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Bosisio Parini, Italy

Zuliani R.,University of Udine | Zuliani R.,University of Edinburgh | Moorhead T.W.J.,University of Edinburgh | Bastin M.E.,University of Edinburgh | And 8 more authors.
Psychiatry Research - Neuroimaging | Year: 2011

Variations in the signalling NRG1-ErbB4 pathway have been associated with genetic susceptibility for both bipolar disorder and schizophrenia, although the underlying neural mechanisms are still uncertain. Reduced integrity of the anterior limb of the internal capsule (ALIC) has been found in association with risk-associated genetic variation in the 5′ region of the NRG1 gene. We hypothesised that variation in the gene encoding the NRG1 receptor, ErbB4, would also be associated with reduced ALIC integrity and with cognitive impairments characteristic of individuals with bipolar disorder and schizophrenia. Using diffusion tensor imaging (DTI), we examined the white matter integrity associations of the ErbB4 polymorphism rs4673628, which resides within intron 12 of the gene encoding ErbB4, in 36 healthy individuals. We also sought to clarify the cognitive effects of any findings. We found that genetic variation at the rs4673628 locus in the ErbB4 gene was significantly associated with ALIC white matter integrity which was also significantly and positively associated with mnemonic function. These findings provide further evidence to support a key role of NRG1-ErbB4 signalling in the pathophysiology of major mental disorders. © 2010 Elsevier Ireland Ltd. Source

Forni D.,University of Leicester | Forni D.,Scientific Institute Irccs Emedea | Martin D.,University of Leicester | Abujaber R.,University of Leicester | And 3 more authors.
BMC Genomics | Year: 2015

Background: Copy number variation (CNV) is a major component of genomic variation, yet methods to accurately type genomic CNV lag behind methods that type single nucleotide variation. High-throughput sequencing can contribute to these methods by using sequence read depth, which takes the number of reads that map to a given part of the reference genome as a proxy for copy number of that region, and compares across samples. Furthermore, high-throughput sequencing also provides information on the sequence differences between copies within and between individuals. Methods: In this study we use high-coverage phase 3 exome sequences of the 1000 Genomes project to infer diploid copy number of the beta-defensin genomic region, a well-studied CNV that carries several beta-defensin genes involved in the antimicrobial response, signalling, and fertility. We also use these data to call sequence variants, a particular challenge given the multicopy nature of the region. Results: We confidently call copy number and sequence variation of the beta-defensin genes on 1285 samples from 26 global populations, validate copy number using Nanostring nCounter and triplex paralogue ratio test data. We use the copy number calls to verify the genomic extent of the CNV and validate sequence calls using analysis of cloned PCR products. We identify novel variation, mostly individually rare, predicted to alter amino-acid sequence in the beta-defensin genes. Such novel variants may alter antimicrobial properties or have off-target receptor interactions, and may contribute to individuality in immunological response and fertility. Conclusions: Given that 81 % of identified sequence variants were not previously in dbSNP, we show that sequence variation in multiallelic CNVs represent an unappreciated source of genomic diversity. © 2015 Forni et al. Source

Sironi M.,Scientific Institute Irccs Emedea | Biasin M.,University of Milan | Forni D.,Scientific Institute Irccs Emedea | Cagliani R.,Scientific Institute Irccs Emedea | And 9 more authors.
AIDS | Year: 2012

Three prime repair exonuclease 1 (TREX1) degrades excess HIV-1 DNA, thereby preventing recognition by innate immunity receptors and type I interferon responses. Analyses performed in two HIV-exposed seronegative (HESN) cohorts did not show any differences in TREX1 sequence, single nucleotide polymorphisms frequency, or expression in HESN compared to controls, suggesting that, despite its central role in the HIV-1 infection process, genetic diversity at TREX1 is not a major determinant of susceptibility to infection in humans. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Biasin M.,University of Milan | Sironi M.,Scientific Institute Irccs Emedea | Saulle I.,University of Milan | De Luca M.,University of Milan | And 11 more authors.
AIDS | Year: 2013

Objective: Haplotype-specific alternative splicing of the endoplasmic reticulum (ER) aminopeptidase type 2 (ERAP2) gene results in either full-length (FL, haplotype A) or alternatively spliced (AS, haplotype B) mRNA. As ERAP2 trims peptides loaded on major histocompatibility complex (MHC) class I and CD8+ T lymphocytes protect against viral infections, we analysed its role in resistance to HIV-1 infection. Methods: ERAP2 polymorphisms were genotyped using a TaqMan probe, and human leukocyte antigen (HLA) typing of class-I HLAB locus was performed by single specific primers-polymerase chain reaction method. To verify whether ERAP2 genotype influences susceptibility to HIV-1 infection in vitro we performed HIV-1 infection assay. We evaluated antigen presentation pathway with PCR array and the viral antigen p24 with ELISA. Results: Genotype analysis in 104 HIV-1-exposed seronegative individuals (HESNs) exposed to HIV through IDU-HESN and 130 controls from Spain indicated that hapA protects from HIV infection. Meta-analysis with an Italian cohort of sexually exposed HESN yielded a P value of 7.6×10-5. HLAB typing indicated that the HLA-B*57 allele is significantly more common than expected among HESN homozygous for haplotype A (homoA). Data obtained in a cohort of 139 healthy Italian controls showed that following in-vitro HIV-1 infection the expression of ERAP2-FL and a number of genes involved in antigen presentation as well as of MHC class I on the surface of CD45+ cells was significantly increased in homoA cells; notably, homoA peripheral blood mononuclear cells , but not isolated CD4+ cells, were less susceptible to HIV-1 infection. Conclusion: ERAP2 hapA is correlated with resistance to HIV-1 infection, possibly secondarily to its effect on antigen processing and presentation. © 2013 Creative Common License. Source

Maggioni E.,University of Bari | Maggioni E.,University of Milan | Zucca C.,Scientific Institute Irccs Emedea | Reni G.,Scientific Institute Irccs Emedea | And 4 more authors.
Human Brain Mapping | Year: 2016

Although the occurrence of concomitant positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to visual stimuli is increasingly investigated in neuroscience, it still lacks a definite explanation. Multimodal imaging represents a powerful tool to study the determinants of negative BOLD responses: the integration of functional Magnetic Resonance Imaging (fMRI) and electroencephalographic (EEG) recordings is especially useful, since it can give information on the neurovascular coupling underlying this complex phenomenon. In the present study, the brain response to intermittent photic stimulation (IPS) was investigated in a group of healthy subjects using simultaneous EEG-fMRI, with the main objective to study the electrophysiological mechanisms associated with the intense NBRs elicited by IPS in extra-striate visual cortex. The EEG analysis showed that IPS induced a desynchronization of the basal rhythm, followed by the instauration of a novel rhythm driven by the visual stimulation. The most interesting results emerged from the EEG-informed fMRI analysis, which suggested a relationship between the neuronal rhythms at 10 and 12 Hz and the BOLD dynamics in extra-striate visual cortex. These findings support the hypothesis that NBRs to visual stimuli may be neuronal in origin rather than reflecting pure vascular phenomena. Hum Brain Mapp 37:2247-2262, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.. Source

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