.

IL10 low-frequency variants in Behçet's disease patients.

Aim: To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility.

Methods: To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.

Mitochondrial translocation of p53 modulates neuronal fate by preventing differentiation-induced mitochondrial stress.

Aims: Apoptosis regulatory proteins, such as p53, play a pivotal role in neural differentiation, through mechanisms independent of cell death. In addition, p53 has been identified as an important regulator of mitochondrial survival response, maintaining mitochondrial DNA (mtDNA) integrity and oxidative protection. The aim of this study was to determine the role of mitochondrial p53 in organelle damage and neural differentiation.

FUT2: filling the gap between genes and environment in Behçet's disease?

Objectives: To identify new susceptibility loci for Behçet's disease (BD), we performed a genome-wide association study (GWAS) using DNA pooling.

Methods: Two replicate pools of 292 Iranian BD cases and of 294 age- and sex-matched controls were allelotyped in quadruplicate on the Affymetrix Genome-Wide Human SNP Array 6.0.

Phenylhydrazones of piperidin-4-ones as AND, OR, NOR, NAND, and INH molecular logic gates.

Phenylhydrazone derivatives of 2,6-diarylpiperidin-4-ones viz., 3-methyl-2,6-diphenylpiperidin-4-one (PMP-PH) and 3-methyl-2,6-di-(9H-fluorenyl)piperidin-4-one (FMP-PH) when illuminated and protonated perform the functions of AND, OR, NOR, NAND Boolean logic gates with all optical outputs. The functions of the AND and the NAND gates rely on changes in absorption and emission of the phenylhydrazone upon isomerization of the photochromic unit.

Amyloid β peptides promote autophagy-dependent differentiation of mouse neural stem cells: Aβ-mediated neural differentiation.

Although regarded as neurotoxic, amyloid β (Aβ) peptides may also mediate a wide range of nonpathogenic processes. Autophagy has been implicated in Aβ-mediated effects, although its precise function in neural differentiation remains unknown. Here, we addressed the role of different Aβ fragments in neural stem cell (NSC) proliferation and differentiation, and investigated whether autophagy is involved in Aβ-induced alterations of neural fate.

Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behçet's disease susceptibility.

Behçet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes.

Distinct regulatory functions of calpain 1 and 2 during neural stem cell self-renewal and differentiation.

Calpains are calcium regulated cysteine proteases that have been described in a wide range of cellular processes, including apoptosis, migration and cell cycle regulation. In addition, calpains have been implicated in differentiation, but their impact on neural differentiation requires further investigation. Here, we addressed the role of calpain 1 and calpain 2 in neural stem cell (NSC) self-renewal and differentiation.

Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet's disease.

Objective: Independent replication of the findings from genome-wide association studies (GWAS) remains the gold standard for results validation. Our aim was to test the association of Behçet's disease (BD) with the interleukin-10 gene (IL10) and the IL-23 receptor-IL-12 receptor β2 (IL23R-IL12RB2) locus, each of which has been previously identified as a risk factor for BD in 2 different GWAS.

Methods: Six haplotype-tagging single-nucleotide polymorphisms (SNPs) in IL10 and 42 in IL23R-IL12RB2 were genotyped in 973 Iranian patients with BD and 637 non-BD controls.

p53 interaction with JMJD3 results in its nuclear distribution during mouse neural stem cell differentiation.

Conserved elements of apoptosis are also integral components of cellular differentiation. In this regard, p53 is involved in neurogenesis, being required for neurite outgrowth in primary neurons and for axonal regeneration in mice. Interestingly, demethylases regulate p53 activity and its interaction with co-activators by acting on non-histone proteins.